Mild-to-Moderate Psoriasis

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Author: Y.M. Koo John | Mark G. Lebwohl | Chai Sue Lee

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DK5988_title 6/22/06 10:21 AM Page 1

Mild-to-Moderate

PSORIASIS John Y. M. Koo University of California San Francisco Medical Center San Francisco, California, U.S.A.

Mark G. Lebwohl Mount Sinai School of Medicine New York, New York, U.S.A.

Chai Sue Lee University of California Davis Medical Center Sacramento, California, U.S.A.

New York London

Informa Healthcare USA, Inc. 270 Madison Avenue New York, NY 10016 © 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government 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: 0-8493-3723-2 (Hardcover) International Standard Book Number-13: 978-0-8493-3723-9 (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, a separate 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. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

Preface Preface

The goal of this book is to provide guidance on state-of-the-art clinical management of mild-to-moderate psoriasis, utilizing the experiences of a group of experts well known in the psoriasis ﬁeld. The treatments covered include topical corticosteroids, calcipotriene, tazarotene, tar, anthralin, salicyclic acid, phototherapy, and lasers. There is a chapter highlighting recent advances in combination therapy. We have also included chapters on palmar plantar 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-tomoderate psoriasis makes this a reference that dermatologists, primary care physicians, residents, medical students, and other health care professionals can turn to again and again for the most updated guidance in taking care of patients with mild-to-moderate psoriasis. John Y. M. Koo Mark G. Lebwohl Chai Sue Lee

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Contents

Preface . . . . iii Contributors . . . . xiii 1. Therapy of Mild-to-Moderate Psoriasis—Introduction . . . . . 1 Mark G. Lebwohl 2. General Approach to Psoriasis Treatment . . . . . . . . . . . . . . 3 Steven R. Feldman Introduction . . . . 3 General Considerations in Treatment of Localized Psoriasis . . . . 5 Conclusions . . . . 6 Reference . . . . 7 3. The Koo–Menter Psoriasis Instrument for Identifying Candidate Patients for Systemic Therapy . . . . . . . . . . . . . . 9 John Y. M. Koo, Jonathan W. Kowalski, Mark G. Lebwohl, Chris M. Kozma, and Alan Menter Introduction . . . . 9 Overview . . . . 10 Components of the Koo–Menter Psoriasis Instrument . . . . 10 Background on the PQOL-12 . . . . 14 Application of the Original PQOL . . . . 14 Development of the PQOL-12 . . . . 15 v

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Study 1: Multicentered Ofﬁce-Based Study . . . . 15 Study 2: Using Data from the Randomized Clinical Trial . . . . 24 Minimally Important Difference . . . . 26 Test–Retest Reliability of the PQOL-12 . . . . 26 Calculating the PQOL-12 Score Within the KMPI . . . . 26 Discussion on KMPI . . . . 27 Conclusion . . . . 27 References . . . . 28 4. General Guidelines for Administration of Topical Agents in the Treatment of Mild-to-Moderate Psoriasis . . . . . . . . Jashin J. Wu and Gerald D. Weinstein Factors of Psoriasis . . . . 30 Medications . . . . 32 References . . . . 38

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5. Topical Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . 41 Jason Givan, Daniel Pearce, and Steven R. Feldman Introduction . . . . 41 Rationale for Psoriasis Therapy . . . . 42 Mechanism of Action and Biologic Potency . . . . 42 Delivery and Physiologic Potency . . . . 44 Adherence . . . . 46 Lessons from Skin Cap1 . . . . 48 Efﬁcacy . . . . 49 Safety . . . . 50 Safer Topical Corticosteroids: Are They Possible? . . . . 51 Cost Considerations . . . . 52 Practical Use of Topical Corticosteroids . . . . 52 Steroid Alternatives: Complementary, Not Really Alternatives . . . . 53 Summary . . . . 54 References . . . . 55 6. Vitamin D3 Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chai Sue Lee and John Y. M. Koo Chemistry and Mechanism of Action . . . . 60 Calcipotriene Monotherapy . . . . 61 Calcipotriene in Children . . . . 61

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Calcipotriene vs. Other Topical Agents . . . . 62 Combination Therapy . . . . 63 Calcipotriene and Topical Steroids . . . . 63 Calcipotriene and Tazarotene . . . . 64 Calcipotriene and Phototherapy . . . . 64 Calcipotriene and Systemic Agents . . . . 65 Adverse Effects . . . . 66 Calcipotriene Application in Psoriasis . . . . 69 Conclusions . . . . 70 References . . . . 70 7. Fixed-Dose Corticosteroid/Calcipotriene Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Chai Sue Lee and John Y. M. Koo Combination Corticosteroid/Calcipotriene Therapy . . . . 76 Clinical Trials and Analyses of Fixed-Combination Formulation of Betamethasone Dipropionate/Calcipotriene . . . . 77 The Fixed-Dose Combination Is More Effective Than Steroid or Calcipotriene Monotherapy . . . . 77 The Fixed-Dose Combination b.i.d. Achieves Greater PASI Reduction Within One Week vs. Steroid Monotherapy . . . . 77 Once-Daily Fixed-Dose Combination Is Safe and Effective . . . . 78 Once-Daily Fixed-Dose Combination Is as Safe and Effective as b.i.d. Therapy . . . . 80 Once-Daily Fixed-Dose Therapy Achieves Higher Clearance and Fewer Adverse Events vs. Monotherapy . . . . 81 Once-Daily Fixed-Dose Therapy Is Effective for Patients with Mild, Moderate, and Severe Psoriasis . . . . 81 Investigators and Patients’ Assessments of Once-Daily Fixed-Dosed Therapy Agree . . . . 82 Long-Term, Once-Daily Fixed-Dose Therapy Is Safe and Effective . . . . 83 Potential Beneﬁts of Fixed-Dose Combination Therapy . . . . 84 In Combination with Biologics . . . . 86 In Combination with Other Systemic Agents . . . . 87 Potential Effects on Compliance . . . . 87

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Conclusions . . . . 87 References . . . . 88 8. Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chai Sue Lee and John Y. M. Koo Chemistry and Mechanism of Action . . . . 91 Tazarotene Monotherapy . . . . 93 Tazarotene vs. Topical Steroids . . . . 93 Combination Therapy . . . . 94 Tazarotene and Topical Steroids . . . . 94 Tazarotene and Topical Steroid-Induced Skin Atrophy . . . . 96 Tazarotene Chemical Compatibility with a Topical Steroid . . . . 96 Tazarotene and Calcipotriene . . . . 97 Tazarotene and UVB Phototherapy . . . . 97 Tazarotene and PUVA Phototherapy . . . . 98 Tazarotene and Nail Psoriasis . . . . 99 Tazarotene Application in Psoriasis . . . . 99 Side Effects . . . . 100 Conclusions . . . . 101 References . . . . 101 9. Topical Calcineurin Inhibitors . . . . . . . . . . . . . . . . . . . . Patricia Tinio and Mark G. Lebwohl Mechanism of Action . . . . 107 Clinical Properties . . . . 107 References . . . . 111 10. Treatment of Mild-to-Moderate Psoriasis with Coal Tar, Anthralin, Salicylic Acid, and Lactic Acid . . . . . . . . . . . Priya Sivanesan and John Y. M. Koo Coal Tar . . . . 115 Anthralin . . . . 119 Salicylic Acid . . . . 121 Lactic Acid . . . . 122 Conclusion . . . . 122 References . . . . 122

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Contents

11. Phototherapy and Laser for the Treatment of Mild-to-Moderate Psoriasis . . . . . . . . . . . . . . . . . . . Holly A. Kerr, Henry W. Lim, and Jennifer Trepte Introduction . . . . 125 Mechanism of Action . . . . 126 Ultraviolet B . . . . 126 Psoralen and UVA . . . . 131 Targeted (Localized) Phototherapy . . . . 137 Ultraviolet A1 . . . . 141 Conclusion . . . . 142 References . . . . 143

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12. Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 147 Wendy Myers, Jennifer Tan, and Alice B. Gottlieb The Rationale for Combination Therapy . . . . 147 Phototherapy Combinations . . . . 148 UV Phototherapy and Topical Medications . . . . 150 Combining Systemic Agents with Topical Therapies in the Treatment of Mild-to-Moderate Psoriasis . . . . 154 Future Therapies for the Combination Treatment of Mild-to-Moderate Psoriasis . . . . 158 References . . . . 159 13. Topical Sequential Therapy of Psoriasis . . . . . . . . . . . . . John Y. M. Koo and Shanthi M. Colaco Introduction . . . . 163 Topical Sequential Therapy: Calcipotriene and Halobetasol Propionate . . . . 164 Optimal Timing to Proceed Down Sequential Therapy Scheme . . . . 167 Sequential Therapy as a Flexible Therapeutic Strategy . . . . 168 Sequential Therapy with New Topical Steroid Formulations . . . . 168 Topical Sequential Therapy Possibilities Beyond Calcipotriene . . . . 169 References . . . . 170

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14. New Developments in Topical Psoriasis Therapy . . . . . . . Chai Sue Lee, John Y. M. Koo, and Shanthi M. Colaco Introduction . . . . 173

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Clobetasol Propionate Spray (Clobex Spray) . . . . 174 Clobetasol Propionate Shampoo (Clobex Shampoo) . . . . 175 Clobetasol Proprionate Lotion (Clobex Lotion) . . . . 176 Hydrogel Patch . . . . 176 Conclusions . . . . 181 References . . . . 181 15. Palmoplantar Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . Brian Bonish and Kenneth B. Gordon Treatment . . . . 185 Topical Therapy . . . . 185 Phototherapy . . . . 188 Systemic Therapy . . . . 189 Biologic Therapies . . . . 190 Summary: A Treatment Approach for Therapy of Palmoplantar Psoriasis . . . . 190 Conclusion . . . . 192 References . . . . 192

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16. Scalp Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 Peter C. M. van de Kerkhof, Marloes M. Kleinpenning, and Rianne M. J. P. Gerritsen Introduction . . . . 195 Epidemiology . . . . 195 Clinical Morphology . . . . 196 Differential Diagnosis . . . . 197 General Therapeutic Aspects . . . . 197 Shampoos . . . . 198 Descaling of the Scalp . . . . 199 Coal Tar and Dithranol . . . . 199 Imidazole Antifungals . . . . 199 Topical Corticosteroids . . . . 200 Vitamin D3 Analogs . . . . 201 Phototherapy . . . . 202 Systemic Treatments . . . . 202 Treatment Strategies in Scalp Psoriasis . . . . 202 Conclusion . . . . 203 References . . . . 203

Contents

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17. Inverse Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert A. Lee and Abby S. van Voorhees Introduction . . . . 207 Epidemiology . . . . 207 Clinical Presentation . . . . 208 Etiology . . . . 209 Differential Diagnosis . . . . 209 Management . . . . 210 Conclusion . . . . 217 References . . . . 217

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18. Psoriasis of the Nails . . . . . . . . . . . . . . . . . . . . . . . . . . Maithily A. Nandedkar-Thomas and Richard K. Scher Introduction . . . . 221 Manifestations of Nail Psoriasis . . . . 222 Association with Psoriatic Arthritis . . . . 226 Associated Genetic Haplotypes . . . . 228 Nail Psoriasis: Childhood vs. Adult Onset . . . . 228 Diagnostic Challenge: Isolated Nail Psoriasis and Its Impersonators . . . . 229 Diagnostic Procedure: The Nail Biopsy . . . . 231 Measurement of Severity: The Nail Psoriasis Severity Index . . . . 231 Treatment Options and Complications from Therapy . . . . 231 References . . . . 237

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19. Summary of Therapeutic Options for Mild-to-Moderate Psoriasis . . . . . . . . . . . . . . . . . . . . . Cindy Berthelot, Jennifer Clay Cather, and Alan Menter Introduction . . . . 243 Topical Therapies . . . . 245 Phototherapy . . . . 256 Summary . . . . 257 References . . . . 257 Index . . . . 263

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Contributors

Cindy Berthelot University of Texas Medical School Southwestern, Dallas, Texas, U.S.A. Brian Bonish Division of Dermatology, Stritch School of Medicine, Loyola University, Maywood, Illinois, U.S.A. Jennifer Clay Cather Division of Dermatology, Baylor University Medical Center, Dallas, Texas, U.S.A. Shanthi M. Colaco Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, 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. Rianne M. J. P. Gerritsen Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands Jason Givan Department of Dermatology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Kenneth B. Gordon Feinberg School of Medicine, Evanston Northwestern Healthcare and Northwestern University, Skokie, Illinois, U.S.A.

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Contributors

Alice B. Gottlieb Department of Dermatology, Tuffs-New England Medical Center, Boston, Massachusetts, 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 Center, 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. Jonathan W. Kowalski Global Health Outcomes Research, Allergan Inc., Irvine, California, U.S.A. Chris M. Kozma University of South Carolina, Columbia, South Carolina, 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. Robert A. Lee Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A. Henry W. Lim Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, U.S.A. Alan Menter Division of Dermatology, Baylor University Medical Center, Dallas, Texas, U.S.A. Wendy Myers Department of Medicine, Division of Clinical Pharmacology, Robert Wood Johnson Medical School, New Brunswick, New Jersey, U.S.A. Maithily A. Nandedkar-Thomas Reston, Virginia, U.S.A.

Professional Dermatology Care, PC,

Daniel Pearce Department of Dermatology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Contributors

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Richard K. Scher Department of Dermatology, Columbia University Medical Center, New York, New York, U.S.A. Priya Sivanesan Department of Dermatology, University of California San Francisco, San Francisco, California, U.S.A. Jennifer Tan Department of Medicine, Division of Clinical Pharmacology, Robert Wood Johnson Medical School, New Brunswick, New Jersey, U.S.A. Patricia Tinio Department of Dermatology, Mount Sinai School of Medicine, New York, New York, U.S.A. Jennifer Trepte Department of Dermatology, Wayne State University, Detroit, Michigan, U.S.A. Peter C. M. van de Kerkhof Department of Dermatology, Radboud University Medical Center, 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, California, U.S.A. Jashin J. Wu Department of Dermatology, University of California, Irvine, California, U.S.A.

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

The therapy of mild-to-moderate psoriasis has come a long way from the days of tar and anthralin, though the latter treatments are still occasionally used. The introduction of topical corticosteroids in the latter third of the 20th century had a dramatic impact on the topical therapy of psoriasis, and topical corticosteroids remain one of the most important treatments available for mild to moderate disease. Because superpotent corticosteroids are associated with hypothalamic–pituitary–adrenal axis suppression, recent innovations in topical corticosteroid development have emphasized more cosmetically elegant vehicles rather than more potent medications. Most recently, the superpotent corticosteroid clobetasol propionate has been developed in foam, spray, lotion, and shampoo vehicles. Corticosteroids are also available in creams, emollient creams, ointments, solutions, gels, and even tapes. Therefore it should not be surprising that corticosteroids are extensively covered in this book and controversies such as tachyphylaxis as well as issues such as compliance with therapy are raised by experts in the ﬁeld. A major breakthrough in the treatment of mild to moderate psoriasis occurred with the introduction of vitamin D analogs. Calcipotriene, also known as calcipotriol, was the ﬁrst agent approved and it was followed by additional vitamin D analogs including tacalcitol, calcitriol, and others.

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Lebwohl

Tazarotene, a retinoid developed for psoriasis, was the next class of agent to be developed for this disease. Other topical agents include the topical immunomodulators, pimecrolimus, and tacrolimus. These agents are not very effective on thick plaques of the elbows and knees, but are highly effective on facial and intertriginous skin, precisely those areas where use of topical corticosteroids is associated with the development of cutaneous atrophy and formation of striae and telangiectasia. All of the above agents are reviewed comprehensively in chapters written by leading authorities. What can the clinician do when monotherapy with topical agents is not sufﬁciently effective but the disease is not severe enough to justify systemic therapy? Combination therapy has proven to be more effective than monotherapy with selected agents. Moreover, combination therapy often eliminates the side effects of monotherapy. For example, the combination of topical corticosteroids and tazarotene is not only more effective than either treatment alone, but tazarotene protects against the atrophy of the corticosteroid while the corticosteroid minimizes the irritation caused by tazarotene. Likewise, the combination of calcipotriene with topical corticosteroids is more effective than either agent alone, allowing reduced use of the corticosteroid and less irritation caused by the calcipotriene. The use of combination therapy has led to the development of yet another new agent that combines calcipotriene with betamethasone dipropionate. When combination therapy is not adequate, use of intralesional corticosteroids may be effective, and when the latter is not sufﬁcient, phototherapy may be warranted. New forms of phototherapy including narrowband ultraviolet B (UVB) and localized targeted high output phototherapy such as that afforded by the excimer laser are often effective for localized refractory plaques of psoriasis. Finally, unique body sites such as the nails or scalp may require different vehicles and approaches to achieve good results. All of these challenges are addressed by experts in Therapy of Mild-to-Moderate Psoriasis with the hope that our patients will beneﬁt from this book.

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. 3

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Addressing psychosocial issues helps to establish a strong working relationship between the physician 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. 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; the purpose of touching the lesions is 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 patient that they should not be afraid of having contact with other people. Dr. J. Lamar Calloway, long-time dermatologist at Duke University, would actually rub his own face after palpating the psoriasis to help communicate to patients that psoriasis is not an infectious condition. 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 and the prescription 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 healthcare 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. The Psoriasis Foundation provides numerous beneﬁts to patients. First, it helps patients feel a part of a group, reducing their sense of isolation due to the disease. Second, the Foundation helps educate patients about available treatment options. Third, the Foundation encourages patients to be compliant with their dermatologists’ recommendations. Fourth, the Psoriasis Foundation empowers patients to work towards 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

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visiting the web sitea, writing to the foundationb, or callingc. Anyone can join, even without paying, though there is a recommended donation of $27 (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 ‘‘Therapy of Moderate to Severe Psoriasis’’ by Weinstein and Gottlieb (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 is also used. When it comes to topical treatments, multiple agents are available including tar, anthralin, topical corticosteroids, topical vitamin D and Vitamin A analogues, 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’ compliance with the topical treatment regimen. When patients with psoriasis have been asked about their compliance with topical therapy, approximately 40% reported noncompliance. In a clinical trial that assessed compliance using both patient diaries and electronic monitors, patients vastly overstated their true compliance. It is clear that patients are not truthful with their doctors about their compliance with topical therapy. Topical therapy is time consuming and messy, and over time, compliance to topical therapy decreases. Indeed, chronic diseases like a

www.psoriasis.org 6600 SW 92nd Avenue, Suite 300, Portland, OR 97223-7195, U.S.A. c 1-800-723-9166 b

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psoriasis—as well as treatment of the chronic condition—are frustrating and wear on people over time. Outcomes of localized psoriasis treatment can be improved by encouraging patients to be compliant. There are a number of things that physicians can do to improve a patient’s compliance. First, as discussed above, physicians should establish a strong working relationship with the patient. They should involve the patient in the treatment-making decision. Vehicles which the patients do not mind applying should be chosen. While it was commonly thought that ointments are more effective, new non-ointment, less messy vehicles may be able to deliver active drugs just as well as traditional ointments, and better compliance with a non-messy product may actually lead to greater efﬁcacy than is seen with ointments. 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 consists of using stronger, faster acting but potentially more risky treatments early in the course of therapy and then transitioning to lower 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. 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 compliance 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 compliant for that length of time. By seeing patients back in just a week, patients are more likely to comply with therapy 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. This short interval between treatment and the return visit may be especially important for patients with scalp psoriasis, as compliance with topical scalp treatment regimens is exceedingly time consuming and difﬁcult. 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 elevated by addressing patients’ psychosocial concerns up front. All patients with psoriasis should be encouraged to join the National Psoriasis Foundation. This helps reduce patients in isolation and increase their knowledge about treatments, ultimately resulting in approved compliance with the physician-recommended treatment regimens.

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Topical treatments are proven for most patients with mild-to-moderate 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, LP. Dr. Feldman has also received support from Connetics, Astellas, Abbott, Amgen, Biogenidec, Centocor, Photomedex, and Genentech. REFERENCE 1. Weinstein GD, Gottlieb AB. Therapy of moderate to severe psoriasis. In: revised and expanded. 2d ed. New York, NY: Marcel Dekker, 2003.

3 The Koo–Menter Psoriasis Instrument for Identifying Candidate Patients for Systemic Therapy 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.

Jonathan W. Kowalski Global Health Outcomes Research, Allergan Inc., Irvine, California, U.S.A.

Mark G. Lebwohl Department of Dermatology, Mount Sinai School of Medicine, New York, New York, U.S.A.

Chris M. Kozma University of South Carolina, Columbia, South Carolina, U.S.A.

Alan Menter Division of Dermatology, Baylor University Medical Center, Dallas, Texas, U.S.A.

INTRODUCTION According to a National Psoriasis Foundation survey, 78% of members with severe psoriasis reported frustration with the efﬁcacy of their current treatment and 32% indicated that the treatment they are receiving is not aggressive enough (1). In addition, 87% of all psoriasis patients were receiving

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only topical medications for their psoriasis and only 26% of patients were very satisﬁed with their treatments. Several highly effective systemic therapies for psoriasis already exist and other potential new systemic therapies are in development for patients with psoriasis. Most psoriasis opinion leaders feel that a greater percentage of the total psoriasis population can beneﬁt from the use of systemic agents. What may be needed is an instrument to assist in the critical decision of whether therapy that is more aggressive may be needed or not. There has been no convenient tool that can assist dermatologists in identifying patients who would beneﬁt from systemic therapy for psoriasis and at the same time justify these decisions to third-party payers. However, tools such as these exist for other chronic diseases treated by rheumatologists (e.g., for rheumatoid arthritis) and urologists (e.g., for benign prostatic hyperplasia). Such a tool for psoriasis would need to incorporate both the assessments of health-related quality-of-life and the other measures of disease severity and associated joint disorder (2). The Koo–Menter Psoriasis Instrument (KMPI) has been designed to be a practical assessment tool, which dermatologists can quickly and easily use in their daily practice to help guide them in identifying patients with psoriasis who may be candidates for systemic therapy. OVERVIEW The KMPI is a two page questionnaire on a single sheet (Figs. 1 and 2). On the front page, the patient completes three brief sections while awaiting evaluation by the physician. The topics of these sections include: validated psoriasis-speciﬁc quality-of-life, parts of body currently affected by psoriasis, and psoriatic arthritis/joint symptomatology. The physician then completes the reverse side of the instrument during the physical examination. The quality-of-life score is easily totaled from the front page; body surface area (BSA) involvement is assessed using the ‘‘rule of nines,’’ and a series of simple ‘‘yes’’ or ‘‘no’’ questions allows the physician to quickly characterize the patient’s disease and treatment history. The physician uses the psoriasis-speciﬁc quality-of-life score, the total percentage of BSA involvement, and the overall clinical assessment of the patient’s psoriasis to determine the need for systemic therapy. COMPONENTS OF THE KOO–MENTER PSORIASIS INSTRUMENT Patient Self Assessment Part 1. Health-Related Quality of Life The patient completes the 12-item Psoriasis Quality-of-Life Questionnaire (PQOL-12).

Koo–Menter Psoriasis Instrument

Figure 1 Koo-Menter psoriasis instrument; patient self-assessment.

11

12

Figure 2 Koo-Menter psoriasis instrument; physician assessment.

Koo et al.

Koo–Menter Psoriasis Instrument

13

Developed from the original 41-item PQOL (which was created a decade ago based on literature review, patient focus groups and pilot testing in 505 patients with psoriasis), the items from the PQOL-12 were identiﬁed using new data from 474 patients with psoriasis and determined to be valid and reliable in assessing the impact of psoriasis on patients across the spectrum of psoriasis severity. In addition, the items of the PQOL-12 are responsive and sensitive in measuring clinically meaningful change and improvement following treatment. The PQOL-12 was chosen as the quality-of-life measure for the KMPI because of its brevity, broad applicability across disease severity, the rigor of its development and psychometric validation, and its psoriasis-speciﬁc focus. The validation data for PQOL-12 will be described later under the section ‘‘Background on the 12-item PQOL-12.’’ Part 2. Patient Indication of Psoriasis Sites The Patient indicates the location of their psoriatic lesions by placing ‘‘X’s’’ on ﬁgures illustrating the front and back of the human body. The patient’s indication of psoriasis sites helps facilitate the physician’s evaluation of the area of psoriatic involvement in the patient. Part 3. Joint Symptoms The patient answers four questions about joint symptoms and psoriatic arthritis. These items, developed based on feedback from leading arthritis experts, are included to facilitate early detection of this important associated condition while ensuring that the decision for systemic therapy is also based on joint symptomatology. Physician Assessment Part 1. Total Quality-of-Life Assessment Score The physician totals the patient’s quality-of-life score from the front page. Part 2. Area of Involvement The physician calculates the patient’s BSA involvement using the rule of nines or by the estimation using the area of open hand as approximately 1% of the total body surface. Part 3. Assessment of Psoriasis Severity The following severity criteria are then assessed by the physician using simple ‘‘yes’’ or ‘‘no’’ options:

Plaque, erythrodermic or pustular psoriasis with more than 10% BSA involvement Guttate psoriasis

14

Koo et al.

Localized psoriasis (less than 10% BSA involvement) that is resistant to topical therapy or is disabling (e.g., palmarplantar psoriasis) One of the serious subtypes of localized psoriasis (less than 10% BSA involvement) that has a possibility of progression (e.g., generalized pustular or erythrodermic psoriasis), or Clinical evidence of psoriatic joint disease as assessed by the patient and physician. Part 4. Feasibility of Phototherapy Lastly, the feasibility and clinical appropriateness of phototherapy is rapidly evaluated in six simple questions. Determination of Candidacy for Systemic Therapy Using the responses to the ‘‘yes’’ or ‘‘no’’ questions in Part 3 and Part 4 of the Physician Assessment, the candidacy for systemic therapy is determined. If the physician has checked at least one of the shaded boxes in both Part 3 and Part 4, then the patient is a candidate for systemic therapy.

BACKGROUND ON THE PQOL-12 The PQOL-12 is a valid and reliable subset of the original PQOL, a 41-item, self-administered, disease-speciﬁc questionnaire initially developed in 1991 by John Koo, M.D.(3–5). The questionnaire items were generated through focus groups in which patients discussed their experiences with psoriasis. A nationwide, population-based, demographically balanced sample of 50,000 households was then used to identify 599 psoriasis patients in the United States for item testing. The 41-item PQOL was qualitatively divided into two domains: psychosocial and physical. The psychosocial domain consisted of 22 items requiring patients to characterize the impact of psoriasis on their interactions with friends and family and on their feelings and self-perception. The physical domain consisted of 19 items requesting that patients rate the impact of their psoriasis symptoms on their daily activities. PQOL items were rated on an 11-point Likert-type scale where 0 ¼ ‘‘not at all,’’ 5 ¼ ‘‘somewhat,’’ and 10 ¼ ‘‘very much.’’ APPLICATION OF THE ORIGINAL PQOL The 41-item PQOL was utilized in a clinical study of 71 patients with stable plaque psoriasis on up to 20% of their total BSA, and plaque elevation of at least moderate severity (6). Psychometric analysis of the 41-item PQOL showed satisfactory reliability, validity, and responsiveness to change (3). Items within each domain had approximately equal variances and

Koo–Menter Psoriasis Instrument

15

contributed equally to the total score and were, therefore, summed without weighting. The 41-item PQOL was scored by computing the mean score for each domain, on a 0 to 10 scale. DEVELOPMENT OF THE PQOL-12 The 41-item PQOL was too lengthy for frequent use in clinical practice, and the assumption of two domains (psychosocial and physical) was not entirely appropriate as analyses following its development had shown overlap among these domains. A shorter instrument measuring unique constructs was needed for clinicians and researchers who were interested in assessing psoriasis-speciﬁc Health-Related Quality-of-Life (HRQOL) in clinical research or daily practice. Factor analysis techniques were used to reﬁne the 41-item PQOL. The resulting questionnaire (PQOL-12) consisted of 12 items measured on one domain. Psychometric properties of the PQOL-12 were assessed using data from an multicentered ofﬁce-based study (Study 1) and a randomized clinical trial (Study 2). STUDY 1: MULTICENTERED OFFICE-BASED STUDY Item Reduction The PQOL was reﬁned and reduced to a 12-item instrument using data from an ofﬁce-based study of 483 patients stratiﬁed by physician-rated psoriasis severity at three U.S. psoriasis centers from October 2001 to May 2002 (7,8). Severity was assessed by the investigator at the time of enrollment, and included a psoriasis area severity index (PASI) evaluation. Physicians completed several different symptom severity assessment questionnaires: global assessment of severity ranging from mild, moderate, and severe based on the BSA affected, PASI, overall lesional assessment (OLA) and severity of symptoms experienced by patients. In addition, each patient was asked to complete a demographic questionnaire, the PQOL, the Dermatology Life Quality Index (DLQI) and a disease severity assessment. Patient-rated severity was deﬁned as mild, moderate, or severe with the question ‘‘How would you rate the overall severity of your psoriasis, during the past month?’’ For this study, one compound question from the 41-item PQOL [i.e., item #22: How much does your psoriasis interfere with making social contacts and relationships?] in the psychosocial domain was divided into two questions, creating a 42-item instrument. A combination of qualitative review and factor analysis was used to reﬁne the questionnaire. Observations were randomly assigned to an exploratory or conﬁrmatory data set. The exploratory data set (n ¼ 301) was used to reduce and reﬁne the existing PQOL instrument and the conﬁrmatory data set (n ¼ 182) was used to test the reliability of the ﬁndings from the exploratory analysis. Each PQOL

16

Koo et al.

item was evaluated for missing values, mean scores, ﬂoor/ceiling effects, reading level, translatability, and applicability to all patients. Qualitative criteria were applied by assessing items for redundancy, wording, and meaning/conceptual characteristics. Factor analysis was used to assess the factor structure and item loadings on factors. An item-retention grid consisting of all analytical parameters was created to evaluate all item parameter estimates simultaneously and to facilitate the item-reduction decision process. Once reduced, all analyses performed on the exploratory data set (i.e., descriptive and factor analysis) were repeated on the revised questionnaire (i.e., PQOL-12) using the conﬁrmatory dataset. The conﬁrmatory analyses yielded results consistent with the exploratory analyses. Validity and Reliability Following the conﬁrmatory analysis, the psychometric properties of the PQOL-12 were assessed using Multitrait Analysis Program-Revised for Windows1PC-SAS1–based software7 (9) and the pooled data set (n ¼ 482). The PQOL-12 demonstrated desirable psychometric properties. Ninety-nine percent of respondents completed the survey providing evidence of appropriate item responses of the PQOL-12. The PQOL-12 also exhibited support for the assumptions of summated scales. The PQOL-12 items had approximately equal variances (so they could be summed) and contributed equally to total score (i.e., no weighting needed). All items demonstrated desirable item internal consistency by exceeding the criteria of 0.40 correlation with the total score. The instrument also demonstrated good potential for responsiveness. Cronbach’s a was 0.95 and the mean inter-item correlation was 0.62, providing evidence of reliability (Tables 1 and 2). Although the questionnaire could have been reduced even further, some questions that have been deemed important in clinical practice were retained. Investigation of construct validity indicated that the mean PQOL-12 score was moderately correlated with clinical measures, and highly correlated with patient-rated psoriasis severity (r ¼ 0.61) and with the DLQI (r ¼ 0.78) (Table 3). Individual item correlations with overall patient-rated severity ranged from 0.40 (‘‘how helpless do you feel with regard to your psoriasis?’’) to 0.61 (physical irritation). There were low to moderate correlations with physician-rated severity. A probable explanation for the more modest correlations with physician-rated severity was that physicians based their severity assessment on BSA using an ordinal scale (mild <5%, moderate 5–10%, severe >10%) and lesion morphology that focused strictly on physical characteristics of the patient’s condition. The correlations between individual PQOL-12 items and the DLQI items ranged from 0.50 to 0.69. The total PQOL-12 score was moderately correlated with OLA (0.38), BSA (0.33), and the PASI (0.36), providing evidence of convergent instrument and construct validity. Mean PQOL-12 scores were calculated for each disease severity level by both patients and physicians (Table 4). All pairwise comparisons of

3.45 3.48 3.25 3.25 3.29 3.39

5.76 5.93 5.09 4.24 4.39 4.11

3.41 3.40 3.40 3.84 2.76

3.39

5.60

5.32 4.98 3.84 5.04 5.03

3.28

SD

6.10

Mean

0–10 0–10 0–10 0–10 0–10

0–10

0–10 0–10

0–10

0–10

0–10

0–10

0–10

Range

Abbreviations: PQOL-12; 12-Item Psoriasis Quality-of-Life Questionnaire; SD, standard deviation.

During the past month, how much have each of the following been affected by your psoriasis? Itching? Physical irritation? Physical pain or soreness? Choice of clothing to conceal psoriasis? Mean PQOL-12 Score

Over the past month . . . How self-conscious do you feel with regard to your psoriasis? How helpless do you feel with regard to your psoriasis? How embarrassed do you feel with regard to your psoriasis? How angry or frustrated do you feel with regard to your psoriasis? To what extent does your psoriasis make your appearance unsightly? How disﬁguring is your psoriasis? How much does your psoriasis impact your overall emotional well-being? Overall, to what extent does your psoriasis interfere with your capacity to enjoy life?

Item

Study 1 (n ¼ 482)

6.58 5.77 4.23 6.15 5.45

3.63

4.21 4.07

5.31

5.99

6.42

6.51

6.56

Mean

2.76 3.07 3.40 3.48 2.13

3.21

2.95 3.11

2.71

2.91

3.03

2.97

2.71

SD

Study 2 (n ¼ 71)

0–10 0–10 0–10 0–10 0.58–9.42

0–9

0–10 0–10

0–10

0–10

0–10

0–10

0–10

Range

Table 1 Item Descriptive Statistics for the PQOL-12 from an Ofﬁce-Based Study (Study 1) and the Clinical Trial at Baseline (Study 2)

Koo–Menter Psoriasis Instrument 17

External validity

Construct validity

Validity Item means and variances

Internal consistency reliability

Reliability Internal item consistency

Property

Cronbach’s a ¼ 0.91

Cronbach’s a ¼ 0.95

PQOL-12 score at baseline correlated signiﬁcantly (p < 0.05) with overall discomfort (0.49), percent BSA

Correlation of items with total score ranged from 0.42 to 0.78

Means of the items were 3.63–6.58 (SD, 2.71– 3.48)

Correlations ranged from 0.42 to 0.78

Study 2 (n ¼ 71)

Correlations ranged from 0.70 to 0.83

Study 1 (n ¼ 483)

Means of the items were Interchangeability of items within 3.84–6.10 (SD, 3.25–3.84) each domain (similar means and variances, so scores can be summed without adjustment) Correlation of items with Relationship of item to domain, total score ranged from assessed by item/domain correlations 0.70 to 0.83 corrected for overlap (similar, moderate item/domain correlations. Items should contribute equally to domain score so that item weighting is unnecessary) Relationship of items to external, PQOL-12 score at baseline often clinical, endpoints (at least correlated signiﬁcantly (p < 0.05) moderate Spearman correlations) with physician rated severity (0.38), patent rated severity (0.61), overall lesional assessment (0.38), BSA

Extent to which each item correlates with the total score (0.40; 0.30 if domain contains many items) Homogeneity of a domain and extent to which domain is free of random error (Cronbach’s a ¼ 0.70–0.95)

Description/rationale (criterion)

Table 2 Summary of the Psychometric Properties of the 12-Item PQOL in Two Studies

18 Koo et al.

Responsiveness Distribution of responses Item acceptability and comprehension of meaning by respondents (responses should span the majority of the scale) Lack of ﬂoor or ceiling Position of initial score effects (initial scores should not be too close to the minimum or maximum values; scales should have sufﬁcient range on either side of the initial score to show improvement or deterioration) Responsive to disease Scores should vary systematically severity across disease severity categories so that milder severity is associated with lower scores than more severe disease

No signiﬁcant ﬂoor (0.0%) or ceiling (0.0%) effects

For physician ratings of severity, there was 1 to 1.5 point difference in scores between mild and severe (p ¼ 0.009), mild and moderate

No signiﬁcant ﬂoor (1.5%) or ceiling (1.0%) effects

For physician ratings of severity, mean PQOL-12 scores were 3.9 for mild, 5.0 for moderate, and 6.4 for severe disease; pairwise comparisons of PQOL-12 means by physician-rated severity groups were

(Continued )

Mean PQOL-12 total score ¼ 5.45, SD ¼ 2.13, Range ¼ 0.58–9.42

affected (0.42), pruritis (0.41), and overall disease severity (0.34); PQOL-12 was not signiﬁcantly correlated with physician assessment of plaque elevation, scaling, or erythema

Mean PQOL-12 total score ¼ 5.03, SD ¼ 2.76, Range ¼ 0–10

(0.33), PASI (0.36) and the DLQI (0.78)

Koo–Menter Psoriasis Instrument 19

Minimally important difference Difference in scores between improvers vs. those who did not change on measures of severity

Not assessed

Difference for improvers vs. those who showed no change was 1.24 (p < 0.05) on the patientrated severity scale and

(p ¼ 0.08) moderate, and severe disease categories (p ¼ 0.08) at baseline For patient-rated severity, there was 1 to 3 point difference in mean PQOL-12 scores between mild and moderate (p ¼ 0.003), mild and severe (p ¼ 0.001) and moderate and severe (p ¼ 0.03) at baseline Within group change from baseline scores were signiﬁcantly different with treatment (p < 0.001)

signiﬁcantly different (p < 0.0002)

For patient-rated severity, mean PQOL-12 scores were 3.2 for mild, 5.2 for moderate, and 7.6 for severe disease; pairwise comparisons were statistically signiﬁcant (p < 0.0001)

Study 2 (n ¼ 71)

Study 1 (n ¼ 483)

The MID deﬁned as the difference in Not assessed mean change from baseline PQOL-12 score for patients who improved by at least one point on the patient or physician rated severity scale, vs. the

Scores change due to treatment-related improvement

Description/rationale (criterion)

Summary of the Psychometric Properties of the 12-Item PQOL in Two Studies (Continued )

Responsive to treatment

Property

Table 2

20 Koo et al.

The MID deﬁned as the difference in Not assessed mean change from baseline PQOL-12 score for patients who showed at least moderate response to treatment, vs. the mean change from baseline for those who showed only slight response (some improvement—about 25%; however, signiﬁcant evidence of study condition remains) or no response to treatment (study condition has not changed)

0.39 (p ¼ 0.45) on the physician-rated severity scale Difference for those who showed moderate improvement vs. those who showed no change or only slight improvement on the physicians’ assessment of the global response to treatment was 1.14 (p ¼ 0.18)

Abbreviations: PQOL-12, 12-Item Psoriasis Quality-of-Life Questionnaire; BSA, body surface area; MID, minimally important difference; SD, standard deviation; SE, standard error; Dermatology Life Quality Index; PASI, psoriasis area severity index.

Difference in scores between improvers vs. those who did not change on global evaluation of response to treatment

mean change from baseline for those who showed no change

Koo–Menter Psoriasis Instrument 21

0.44 0.46 0.51 0.54 0.44 0.42

0.23 0.25 0.35 0.41 0.26 0.27

0.58 0.61 0.57 0.49 0.61

0.40

0.20

0.35 0.40 0.33 0.37 0.38

0.48

0.26s

Patient RS (n ¼ 481)

0.41 0.44 0.40 0.33 0.38

0.25

0.36 0.23

0.28

0.29

0.23

0.26

0.25

OLA (n ¼ 480)

0.32 0.34 0.31 0.29 0.33

0.25

0.38 0.26

0.30

0.21

0.20

0.20

0.20

BSA (n ¼ 481)

0.36 0.38 0.36 0.32 0.36

0.26

0.40 0.26

0.30

0.24

0.22

0.22

0.22

PASI (n ¼ 482)

0.62 0.65 0.66 0.68 0.78

0.69

0.66 0.64

0.66

0.58

0.64

0.50

0.64

DLQI (n ¼ 482)

a Spearman correlations for ordinal measurement scales (physician- and patient-rated severity) and Pearson correlations for interval measurement scales (OLA, BSA, PASI, DLQI). Abbreviations: PQOL-12, 12-Item Psoriasis Quality-of-Life Questionnaire; BSA, body surface area; DLQI, dermatology life quality index; OLA, overall lesional assessment; RS, rated severity; PASI, psoriasis area and severity index.

During the past four weeks, how much have each of the following been affected by your psoriasis? Itching? Physical irritation? Physical pain or soreness? Choice of clothing to conceal psoriasis? Mean PQOL-12 Score

In the past four weeks . . . How self-conscious do you feel with regard to your psoriasis? How helpless do you feel with regard to your psoriasis? How embarrassed do you feel with regard to your psoriasis? How angry or frustrated do you feel with regard to your psoriasis? To what extent does your psoriasis make your appearance unsightly? How disﬁguring is your psoriasis? How much does your psoriasis impact your overall emotional well-being? Overall, to what extent does your psoriasis interfere with your capacity to enjoy life?

Question

Physician RS (n ¼ 474)

Table 3 Correlationsa Between Final PQOL-12 and Clinical or Other Patient-Reported Measures (Study 1) 22 Koo et al.

Cleared Mild Moderate Severe Cleared Mild Moderate Severe

Severity 0 168 151 155 0 185 178 118

n NA 3.9 (2.6) 5.0 (2.8) 6.4 (2.3) NA 3.2 (2.3) 5.2 (2.3) 7.6 (1.8)

Mean (SD) 0 7 47 17 0 17 35 18

n 0 3.90 5.36 6.36 0 3.59 5.64 6.80

(0) (2.19) (1.89) (2.41) (0) (1.42) (1.99) (1.81)

Mean (SD)

Baseline

Note: Total n < 483 (ofﬁce-based study) or < 71 (clinical trial) due to missing physician- or patient-rated severity data.

Patient

Physician

Rater

Ofﬁce-based study (Study 1)

8 38 24 1 1 26 15 5

n

3.35 (1.92) 3.13 (2.21) 4.89 (2.72) 8.00 (NA) 2.25 (NA) 2.38 (1.42) 4.74 (2.26) 6.18 (2.35)

Mean (SD)

End of treatment

Clinical trial (Study 2)

Table 4 Mean PQOL-12 Scores at Baseline and End-of-Treatment, by Physician- and Patient-Rated Severity

Koo–Menter Psoriasis Instrument 23

24

Koo et al.

PQOL-12 means for both physician and patient ratings of severity in the ofﬁce-based study were statistically signiﬁcant (p < 0.001), providing evidence of discriminant validity. Responsiveness The potential for responsiveness was assessed in this ofﬁce-based crosssectional study (Study 1) using the PQOL-12. The mean score for the PQOL-12 was 5.03 (SD, 2.76). Only 1.5% of the responses were at the ﬂoor and 1% of responses were at the ceiling, indicating that the scale has the capability to assess both extremes and that the instrument would be capable of detecting changes during a clinical trial. Responsiveness was further assessed with the following clinical trial data (Study 2). STUDY 2: USING DATA FROM THE RANDOMIZED CLINICAL TRIAL In Study 2, data from the clinical trial on the 41-item PQOL was used to evaluate psychometric properties of the PQOL-12. Disease severity was measured from both physician and patient perspectives. Physicians were asked to evaluate overall patient discomfort, overall disease severity deﬁned as mild, moderate, or severe, percent BSA involvement, signs and symptoms of disease (e.g., pruritis), and overall response to treatment. Patients were asked to complete the 41-item PQOL and an overall evaluation of their disease severity. Patient severity was deﬁned as cleared, mild (trace, mild), moderate (moderate), or severe (severe, very severe) with the question ‘‘How would you rate the overall severity of your psoriasis at this time?’’ The 12 items of the PQOL were used to retrospectively assess validity, reliability, responsiveness, and the minimally important difference (MID) (10) (i.e., a change in the PQOL-12 questionnaire that would indicate the need for a change in therapy). The PQOL-12 demonstrated validity and reliability. Item-to-total correlations were moderate to high, and Cronbach’s a was 0.91. Correlations of the total PQOL-12 score and the individual PQOL-12 items with the clinical measures were moderate for all measures (Table 5). The PQOL-12 also discriminated among physician and patientrated severity at baseline and at end of treatment (Table 4). Responsiveness In Study 2 (using the clinical trial data retrospectively), the responsiveness assessment included examination of ﬂoor and ceiling effects, differences in severity levels, and treatment effects. There were no ﬂoor or ceiling effects observed for the PQOL-12, indicating that it has the capability to detect improvement and decline in this patient population. Mean PQOL-12 scores

Koo–Menter Psoriasis Instrument

25

Table 5 Spearman Correlations Between PQOL-12 Items and Clinical Measures (Study 2) Question In the past four weeks . . . How self-conscious do you feel with regard to your psoriasis? How helpless do you feel with regard to your psoriasis? How embarrassed do you feel with regard to your psoriasis? How angry or frustrated do you feel with regard to your psoriasis? To what extent does your psoriasis make your appearance unsightly? How disﬁguring is your psoriasis? How much does your psoriasis impact your overall emotional well-being? Overall, to what extent does your psoriasis interfere with your capacity to enjoy life? During the past four weeks, how much have each of the following been affected by your psoriasis? Itching? Physical irritation? Physical pain or soreness? Choice of clothing to conceal psoriasis? Mean PQOL-12 Score

Disease discomfort

Disease severity

Percentage BSA

Pruritis

0.34a

0.29a

0.43a

0.30a

0.32a

0.14

0.25a

0.25a

0.35a

0.13

0.30a

0.25a

0.44a

0.19

0.28a

0.28a

0.37a

0.36a

0.36a

0.22

0.31a

0.34a

0.59a

0.18

0.50a

0.32a

0.29a

0.22

0.31a

0.23

0.28a

0.04

0.38a 0.36a 0.31a 0.22

0.22 0.31a 0.28a 0.15

0.16 0.25a 0.17 0.35a

0.67a 0.60a 0.33a 0.22

0.49a

0.34a

0.42a

0.41a

a

Signiﬁcant at the a ¼ 0.05 level. Abbreviations: PQOL-12, 12-Item Psoriasis Quality-of-Life Questionnaire; BSA, body surface area.

were calculated for each disease severity level by both patients and physicians. Both at the baseline and at the end of treatment, differences between severity levels were generally 1 or 2 points for both physician and patient ratings (Table 4).

26

Koo et al.

MINIMALLY IMPORTANT DIFFERENCE The MID was assessed using an anchor-based approach. The MID is the smallest (or minimal) change in an HRQOL measure that is considered meaningful (or important) by either a clinician or a patient (8). A technique adapted from Juniper et al. was used to calculate the MID using data from Study 2 (8). Three anchors or measures of improvement were investigated including: patient-rated disease severity, physician-rated disease severity, and physician-evaluated global response to treatment. A difference of 1.24 points was observed between those who improved and those who reported no change in the patient-rated severity. The difference in the means of these two groups was statistically signiﬁcant, indicating an important and statistically signiﬁcant difference between these two groups. Differences between those who improved and those who did not experience a change was calculated as 1.14 using the physician rating of global response to treatment, although the means were not statistically signiﬁcant between these two groups. In contrast, differences between physician ratings of severity were smaller (0.39) and the means of improvers and patients who did not experience change were not statistically signiﬁcant. This ﬁnding suggests that a 0.4-point change may be sufﬁcient to distinguish these groups on this measure. In summary, these results suggest that the MID for PQOL-12 score is about 1 point, although it may be as low as 0.4 points. TEST–RETEST RELIABILITY OF THE PQOL-12 Although the above study designs precluded assessment of the test–retest reliability of PQOL-12, preliminary analyses from subsequent research indicate that the test–retest correlation of PQOL-12 exceeds 0.80 when conducted over a period of 2 to 30 days. CALCULATING THE PQOL-12 SCORE WITHIN THE KMPI To be consistent with the desire for the KMPI to be a simple and easily used tool within clinical practice, the calculation of the PQOL-12 score for use within the KMPI differs from how the PQOL-12 score is reported above. Whereas the PQOL-12 score above ranges from 0 (best) to 10 (worst) and is calculated by taking the mean of the item scores, the scoring for the PQOL-12 within the KMPI does not involve calculating mean item score but rather uses a simple sum of the item scores for a score that ranges from 0 (best) to 120 (worst). As the burden of psoriasis on a patient’s health-related and psoriasisspeciﬁc quality-of-life is determined by a range of variables unique to each patient’s disease symptoms and life-circumstances, a comprehensive and practical approach was employed to determine a PQOL-12 score criterion

Koo–Menter Psoriasis Instrument

27

for use within Part 3 of the KMPI. Qualitative review of the data from Study 1 and Study 2 along with quantitative analyses (i.e., exploratory cluster analysis) was conducted to identify if there was a natural ‘‘cut-point’’ between patients with mild and moderate psoriasis that was relatively stable over the various patient- and physician-rated severity measures. In addition, we sought to balance this with a cut-off point where a therapeutic intervention might be expected to have an impact on psoriasis-speciﬁc quality-of-life, while also accounting for the minimum important difference on the PQOL-12, which is approximately 1 to 2 points. Analysis results indicated that such a cut-off point might be as low as a score of 25 using the scoring method for the PQOL-12 within the KMPI, however, clinical opinion suggested the use of a more conservative 50 points for the ﬁnal instrument. Further research is needed to better understand the minimum point where treatment might positively impact psoriasis patients based on their PQOL-12 score.

DISCUSSION ON KMPI The KMPI provides a quick and easy way to identify and document patients with psoriasis who require systemic therapy. The KMPI is short enough to be completed during a routine visit to a dermatologist. It takes approximately ﬁve minutes for the patient to complete the front page of the instrument while waiting in the reception area or the examination room prior to being seen by the physician. Similarly, the physician assessment takes approximately ﬁve to seven minutes to complete and the resulting instrument can become part of the patient’s medical record for reference at subsequent patient visits. The KMPI is unique in providing a complete evaluation of the patient’s disease status-incorporating assessments of psoriasis-speciﬁc quality-of-life with a validated questionnaire (PQOL-12), psoriasis severity and psoriatic joint disease. The KMPI alerts the physician and patient of the need to assess health-related quality-of-life and joint-related symptoms in the clinical evaluation of psoriasis and determines the suitability (or otherwise) for systemic therapy in individual patients. The KMPI has the potential to improve physician–patient communication by involving the patient in characterizing their disease and its impact on their lives.

CONCLUSION The KMPI is a practical assessment tool that dermatologists can quickly and easily use in their daily practice to help guide them in identifying

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patients with psoriasis who may be candidates for systemic therapy, as well as to justify these decisions to third-party payers. REFERENCES 1. 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; 137:280–284. 2. Krueger GG, Feldman SR, Camisa C, et al. Two considerations for patients with psoriasis and their conicians: What deﬁnes mild, moderate, and severe psoriasis? What constitutes a clinically signiﬁcant improvement when treating psoriasis? J Am Acad Dermatol 2000; 43:281–285. 3. Koo J, Kozma CM, Reinke K. The development of a disease-speciﬁc questionnaire to assess the quality of life for psoriasis patients: an analysis of the reliability, validity, and responsiveness of the psoriasis quality of life questionnaire. Dermatologie Psychosomatik 2002; 3:171–179. 4. Feldman S, Koo J, Menter A, Bagel J. Decision points for the initiation of systemic treatment for psoriasis. JAAD 2005; 53(1):101–107. 5. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin 1996; 14:485–496. 6. Koo JY, Martin D. Investigator-masked comparison of tazarotene gel q.d. plus mometasone furoate cream q.d. vs. mometasone furoate cream b.i.d. in the treatment of plaque psoriasis. Int J Dermatol 2001; 40:210–212. 7. Koo J, Menter A, Lebwohl M, et al. The relationship between quality of life and disease severity: results from a large cohort of mild, moderate, and severe psoriasis patients [abstr]. Br J Dermatol 2002; 147:1078. 8. Koo J, Kozma CM, Menter A, et al. Development of a disease-speciﬁc quality of life questionnaire: the 12-item Psoriasis Quality of Life Questionnaire (PQOL-12). 61st Annual Meeting of the American Academy of Dermatology, 2003. 9. Ware JE, Harris, Gandek WJ, Rogers BW, Reese PR. MAP-R for Windows: multitrait/multi-tem scale analysis software user’s manual, Boston, MA, 1997. 10. Juniper EF, Guyatt GH, Willan A, Grifﬁth LE. Determining a minimal important change in a disease-speciﬁc quality of life questionnaire. J Clin Epidemiol 1994; 47(1):81–87.

4 General Guidelines for Administration of Topical Agents in the Treatment of Mild-to-Moderate Psoriasis Jashin J. Wu and Gerald D. Weinstein Department of Dermatology, University of California, 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, 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 <20% of body surface area (BSA) affected or a psoriasis area severity index (PASI) score of <10], and for which topical therapy can provide reasonable improvement (5). Topical therapies are usually considered ﬁrst-line treatment (especially by primary care physicians), safe and effective, easy to administer, and cost effective. However, it is not a realistic expectation that topical therapy will result in total clearance of psoriatic lesions (6). Nevertheless, medical advances in the last 30 years, particularly systemic therapy and phototherapy, have given many psoriasis patients temporary partial to total clearance of their disease and relief from their symptoms. In this chapter, we will discuss the various factors to consider when choosing whether to use topical agents versus systemic therapies. We will 29

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then discuss the different factors to consider before prescribing topical agents for psoriasis. We hope these general guidelines for the use of topical therapies will help physicians choose the optimal topical therapy for their patients. FACTORS OF PSORIASIS Body Surface Area When considering therapies, it is often useful to classify psoriasis as mild, moderate, or severe. The BSA is often the most important factor in determining the severity of psoriasis. Generally, the experienced dermatologist can estimate in a brief examination the extent of disease and likely severity. To be more quantitative as measured in clinical trials, the patient’s palm including the ﬁngers and the thumb (i.e., from the wrist to the tip of the ﬁngers) constitutes approximately 1% of the total BSA. According to the National Psoriasis Foundation, up to 3% BSA is considered mild psoriasis, and it can typically be managed with topical therapies alone. Between 3% and 10% BSA is considered moderate psoriasis, and greater than 10% BSA is considered severe psoriasis. However, it remains controversial where the mild and moderate values start. For those with a BSA greater than 10%, it may be too time consuming and impractical to apply topical therapies to all the affected areas. Further, it would become difﬁcult to obtain an adequate supply of topical therapy for sufﬁcient coverage. Some topical medications such as topical steroids and calcipotriene have safety limitations on the amount of drug that is absorbed per unit of time as described elsewhere. Moderate-to-severe psoriasis usually requires systemic medications or phototherapy supplemented by topical therapies or systemic retinoids. Psoriasis Area Severity Index The PASI is a quantitative instrument that allows the dermatologist to make a speciﬁed measurement of disease severity combining BSA with the degree of erythema, scaling, and thickness (induration). However, the actual practice of calculating the PASI is generally too cumbersome in the clinical practice setting. The PASI is essentially only used in the setting of clinical trials, which are required for drug approval by the Food and Drug Administration (FDA). For more details on using the PASI index (7–10). In contrast to the maximum BSA of 100%, the maximum PASI score is 72.0, which represents 100% BSA and a score of four (or severe) for erythema, scaling, and thickness. It has been recently suggested that PASI <7.0 should correspond to mild plaque psoriasis, PASI 7.0–12.0 to moderate disease, and PASI >12.0 to severe disease (11). PASI is also used to measure relative clinical changes, and these changes are often endpoints measured in clinical trials and published in the literature. A PASI50 improvement means that there is a 50% improvement

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in the absolute PASI score compared to that same patient’s baseline PASI score. For example, if a patient starts with a PASI score of 40, and two months later has a PASI score of 20, it means that there is a 50% improvement or a PASI50 improvement. PASI50 and PASI75 are the most commonly measured endpoints for efﬁcacy (12). Location on Body and Types of Psoriasis Aside from extent of BSA, other important factors include location of psoriasis, as it affects social or economic impact, or ease of therapeutic response. The face is often the most concerning area of the body for the patient, so more aggressive topical therapies would be warranted. Further, a person who may appear in public may also wish to have exposed areas to be more aggressively treated such as the hands and forearms. However, topical steroids should be used carefully and sparingly on the face since the skin is relatively thin, and side effects such as acne/rosacea may occur. The eyelids are another area where thin skin should limit the use of strong topical steroids. Inverse psoriasis may affect any area where two layers of skin are in constant contact with each other, such as the axilla and groin. With a natural occlusion caused by two skin planes, the potency of topical steroids may increase 10–100 times (13). Potent topical steroids should be avoided in these self-occluded areas since the risk of skin atrophy is signiﬁcantly increased. Calcipotriene, pimecrolimus, tacrolimus, or less potent topical steroids are safer therapies for inverse psoriasis. In palmar-plantar psoriasis, the thickness of the skin of the palms and soles diminishes the ability of topical therapies to penetrate the skin. Although these areas may have a small BSA, lesions on palms or soles may be disabling, and topical therapies in combination with systemic therapy or phototherapy may be necessary. Response to Therapy Phototherapy and/or systemic therapy should be considered in even mild psoriasis if the lesions are unresponsive to topical therapies. Sometimes the localized involvement is in an area that is physically, socially, emotionally, or occupationally disabling to the patient. As mentioned above, the face and hands are particular areas of concern, and appropriate aggressive treatment of these areas with phototherapy and/or systemic therapy in combination with topical therapies may greatly improve quality of life. Presence or Absence of Psoriatic Arthritis It is believed that 10% to 40% of patients with psoriasis have psoriatic arthritis (14). Patients with mild psoriasis are much less likely than patients with moderate-to-severe psoriasis to be subsequently affected by psoriatic arthritis. A patient whose psoriasis clears completely should not have any scarring

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(unless there were excoriations or other damage done), and it might not be possible to tell that the patient had psoriasis in the ﬁrst place. However, psoriatic arthritis causes permanent bony changes that are irreversible, even if the patient is treated with disease-modifying systemic therapy. None of the topical therapies have been shown to have any efﬁcacy in resolving the pain or slowing joint destruction caused by psoriatic arthritis. If the patient does have mild psoriasis but with psoriatic arthritis that is adversely affecting everyday life or work, the patient should be considered for disease-modifying systemic therapies such as etanercept, inﬂiximab, or methotrexate. These medications have been shown to improve clinical features of the disease and slow radiographic progression of joint damage (15,16). Psoriatic arthritis may have a crippling effect on the patient, and it is best to treat the disease early in its course to prevent joint destruction, as has been demonstrated with etanercept (15). MEDICATIONS There are several topical therapies available (Table 1), and a brief overview is presented here. When choosing a topical agent, it is best to understand the side effect proﬁle, appropriate patient selection, efﬁcacy, and expected results, and otherwise to master the use of a few therapies rather than to use all available topical therapies. In fact, topical therapies for psoriasis are fewer in number than the phototherapy and systemic treatments now available. The main topical therapies used are topical steroids, calcipotriene, and tazarotene, each of which has quantitative data on efﬁcacy. Tacrolimus and pimecrolimus, which are topical immunomodulators, have been tested particularly for inverse psoriasis, but they are only moderately effective. They are now used occasionally as off-label medications for psoriasis. Anthralin and coal tar preparations are older therapies that are less effective, difﬁcult to obtain, and signiﬁcantly messy. Thus, they are infrequently used today. Table 1 The Major Topical Therapies Used to Treat Psoriasis Topical steroids Calcipotriene Tazarotene Anthralin Crude coal tar Lactic acid Salicylic acid Pimecrolimus Tacrolimus Nonmedicated moisturizers

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Keratolytics such as lactic acid, salicylic acid, and the numerous available nonmedicated moisturizers are complementary therapies that help to improve quality of life symptoms. The keratolytics are useful for thick scaling areas, as on palms and soles. The moisturizers (lotions, creams, and ointments) are helpful in general for dry, scaly skin disease and dry climates. Lotion preparations are more useful for scalp and intertriginous areas, while thick creams to ointments are superior for trunk and extremities. Fissured psoriatic lesions that appear on palms and soles may beneﬁt with thick ointments or petrolatum. Patients with psoriasis should be encouraged to use a moisturizer on a regular basis as part of dry skin care. Algorithm of Which Topical Agent to Use The selection of which topical medication to use initially is a matter of choice, experience, cost, and prior patient responses to these therapies. A prescribing algorithm is presented here. First-line topical therapies: 1. Topical steroids: choice of potency depends on severity and location of disease:

Range of potencies from weak to moderate to potent to superpotent (seven classes of potency). It is the authors’ suggestion that physicians new to the use of topical corticosteroids select one steroid from one of the weak, moderate, and potent classes to learn what formulations are available (lotion, cream, ointment, etc.), packaging sizes [30 g (1 oz), 60 g, 120 g tubes, etc.], and generic/brand names. This will facilitate writing prescriptions and providing an adequate amount of medication for the extent of BSA that is to be treated. Weak potencies for children. Weak to moderate potencies for face and intertriginous areas, e.g., groin, axillae, inframammary, to minimize risks of skin atrophy. Potent to superpotent strength for trunk/extremity areas. Lotion, foam, solution, or gel formulation is usually preferred for scalp. Lotion or cream is usually preferred for intertriginous areas. All classes of topical steroids have generic preparations to decrease cost. If used correctly, side effect proﬁle for steroids is minimal. One of the disappointing aspects of using topical steroids is its relatively limited duration of effectiveness. This is described with the term tachyphylaxis, which implies the development of resistance or loss of effectiveness over a period of two to

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four months. Early clinical trials with topical steroids lasted only about one month during which time a good therapeutic response was obtained leading to the approval of these drugs. Subsequent experience and few studies suggest a loss of efﬁcacy over the next several months (17). If discontinued, topical steroids will have some effectiveness several months later. 2. Calcipotriene Cream, solution, and ointment preparations used twice a day (BID). Slow effectiveness, approximately two months for best effect. Maintains effectiveness without tachyphylaxis in contrast to topical steroids. Minimal side effect proﬁle. Expensive, proportional to amount of use and BID application. A synergistic response occurs when used in combination with topical steroids. It is expensive, especially if used BID. 3. Tazarotene Tazarotene is a unique retinoid available as a gel or cream in 0.05% and 0.1% concentrations. It is applied once daily. Irritation is the main side effect. It has a longer remission time compared to topical steroids. 4. Combination topical therapies Medium to potent topical corticosteroids when used in combination with either calcipotriene or tazarotene preparations will produce a higher response level approximating 70–90% in some clinical trials (18–21). These combinations may be most useful in patients with difﬁcult but limited lesions of psoriasis. Combinations produce signiﬁcantly higher costs. Depending on amount of skin being treated these costs can begin to approach those of systemic therapy (28). Amount to Dispense In contrast to phototherapy or systemic therapies, the amount, cost, and time/ effort of topical therapy is obviously proportional to the BSA involvement. One must estimate the amount of topical therapy required to treat the area involved and the frequency of applications. A rule of thumb is that approximately 30 g (1 oz) can cover the entire body. For example, both arms fully

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affected would be 18% of BSA and would require one-ﬁfth or 20% of 30 g (6 g) for daily applications. For 30 days of drug application, the patient would need a prescription for 180 g or 6 oz of medication in one prescription. Unfortunately, the prescribed amount of topical agents is frequently too little for the amount of skin involved and expected duration of treatment. Type of Vehicle Topical therapies are available as creams, foams, gels, liquid solutions, lotions, ointments, and drug-impregnated tapes. The appropriate vehicle depends on the location of the lesions, the patient’s symptoms, and the patient’s preference. Patient preference often takes precedence as long as there are no safety concerns. Thicker (ointment) vehicles are generally more effective and more moisturizing based on a quasiocclusion effect produced by the ointments such as a Vaseline base. Thus, based on the same active ingredients, ointments are stronger than creams, which are stronger than lotions. Creams spread across the skin easily and quickly, are more quickly absorbed than ointments, and do not produce a greasy effect on clothes. Thus, creams may have better compliance in the morning when the patient is wearing dress clothes for work or school. Ointments are more acceptable in the evenings when patients have more time to apply the medicine and are less worried about staining their clothing. Patients usually appreciate a prescription for both a cream and an ointment of the same therapy. The symptoms may also guide the vehicle choice. Dry or itchy skin may beneﬁt from an ointment or cream, which are better for moisturizing. Fissured psoriatic lesions that appear on palms and soles may beneﬁt from thick ointment or petrolatum. Gels and foams are particularly drying and may be better suited for those who have oily skin or dislike the greasiness of ointments and creams. Patients with ﬁssures or cracked lesions will complain of stinging pain if an alcohol-based vehicle such as a liquid solution or foam is prescribed. The location of the psoriasis may guide which vehicle to use. The scalp is an area of therapeutic challenge since the hair blocks the direct application to the lesions and prevents patients from using cosmetically unsuitable vehicles such as ointments and creams. Gels, foams, liquid solutions, and lotions are typically the best vehicles for the scalp. However, some African-American patients with scalp psoriasis may prefer ointments. In the intertriginous areas of the body, such as axillae, groin or inframammary folds, a lotion or cream will be more comfortable than an ointment. Weather or environmental conditions may suggest the appropriate type of vehicle/medication. For example, in a warm and moist climate, lotions and creams will be better tolerated than ointments. The opposite would be true for dry or cold climates.

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Patients should be instructed on the correct use of these agents. Most therapies can be applied either on a damp scalp after towel drying or on a dry scalp. It is imperative to instruct the patient on appropriate application so that the agent reaches the scalp lesions and not just the hair. Demonstrating the application in the ofﬁce may help with compliance. Patients should also be taught that these medicines must be left on the scalp and thus used after a shampoo rather than before. Active medications to the scalp are often applied at night and shampooed out in the morning with standard hair preparations and conditioners as desired. Patients should be instructed in the quantity of topical medications applied to the skin. Basically, one should be rubbing in a thin ﬁlm to the skin without leaving a thick or visible coating on the surface. That is wasteful and expensive since the excessive medication will be rubbed off by the clothes. Keep in mind that in optimal conditions, only about 1% of the active ingredient, e.g., corticosteroid, applied to the skin actually penetrates into the skin. Indeed, topical therapy is less than a wonderful way to get a drug into the skin. However, it does have the obvious advantage of limiting the drug to only the skin in contrast to taking a drug orally, e.g., oral prednisone versus topical steroids. There are vasoconstriction assays with topical steroids that show penetration into the stratum corneum ‘‘reservoir.’’ Plastic ﬁlm occlusion several days after steroid application will produce vasoconstriction. Some topical agents are most effective when applied twice a day, e.g., many topical steroids, or calcipotriene. The patient who is not happy with a particular vehicle for practical reasons is much less likely to use the agent as directed and may report that the therapy is ineffective when it actually would be effective if used correctly. This may limit the doctor’s therapeutic options and force the use of stronger medications. It is best to encourage the patients to use their therapies as directed and to ask their opinion and feedback about the prescribed medicine. Strength of the Agent The strength of the agent applies mostly to topical steroids, so we leave that detailed discussion to Chapter 4. However, it is very important to consider the age of the patient. Due to their thinner skin, pediatric and elderly patients are more susceptible to the side effects of topical steroids. Techniques to Enhance Topical Therapy Special tape that is impregnated with steroids (ﬂurandrenolide tape) produces an occlusive effect can be used when patients have a small number of lesions and are willing to take the time to cut the tape to ﬁt each plaque. Lesions on the extremities may be good candidates for this treatment since

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they are thick, usually resistant to traditional treatment, and are less likely to develop skin atrophy from the constant contact with steroids. Occlusion is another technique that is used to enhance topical therapy (steroids in particular). For example, for psoriasis involving the soles of the feet, hands, and extremities, the patient can apply a low- to medium-class topical steroid, and cover these locations (e.g., wrap around the extremity) with a kitchen plastic wrap (e.g., Saran wrap), or place a small plastic baggie or thin plastic glove over the feet or hands. One can use a sock or thin cotton glove to keep the plastic in place. Application of steroids under occlusion is only done for a few hours or in the evening. Occlusion produces a greater penetration of the steroid into the skin lesions. Extensive use of steroids under occlusion can produce side effects including atrophy of the skin leading to fragility of the skin and purpura. In past years for severe psoriasis, steroids and occlusion were used extensively or even to the entire body leading to risks of systemic steroid effects including damage involving the hypothalamus–pituitary–adrenal gland axis or the eventual development of pustular psoriasis in some patients. Fortunately, with the advent of many more treatments for moderate-to-severe psoriasis, extensive steroid/occlusion is rarely used today. For patients with small 1–4 in lesions on the trunk and extremities, a quasitopical approach would be an intralesional technique utilizing the injection of small doses of corticosteroids, mainly triamcinolone in an aqueous formulation. The most typical injection formulation is in a vial with a concentration of 10 mg/mL. Using dilutions with normal saline, a concentration of 2.5 mg/mL is prepared in the vial or syringe and injected intradermally and superﬁcially into the upper dermis. As concentrations are increased to 5 or 10 mg/mL, the risk of atrophy in the injection site is increased. The injection approach is often very effective for small, scattered lesions and can produce a beneﬁcial effect that will last several months. Combination, Rotational, and Sequential Therapy Patients with more resistant psoriasis may beneﬁt from combination, rotational, or sequential therapy. These techniques will be further discussed in later chapters, but we will present the general rationale behind each one. Combination therapy works on the premise of two medications that act by different mechanisms to maximize clinical results and to minimize side effects of each individual agent. A treatment with a rapid onset of action but unfavorable side effect proﬁle, such as a topical steroid, can be effectively combined with a slower-acting agent but more favorable side effect proﬁle, such as calcipotriene or tazarotene. However, this combination effect has a greater expense by using two different medications. A new combination of calcipotriol/betamethasone dipropionate ointment, which has been recently approved by the FDA, has been shown to be safe

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and effective in patients with psoriasis vulgaris (22–24). Commonly used combinations involving topical therapies are with immunomodulators, phototherapy, and retinoids that are useful for difﬁcult sites like elbows, knees, etc. (25,26). Rotational therapy decreases cumulative toxicity by switching between medications with differing toxicity proﬁles. This technique is more commonly used with systemic therapies than with topical therapies (27). Sequential therapy is when medications are used in a set sequence to maximize the initial speed of improvement while minimizing long-term toxicity. The three phases of this technique are the clearing phase, the transitional phase, and the maintenance phase. Although the classic example is halobetasol propionate and calcipotriene, sequential therapy can be performed with any combination of a rapid-acting therapy and a maintenance medication that is safe to use long term. REFERENCES 1. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin 1996; 14:485–496. 2. Fleischer AB Jr., Feldman SR, Bradham DD. Ofﬁce-based physician services provided by dermatologists in the United States in 1990. J Invest Dermatol 1994; 102:93–97. 3. Thompson TT, Feldman SR, Fleischer AB Jr. Only 33% of visits for skin disease in the U.S. in 1995 were to dermatologists: is decreasing the number of dermatologists the appropriate response? Dermatol Online J 1998;4:3. 4. Peckham PE, Weinstein GD, McCullough JL. The treatment of severe psoriasis. A national survey. Arch Dermatol 1987; 123:1303–1307. 5. Bruner CR, Feldman SR, Ventrapragada M, Fleischer AB Jr. A systematic review of adverse effects associated with topical treatments for psoriasis. Dermatol Online J 2003;9:2. 6. Al-Suwaidan SN, Feldman SR. J Am Acad Dermatol 2000; 42:796–802. 7. Fleischer AB Jr., Rapp SR, Reboussin DM, Vanarthos JC, Feldman SR. Patient measurement of psoriasis disease severity with a structured instrument. J Invest Dermatol 1994; 102:967–969. 8. Langley RG, Ellis CN. Evaluating psoriasis with psoriasis area and severity index, Psoriasis Global Assessment, and Lattice System Physician’s Global Assessment. J Am Acad Dermatol 2004; 51:563–569. 9. Jacobson CC, Kimball AB. Rethinking the psoriasis area and severity index: the impact of area should be increased. Br J Dermatol 2004; 151:381–387. 10. Feldman SR, Fleischer AB Jr., Reboussin DM, et al. The self-administered psoriasis area and severity index is valid and reliable. J Invest Dermatol 1996; 106:183–186. 11. Schmitt J, Wozel G. The psoriasis area and severity index is the adequate criterion to deﬁne severity in chronic plaque-type psoriasis. Dermatology 2005; 210:194–199.

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12. Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the psoriasis area and severity index (PASI 50) is a clinically signiﬁcant endpoint in the assessment of psoriasis. J Am Acad Dermatol 2004; 50:859–866. 13. Koo J, Kochavi G, Kwan JC. Topical medications for psoriasis. In: Kwan JC, ed. Contemporary diagnosis and management of psoriasis. 1st ed. Newtown, Pa.: Handbooks in Health Care Co., 2004:18–38. 14. Koo J, Kochavi G, Kwan JC. Determining disease severity. In: Kwan JC, ed. Contemporary diagnosis and management of psoriasis. 1st ed. Newtown, Pa.: Handbooks in Health Care Co., 2004:15–17. 15. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356:385–390. 16. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained beneﬁts of inﬂiximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the inﬂiximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2005; 52:1227–1236. 17. Jegasothy B, Jacobson C, Levine N, et al. Clobetasol propionate versus ﬂuocinonide creams in psoriasis and eczema. Int J Dermatol 1985; 24:461–465. 18. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 1998; 39:447–450. 19. Kragballe K, Barnes L, Hamberg KJ, et al. Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis: tolerability and efﬁcacy. Br J Dermatol 1998; 139:649–654. 20. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998; 39:590–596. 21. Gollnick H, Menter A. Combination therapy with tazarotene plus a topical corticosteroid for the treatment of plaque psoriasis. Br J Dermatol 1999; 140:18–23. 22. Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002; 82:131–135. 23. Parslew R, Traulsen J. Efﬁcacy and local safety of a calcipotriol/betamethasone dipropionate ointment in elderly patients with psoriasis vulgaris. Eur J Dermatol 2005; 15:37–39. 24. Kragballe K, Noerrelund KL, Lui H, et al. Efﬁcacy of once-daily treatment regimens with calcipotriol/betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris. Br J Dermatol 2004; 150:1167–1173. 25. Koo J, Kochavi G, Kwan JC. Combination, rotational, and sequential therapy. In: Kwan JC, ed. Contemporary diagnosis and management of psoriasis. 1st ed. Newtown, PA: Handbooks in Health Care Co, 2004:59–66. 26. van de Kerkhof PC. Therapeutic strategies: rotational therapy and combinations. Clin Exp Dermatol 2001; 26:356–361. 27. Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993; 28:454–459.

5 Topical Corticosteroids Jason Givan, Daniel Pearce, and Steven R. Feldman Department of Dermatology, Center for Dermatology Research, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

INTRODUCTION While psoriasis is a common, chronic condition affecting 1% to 3% of the general population, the majority of these individuals suffer from limited disease, with lesions that encompass a relatively small portion of their total body surface area (1,2). Accordingly, most patients with psoriasis can be treated with topical medications. Topical corticosteroids, either exclusively or in combination with other treatments, remain the mainstay of treatment in the United States. Approximately 50% of all patients with psoriasis are treated exclusively with topical corticosteroids. An additional 26% of patients seeking medical care for psoriasis treatment are prescribed topical corticosteroids in combination with another medication (1). Topical corticosteroids are a cornerstone of dermatologic treatment for many inﬂammatory skin conditions. There is seemingly an inﬁnite number of topical corticosteroid agents available; they may be categorized by potency and/or formulation (the latter including creams, ointments, lotions, sprays, foams, shampoos, oils, tape, etc.). Understanding the nuances of topical corticosteroid vehicles and potency is a critical aspect of dermatologic care in general and psoriasis treatment in particular. Each formulation has advantages and disadvantages, and the wide variety of formulations provides the clinician great ﬂexibility when prescribing

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these medications. This chapter will address many aspects of topical corticosteroid use, challenging existing paradigms and offering new approaches to optimize topical corticosteroid treatment. RATIONALE FOR PSORIASIS THERAPY Psoriasis is a complex immune-mediated disease where inﬂammation and hyperproliferation are key features. A current model for psoriasis involves presentation of an unknown antigen by an antigen presentation cell to patrolling na€ve T-cells. Following complex intercellular signaling and recruitment of memory T-cells to the psoriasis lesion, there is extensive inﬂammation that is propagated by cytokines and growth factors that are necessary for immune response. Several of these cytokines function both as inﬂammatory mediators and growth factors and help to explain the clinical characteristics of plaque psoriasis. Topical corticosteroids work by modulating complex intracellular signaling of the immune system and by limiting vascular permeability that propagate the immune-mediated inﬂammatory response. A reduction in the local production of cytokines and vasodilatory substances in lesional skin explain three essential abilities of topical corticosteroids: 1. suppression of the local immune response; 2. reduction of inﬂammation; 3. slowing of hyperproliferation. MECHANISM OF ACTION AND BIOLOGIC POTENCY The ﬁrst recorded clinical use of corticosteroids occurred in 1948 when a woman with severe rheumatoid arthritis was successfully treated with an oral preparation of corticosteroid. Two years later, in 1950, the Nobel Prize was awarded for the discovery of this new class of anti-inﬂammatory medication. Sulzberger and Witten’s description of ‘‘compound F’’ in 1952 is the ﬁrst documented account of topical corticosteroid use. The biological and pharmacological activity of the corticosteroid molecule primarily stems from its ability to alter gene transcription and, ultimately, protein expression. For this to occur, the corticosteroid molecule must ﬁrst pass through the cell wall where it reversibly binds to a corticosteroid receptor in the cellular cytoplasm. This newly formed corticosteroid–corticosteroid receptor complex, with increased DNA binding capacity via an allosteric change in conﬁguration, then diffuses into the cell nucleus where it binds to the cell’s DNA. Once bound to the cell’s DNA, the corticosteroid complex modulates the transcription of messenger RNA (mRNA) (3). One downstream effect of corticosteroid-modulated transcription is a decrease in the

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production of inﬂammatory protein mediators such as interleukin (IL)-1, IL-2, IL-6, and interferon alpha. Corticosteroids exert their vasoconstrictive abilities by decreasing the production of key vasodilatory proteins using this same mechanism (4). Though the efﬁcacy of a given topical corticosteroid is determined by several factors, the ﬁrst key element is the quantitative ability of the active molecule to bind corticosteroid receptors and subsequent transcriptional modulation. Almost immediately following the discovery and ﬁrst descriptions of hydrocortisone, attempts to increase its potency were initiated. One way to increase potency is halogenation (with ﬂuoride or chlorine) at the C-6 alpha or C-9 alpha structural positions (Fig. 1). Additionally, ﬂuorination in part produces a molecule with superior potency via protection of the steroid ring backbone structure from routine metabolic breakdown (5). As more potent corticosteroids were developed, side effects of corticosteroid

Figure 1 Functional effects of changing corticosteroid structural elements. The steroid base contains four rings. Corticosteroids have a dihydroxyacetone side chain attached to the carbon atom at position 17. The addition of a double bond between the C-1 and C-2 atoms of the cholesterol backbone (A) increases potency by increasing the lipophilicity of the molecule. Halogenation (with ﬂuoride or chlorine) at the C-6 or C-9 structural positions (B) increases corticosteroid potency through interactions with the corticosteroid receptor. Reduced polarity of the molecule (and therefore greater lipophilicity) can also be achieved by removal of the (C) C-16 alpha hydroxyl group or (D) the C-17 dihydroxyacetone side chain or (E) by masking hydrophilic side groups, via esteriﬁcation of the C-17 or C-21 positions.

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treatment became evident. Historically, more potent corticosteroids were created by ﬂuorination; thus, ﬂuorinated products became associated with higher risk of adverse events. But clearly, it is not ﬂuorination (or halogenation) per se that results in corticosteroid side effects. To the extent that a given compound is able to activate the corticosteroid receptor, so too will be its capacity to produce unwanted and detrimental side effects, irrespective of the potency-enhancing mechanism. It is an incorrect assumption bordering on myth that nonhalogenated corticosteroids are in any way safer than halogenated ones; we can expect that corticosteroids of similar potency will have similar side effect proﬁles. DELIVERY AND PHYSIOLOGIC POTENCY As with systemic corticosteroid therapy, topical corticosteroid therapy and efﬁcacy relies upon activation of the cytoplasmic corticosteroid receptor. However, unlike systemic corticosteroids, which are ingested or injected intramuscularly, topical corticosteroids must reach their target cells by ﬁrst diffusing across the stratum corneum. Therefore, it is essential to realize that topical corticosteroid potency is a function of not only the agent’s physiologic potency to activate its cellular receptor but also the ability of that agent to ﬁrst gain access to the intended area. The ability of a given corticosteroid compound to traverse the stratum corneum involves complex physical chemistry. Furthermore, the ability of a formulation to deliver a corticosteroid cannot be predicted and must be assessed, or measured, clinically. A key concept of the potency of a formulation is the ability of the active agent to separate from the vehicle and diffuse across the stratum corneum. We can envision this as a two-phase system, one in which the vehicle sits on the stratum corneum (much as olive oil sits on water in Italian dressing). How much drug reaches the targeted skin is determined in large part by how the drug partitions between the vehicle and stratum corneum phases. A corticosteroid that partitions from the vehicle into the skin will have a greater potency than a comparable corticosteroid agent that tends to stay in the vehicle despite equal inherent receptor activating ability. Vehicles that drive the corticosteroid into the skin because of good partitioning—whether they be ointments, creams, gels, solutions, foams, lotions, or other vehicles—will tend to be potent agents. Alterations of the corticosteroid, its vehicle, or the stratum corneum may affect partitioning. For instance, polar, hydrophilic molecules move poorly through the stratum corneum and lipophilic, nonpolar molecules diffuse through this barrier well (6–8). There are several methods by which the lipophilicity, and thus the diffusion capacity, of the active corticosteroid may be enhanced. These include the removal of the C-17 dihydroxyacetone side chain or the C-16 alpha hydroxyl group and the addition of a double bond between the C-1 and C-2 atoms of the cholesterol backbone (Fig. 1).

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Alternatively, by masking hydrophilic side groups, via esteriﬁcation of the C-17 or C-21 positions or by the addition of acetonide side groups (Fig. 1), a more lipophilic and soluble molecule is created. Increasing the concentration of the active drug within the vehicle generally (but not always) tends to increase the delivery of the active drug from the vehicle to the skin. Propylene glycol is often present in topical corticosteroid vehicles. This large molecule binds water, increasing the effective concentration of the active drug, diffusion of the drug into skin, and potency. Contrary to what one might think, however, changing the concentration of the corticosteroid compound does not always lead to predictable effects on potency. If one increases the concentration to the point that a drug crystallizes out of solution, the drug may lose all potency. A compound’s partition coefﬁcient may also be affected by concentration; increasing the concentration of a corticosteroid may increase potency, but it may not. Indeed, when 0.1% triamcinolone cream is diluted 1:1 with another base, the resulting 0.05% concentration may have similar, higher, or lower potency compared to the original 0.1% cream. The potency effects of changes to a formulation (such as dilution with another vehicle or combined use with other agents) cannot be predicted. The only way to know is to test the actual preparation in clinical studies. Alteration of the stratum corneum by increasing its permeability generally enhances the delivery of the agent to the targeted skin. Pretreatment with catalytic or fat solvents, removal of scale by chemical or physical modalities, increased hydration, and temperature elevation all tend to result in a more permeable stratum corneum (5,6). Given the multitude of variables that affect the potency of a given topical corticosteroid, the clinical potency of a compound is unpredictable until clinical testing is done. The standard modality of objectively measuring corticosteroid potency is the vasoconstrictor assay, introduced by McKenzie and Stoughton in 1962 (9,10). Topical corticosteroid application results in vasoconstriction of the dermal blood supply via the alteration of gene transcription and subsequent vasoactive mediator production. The vasoconstrictor assay assesses the blanching properties of a given compound over time. Thus, by measuring objective data produced by corticosteroid receptor activation, the vasoconstrictor assay provides information regarding not only the compound’s inherent ability to activate its receptors but also the ability of the topical corticosteroid vehicle to deliver the active drug. The vasoconstrictor assay is a good guide to how compounds will perform in clinical practice, although because this assay is performed on normal skin, it may not fully reﬂect the potency of drugs used on diseased skin. The vasoconstrictor assay is used to place a formulation into one of seven potency classes. The potency of topical drugs is dependent on characteristics of the vehicle, but the speciﬁcs of which vehicles are more potent are not always predictable. Many clinicians have been taught that ointments, primarily

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due to their occlusive properties and superior hydration of the stratum corneum, are inherently more potent than creams (as an aside, there are no strict deﬁnitions of what is an ointment vs. a cream; these names are applied by manufacturers). Though some ointments may be more potent than creams, lotions, liquids, and so on, this concept does not necessarily hold across all topical corticosteroids (11). ‘‘Approved clobetasol propionate foam (Olux1, Connetics Corporation; Palo Alto CA), lotion and spray (both Clobex1, Galderma Laboratories, L.P.; Forth worth, Texas) preparations are similar in potency to ointment preparations as demonstrated by comparable vasoconstriction scores and by roughly similar efﬁcacy rates in clinical trials (11a).’’ ADHERENCE Discussing the biologic properties and factors that affect the delivery of a topical corticosteroid to target skin may overlook the key determinant of efﬁcacy, adherence. A corticosteroid that partitions through the stratum corneum easily and strongly activates corticosteroid receptors may not be very potent if the medication is never applied. Adherence, or compliance, describes the tendency of a patient to apply a medication as prescribed. Patient compliance is a tremendously complex issue and one that, at best, is only partially understood and appreciated. Numerous factors affect a patient’s willingness to adhere to a given prescribed regimen of topical corticosteroids. Among the most prevalent of these factors is patient apprehension regarding possible adverse effects related to topical corticosteroid application. In a questionnaire-based study of 200 dermatology outpatients with atopic eczema, nearly 75% of patients expressed concern over the possibility of experiencing adverse effects related to topical corticosteroid usage. Overall, 24% of the 200 patients questioned admitted to noncompliance at some point secondary to this concern. Of most concern to patients were the possibilities of skin thinning and nonspeciﬁc long-term effects (12). Vehicle preference is also a key component that is thought to affect compliance. Several factors inﬂuence a patient’s preference with regard to the vehicle utilized to deliver the corticosteroid agent. Among these are product characteristics such as subjective greasiness, messiness, and the degree to which the product stains clothing. As a general rule, patients prefer nonmessy preparations, such as solution and foam vehicles, to others (13). Nevertheless, individual patient preference with regard to desirable vehicle characteristics may be difﬁcult to predict. For instance, some patients with psoriasis prefer ointment-based agents. This is perhaps partially due to the immediate ‘‘disappearance’’ (we use the word ‘‘disappearance’’ literally) of scale that results from ointment application (14). While the scale is no longer visible, the scale is still present and would be seen histologically. The immediate alteration of the scale’s refractive index, and therefore its

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visibility, may be gratifying to the patient, potentially increasing patient satisfaction and compliance. Another patient may prefer a less messy vehicle on exposed areas. It may not be possible to predict patients’ preferences for different vehicles. We suggest that clinicians discuss the options with patients and ﬁnd vehicles that best meet patients’ lifestyles and needs. Application frequency and simplicity, as well as treatment duration, also inﬂuence patient compliance (14). The astute clinicians, in an effort to maximize patient compliance, integrate their patients’ individual preferences with regard to each of the characteristics when prescribing a topical corticosteroid regimen. Measuring compliance as it pertains to the ‘‘real-world’’ practice of medicine is difﬁcult, even more so in dermatology where often an arbitrary amount of a topical is applied to a skin region. Self-reported compliance measures are not to be trusted; electronic monitoring permits a more accurate account of patient compliance. In a trial of 30 patients treated with topical 6% salicylic acid gel twice daily, adherence rates were consistently lower when measured by electronic monitoring caps than when calculated based upon patient medication logs or medication weights, the traditional methods of determining patient compliance. In addition, there was a sudden initial decrease in compliance within ﬁve days following the clinical encounter with a continued gradual decrease over subsequent weeks. Compliance rates measured by electronic monitors declined from 85% to 51% over the course of the eight-week trial (15). Considering that this study was done with presumably highly motivated individuals who were paid to participate in a clinical trial, it is not unrealistic to predict that compliance rates in practice may be even lower. Another interesting feature of the salicylic acid gel trials was an intermittent increase in compliance, which appeared related to study visits at two-week intervals. An increase in compliance shortly before visits should not be unexpected, especially by those of us who ﬂoss more often before they see the dentist (we therefore term this effect the ‘‘dental ﬂoss effect’’). Frequent return visits are common in clinical trials and may explain in part the tendency for clinical trials of a topical agent to show greater efﬁcacy than the same topical agent in clinic populations. Thus, clinicians may be able to improve patients’ compliance by offering a return visit in one to two weeks. We believe that compliance over the ﬁrst one to two weeks may be improved by this early return visit. Psychologically, it is far easier to comply with a request for daily application for one week than for an eight-week or longer period. Setting such short-term goals may help foster compliance over the long run and improve outcomes and reduce costs. The concept of tachyphylaxis deserves to be discussed at this point. Tachyphylaxis can be deﬁned as a ‘‘rapidly decreasing response to a drug or physiologically active agent after administration of a few doses’’ (16). While tachyphylaxis to topical corticosteroids is widely recognized in

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clinical practice and there is some physiologic evidence from mouse models, there are little objective data from clinical trials to support the phenomenon. No tachyphylaxis was observed in a 12-week study of psoriasis treated with twice-daily application of betamethasone dipropionate 0.05% ointment (16). The authors suggested that perhaps tachyphylaxis was more frequently observed in clinical practice because of greater noncompliance in the clinic setting compared to the clinical trial setting. The observation of a steady reduction in the use of the 6% topical salicylic acid gel over an eight-week study also suggests that—with regard to topical corticosteroid treatment—a better deﬁnition of tachyphylaxis is ‘‘a decreased response to topical corticosteroids during chronic administration as the patient gradually stops putting it on because they are tired of doing it.’’ In medicine, it is appreciated that adherence is an important concept, though it may clash with paternalism. One goal of dermatology is how to better intervene and improve compliance, which will ideally improve outcomes and lower long-term costs of psoriasis therapy. LESSONS FROM SKIN CAP1 Skin Cap1, an over-the-counter spray marketed as a psoriasis treatment, was introduced in North America in 1995 (17). It was marketed as having zinc pyrithione as its active ingredient. Skin Cap1 quickly became a popular treatment option; patients, as well as dermatologists, enjoyed the remarkable efﬁcacy the product offered to even the most therapeutically challenging psoriatic patient. The formulation provided for easy and nonmessy application, and no adverse effects were expected for a zinc pyrithione spray. It was so effective that it was suggested that psoriasis patients no longer needed corticosteroid injections, methotrexate, or psoralen and ultraviolet A (PUVA). Resistant scalp psoriasis cleared in as little as four days (18). At the height of the clinical success of Skin Cap1 spray, however, reports began to surface in Europe that the product contained potent corticosteroids. In 1997, the Food and Drug Administration (FDA) removed Skin Cap1 from the U.S. market when several independent laboratories discovered that it contained clobetasol propionate. Some clinicians noted, though, that Skin Cap1 seemed far more effective than topical clobetasol propionate ointment. Some suggested the possibility of a synergistic effect existing between the zinc and the corticosteroid (17). The cytoplasmic corticosteroid receptor contains ‘‘zinc ﬁngers,’’ giving a basis for this synergistic hypothesis (19). A left/right comparison trial was performed in which clobetasol propionate was applied to all lesions and zinc pyrithione to half the body and zinc pyrithione vehicle to the other half. The zinc-treated side did no better than the control side (indeed, the side that got zinc did marginally worse—though not statistically signiﬁcantly worse—than the side that did not get zinc) (20). Three factors probably accounted for the dramatic efﬁcacy of Skin Cap1 compared to other clobetasol propionate preparations: compliance,

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compliance, and compliance! As discussed above, ointment vehicles are not inherently more potent than other vehicles and could be less potent if patients do not apply them (for many dermatologists, the efﬁcacy of Skin Cap1 may be the best clinical evidence that a drying spray can be as effective or more effective than an ointment containing the same active ingredient!). Because Skin Cap1 is easily applied, compliance is likely improved. Secondly, patients are concerned about potential adverse effects with regard to the use of topical corticosteroids (12). When patients are told to apply clobetasol, they are warned about cutaneous and internal risks. When doctors recommended Skin Cap1, it was without these warnings (and without the many other scary warnings in topical corticosteroid package inserts), also likely enhancing compliance. Finally, because patients paid for Skin Cap1 themselves, they were probably more invested in the product and more likely to use it. The Skin Cap1 story provides us important guidance to success with topical corticosteroids for psoriasis. High levels of efﬁcacy can be expected if we can improve our patients’ adherence to the treatment regimen. Patients should be involved in the choice of treatment, vehicles and application frequencies should be chosen that ﬁt patients’ lifestyles, and potential side effects of treatment should not be overstated. EFFICACY The clinical effectiveness of topical corticosteroids in treating inﬂammatory dermatoses has been documented in numerous clinical studies. From vasoconstrictor assays and clinical trials, it is known that superpotent, or class I, topical corticosteroids are most effective at treating plaque-type psoriasis. Several studies using traditional ointment/cream vehicles for class I agents demonstrate marked rapid improvement in approximately 80% of subjects (21–23). More recently, formulations of the superpotent corticosteroid clobetasol in a more elegant foam vehicle have produced ‘‘clear or almost clear’’ in 68% of subjects (24). Less potent topical corticosteroids may also be effective at treating psoriasis. All other factors being equal, it can be expected that for the same type of psoriasis plaque, class I medications, if an option, will provide faster clearing/improvement relative to class II–VI drugs. Lower class preparations are extremely helpful in situations where class I agents are to be avoided or minimized. For relatively thin plaque psoriasis, a mid-potency steroid is often appropriate, as it can be expected that penetration of the corticosteroid molecule is enhanced relative to thick plaques. Areas of the body where the stratum corneum is relatively thin, such as the face, intertriginous areas, and genitals, are excellent areas to institute therapy with a relatively low-strength topical corticosteroid; there are also several noncorticosteroid topicals now available. Prudent use of lower-potency topical corticosteroids helps to ensure that adverse events are minimized.

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Also, there are additional vehicles available when prescribing class II to VII agents including oils, gels, tape, and injectable preparations. It is the opinion of this chapter’s authors that ﬂurandrenolide-impregnated tape (Cordran1) is an invaluable resource for small to medium or stubborn plaques; the application of the tape one to three times weekly helps to avoid problems with poor compliance. It is difﬁcult to classify ﬂurandrenolide tape in the traditional class system. Flurandrenolide is a class V corticosteroid, but when used in the occlusive tape, it is expected that the bioavailability below to the dermis and epidermis is enhanced; monitoring for adverse events is important. The efﬁcacy of many corticosteroids may be enhanced when combined with certain noncorticosteroid topical agents, a practice that is commonplace in dermatology. SAFETY Fear of adverse effects from the use of topical corticosteroids is widespread among patients and physicians alike and may represent a signiﬁcant barrier to effective treatment of inﬂammatory skin diseases like psoriasis. Nearly 75% of patients prescribed with topical corticosteroids have some degree of concern regarding the potential adverse affects related to their use; the greatest concerns are skin atrophy, or thinning, and the fear of absorption (25). As the patients from the aforementioned study highlight, adverse events from corticosteroid use are best grouped into local, or cutaneous, and systemic. It should also be noted that most adverse events that engender fear are those associated with chronic therapy with the exception of sequelae from direct injection of psoriasis plaques and transient irritation. Numerous studies have been reported regarding local skin atrophy and striae formation at the site of topical corticosteroid application. Historically, these investigations have varied with regard to the atrophogenic potential of this medication category, at least partially due to difﬁculties related to the histological evaluation of sample tissue (26,27). Recently, improved ultrasound techniques have provided objective evidence of skin thinning by potent and very potent topical corticosteroids within six weeks of treatment onset (12,28–31). However, the precise degree of skin thinning required for clinical signiﬁcance has yet to be determined. Other cutaneous and systemic side effects are summarized in Table 1. Perhaps the most worrisome aspect of therapy with topical corticosteroids is the potential for systemic absorption and subsequent metabolic derangements. Disturbance of the hypothalamic–pituitary axis, iatrogenic Cushing’s syndrome, adrenal insufﬁciency, and necrosis of the femoral head are a few reported examples of systemic effects from topical corticosteroids (32–35). Several reports have failed to demonstrate evidence of cortisol suppression with the use of low, mid-level, or high-potency topical corticosteroids (12,36–41). Other evidence supports mild, transient cortisol

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Table 1 Potential Side Effects from Topical Corticosteroid Use Cutaneous effects Allergic/contact dermatitis Irritation Atrophy Striae Telangectasia Ecchymoses/purpura Hypopigmentation Steroid rosacea Perioral dermatitis Folliculitis Rebound/pustular ﬂare Systemic effects Hypothalamus-pituitary axis suppression Iatrogenic Cushing’s syndrome Iatrogenic adrenal suppression Avascular necrosis of the femoral head

suppression with high-potency topical corticosteroid use (12,42–44). Though there are some evidences for these systemic events, they are rare, making the clinical signiﬁcance relatively low. Patients who have extensive psoriasis are at the highest risk for systemic effects though the amount required to create systemic side effects is not well described. A reasonable rule of thumb is no more than 50 g of a class I agent or 100 g of a class II agent each week should be used in appropriate regions.

SAFER TOPICAL CORTICOSTEROIDS: ARE THEY POSSIBLE? Since Sulzberger and Witten’s description of ‘‘compound F,’’ there have been great strides in the development and formulation of topical corticosteroids. The potency of today’s topical corticosteroids has reached a level capable of effectively treating challenging and recalcitrant inﬂammatory dermatoses. With greater potency comes a greater potential for adverse events. Research and development have attempted to dissociate potency from adverse events in order to create safer potent topical corticosteroids. Improving the safety proﬁle of topical corticosteroids has proven every bit as challenging as increasing their potency. Creating nonﬂuorinated potent corticosteroids is not the solution; it is the strength of the corticosteroid, not the ﬂuorine atom covalently bound in the molecule that contributes to adverse events. There is no reason whatsoever to expect that potent nonﬂuorinated corticosteroids will have any less side effects than ﬂuorinated

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corticosteroids of equal potency. Mometasone furoate uses chlorination rather than ﬂuorination to achieve potency. Some studies claim a reduced risk of adverse effects with mometasone furoate (28,45). These studies, however, were not adequately designed to demonstrate comparable potency while decreasing adverse event rates. For example, one study comparing mometasone to hydrocortisone found greater potency with mometasone but not signiﬁcantly greater adverse events; this study was powered to ﬁnd differences in efﬁcacy but was not powered to identify the likely real differences in adverse event proﬁles (46). Studies of the nonﬂuorinated prednicarbate have also claimed a dissociation between beneﬁt and risk. While both a reduction in adverse effect rate and equal potency have been demonstrated independently (30,31,47,48), studies have not shown the occurrence of both outcomes simultaneously under identical conditions. Therefore, we conclude that the existence of safer topical corticosteroids with equal potency is elusive and has yet to be demonstrated. COST CONSIDERATIONS Very recently, there has been increasing attention given to the economics of psoriasis care. Annual U.S. cost estimates of treating psoriasis range from $650 million to $2 billion (49). Topical corticosteroids are the most common class of medications used to treat psoriasis and there are economic considerations for their use as adjunctive or primary therapy. The ﬁrst and most obvious is the ability of the patient (plus or minus potential third party payers) to pay for a certain medication. In today’s complex setting of co-pays and insurance caps, a discussion centered on a patient’s ability to afford a medication should be given. There is tremendous variation seen not only among classes of topical steroids, but also within them as well, as seen in Figure 1 (50); there are generic alternatives regardless of the desired class. Also, on a macro-scale, the effect of corticosteroids on the cost of caring for psoriasis patients needs to be considered. A recent analysis demonstrated that the use of topical corticosteroids is a primary driver for reduced health care costs (51). This study highlights the concept of topical corticosteroids as controller medications that reduce cost and improve well-being. PRACTICAL USE OF TOPICAL CORTICOSTEROIDS In reality, the potency and documented clinical efﬁcacy of a given topical corticosteroid is meaningless if the patient does not apply the product as instructed. Therefore, maximization of patient compliance is crucial to the practical use of topical corticosteroids, as well as all topical and oral medications. There are numerous factors that inﬂuence an individual patient’s medication adherence. These include patient, physician, and vehicle factors. While it may not be practical to change patients’ compliance proclivities,

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physicians can work to increase compliance in a number of practical ways. First, physicians should establish a close, empathetic relationship with psoriasis patients. Greater compliance can be expected when clinicians touch the psoriasis, and ask questions about the patient’s disease how it affects the patient’s life. Second, physicians should encourage patients to join the National Psoriasis Foundation and make use of the Foundation’s educational resources. The Foundation encourages patients to adhere to their dermatologists’ treatment recommendations. Through increasing patients’ understanding of psoriasis, the National Psoriasis Foundation also empowers patients to take control of their disease and its treatments; such an approach likely leads to greater adherence and better treatment outcomes. Next, physicians should involve the patient in treatment planning and choose treatment options that the patient ﬁnds acceptable. If less messy vehicles are preferred, solution, foam, or lotion vehicles may be offered. Ointments should be prescribed to those patients who prefer them. Finally, physicians should consider several psychological factors known to inﬂuence patient compliance. Duration of treatment has been documented to affect compliance rates for those patients on chronic medication regimens, as is often the circumstance with psoriasis patients. Compliance decreases as treatment duration lengthens in patients requiring chronic oral calcium channel blocker therapy (52). Frequent ofﬁce visits provide reinforcement of behaviors that will hopefully prevent discouragement, noncompliance, and treatment failure. Patient compliance increases during the period surrounding a clinical encounter with a physician or other health care provider. Compliance rates of 88% and 86% to epilepsy medications were observed ﬁve days before and after a clinical visit, respectively. However, compliance rates fell to approximately 73% when measured one month following the patient’s clinical visit (53). Similarly, a clinical study of 30 patients on stable antiepileptic drug regimens demonstrated a 33% increase in drug levels simply by decreasing average clinic visit intervals from three months to one month (54). This phenomenon has been referred to in the medical literature as the ‘‘toothbrush effect,’’ ‘‘white coat effect’’ (55), and, most recently, the ‘‘dental ﬂoss effect.’’ Irrespective of the terminology, the phenomenon is well established and should be exploited by the practitioner in an effort to maximize patient compliance. A return visit one or two weeks after initiating topical treatment may be a strong incentive to adhere to the treatment. STEROID ALTERNATIVES: COMPLEMENTARY, NOT REALLY ALTERNATIVES The perceived and actual potential for adverse effects associated with longterm high-potency topical corticosteroid use propels a search for even safer topical therapies. Topical calcipotriene (Dovonex1) obtained FDA approval in December of 1993. It is a synthetic vitamin D3 derivative indicated for

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the topical treatment of psoriasis. Topical calcipotriene quickly replaced anthralin and tars as the primary noncorticosteroid treatment for psoriasis, and by 1996 it accounted for 71% of the noncorticosteroid medications used at psoriasis visits (1). While approved for monotherapy in the topical treatment of psoriasis, dermatologists swiftly realized the drug’s limitations and the need to use it as an adjunct to topical corticosteroids rather than as a substitute for corticosteroids. In 1994, the drug’s inaugural year of FDA approval, it was utilized as monotherapy in 44% of the patients to whom it was prescribed. By 1996, this number had fallen to only 16%. Conversely, cases in which the drug was utilized as an adjunct to topical corticosteroids increased from 17% to 84% between these same years (1). Central to calcipotriene’s decline as a monotherapy agent are the extended treatment period prior to clinical response and the agent’s principal adverse effect, skin irritation. Fortunately, both of these factors are lessened by combined use with a topical corticosteroid agent (56–58). Thus, calcipotriene exists today more as a topical corticosteroid adjunct than as an alternative. A second topical agent heralded as a corticosteroid alternative in the treatment of psoriasis, topical tacrolimus (Protopic), is an immunosuppressant agent produced by Streptomyces tsukubaensis. Clinical studies of topical tacrolimus for psoriasis are more limited than those concerning topical calcipotriene. One clinical trial found 0.03% topical tacrolimus, applied once daily, to be no more effective than placebo (59). However, 0.1% topical tacrolimus is effective in the treatment of facial and inverse psoriasis, with 81% of patients demonstrating complete clearing (60). The increased efﬁcacy of topical tacrolimus in the treatment of facial and inverse psoriasis is likely a direct result of the improved penetration of topical agents typically observed in these regions. When topical tacrolimus is combined with salicylic acid, a penetration enhancing agent, it is efﬁcacious for common plaque psoriasis (59). Topical tacrolimus may be an acceptable alternative to topical corticosteroids in the treatment of facial and inverse psoriasis or it may be used in combination with topical corticosteroids as has been done with topical calcipotriene. With regard to plaque psoriasis located elsewhere, topical tacrolimus may be used with penetration enhancers or perhaps new formulations will help better deliver the product. SUMMARY Psoriasis is a common, chronic, inﬂammatory skin condition requiring longterm medical management. The vast majority of psoriasis patients have mild to moderate disease that can be managed with topical corticosteroids. The chronicity of the disease and its treatment are major hurdles for patients and their dermatologists. Chronic adherence to the use of any medication is problematic, and chronic applications of time consuming, messy topical preparations are particularly difﬁcult.

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Selection of the appropriate agent for a given patient is critical in order to maximize compliance; no agent, regardless of biologic/physiologic potency, can be effective if it is not applied. For the prescriber, this means taking the time to involve patients in the choice of topical corticosteroids. Characteristics including ease and frequency of application, messiness, cost, and duration of therapy inﬂuence patient compliance. Concerns regarding adverse effects are common among patients prescribed topical corticosteroids and are a frequent source of noncompliance. To maximize the beneﬁts of topical corticosteroids, physicians should seek to identify and minimize these barriers. When used well, how effective are topical corticosteroids for psoriasis? Clinical studies and clinical experience with Skin Cap1 demonstrate the high level of efﬁcacy that can be achieved with topical corticosteroids when patients actually apply them. By paying attention to the factors that inﬂuence patients’ adherence to topical agents, topical corticosteroids can be among our most potent psoriasis treatment options. ACKNOWLEDGMENTS Center for Dermatology Research is funded by a grant from Galderma Laboratories, LP. Dr. Feldman has also received support from Connetics, Astellas, Abbott, Amgen, Biogenidec, Centocor, Photomedex, and Genentech.

REFERENCES 1. Feldman SR, Fleischer AB, Cooper JZ. New topical treatments change the pattern of treatment of psoriasis: dermatologists remain the primary providers of this care. Int J Dermatol 2000; 39(1):41–44. 2. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin 1996; 14(3):485–496. 3. Kragballe K. Topical corticosteroids: mechanisms of action. Acta Derm Venereol Suppl (Stockh) 1989; 151:7–10. 4. Van de Kerkhof PC, Vissers WH. The topical treatment of psoriasis. Skin Pharmacol Appl Skin Physiol 2003; 16(2):69–83. 5. Murray JR. The history of corticosteroids. Acta Derm Venereol Suppl (Stockh) 1989; 151:4–6. 6. Fritz KA, Weston WL. Topical glucocorticosteroids. Ann Allergy 1983; 50(2): 68–76. 7. Lee SS. Topical steroids. Int J Dermatol 1981; 20(10):632–641. 8. Katz M, Shaikh ZI. Percutaneous corticosteroid absorption correlated to partition coefﬁcient. J Pharm Sci 1965; 54(4):591–594. 9. Hepburn DJ, Aeling JL, Weston WL. A reappraisal of topical steroid potency. Pediatr Dermatol 1996; 13(3):239–245. 10. McKenzie AW, Stoughton RB. Method for comparing percutaneous absorption of steroids. Arch Dermatol 1962; 86:608–610.

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11. Gao HY, Li Wan PA. Topical formulations of ﬂuocinolone acetonide. Are creams, gels and ointments bioequivalent and does dilution affect activity? Eur J Clin Pharmacol 1994; 46(1):71–75. 11a.Warino L, Balkrishnan RB, Feldman SR. Clobetasol propionate fox Psoriasis: Are Ointments really more potent? J Drugs Dermatol 2006; 5(6):432–437. 12. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 2000; 142(5):931–936. 13. Feldman S, Housman T. Patients’ vehicle preference for corticosteroid treatments of psoriasis. Am J Clin Dermatol 2003; 4(4):221–224. 14. Van de Kerkhof PC, Steegers-Theunissen RP, Kuipers MV. Evaluation of topical drug treatment in psoriasis. Dermatology 1998; 197(1):31–36. 15. Carroll CL, Feldman SR, Camacho FT, Manuel JC, Balkrishnan R. 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(2):212–216. 16. Miller JJ, Roling D, Margolis D, Guzzo C. Failure to demonstrate therapeutic tachyphylaxis to topically applied steroids in patients with psoriasis. J Am Acad Dermatol 1999; 41(4):546–549. 17. Smith K. Skin Cap: what have we learned, and when did we learn it? [editorial]. Dermatol Online J 1997; 3(2):11c. 18. Shelley WB, Shelley ED. A dermatologic diary. Portrait of a practice. Cutis 1997; 59(4):181–182. 19. Danielsen M, Hinck L, Ringold GM. Two amino acids within the knuckle of the ﬁrst zinc ﬁnger specify DNA response element activation by the glucocorticoid receptor. Cell 1989; 57:1131–1138. 20. Housman TS, Keil KA, Mellen BG, McCarty MA, Fleischer AB Jr., Feldman SR. 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(1):79–82. 21. Goldberg B, Hartdegen R, Presbury D, Smith EH, Yawalkar S. A double-blind, multicenter comparison of 0.05% halobetasol propionate ointment and 0.05% clobetasol propionate ointment in patients with chronic, localized plaque psoriasis. J Am Acad Dermatol 1991; 25(6 Pt 2):1145–1148. 22. Blum G, Yawalkar S. A comparative, multicenter, double blind trial of 0.05% halobetasol propionate ointment and 0.1% betamethasone valerate ointment in the treatment of patients with chronic, localized plaque psoriasis. J Am Acad Dermatol 1991; 25(6 Pt 2):1153–1156. 23. Katz HI, Gross E, Buxman M, Prawer SE, Schwartzel EH, Gibson JR. A doubleblind, vehicle-controlled paired comparison of halobetasol propionate cream on patients with plaque psoriasis. J Am Acad Dermatol 1991; 25(6 Pt 2):1175–1178. 24. Gottleib AB, Ford RO, Spellman MC. The efﬁcacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg 2003; 7:185–192. 25. Charman C, Chambers C, Williams H. Measuring atopic dermatitis severity in randomized controlled clinical trials: what exactly are we measuring? J Invest Dermatol 2003; 120(6):932–941. 26. Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs 1988; 36(suppl 5):51–61.

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27. Jones EW. Steroid atrophy—a histological appraisal. Dermatologica 1976; 152(suppl 1):107–115. 28. Kerscher MJ, Hart H, Korting HC, Stalleicken D. In vivo assessment of the atrophogenic potency of mometasone furoate, a newly developed chlorinated potent topical glucocorticoid as compared to other topical glucocorticoids old and new. Int J Clin Pharmacol Ther 1995; 33(4):187–189. 29. Kerscher MJ, Korting HC. Comparative atrophogenicity potential of medium and highly potent topical glucocorticoids in cream and ointment according to ultrasound analysis. Skin Pharmacol 1992; 5(2):77–80. 30. Kerscher MJ, Korting HC. Topical glucocorticoids of the non-ﬂuorinated double-ester type. Lack of atrophogenicity in normal skin as assessed by highfrequency ultrasound. Acta Derm Venereol 1992; 72(3):214–216. 31. Korting HC, Vieluf D, Kerscher M. 0.25% prednicarbate cream and the corresponding vehicle induce less skin atrophy than 0.1% betamethasone-17-valerate cream and 0.05% clobetasol-17-propionate cream. Eur J Clin Pharmacol 1992; 42(2):159–161. 32. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufﬁciency: clinical implications. Am J Clin Dermatol 2002; 3(3):141–147. 33. Nathan AW, Rose GL. Fatal iatrogenic Cushing’s syndrome. Lancet 1979; 1(8109):207. 34. Kubo T, Kojima A, Yamazoe S, Ueshima K, Yamamoto T, Hirasawa Y. Osteonecrosis of the femoral head that developed after long-term topical steroid application. J Orthop Sci 2001; 6(1):92–94. 35. Katz HI, Hien NT, Prawer SE, Mastbaum LI, Mooney JJ, Samson CR. Superpotent topical steroid treatment of psoriasis vulgaris—clinical efﬁcacy and adrenal function. J Am Acad Dermatol 1987; 16:804–811. 36. Munro DD. The effect of percutaneously absorbed steroids on hypothalamic– pituitary–adrenal function after intensive use in in-patients. Br J Dermatol 1976; 94(suppl 12):67–76. 37. Crespi HG. Topical corticosteroid therapy for children: alclometasone dipropionate cream 0.05%. Clin Ther 1986; 8(2):203–210. 38. Lucky AW, Grote GD, Williams JL, et al. Effect of desonide ointment, 0.05%, on the hypothalamic–pituitary–adrenal axis of children with atopic dermatitis. Cutis 1997; 59(3):151–153. 39. Rasmussen JE. Percutaneous absorption of topically applied triamcinolone in children. Arch Dermatol 1978; 114(8):1165–1167. 40. Van Der Meer JB, Glazenburg EJ, Mulder PG, Eggink HF, Coenraads PJ. The management of moderate to severe atopic dermatitis in adults with topical ﬂuticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group. Br J Dermatol 1999; 140(6):1114–1121. 41. Vernon HJ, Lane AT, Weston W. Comparison of mometasone furoate 0.1% cream and hydrocortisone 1.0% cream in the treatment of childhood atopic dermatitis. J Am Acad Dermatol 1991; 24(4):603–607. 42. Weston WL, Sams WM Jr, Morris HG, Arthur JM, Blakeman GJ, Andresen M. Morning plasma cortisol levels in infants treated with topical ﬂuorinated glucocorticosteroids. Pediatrics 1980; 65(1):103–106. 43. Queille C, Pommarede R, Saurat JH. Efﬁcacy versus systemic effects of six topical steroids in the treatment of atopic dermatitis of childhood. Pediatr Dermatol 1984; 1(3):246–253.

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44. Juhlin L. Comparison of ﬂuticasone propionate cream, 0.05%, and hydrocortisone17-butyrate cream, 0.1%, in the treatment of eczema. Cutis 1996; 57(suppl 2):51–56. 45. Kelly JW, Cains GD, Rallings M, Gilmore SJ. Safety and efﬁcacy of mometasone furoate cream in the treatment of steroid responsive dermatoses. Australas J Dermatol 1991; 32(2):85–91. 46. Bhardwaj SS, Camacho F, Derrow A, Fleischer AB Jr, Feldman SR. Statistical signiﬁcance and clinical relevance: the importance of power in clinical trials in dermatology. Arch Dermatol 2004; 140(12):1520–1523. 47. Korting HC, Unholzer A, Schafer-Korting M, Tausch I, Gassmueller J, Nietsch KH. Different skin thinning potential of equipotent medium-strength glucocorticoids. Skin Pharmacol Appl Skin Physiol 2002; 15(2):85–91. 48. Schafer-Korting M, Korting HC, Kerscher MJ, Lenhard S. Prednicarbate activity and beneﬁt/risk ratio in relation to other topical glucocorticoids. Clin Pharmacol Ther 1993; 54(4):448–456. 49. Javitz HS, Ward MM, Farber E, Nail L, Vallow SG. The direct cost of care for psoriasis and psoriatic arthritis in the United States. J Am Acad Dermatol 2002; 46(6):850–860. 50. Pearce DJ, Thomas CG, Fleischer AB Jr, Feldman SR. The cost of psoriasis therapies: considerations for therapy selection. Dermatol Nurs 2004; 16(5):421–428, 432. 51. Kulkarni AS, Balkrishnan R, Richmond D, Pearce DJ, Feldman SR. Medicationrelated factors affecting health care outcomes and costs for patients with psoriasis in the United States. J Am Acad Dermatol 2005; 52(1):27–31. 52. Farmer KC, Jacobs EW, Phillips CR. Long-term patient compliance with prescribed regimens of calcium channel blockers. Clin Ther 1994; 16(2):316–326. 53. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med 1990; 150(7):1509–1510. 54. Wannamaker BB, Morton WA Jr, Gross AJ, Saunders S. Improvement in antiepileptic drug levels following reduction of intervals between clinic visits. Epilepsia 1980; 21(2):155–162. 55. Feinstein AR. On white-coat effects and the electronic monitoring of compliance. Arch Intern Med 1990; 150(7):1377–1378. 56. Ruzicka T, Lorenz B. Comparison of calcipotriol monotherapy and a combination of calcipotriol and betamethasone valerate after 2 weeks’ treatment with calcipotriol in the topical therapy of psoriasis vulgaris: a multicentre, double-blind, randomized study. Br J Dermatol 1998; 138(2):254–258. 57. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 1996; 35(2 Pt 1):268–269. 58. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 1998; 39:447–450. 59. Carrol CL, Clarke J, Camacho F, Balkrishnan R, Feldman SR. Topical tacrolimus ointment in combined with 6% salicylic acid gel for plaque psoriasis treatment. Arch Dermatol 2005; 141(1):43–46. 60. Freeman AK, Linowski GJ, Brady C, et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 2003; 48(4):564–568.

6 Vitamin D3 Analogs Chai Sue Lee Department of Dermatology, University of California Davis Medical Center, Sacramento, California, U.S.A.

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.

Calcipotriene (Dovonex1) is the ﬁrst topical vitamin D3 analog approved for the treatment of plaque psoriasis in the United States. Calcipotriene is known as calcipotriol (Daivonex1) outside of the United States, Canada, Japan, etc. It is the ﬁrst elegant nonsteroidal topical alternative for the treatment of psoriasis and is available as an ointment, cream, or scalp solution. Other topical vitamin D3 analogs are available outside of the United States for the treatment of psoriasis, such as calcitriol (Silkis1), tacalcitol (Bonalfa1), and maxacalcitol (Oxarol1). Calcipotriene ointment was found to be signiﬁcantly more effective than calcitriol ointment in a randomized, double-blind study (1). In another large multicenter, randomized, double-blind study, calcipotriene was found to be signiﬁcantly more effective than tacalcitol when calcipotriene ointment was compared to tacalcitol ointment based on their marketed treatment schedule of twice a day for calcipotriene and once daily for tacalcitol (2). Calcipotriene ointment once daily and maxacalcitol ointment once daily was shown to have similar efﬁcacy (3). However, acute renal failure associated with hypercalcemia has been reported with maxacalcitol (4,5). In the package insert of maxacalcitol, the

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Japanese Food and Drug Administration (FDA) recommends checking serum calcium and renal function tests periodically (once after the ﬁrst two to four weeks of treatment and as required thereafter). Furthermore, the Japanese FDA recommends close monitoring for patients with extensive psoriasis or severe psoriasis using maxacalcitol with periodic serum calcium and renal function tests since the impaired skin barrier function can cause increased transdermal absorption of maxacalcitol, and thus hypercalcemia is more likely to occur. Although hypercalcemia can also occur with calcipotriene, the risk seems less, and there is no recommendation by the U.S. FDA to check serum calcium level or renal function tests periodically. Calcipotriene is the only vitamin D3 analog available in the United States, since maxacalcitol was clinically tested in the United States and the ﬁnal decision was not to market it in the United States. Since calcipotriene is the most widely used topical vitamin D3 analog worldwide and it is also the most extensively studied in terms of combination, sequential, and in comparison with other topical agents, and it is probably one of the most favorable agents in terms of efﬁcacy and side effect proﬁle, the rest of this chapter will focus on calcipotriene. CHEMISTRY AND MECHANISM OF ACTION The chance discovery in 1985 by Japanese researchers that calcitriol, which is the most active metabolite of vitamin D3, improves psoriasis provided the impetus for the development of analogs of this compound, including calcipotriene, which might prove useful for the treatment of psoriasis with much less effect on calcium homeostasis (6). Figure 1 shows the chemical structure of calcipotriene and other vitamin D3 analogs. Calcipotriene is a synthetic analog of 1a,25-dihydroxycholecalciferol (calcitriol). At the molecular level, calcitriol and its analogs, including calcipotriene, elicit most of their biologic effects by binding to a speciﬁc intracellular receptor, the vitamin D receptor, and regulating gene transcription (7). Calcipotriene has been shown to have an afﬁnity for vitamin D receptors similar to that of calcitriol (8–10). The beneﬁcial effects of calcipotriene on psoriasis are similar to those of calcitriol and include, most notably, inhibition of proliferation of keratinocytes and increased terminal differentiation (11,12). However, calcipotriene is 100 times less potent in its effects on calcium metabolism (13). Flow cytometric analysis has shown signiﬁcant decreases relative to placebo in numbers of proliferating basal keratinocytes in psoriatic skin treated with topical calcitriol (14). In addition, application of calcipotriene ointment twice daily for up to eight weeks has been shown to result in partial recovery of the stratum corneum, complete recovery of the stratum granulosum, and correction of intercellular spacing and number and structure of desmosomes (15,16). Furthermore, application of calcipotriene ointment for four weeks

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Figure 1 Chemical structures of vitamin D3 analogs.

has been shown to be associated with suppression of epidermal T cell and polymorphonuclear leukocyte accumulation in psoriatic skin (15). CALCIPOTRIENE MONOTHERAPY Multiple clinical trials have conﬁrmed the efﬁcacy and safety of all formulations (ointment, cream, and solutions) of calcipotriene in the treatment of psoriasis in adults (11,12,17). In addition, long-term studies have shown that the beneﬁts of calcipotriene therapy were maintained for up to one year (18–22). In a noncomparative study, 40 patients receiving twice daily calcipotriene ointment had a mean time to healing of 53.5 days (range 14–78 days), with a mean time to relapse of 43.3 days (range 14–112 days) (23). At the time of relapse, patients recommenced treatment with calcipotriene ointment, with a mean time to healing following relapse of 44.6 days (range 14–57 days). Furthermore, the time to heal following relapse signiﬁcantly correlated with the duration of the ﬁrst treatment period. Those treated for less than eight weeks initially healed after relapse in 40.6 days (range 14–56 days) versus 69.6 days (range 63–78 days) in those requiring more than eight weeks’ treatment during the initial phase. Therefore, there appears to be faster and slower responders to calcipotriene therapy. CALCIPOTRIENE IN CHILDREN There are only limited data on the efﬁcacy of calcipotriene in children. In a multicenter, randomized, double-blind, placebo-controlled study, signiﬁcantly

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more patients achieved a marked improvement or clearance of psoriasis in the calcipotriene-treatment group than placebo after eight weeks of treatment in children aged 2 to 14 years according to investigator-assessed overall responses (60% vs. 44%), although patient- or guardian-assessed response rates did not differ signiﬁcantly between the two groups (24). However, there was no significant difference in the reduction in overall disease severity between twice-daily calcipotriene ointment and placebo (52% vs. 37% reduction). A similar response with calcipotriene therapy was also observed in a noncomparative, nonblind study in 66 children aged 3 to 14 years (25). In a long-term noncomparative study in 12 children aged 8 to 15 years, calcipotriene ointment twice daily was shown to be effective in reducing disease severity (26). The mean overall psoriasis area and severity index score was reduced by 65% following calcipotriene treatment for a mean duration of 40 weeks (range 12–106 weeks). CALCIPOTRIENE VS. OTHER TOPICAL AGENTS Calcipotriene ointment was shown to have similar or superior efﬁcacy compared to topical corticosteroids in several clinical studies. In three large multicenter studies, subjective response rates after six weeks were signiﬁcantly better with twice-daily calcipotriene ointment than with twice-daily betamethasone valerate ointment (27–29). In addition, twice-daily calcipotriene ointment was shown to have similar efﬁcacy compared to twice-daily betamethasone dipropionate plus salicyclic acid (dosages not reported) (30). Furthermore, twice-daily calcipotriene ointment was shown to be signiﬁcantly better than twice-daily ﬂuocinonide ointment (13). Calcipotriene ointment twice daily was signiﬁcantly more effective than twice-daily 5% coal tar plus 2% allantoin and 0.5% hydrocortisone (32). In addition, twice-daily calcipotriene ointment provided similar or superior efﬁcacy to once-daily short-contact 0.1% to 3% dithranol (33–35). Calcipotriene ointment also had a signiﬁcantly greater cosmetic acceptability than short-contact dithranol cream (33). A comparison of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream once daily versus calcipotriene ointment twice daily found similar efﬁcacy after eight weeks of treatment (36). At the end of eight weeks, 59% of patients in the calcipotriene group versus 60% in the tazarotene plus mometasone group achieved a marked or 75% improvement in severity of psoriasis based on investigator assessment. In addition, there were no differences in plaque elevation or scaling scores between the two treatment groups, although erythema scores were signiﬁcantly better in the tazarotene plus mometasone group. Calcipotriene was better tolerated than tazarotene plus mometasone. Signiﬁcantly fewer patients in the calcipotriene group experienced burning (8% vs. 42%), pruritus (13% vs. 32%), skin irritation (12% vs. 28%), or erythema (7% vs. 25%) than the tazarotene plus mometasone group.

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COMBINATION THERAPY Combination therapy is often used to increase the efﬁcacy of treatments through additive/synergistic effects and/or to minimize adverse effects. Most dermatologists in the United States use calcipotriene not as monotherapy but rather in combination with other treatments. Combination of calcipotriene with other treatments not only increases the rate of improvement and offers greater improvement but minimizes adverse effects in some cases; for instance in the case of topical steroids, the topical steroid decreases the risk of skin irritation by calcipotriene, and calcipotriene prevents skin atrophy by the topical steroid.

CALCIPOTRIENE AND TOPICAL STEROIDS In a two-week study of 127 patients with moderate plaque psoriasis, the combination of once-daily calcipotriene ointment (applied in the morning) and once-daily halobetasol ointment (applied in the evening) was signiﬁcantly better than either twice-daily calcipotriene or twice-daily halobetasol (37). The study protocol required that one agent be applied in the morning and the other agent in the evening. It is possible that when both calcipotriene and halobetasol are applied twice daily, their efﬁcacy may be even further improved since both calcipotriene and halobetasol are known to be more effective when used twice a day instead of once a day (38). One of the authors’ favorite topical combination therapy for psoriasis is sequential therapy using a class I superpotent topical steroid and calcipotriene. Sequential therapy is discussed in detail in Chapter 13. In another study, pulse therapy with betamethasone dipropionate once daily (weeks one and three) and calcipotriene ointment twice daily (weeks two and four) was signiﬁcantly better than betamethasone dipropionate once daily for four weeks (39). Moreover, signiﬁcantly more patients achieved a marked improvement or complete clearance with pulse therapy than with monotherapy according to both physicians’ (96% vs. 41%) and patients’ (96% vs. 37%) assessment. A multicenter, randomized, double-blind six-month study investigated the duration of remission with topical combination therapy with twice-daily calcipotriene ointment on weekdays and twice-daily halobetasol ointment on weekends in 40 patients with plaque psoriasis (40). Signiﬁcantly more patients in the combination pulse therapy with calcipotriene ointment (applied twice daily on weekdays) plus halobetasol ointment (applied twice daily during the weekend) remained in remission throughout the six-month study period than patients receiving halobetasol ointment twice daily on weekends and placebo ointment twice daily during the week (76% vs. 40%). Remission was deﬁned as achieving or maintaining marked improvement (75% improvement or a global evaluation score of 2) for six months.

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CALCIPOTRIENE AND TAZAROTENE According to available published data, although calcipotriene and tazarotene might not be as potent as class I topical steroids when each is used as monotherapy, they appear to have synergistic effects when combined, with similar efﬁcacy and rapidity as a class I superpotent topical steroid (41). In a prospective, open-label, left–right comparison study, combination therapy of calcipotriene ointment twice daily with tazarotene 0.1% gel once daily was comparable to clobetasol ointment twice daily (41). The study consisted of 15 patients who underwent a two-week treatment course, followed by a four-week post-treatment observation. At the end of the two weeks, lesions treated with calcipotriene and tazarotene had the same improvement in overall lesion severity, reduction in plaque elevation and scaling as the clobetasol-treated lesions. Not surprisingly, erythema improved more in the clobetasol-treated lesions. Adverse events were more frequent in calcipotriene–tazarotene-treated lesions than in those treated with clobetasol. The most common adverse effects related to treatment with calcipotriene and tazarotene were asymptomatic erythema and mild peeling. However, no patient had to withdraw or interrupt treatment because of adverse events. The results of this study suggest that there does not appear to be any clinically relevant chemical incompatibility between calcipotriene ointment and tazarotene gel, as was shown by their apparently synergistic effects on improving psoriasis. CALCIPOTRIENE AND PHOTOTHERAPY Outpatient ultraviolet B (UVB) phototherapy should be performed three to ﬁve times a week. Twice-weekly UVB phototherapy is often inadequate to achieve satisfactory results. However, calcipotriene cream combined with twice-weekly broadband UVB phototherapy has demonstrated efﬁcacy equivalent to three times per week UVB with only the vehicle of calcipotriene cream (42). The reduction in UVB therapy from three to two times a week is a critical therapeutic improvement because one of the most challenging aspects of successful phototherapy is getting a commitment from patients for three visits per week. In another study, calcipotriene plus narrowband UVB (NB-UVB) phototherapy was shown to have a UVB-sparing effect compared with NB-UVB alone (43). In contrast, Brands and colleagues (44) did not ﬁnd signiﬁcant improvement with combination calcipotriene and NBUVB versus NB-UVB alone. The authors suggest that differences in the comparisons with UVB phototherapy may reﬂect differences in UVB phototherapy techniques, patient noncompliance in applying calcipotriene ointment, or a UVB blocking action of calcipotriene ointment. Addition of calcipotriene ointment therapy to thrice-weekly psoralen and ultraviolet A (PUVA) phototherapy signiﬁcantly improved the response of

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patients to PUVA therapy, but in another study using twice-weekly PUVA treatments the response in the two treatment groups was similar (45,46). Frappaz and Thivolet (45) showed that the combination of twice-daily calcipotriene ointment and PUVA phototherapy three times a week was more effective than PUVA alone. In contrast, in another study calcipotriene ointment plus twice-weekly PUVA phototherapy provided similar reductions in overall disease severity scores to PUVA monotherapy (46). Both studies, however, showed a signiﬁcant decrease in the duration of PUVA therapy, in the cumulative ultraviolet A (UVA) dose, and number of UVA irradiations when PUVA was used in combination with calcipotriene compared with PUVA monotherapy (45,46). For example, in the larger study the duration of PUVA therapy was reduced from 34 to 22 days, the cumulative UVA dose reduced from 57 to 30 J/cm2, and the number of UVA irradiations administered reduced from 15 to 10 (45). CALCIPOTRIENE AND SYSTEMIC AGENTS In 1998, van de Kerkhof et al. (47) reported the addition of calcipotriene ointment twice daily to systemic treatment with acitretin was signiﬁcantly more effective than acitretin plus placebo ointment. All patients were treated with a starting dose of 20 mg/day of acitretin. The dose was increased every two weeks in increments of 10 mg/day until a maximum dose of 70 mg/day was reached, clearance was achieved, or patients developed unacceptable side effects to acitretin. After 12 weeks, 67% of the patients in the calcipotriene and acitretin group achieved clearance or marked improvement compared to 41% of the patients in the acitretin plus placebo ointment group (47). Furthermore, the median total dose of acitretin required to reach clearing or marked improvement was signiﬁcantly reduced in the combination therapy group compared with acitretin alone (1680 vs. 2100 mg). In a more recent study with a longer duration of treatment, the duration of treatment and total dose of retinoid required to achieve clearance were slightly lower in the calcipotriene and acitretin group; however, the difference was not statistically signiﬁcant (48). After 52 weeks, 60% in the calcipotriene and acitretin combination therapy group and 40% in the acitretin monotherapy group achieved complete clearance. The addition of calcipotriene did not signiﬁcantly reduce the total duration of treatment (82.8 vs. 92.8 days) and cumulative dose of acitretin required to reach clearance state (1613 vs. 2205 mg). Even though the result of the second study did not reach statistical signiﬁcance, the consistent trend and the notable difference between the calcipotriene and acitretin group compared with acitretin monotherapy group may indicate that with a large enough number of subjects, statistical signiﬁcance might have been achieved. Combination therapy with calcipotriene ointment twice daily and oral cyclosporine 2 mg/kg/day signiﬁcantly improved disease severity compared

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with cyclosporine 2 mg/kg/day alone (49). After six weeks, complete clearing or 90% improvement in psoriasis area and severity index score occurred in 50% of patients in the calcipotriene and cyclosporine group compared to 12% of the patients in the cyclosporine plus placebo ointment group (49). De Jong et al. (50) has shown that when methotrexate therapy is discontinued, topical therapy with calcipotriene ointment twice daily results in an extension of the remission time before a relapse of psoriasis occurs compared with maintenance treatment with the vehicle only (113 vs. 35 days). Furthermore, the weekly dose of methotrexate needed to treat psoriasis is lower by combining methotrexate with calcipotriene than by combining methotrexate with the vehicle. The mean weekly dose of methotrexate was 6.5 mg/wk in the patient group treated with calcipotriene versus 9.9 mg/wk in the patient group treated with the vehicle (50). This results in lower cumulative dosage and therefore in a substantial reduction of the risk of short- and long-term side effects of methotrexate. ADVERSE EFFECTS One of the most important features of calcipotriene, which makes it an excellent agent for primary care physicians as well as for dermatologists, is its safety proﬁle. Calcipotriene is steroid free, and thus free from steroid side effects such as skin thinning, striae formation, and adrenal suppression. It is generally well tolerated. There were no signiﬁcant differences in the nature and incidence of adverse events with the different formulations (11,12). Irritation The only signiﬁcant cutaneous side effect of calcipotriene is lesional and perilesional (around the lesion) irritation, which occurs in 12% to 20.1% of patients in clinical trials (27,31,33,51,52). Irritation from calcipotriene usually presents with a red ring of inﬂamed skin surrounding the treated lesions (Fig. 2). Patients usually report a mild stinging, itching, or burning sensation. This is usually mild to moderate in severity. It is usually transient, and patients quickly become accustomed to it. In clinical trials, only one of 25 patients had to discontinue treatment because of skin irritation from calcipotriene (53). Irritation from calcipotriene is more frequent on the face and intertriginous areas such as the axilla and groin. It appears to depend largely on the penetration of calcipotriene through the skin. The skin-to-skin occlusion inherent in intertriginous areas enhances penetration of calcipotriene, which is thought to account for the increased rate of irritation in these areas. Calcipotriene is lipophilic and more readily absorbed by skin containing oily sebaceous glands, such as the face, which also helps explain why it tends to be more irritating on the face.

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Figure 2 (See color insert) Skin irritation from calcipotriene.

Irritation from calcipotriene can usually be resolved by using smaller amounts and/or less frequent application (e.g., once a day or every other day instead of twice a day). Once this regimen is tolerated, the frequency and dose can again be increased carefully. Also, using the cream formulation instead of the ointment formulation can often minimize the risk of irritation. Diluting calcipotriene with a lubricant, such as petroleum jelly or a moisturizer, is another method of reducing potency and irritation. In rare patients, calcipotriene may cause excessive peeling and apparent expansion of erythema beyond the original border of the psoriasis (Fig. 3). If this peculiar perilesional peeling occurs, and if the sensation is not bothersome, one can reassure the patient and encourage continued use of calcipotriene until everything, including the expanded erythematous or peeling area, resolves. Another strategy used by most clinicians at the initiation of therapy is combining calcipotriene with a class I topical steroid. The risk of developing irritation with calcipotriene is greatly reduced when it is used in conjunction with a topical steroid (37). Hypercalcemia and Hypercalciuria The systemic side effect to be aware of when using calcipotriene is hypercalcemia and hypercalciuria. Although several studies have investigated the effects of calcipotriene twice daily (up to 100 g/wk) on serum and urine

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Figure 3 (See color insert) Skin irritation from calcipotriene.

calcium levels in patients with psoriasis (54–59), only one study showed a small but signiﬁcant increase in urine calcium levels (55). In clinical practice, however, there have been isolated case reports of hypercalcemia and hypercalciuria (17). The majority of cases of hypercalcemia have occurred in patients who exceeded the recommended maximum topical dosage of 100 g/wk, although a few occurred in patients using <100 g/wk. All reported episodes of hypercalcemia and hypercalciuria have resolved on discontinuation of calcipotriene. A good guideline to follow is to limit total weekly use of calcipotriene in all formulations (ointment, cream, solution) to 100–120 g/wk to avoid the risk of hypercalcemia. Since calcipotriene is available as a 120 g tube, one can instruct the patient to use no more than one large tube a week.

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CALCIPOTRIENE APPLICATION IN PSORIASIS Patients need to be well educated when they are given a prescription for calcipotriene. If the patient is to use calcipotriene as monotherapy, it is critical to communicate to the patient the importance of using it twice a day, and to warn the patient of possible skin irritation as well as possible slow onset of action, especially if calcipotriene monotherapy is only used once a day. In clinical practice, it is difﬁcult to ﬁnd patients who actually comply with the twice-daily recommended usage. To maximize the chance that a patient will use it this way, it is best to prescribe calcipotriene cream as well as ointment so that the patient can use the more elegant but slightly less effective cream in the morning, and more effective but less elegant ointment formulation at night. Adult patients should also be instructed to use no more than 100–120 g/wk of calcipotriene to avoid the risk of hypercalcemia. For example, if the patient is using calcipotriene cream in the morning and calcipotriene ointment in the evening, then the patient should not use more than 50–60 g/wk of calcipotriene cream and 50–60 g/wk of calcipotriene ointment. Currently, in the United States, there are no dosage recommendations available for the use of calcipotriene in children, whereas in the United Kingdom, the maximum recommended dosage in children aged 6–12 years is 50 g/wk increasing to 75 g/wk in those aged over 12 years (17). No dosage recommendations are available for children less than six years of age (17). Calcipotriene is contraindicated in patients with known calcium metabolism disorders, evidence of vitamin D toxicity, or hypersensitivity to calcipotriene or any other constituents of the ointment. It is pregnancy category C, and safety of calcipotriene in pregnancy has not yet been fully established. As hypercalcemia is extremely rare in patients applying calcipotriene no more than 100–120 g/wk, serum and urine calcium levels do not need to be monitored, except possibly in those with generalized pustular or erythrodermic psoriasis, who may be susceptible to hypercalcemia (60). Calcipotriene is a relatively unstable molecule and is inactivated by acidic pH. It is not compatible and should not be mixed or applied in conjunction with salicylic acid, lactic acid, or ammonium lactate lotion unless application times are separated by at least two hours. Signiﬁcant degradation was found in combination with hydrocortisone-17-valerate 0.2% ointment but it was found to be compatible with halobetasol propionate 0.05% ointment and cream, tazarotene gel, and Estargel (13). When combined with phototherapy, calcipotriene should be applied a minimum of two hours before light treatment to prevent inactivation by the UVA wavelengths and rare burning sensations from UVB wavelengths.

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CONCLUSIONS Calcipotriene is valuable as a ﬁrst- or second-line therapy option for the management of mild to moderate psoriasis and in combination with other antipsoriatic agents for more severe psoriasis. In clinical trials, calcipotriene monotherapy is at least as effective as a class II topical corticosteroid when used faithfully twice a day. Unlike topical corticosteroid, long-term calcipotriene therapy is not associated with skin atrophy or prominent concern regarding tachyphylaxis. In addition, calcipotriene is not associated with the rebound effect observed with several topical steroids whereby psoriasis worsens upon discontinuation of therapy. Most dermatologists in the United States use calcipotriene not as monotherapy but rather in combination with other treatments. Used in combination with a superpotent topical steroid, the two drugs have a synergistic effect and are superior to either agent alone. This has been demonstrated with halobetasol ointment (Ultravate1) and clobetasol foam (OLUX1) (see Chapter 13 for detail). Furthermore, the combination of the two drugs appears to offset the adverse effects of each. The topical steroid helps to decrease the risk of skin irritation from calcipotriene, and calcipotriene helps to prevent skin atrophy by the topical steroid. Calcipotriene is also beneﬁcial in combination with UVB or PUVA phototherapy.

REFERENCES 1. Bourke JF, Iqbal SJ, Hutchinson PE. A randomized double-blind comparison of the effects on systemic calcium homeostasis of topical calcitriol (3 micrograms/g) and calcipotriol (50 micrograms/g) in the treatment of chronic plaque psoriasis vulgaris. Acta Derm Venereol 1997; 77(3):228–230. 2. Veien NK, Bjerke JR, Rossmann-Ringdahl I, et al. Once daily treatment of psoriasis with tacalcitol compared with twice daily treatment with calcipotriol. A double-blind trial. Br J Dermatol 1997; 137(4):581–586. 3. Barker JN, Ashton RE, Marks R, et al. Topical maxacalcitol for the treatment of psoriasis vulgaris: a placebo-controlled, double-blind, dose-ﬁnding study with active comparator. Br J Dermatol 1999; 141(2):274–278. 4. Anonymous. The report of post-marketing vigilance system to collect information of side effects regarding 22-oxacalcitol in 2002. Japan: Maruho Pharmaceutical Company, 2002. 5. Ohigashi S, Tatsuno I, Uchida D. Topical treatment with 22-oxacalcitriol (OCT), a new vitamin D analogue, caused severe hypercalcemia with exacerbation of chronic renal failure in a psoriatic patient with diabetic nephropathy; a case report and analysis of the potential for hypercalcemia. Intern Med 2003; 42(12):1202– 1205. 6. Morimoto S, Kumahara Y. A patient with psoriasis cured by 1a-hydroxyvitamin D3. Med J Osaka Univ 1985; 35:51–54.

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7. Hansen CM, Mathiasen IS, Binderup L. The anti-proliferative and differentiation-inducing effects of vitamin D analogs are not determined by the binding afﬁnity for the vitamin D receptor alone. J Invest Dermatol Symp Proc 1996; 1:44–148. 8. Berg JP, Liane KM, Bjørhovde SB, et al. Vitamin D receptor binding and biological effects of cholecalciferol analogues in rat thyroid cells. J Steroid Biochem Mol Biol 1994; 50(3/4):145–150. 9. Binderup L. Comparison of calcipotriol with selected metabolites and analogues of vitamin D3: effects on cell growth regulation in vitro and calcium metabolism in vivo. Pharmacol Toxicol 1993; 72:240–244. 10. Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988; 37(5):889–895. 11. Murdoch D, Clissold SP. Calcipotriol: a review of its pharmacological properties and therapeutic use in psoriasis vulgaris. Drugs 1992; 43:415–429. 12. Lea AP, Goa KL. Calcipotriol: a review of its pharmacological properties and therapeutic efﬁcacy in the management of psoriasis. Clin Immunother 1996; 5:230–248. 13. Callis KP, Krueger GG. Topical agents in the treatment of moderate-to-severe psoriasis. In: Weinstein GD, Gottlieb AB, eds. Therapy of Moderate-to-Severe Psoriasis. 2d ed. New York: Marcel Dekker Inc., 2003:29–51. 14. Glade CP, Van Erp PE, Van Hooijdonk CA, et al. Topical treatment of psoriatic plaques with 1-a 24 dihydroxyvitamin D3: a multiparameter ﬂow cytometrical analysis of epidermal growth, differentiation and inﬂammation. Acta Derm Venereol 1995; 75:381–385. 15. Van Der Vleuten CJM, De Jong E, Van de Kerkhof PCM. Epidermal differentiation characteristics of the psoriatic plaque during treatment with calcipotriol. Arch Dermatol Res 1996; 288:366–372. 16. Cavicchini S, Brezzi A, Gasparini G, et al. Skin ultrastructure after calcipotriol treatment: a transmission electron microscopic and freeze-fracture study on psoriatic patients. Acta Derm Venereol 1996; 76:186–189. 17. Scott LJ, Dunn CJ, Goa KL. Calcipotriol ointment: a review of its use in the management of psoriasis. Am J Clin Dermatol 2001; 2(2):95–120. 18. Cullen SI, Calcipotriene Study Group. Long-term effectiveness and safety of topical calcipotriene for psoriasis. Calcipotriene Study Group. South Med J 1996; 89:1053–1056. 19. Ellis JP, Grifﬁths WAD, Klaber MR. Long-term treatment of chronic plaque psoriasis with calcipotriol ointment in patients unresponsive to short-contact dithranol. Eur J Clin Res 1995; 7:247–257. 20. Ohgawara A, Kobayashi H, Tangami H, et al. Long-term treatment with MC903 (calcipotriol) ointment in patients with psoriasis vulgaris: an open clinical trial [in Japanese]. Rinsho Iyaku 1995; 11(12):2589–2607. 21. Poyner T, Hughes IW, Dass BK, et al. Long-term treatment of chronic plaque psoriasis with calcipotriol. J Dermatol Treat 1993; 4:173–177. 22. Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 1994; 189:260–264. 23. Giannotti B, Carli P, Varotti C, et al. Treatment of psoriasis with calcipotriol: time of onset and healing relapses. Eur J Dermatol 1997; 7:275–278.

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24. Oranje AP, Marcoux D, Svensson A, et al. Topical calcipotriol in childhood psoriasis. J Am Acad Dermatol 1997; 36(2 Pt 1):203–208. 25. Darley CR, Cunliffe WJ, Green CM, et al. Safety and efﬁcacy of calcipotriol ointment (Dovonex) in treating children with psoriasis vulgaris. Br J Dermatol 1996; 135:390–393. 26. Park SB, Suh DH, Youn JI. A pilot study to assess the safety and efﬁcacy of topical calcipotriol treatment in childhood psoriasis. Pediatr Dermatol 1999; 16: 321–325. 27. Cunliffe WJ, Berth-Jones J, Caudy A, et al. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26(5 Pt 1):736–743. 28. Kragballe K, Gjertsen BT, De Hoop D, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris [published erratum appears in Lancet 1991; 337(8747):988]. Lancet 1991; 337(8735):193–196. 29. Ohgawara A, Kobayashi H, Iizuka H, et al. Clinical evaluation of MC903 (calipotriol) ointment in patients with psoriasis vulgaris: a right to left comparative study against betamethasone valerate ointment (phase III study) [in Japanese]. Rinsho Iyaku 1995; 11(12):2573–2587. 30. Crosti C, Finzi AB, Mian E, et al. Calcipotriol in psoriasis vulgaris: a controlled trial comparing betamethasone dipropiante þ salicylic acid. Int J Dermatol 1997; 36:537–541. 31. Bruce S, Epinette WW, Funicella T, et al. Comparative study of calcipotriene (MC 903) ointment and ﬂuocinonide ointment in the treatment of psoriasis. J Am Acad Dermatol 1994; 31(5 Pt 1):755–759. 32. Pinheiro N. Comparative effects of calcipotriol ointment (50 micrograms/g) and 5% coal tar/2% allantoin/0.5% hydrocortisone cream in treating plaque psoriasis. Br J Clin Pract 1997; 51:16–19. 33. Berth-Jones J, Chu AC, Dodd WA, et al. A multicentre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992; 127:266–271. 34. Christensen OB, Mørk N-J, Ashton R, et al. Comparison of a treatment phase and a follow-up phase of short-contact dithranol and calcipotriol in outpatients with chronic plaque psoriasis. J Dermatol Treat 1999; 10(4):261–265. 35. Wall AR, Poyner TF, Menday AP. A comparison of treatment with dithranol and calcipotriol on the clinical severity and quality of life in patients with psoriasis. Br J Dermatol 1998; 139:1005–1011. 36. Guenther LC, Poulin YP, Pariser DM. A comparison of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream once daily versus calcipotriene 0.005% ointment twice daily in the treatment of plaque psoriasis. Clin Ther 2000; 22(10):1225–1238. 37. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 1996; 35:268–269. 38. Koo J, Lebwohl MG, Menter A, et al. Topical psoriasis update: today’s topical treatment strategies to optimize patient response and quality of life. Dermatology Times 2004:1–15.

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39. Singh S, Reddy DC, Pandey SS. Topical therapy for psoriasis with the use of augmented betamethasone and calcipotriene on alternate weeks. J Am Acad Dermatol 2000; 43(1 Pt 1):61–65. 40. Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 1998; 39:447–450. 41. Bowman PH, Maloney JE, Koo JY. Combination of calcipotriene (Dovonex) ointment and tazarotene (Tazorac) gel versus clobetasol ointment in the treatment of plaque psoriasis: a pilot study. J Am Acad Dermatol 2002; 46(6): 907–913. 42. Ramsay CA, Schwartz BE, Lowson D, et al. Calcipotriol cre`me combined with twice weekly broad-band UVB phototherapy: a safe, effective and UVB-sparing antipsoriatic combination treatment. Dermatology 2000; 200:17–24. 43. Woo WK, McKenna KE. Combination TL01 ultraviolet B phototherapy and topical calcipotriol for psoriasis: a prospective randomized placebo-controlled clinical trial. Br J Dermatol 2003; 149:146–150. 44. Brands S, Brakman M, Bos JD, et al. No additional effect of calcipotriol ointment on low-dose narrow band UVB phototherapy in psoriasis. J Am Acad Dermatol 1999; 41:991–995. 45. Frappaz A, Thivolet J. Calcipotriol in combination with PUVA: a randomized double blind placebo study in severe psoriasis. Eur J Dermatol 1993; 3:351–354. 46. Youn J-L, Park B-S, Park S-B, et al. Comparison of calcipotriol-PUVA with conventional PUVA in the treatment of psoriasis. J Dermatol Treat 2000; 11:125–130. 47. Van De Kerkhof PC, Cambazard F, Hutchinson PE, et al. The effect of addition of calcipotriol ointment (50 micrograms/g) to acitretin therapy in psoriasis. Br J Dermatol 1998; 138(1):84–89. 48. Rim JH, Park JY, Choe YB, et al. The efﬁcacy of calcipotriolþacitretin combination therapy for psoriasis: comparison with acitretin monotherapy. Am J Clin Dermatol 2003; 4(7):507–510. 49. Grossman RM, Thivolet J, Claudy A, et al. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: results of a multicenter placebo-controlled study. J Am Acad Dermatol 1994; 31(1):68–74. 50. De Jong EM, Mork NJ, Seijger MM. The combination of calcipotriol and methotrexate compared with methotrexate and vehicle in psoriasis: results of a multicentre placebo-controlled randomized trial. Br J Dermatol 2003; 148(2):318–325. 51. Highton A, Quell J. Calcipotriene ointment 0.005% for psoriasis: a safety and efﬁcacy study. Calcipotriene Study Group. J Am Acad Dermatol 1992; 32: 67–72. 52. Katz HI. Combined topical calcipotriene ointment 0.005% and various systemic therapies in the treatment of plaque-type psoriasis vulgaris: review of the literature and results of a survey sent to 100 dermatologists. J Am Acad Dermatol 1997; 37(3 Pt 2):S62–S68. 53. Koo J, Kochavi G, Kwan JC. Topical medications for psoriasis. In: Contemporary Diagnosis and Management of Psoriasis. 1st ed. Newtown, PA: Handbooks in Health Care Co., 2004:18–38.

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54. Mortensen L, Kragballe K, Wegmann E, et al. Treatment of psoriasis vulgaris with topical calcipotriol has no short-term effect on calcium or bone metabolism: a randomized, double-blind, placebo-controlled study. Acta Derm Venereol 1993; 73:300–304. 55. Berth-Jones J, Bourke JF, Iqbal SJ, et al. Urine calcium excretion during treatment of psoriasis with topical calcipotriol. Br J Dermatol 1993; 129:411–414. 56. Gumowski-Sunek D, Rizzoli R, Saurat J-H. Effects of topical calcipotriol on calcium metabolism in psoriatic patients: comparison with oral calcitriol. Dermatologica 1991; 183:275–279. 57. Berth-Jones J, Bourke JF, Elouzi H, et al. Immediate and long term effects of topical calcipotriol on calcium homeostasis during treatment of psoriasis. Br J Dermatol 1992; 127(suppl 40):17–18. 58. Saurat J-H, Gumowski-Sunek D, Rizzoli R. Topical calcipotriol and hypercalcaemia [letter]. Lancet 1991; 337:1287. 59. Gumowski-Sunek D, Rizzoli R, Saurat J-H. Calcium tolerance test in patients with extended body surface psoriasis and treated with calcipotriol. Dermatology 1992; 185(3):229–230. 60. Gawkrodger DJ. Current management of psoriasis. Audit Subcommittee of the British Association of Dermatologists. J Dermatol Treat 1997; 8:27–55.

7 Fixed-Dose Corticosteroid/Calcipotriene Combination Therapy Chai Sue Lee Department of Dermatology, University of California Davis Medical Center, Sacramento, California, U.S.A.

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.

Recent advances in psoriatic therapy have predominantly revolved around the development of biologics for the treatment of moderate-to-severe psoriasis and the use of targeted phototherapy. However, the majority of patients with mild to moderate disease are still managed with topical therapy (1). The two most widely prescribed topical therapies for psoriasis are corticosteroids and vitamin D3 analogs. In a survey of 650 patients from an academic dermatology practice in the United States, 79% of patients were prescribed topical steroids (2). In Europe, the most widely prescribed topical therapy is reported to be the vitamin D3 analog calcipotriene (calcipotriol) (3). Unfortunately, there have not been many new topical therapies for psoriasis developed in the past few years. Despite their widespread use and demonstrated efﬁcacy, the chronic use of topical corticosteroids or vitamin D3 analogs is associated with safety and efﬁcacy concerns. Potential side effects from topical corticosteroids

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include cutaneous atrophy, striae, and, suppression of the hypothalamicpituitary-adrenal axis. The efﬁcacy of long-term topical corticosteroid therapy may be compromised by tachyphylaxis (4). Although this issue is unresolved at this time, potential explanations include inability of topical corticosteroid monotherapy to completely clear lesions, exacerbation unrelated to the topical steroid, and impaired compliance. The most common side effect of topical vitamin D3 analogs is irritation of the lesions and/or the surrounding skin (5) In addition, topical calcipotriene in excess of 100 to 200 g/wk has been associated with hypercalcemia (6). COMBINATION CORTICOSTEROID/CALCIPOTRIENE THERAPY To maximize the beneﬁts of topical therapy, topical corticosteroids are often administered in combination with a second topical agent such as calcipotriene. Potential beneﬁts of combination therapy include improved disease control and decreased adverse events. Beneﬁts of combination therapy are derived from differing mechanisms of action and less overall exposure to the individual components. For example, the combination of a topical corticosteroid plus topical calcipotriene is reported to be particularly effective at clearing psoriatic lesions without signiﬁcant cutaneous irritation from the latter or skin atrophy from the former. In fact, combination topical therapy with calcipotriene in the morning and corticosteroid in the evening has been demonstrated to be more effective than either agent applied b.i.d. as monotherapy (7–9). Unfortunately, combination therapy has its own pitfalls. For example, stacking or combining different agents may inactivate one or both products or require complicated dosing schedules. These issues may negatively impact compliance because of lack of anticipated efﬁcacy or difﬁculties with compliance. A ﬁxed-dose corticosteroid/calcipotriene ointment has been available in Europe and Canada (Dovobet1, Daivobet1) for a few years and recently was approved by the U.S. Food and Drug Administration (Taclonex1). It is one of the few new topical agents to become available. The product is a ﬁxed-dose formulation of 0.064% betamethasone dipropionate (equivalent to 0.5 mcg of betamethasone dipropionate), a class II high-potency (U.S.A. classiﬁcation) synthetic ﬂuorinated corticosteroid, and 0.005% calcipotriene ointment (equivalent to 50 mcg of calcipotriene), a synthetic 1,24-dihydroxyvitamin D3 analog. A stable formulation of the two active agents was achieved by mixing them in a novel anhydrous vehicle. The atrophogenic potential and bioavailability of betamethasone dipropionate in the two-drug combination appears equal to that in betamethasone dipropionate (Diprosone1) ointment (10,11). Moreover, the biologic activity of calcipotriene in the combination is the same as it is in calcipotriene (Dovonex1, Daivonex1) ointment (12).

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CLINICAL TRIALS AND ANALYSES OF FIXED-COMBINATION FORMULATION OF BETAMETHASONE DIPROPIONATE/CALCIPOTRIENE Topical ﬁxed-dose betamethasone dipropionate/calcipotriene has been evaluated in seven large international trials involving more than 7000 patients with psoriasis involving 10% to 30% of total body surface area. In all trials, psoriasis severity was assessed at baseline, during, and at the end of treatment using the Psoriasis Area and Severity Index (PASI). All seven trials demonstrated consistent reduction in PASI of approximately 40% after one week and 70% after four weeks of betamethasone dipropionate/calcipotriene therapy (13). THE FIXED-DOSE COMBINATION IS MORE EFFECTIVE THAN STEROID OR CALCIPOTRIENE MONOTHERAPY In a four-week, double-blind study, 1106 patients were randomized into one of three groups: (i) b.i.d. betamethasone dipropionate/calcipotriene ointment, (ii) b.i.d. betamethasone dipropionate ointment, and (iii) b.i.d. calcipotriene ointment (13). The four-week, double-blind phase of the trial was followed by an open-label phase in which patients were treated with calcipotriene ointment b.i.d. for four weeks. The baseline PASI scores were 10.8, 10.5, and 10.9 for the combination, betamethasone dipropionate, and calcipotriene groups, respectively. The mean percentage changes in PASI at one week were 47.4%, 39.8%, and 31.0% for the combination, betamethasone dipropionate, and calcipotriene groups, respectively; mean percentage changes in PASI at the end of the four-week, double-blind phase were 74.4%, 61.3%, and 55.3% for the combination, betamethasone dipropionate, and calcipotriene groups, respectively. Overall, the mean reduction in PASI observed with the combination was signiﬁcantly greater (p < 0.001) than that elicited by the individual components. The percentages of patients with at least 75% improvement in their PASI at the end of the double-blind phase were 68.0%, 46.6%, and 38.9% for the combination, betamethasone dipropionate, and calcipotriene groups, respectively. The percentages of patients with lesional/perilesional adverse reactions during the four-week, double-blind phase (i.e., after only four weeks of therapy) were 8.1%, 4.7%, and 12.0% for the combination, betamethasone dipropionate, and calcipotriene groups, respectively. THE FIXED-DOSE COMBINATION B.I.D. ACHIEVES GREATER PASI REDUCTION WITHIN ONE WEEK VS. STEROID MONOTHERAPY In a double-blind, four-week study, 1040 patients with psoriasis (mean PASI on inclusion: 10.8) were randomized into one of four groups: (i) b.i.d. betamethasone dipropionate/calcipotriene in the new vehicle, (ii) b.i.d. betamethasone

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dipropionate in the new vehicle, (iii) b.i.d. calcipotriene in the new vehicle, and (iv) b.i.d. with the new vehicle alone (14). The mean decrease in PASI at one week for the combination group was 48.1%, which already was statistically signiﬁcantly greater ( p < 0.001) than the decreases observed in the betamethasone dipropionate, calcipotriene, and vehicle groups (41.4%, 28.4%, and 21.5%, respectively). The mean decreases in PASI after four weeks were 73.2%, 63.1%, 48.8%, and 28.8%, respectively for the combination, betamethasone dipropionate, calcipotriene, and vehicle groups with the decrease in patients receiving the combination signiﬁcantly greater ( p < 0.001) than in the comparator groups. Lesional/perilesional adverse events were reported in 9.9%, 8.6%, 17.2%, and 15.7% of patients, respectively for the combination, betamethasone dipropionate, calcipotriene, and vehicle groups. There were signiﬁcantly more adverse events in the calcipotriene-only group than in the other groups ( p ¼ 0.023). Both of the above studies show the combination to be well tolerated, more effective, and with a more rapid onset of action than either active agent used alone. ONCE-DAILY FIXED-DOSE COMBINATION IS SAFE AND EFFECTIVE In another double-blind, four-week study, 1603 patients were randomized into one of four groups: (i) once-daily betamethasone dipropionate/calcipotriene ointment, (ii) once-daily betamethasone dipropionate ointment in the same anhydrous vehicle, (iii) once-daily calcipotriene ointment in the same anhydrous vehicle, and (iv) the vehicle alone (15). Baseline PASI scores were 9.9, 9.8, 10.4, and 9.5 for the combination, betamethasone dipropionate, calcipotriene, and vehicle-only groups, respectively. After one week of treatment, the mean percentage changes in PASI were 39.2%, 33.3%, 23.4%, and 18.1% for the combination, betamethasone dipropionate, calcipotriene, and vehicle-only groups, respectively (Fig. 1). The mean difference in PASI reduction was signiﬁcantly greater (p < 0.001) for the combination group than for the comparator groups. The mean percentage changes in PASI after four weeks were 71.3%, 57.2%, 46.1%, and 22.7% for the combination, betamethasone dipropionate, calcipotriene, and vehicle-only groups, respectively (15). The percentages of patients having controlled disease (classiﬁed as having ‘‘absence of disease’’ or ‘‘very mild disease’’) as determined by using the Investigators’ Global Assessment (IGA) were 56.3%, 37.0%, 22.3%, and 10.2% for the combination, betamethasone dipropionate, calcipotriene, and vehicleonly groups, respectively (Fig. 2). The odds ratio of having controlled disease was signiﬁcantly greater (p < 0.001) in patients treated with the combination. The percentages of patients with lesional/perilesional adverse reactions were 6.0%, 4.9%, 11.4%, and 13.6% for the combination, betamethasone dipropionate, calcipotriene, and vehicle-only groups, respectively. The rates of adverse reactions were similar between the betamethasone dipropionate/calcipotriene combination and betamethasone dipropionate ointment, while calcipotriene

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Figure 1 Once-daily ﬁxed-dose combination therapy versus monotherapy. Oncedaily ﬁxed-dose combination therapy achieves greater and more rapid improvement in psoriasis area and severity index scores than monotherapy.

ointment and even the vehicle alone had signiﬁcantly higher rates of adverse reactions compared with the betamethasone dipropionate/calcipotriene combination. Thus, this study conﬁrmed that once-daily use of the ﬁxed-dose combination could produce rapid and sustained clearance of psoriatic lesions. In addition, more patients treated with the formulation achieved disease control than those randomized to monotherapy.

Figure 2 Once-daily ﬁxed-dose combination therapy versus monotherapy. More patients achieve disease control with ﬁxed-dose combination therapy.

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ONCE-DAILY FIXED-DOSE COMBINATION IS AS SAFE AND EFFECTIVE AS B.I.D. THERAPY A four-week study addressed the efﬁcacy of once-daily versus b.i.d. therapy (16). In this study, 828 patients were randomized to four groups: (i) oncedaily betamethasone dipropionate/calcipotriene ointment and once-daily vehicle, (ii) b.i.d. betamethasone dipropionate/calcipotriene ointment, (iii) b.i.d. calcipotriene ointment, and (iv) b.i.d. vehicle. Mean PASI at entry was 9.9, 10.6, 10.8, and 10.4 for the q.d. combination, b.i.d. combination, b.i.d. calcipotriene, and b.i.d. vehicle groups, respectively. After one week, the average reductions in PASI were 45.5%, 47.6%, 33.6%, and 20.0% for the q.d. combination, b.i.d. combination, b.i.d. calcipotriene, and b.i.d. vehicle groups, respectively. The differences in PASI from baseline in the patients treated with either b.i.d. or q.d. combination were signiﬁcantly greater (p < 0.001) than the calcipotriene and vehicle groups. There was no statistical difference in PASI between the q.d. and b.i.d. combination group (Fig. 3). After four weeks, the mean reductions in PASI were 68.6%, 73.8%, 58.8%, and 26.6% for the q.d. combination, b.i.d. combination, b.i.d. calcipotriene, and b.i.d. vehicle groups, respectively. Similar to results observed after one week, the reduction in PASI elicited by either combination regimen was signiﬁcantly greater (p < 0.001) than that of the other treatments. Similar efﬁcacy is seen with once-daily versus b.i.d. treatment with betamethasone dipropionate/calcipotriene ointment. The percentages of patients with at least 75% improvement were 73.5%, 63.3%, 50.7%, and 9.2% for the b.i.d. combination, q.d. combination, b.i.d. calcipotriene, and b.i.d. vehicle groups,

Figure 3 Once-daily versus twice-daily ﬁxed-dose combination therapy. There was no statistical difference in psoriasis area and severity index between once-daily and twice-daily combination groups.

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respectively. Lesional/perilesional adverse events were reported in 10.6%, 9.9%, 19.8%, and 12.5% of patients for the b.i.d. combination, q.d. combination, b.i.d. calcipotriene, and b.i.d. vehicle groups, respectively. The proportion of patients who experienced adverse reactions was lower in the combined formulation groups than in the calcipotriene group (p < 0.01). Therefore, the efﬁcacy of once-daily application was not shown to be different from that of b.i.d. use, and once-daily combination was shown to be more effective and better tolerated than b.i.d. calcipotriene ointment.

ONCE-DAILY FIXED-DOSE THERAPY ACHIEVES HIGHER CLEARANCE AND FEWER ADVERSE EVENTS VS. MONOTHERAPY In an investigator-blinded study involving 972 patients, two different regimens involving betamethasone dipropionate/calcipotriene ointment were compared with eight weeks of b.i.d. calcipotriene ointment therapy (17). In one group, betamethasone dipropionate/calcipotriene ointment was applied daily for eight weeks; in the second group, it was applied daily for four weeks followed by four weeks of intermittent therapy (betamethasone dipropionate/calcipotriene ointment once daily on Saturday and Sunday, and calcipotriene ointment once daily on weekdays). Mean PASI at baseline was 10.3, 10.4, and 10.9 for the combination-only, combination weekend/calcipotriene weekday, and calcipotriene-only groups, respectively. At eight weeks, the mean percentage reductions in PASI were 73.3% in the once-daily betamethasone dipropionate/calcipotriene group, 68.2% in the weekday–weekend betamethasone dipropionate/calcipotriene group, and 64.1% in the calcipotriene group. Signiﬁcantly greater improvement (p < 0.001) was noted after eight weeks of once-daily betamethasone dipropionate/calcipotriene therapy compared with four weeks of weekday–weekend therapy, but there was a plateau in the effect at ﬁve weeks. Lesional/perilesional adverse events were reported in 10.9%, 11.5%, and 22.3% of patients for once-daily betamethasone dipropionate/calcipotriene group, weekday–weekend betamethasone dipropionate/calcipotriene group, and the calcipotriene group, respectively, with signiﬁcantly fewer (p < 0.001) adverse events occurring in the groups receiving combination therapy compared with calcipotriene alone.

ONCE-DAILY FIXED-DOSE THERAPY IS EFFECTIVE FOR PATIENTS WITH MILD, MODERATE, AND SEVERE PSORIASIS Menter et al. (18) reported the results of a pooled analysis of six randomized, double-blind, vehicle- and/or active-controlled studies using the ﬁxed-dose betamethasone dipropionate/calcipotriene combination in patients with mild (PASI 6), moderate (PASI 6.1–12), and severe (PASI >12) psoriasis.

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Figure 4 Psoriasis activity and severity index reduction with once-daily ﬁxed-dose combination therapy in mild, moderate, and severe psoriasis. Once-daily ﬁxed-dose combination therapy produces consistent efﬁcacy across all degrees of disease severity.

Although the analysis was somewhat limited by use of a correlation between the IGA and imputed PASI scores and by the failure of all investigators to report both IGA and PASI scores, it demonstrated that the ﬁxed-dose combination used once-daily produced consistent efﬁcacy across all degrees of disease severity (Fig. 4). At the end of one, two, and four weeks, the mean percent PASI reduction from baseline with the ﬁxed-drug combination was 38.7%, 56.7%, and 67.6%, respectively, in mild disease; 37.8%, 55.3%, and 68.1%, respectively, in moderate disease; and 41.2%, 59.5%, and 71.5%, respectively, in severe disease. Thus, the combination had a more rapid onset of action than the comparators and demonstrated efﬁcacy in patients with a spectrum of disease severities.

INVESTIGATORS AND PATIENTS’ ASSESSMENTS OF ONCE-DAILY FIXED-DOSED THERAPY AGREE In this study, the investigators randomized 501 patients with stable psoriasis to receive either the combination for four weeks followed by calcipotriene for four weeks or tacalcitol only for eight weeks (19). The mean PASI at baseline for all patients was 9.7 for the combination/calcipotriene group and 9.9 for the tacalcitol group. Treatment with the combination followed by calcipotriene was signiﬁcantly more effective than tacalcitol monotherapy in terms of mean percentage PASI reduction (65.0% vs. 33.3% at week 4 and 59.0% vs. 38.4% at week 8; p < 0.001 for both). During the ﬁrst four weeks, the number of patients experiencing lesional or perilesional irritation was greater in the tacalcitol group (11.8%) than in the combination/calcipotriene group (2.9%; p < 0.001).

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LONG-TERM, ONCE-DAILY FIXED-DOSE THERAPY IS SAFE AND EFFECTIVE Kragballe et al. completed a study designed to investigate the efﬁcacy and safety of three treatment regimens involving use of the ﬁxed-dose combination for up to 52 weeks (20). In this study, 634 patients were randomized to once-daily treatment with 52 weeks of the ﬁxed-dose combination, or 52 weeks of alternating four-week periods of the combination agent and calcipotriene, or four weeks of the ﬁxed-dose combination agent followed by 48 weeks of calcipotriene ointment. All treatments were used once-daily, intermittently, on an as-needed basis. Patients were instructed to use as much of their assigned experimental drug as necessary to relieve symptoms and promote clearance. The clinical response observed in the initial four-week period when all patients received the combination reﬂected what was seen in the short-term studies reviewed above—rapid onset of action and reliable lesion clearance. These clinical beneﬁts were best maintained in the group using the combination agent only (Fig. 5). Importantly, there was no apparent loss of efﬁcacy or perceived tachyphylaxis in the ﬁxed-dose combination arm. About 76.9% of the patients using the ﬁxed-dose combination as needed for 52 weeks were clear or almost clear. The group that alternated between the combination agent and calcipotriene ointment ‘‘ﬂip-ﬂopped’’ back and forth between better- and lesser control with better control periods affected by the use of the combination agent. Finally, the group that mostly used calcipotriene showed more loss of efﬁcacy than the other two groups when they were switched from the combination agent to calcipotriene at four weeks of study. This group did least well of the three groups and

Figure 5 Efﬁcacy of once-daily ﬁxed-dose combination therapy up to 52 weeks. Once-daily ﬁxed-dose combination therapy produces consistent long-term efﬁcacy.

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the control of disease never approached the group who used the combination agent only. With regard to long-term safety, drug-related adverse events occurring in more than 2% of patients were signiﬁcantly lower in the group receiving the ﬁxed-dose combination for 52 weeks than with either comparator groups (Table 1). This study establishes that the efﬁcacy of once-daily ﬁxed-dose combination therapy can be maintained for as long as one year. In addition, long-term ﬁxed-dose combination therapy was not associated with an increased risk of cutaneous atrophy compared to the other interventions. In summary, the above-mentioned clinical studies have shown that ﬁxed-dose betamethasone dipropionate/calcipotriene ointment once daily has greater efﬁcacy and a faster onset of improvement than the individual components. It is associated with similar cutaneous adverse events to betamethasone dipropionate and approximately 50% less compared with calcipotriene.

POTENTIAL BENEFITS OF FIXED-DOSE COMBINATION THERAPY The new betamethasone dipropionate/calcipotriene combination appears to be more than an agent with just two-in-one convenience. The innovative anhydrous vehicle has achieved two highly advantageous characteristics: 1. Well-documented synergy between the two components allowing the combination agent to have signiﬁcantly higher efﬁcacy than the high strength topical steroid betamethasone dipropionate. Also, in all likelihood, the combination agent with two ingredients each contributing to efﬁcacy allowed more efﬁcacy with less risk. Not only is the irritation risk of calcipotriene decreased by the topical steroid ingredient but the combination agent also can be characterized as ‘‘high-strength topical steroid that performs like a super high-strength topical steroid.’’ It clearly performs better than a high-strength topical steroid (i.e., betamethasone dipropionate) but is only expected to have a risk proﬁle of high strength rather than a super high-strength topical steroid. 2. Allowed once-daily application of a calcipotriene-containing agent to work as effectively as b.i.d. application. Generally, calcipotriene is appreciated as having much better efﬁcacy when it is applied b.i.d. than once a day. However, this combination agent in anhydrous innovative vehicle breaks this rule by allowing outstanding efﬁcacy even though this calcipotriene containing combination agent is only used once a day (Figs. 6A and B). The synergistic and once-daily administration schedule lead to clinical utility in that the combination agent seemed capable of treating widespread

0 0 1 2 0 0 1 0 4 2 0 0 11 10

Adrenal insufﬁciency Cellulitis Ecchymosis Folliculitis Furuncle Hypertrichosis Purpura Rash, pustular Skin atrophy Skin depigmentation Skin papilloma Skin striae Total number of adverse events Total number of points (%) 4.8

0.0 0.0 0.5 1.4 0.0 0.0 0.5 0.0 1.9 1.0 0.0 0.0

Percentage 0 0 0 1 2 0 0 1 1 0 1 1 7 6

n

2.8

0.0 0.0 0.0 0.5 0.9 0.0 0.0 0.5 0.5 0.0 0.5 0.5

Percentage

Fixed-dose combination/ calcipotriene (alt. 4 wk; n ¼ 213)

Note: No statistically signiﬁcant differences found between treatment groups. Source: From Ref. 21.

n

Event

Fixed-dose combination only (52 wk; n ¼ 207)

Table 1 Safety of Once-Daily Fixed-Dose Combination Therapy up to 52 Weeks

1 1 0 0 0 1 1 0 2 0 0 0 6 6

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Percentage

Fixed-dose combination 4 wk/ calcipotriene (48 wk; n ¼ 206)

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Figure 6 (See color insert) Rapid clinical improvement in patient treated with ﬁxed dose combination therapy. The two ﬁgures demonstrate (A) before treatment and (B) rapid clinical improvement in disease on his shin in two weeks with once daily application of the ﬁxed-dose combination.

psoriasis signiﬁcantly beyond the body surface area of involvement which was understood to be treatable with traditional topical agents. This is made possible by the excellent once-a-day efﬁcacy, which allows twice as much area to be covered as compared to the traditional agents such as triamcinolone, clobetasol, halobetasol, or calcipotriene, where optimal efﬁcacy is not seen unless these agents are applied b.i.d. Moreover, the rapid onset of action, which diminished PASI score by almost half within one week, also makes it feasible for this topical agent to adequately treat those with widespread involvement, by rapidly shrinking the area of psoriatic involvement.

IN COMBINATION WITH BIOLOGICS The fact that this combination agent is capable of treating widespread psoriasis topically makes it possible to use this agent to ‘‘jump start’’ biologic agents such as etanercept or efalizumab. The biologic agents that are currently approved by the Food and Drug Administration for psoriasis use in the United States are notable for their relative safety compared to prebiologic systemic agents. However, the onset of action is often slow in many patients. Consequently, clinicians often have to ‘‘hold the hands’’ of the patient until the efﬁcacy of these biologic agents eventually become effective. If something as simple as a topical combination agent can be used to jump start improvement of biologic agents, it would be a highly advantageous use of this novel topical combination. In a retrospective analysis of pooled data from six of the pivotal trials of ﬁxed-dose combination calcipotriene/ betamethasone dipropionate, Anstey and Kragballe demonstrated that, in

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patients with severe psoriasis, the two-compound product may have efﬁcacy comparable to a full course of biologics as reported in the literature (22). Although not a direct head-to-head comparative trial, treatment with the ﬁxed-dose combination formulation for four weeks and biologics for 12 weeks produced PASI-50 and PASI-75 response rates of 80% and 50% versus 56% to 74% and 27% to 49%, respectively. IN COMBINATION WITH OTHER SYSTEMIC AGENTS There are many published studies that have established that calcipotriene can enhance the outcome of treatment modalities such as acitretin, methotrexate, cyclosporine (only low-dose cyclosporine was tested), ultraviolet B phototherapy, and psoralen plus ultraviolet A phototherapy (8,23–25). Because the ﬁxed-dose combination agent is signiﬁcantly more efﬁcacious than the use of calcipotriene monotherapy, one can speculate that whatever the enhancement of efﬁcacy that has been demonstrated experimentally with calcipotriene, the use of this combination agent is likely to result in more enhancement. POTENTIAL EFFECTS ON COMPLIANCE Lastly, psoriasis is a chronic disease and, therefore, requires compliance with a long-term treatment regimen. However, only 60% of patients are compliant with their therapy (26). There are several reasons why psoriasis patients are not compliant with their treatments (27). The treatments may not work well or they have worrisome potential for rare but serious side effects especially with systemic agents. Other reasons are that the treatments are inconvenient or relapse occurs too quickly. The new ﬁxed-dose betamethasone dipropionate/calcipotriene combination agent should improve patient compliance, which is critical to any long-term strategy. Supporting data from the clinical trials of the ﬁxed-combination product indicate that the compliance rates were 68% and 81% when the ointment was applied b.i.d. and once daily, respectively (13,15). CONCLUSIONS Although corticosteroids and calcipotriene share similar antipsoriatic properties, they work by different mechanisms. Advances in drug formulation have led to the development of a ﬁxed-dose combination of the two drugs, which overcomes their inherent physiochemical incompatibilities. In the seven clinical trials described in this chapter, the combination has been shown to be effective, safe, and work rapidly. Treatment is associated with both statistically and clinically signiﬁcant improvements in PASI scores. In addition, clinical responses to the topical preparation are sustained for up to one year and are not associated with signiﬁcant cutaneous atrophy

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or irritation. Thus, the accumulated clinical evidence presented in this chapter support the use of this drug for patients with a spectrum of disease severity, both as monotherapy and in combination with other interventions including phototherapy, and systemic and biologic interventions. REFERENCES 1. Schon MP, Boehncke WH. Psoriasis. N Engl J Med 2005; 352:1899–1912. 2. Pearce DJ, Spencer L, Hu J, Balkrishnan R, Fleischer AB Jr., Feldman SR. Class I topical corticosteroid use by psoriasis patients in an academic practice. J Dermatolog Treat 2004; 15:235–238. 3. Salonen S-H, for the EUROPSO Study Group. The EUROPSO psoriasis patient study: treatment history and satisfaction reported by 17,990 members of European psoriasis patient associations. Available at: http://www.psori.ﬁ/ doc/patient_survey_1st_phase (2002).pdf. Accessed May 10, 2006. 4. Miller JJ, Roling D, Margolis D, Guzzo C. Failure to demonstrate therapeutic tachyphylaxis to topically applied steroids in patients with psoriasis. J Am Acad Dermatol 1999; 41:546–549. 5. Ashcroft DM, Po AL, Williams HC, Grifﬁths CE. Systematic review of comparative efﬁcacy and tolerability of calcipotriol in treating chronic plaque psoriasis. BMJ 2000; 320:963–967. 6. Kawahara C, Okada Y, Tanikawa T, Fukusima A, Misawa H, Tanaka Y. Severe hypercalcemia and hypernatremia associated with calcipotriol for treatment of psoriasis. J Bone Miner Metab 2004; 22:159–162. 7. Kragballe K, Barnes L, Hamberg KJ, et al. Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis: tolerability and efﬁcacy. Br J Dermatol 1998; 139:649–654. 8. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 1996; 35:268–269. 9. Ruzicka T, Lorenz B. Comparison of calcipotriol monotherapy and a combination of calcipotriol and betamethasone valerate after 2 weeks’ treatment with calcipotriol in the topical therapy of psoriasis vulgaris: a multicentre, doubleblind, randomized study. Br J Dermatol 1998; 138:254–258. 10. Traulsen J, Hughes-Formella BJ. The atrophogenic potential and dermal tolerance of calcipotriol/betamethasone dipropionate ointment compared to betamethasone dipropionate ointment. 10th Congress of the European Academy of Dermatology and Venereology, Munich, Oct 10–14, 2001. 11. Traulsen J. The bioavailability of betamethasone dipropionate in an ointment combination with calcipotriol (Dovobet ointment) is equal to that of betamethasone dipropionate alone in Diprosone1 ointment. 10th Congress of the European Academy of Dermatology and Venereology, Munich, Oct 10–14, 2001. 12. Hansen J. Mixing the unmixable. Verbal communication at the Leo Satellite Symposium. 10th Congress of the European Academy of Dermatology and Venereology, Munich, Oct 10–14, 2001. 13. Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone

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15.

16.

17.

18.

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20. 21.

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26. 27.

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dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002; 82(2):131–135. Papp KA, Guenther L, Boyden B, et al. Early onset of action and efﬁcacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol 2003; 48(1):48–54. Kauffmann R, Bibby AJ, Bissonnette R, et al. A new calcipotriol/betamethasone dipropionate formulation (DaivobetTM) is an effective once daily treatment for psoriasis vulgaris. Dermatology 2002; 205(4):389–393. Guenther L, Cambazard F, van de Kerhof PCM, et al. Efﬁcacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris; a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 2002; 147:316–323. Kragballe K, Noerrelund KL. A highly effective once-daily treatment with a new calcipotriol/betamethasone ointment in psoriasis vulgaris [poster]. J Eur Acad Dermatol Venereol 2002; 16(Suppl 1):276. Menter A, et al. Comparative efﬁcacy of calcipotriene/betamethasone combination product after 1, 2, 4 weeks of treatment of mild, moderate, and severe psoriasis. 63rd Annual Meeting of the American Academy of Dermatology, 2006. Ortonne JP, Kaufmann R, Lecha M, et al. Efﬁcacy of treatment with calcipotriol/betamethasone dipropionate followed by calcipotriol alone compared with tacalcitol for the treatment of psoriasis vulgaris: a randomized, double-blind trial. Dermatology 2004; 209:308–313. Kragballe K, et al. 13th Annual Congress of the European Academy of Dermatology and Venereologym, Florence, Italy, Nov 17–21, 2004. Kragballe K, et al. A 52-week safety study of a calcipotriol/betamethasonedipropionate two-compound product (Daivobet1/Dovobet1) in the treatment of psoriasis vulgaris. Br J Dermatol. In Press. Anstey AV, Kragballe K. A retrospective assessment of PASI 50 and PASI 75 attainment with a calcipotriol/bethmethasone dipropionate ointment. Int J Dermatol. In press. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 1998; 39:447–450. Frapazz A, Thivolet J. Calcipotriol in combination with PUVA: a randomized double blind placebo study in severe psoriasis. Eur J Dermatol 1993; 3:351–354. Gossman RM, Thivolet J, Claudy A, et al. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: results of a multicenter placebo-controlled study. J Am Acad Dermatol 1994; 31(1):68–74. Zaghloul SS, Goodﬁeld JJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol 2004; 140(4):408–414. 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. Guenther LC. Fixed-dose combination therapy for psoriasis. Am J Clin Dermatol 2004; 5(2):71–77.

8 Tazarotene Chai Sue Lee Department of Dermatology, University of California Davis Medical Center, Sacramento, California, U.S.A.

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.

Tazarotene (Tazorac1) is the ﬁrst topical retinoid approved for the treatment of plaque psoriasis in the United States in 1997. It is available as a gel or cream in a concentration of either 0.1% or 0.05%. Despite its proven efﬁcacy in the treatment of psoriasis, many patients experience signiﬁcant local irritation that limits its use as monotherapy. In general, tazarotene is used most effectively in the treatment of psoriasis in combination with other forms of therapy, such as topical corticosteroids, calcipotriene (Dovonex1), and phototherapy to optimize efﬁcacy and tolerability.

CHEMISTRY AND MECHANISM OF ACTION Figure 1 shows the chemical structure of tazarotene. Tazarotene is a vitamin A derivative that is rapidly converted in vivo to its biologically active free-acid metabolite, tazarotenic acid (1). There are two types of retinoid receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The RARs and RXRs are each composed of three distinct subtypes, labeled a, b, and c (2). These subtypes 91

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H3C

COC3H6

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Figure 1 Chemical structure of tazarotene.

are found in a tissue-speciﬁc manner. RARa is primarily expressed in many embryonic and adult tissues, and RARb is found exclusively in dermal ﬁbroblasts. RARc is the most ubiquitous retinoic acid receptor in human adult epidermis and is thought to be the key mediator of retinoid effects on keratinocytes (3). In keratinocytes, these retinoid receptors exist as dimers, and for activation of gene regulation, RARs are always linked with RXRs. Besides RAR–RXR dimers, RXRs can exist as homodimers and as heterodimers with a wide range of other intracellular receptors, such as thyroid hormone, vitamin D3, estradiol, and glucocorticoids (4). These retinoid receptors belong to a large superfamily of receptors also consisting of glucocorticosteroid, thyroid hormone, and vitamin D3 receptors, all of which are DNA-binding proteins and functioning as trans-acting transcription modulating factors. Tazarotenic acid, the active metabolite of tazarotene, binds to all three RAR-subtypes, especially RARc and RARb, without having any effect on RXRs (5). Retinoids elicit their biological effects by activating nuclear receptors and regulating gene transcription (6). The exact molecular mechanism by which tazarotene is able to exert its effects on psoriasis is unknown, but it is thought to affect the three major pathogenic causes of psoriasis: in keratinocytes, tazarotene has antiproliferative effects, normalizes their abnormal differentiation, and decreases the expression of inﬂammatory markers on their cell surface (6). Studies have shown that 0.05% tazarotene gel applied twice daily for 14 days improves keratinocyte differentiation through a reduction of hyperkeratosis and acanthosis and by reappearance of the granular layer (7). Histochemically, pathogenic overexpression of epidermal differentiation markers such as involucrin, keratinocyte transglutaminase, skin-derived antileukoproteinase (also known as elaﬁn), and migration-inhibitory related factor 8 (also known as calgranulin A) is signiﬁcantly reduced (6). In addition, tazarotene elevates markers like ﬁlaggrin in psoriatic lesions, implicating a return to a more normal and quiescent skin status (7,8).

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TAZAROTENE MONOTHERAPY Multiple clinical trials have conﬁrmed the efﬁcacy and safety of tazarotene gel and cream in the treatment of psoriasis (9–11). Tazarotene 0.1% was generally more effective than the 0.05% concentration, although it was less tolerated secondary to skin irritation. In addition, the cream formulations of tazarotene (0.05% and 0.1%) might have a potentially more acceptable tolerability proﬁle than the respective gel preparations (11). TAZAROTENE VS. TOPICAL STEROIDS In a multicenter, randomized clinical trial, the safety and efﬁcacy of 0.1% and 0.05% tazarotene gels once daily was compared to 0.05% ﬂuocinonide cream twice daily (12). A total of 348 psoriasis patients were enrolled for 12 weeks of treatment followed by 12 weeks of post-treatment observation. Treatment success rates, deﬁned as improvement of 50% or more, during the treatment and post-treatment periods are shown in Figure 2. Treatment success rates were statistically signiﬁcantly higher in the ﬂuocinonide group at week 4 than in the tazarotene 0.1% group and at week 2 to 8 than in the tazarotene 0.05% group, whereas by the end of treatment week 12 the ﬂuocinonide and tazarotene groups were statistically similar. Post-treatment return of psoriasis was most rapid with ﬂuocinonide, especially during the ﬁrst four weeks after the cessation of therapy. Signs and symptoms of local irritation were more common with tazarotene than with ﬂuocinonide. During the treatment period, 18%, 14%, and 11% of patients experienced 0.1% 0.06% FL0.06%

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Figure 2 Global treatment success rates for once-daily tazarotene 0.1% gel, oncedaily tazarotene 0.05% gel, and twice-daily ﬂuocinonide cream in the treatment of plaque psoriasis. Treatment success represents improvement of 50% or more. Signiﬁcant differences (p < 0.05): ﬂuocinonide versus tazarotene 0.1% at week 4; ﬂuocinonide versus tazarotene 0.05% at week 2 to 8. Source: From Ref. 12.

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pruritus, burning, and erythema, respectively, with 0.1% tazarotene; 9%, 9%, and 11%, respectively, with 0.05% tazarotene; and 1%, 7%, and 1%, respectively, with ﬂuocinonide cream. COMBINATION THERAPY In order to minimize unwanted side effects and improve patient tolerability, tazarotene is optimally used in combination with either mid- or high-potency topical corticosteroids, calcipotriene, ultraviolet B (UVB) phototherapy, and psoralen and ultraviolet A (PUVA) rather than as monotherapy. TAZAROTENE AND TOPICAL STEROIDS The concomitant use of tazarotene with a mid- or high-potency corticosteroid achieves a more rapid and greater efﬁcacy and decreases irritation as compared to tazarotene monotherapy, followed by a more prolonged duration of remission compared to corticosteroid monotherapy (12–15). In a large-scale study to evaluate the efﬁcacy of a combination treatment of tazarotene with a topical steroid, 300 psoriasis patients were randomly assigned to one of four treatment groups: 0.1% tazarotene gel once daily in combination with either once-daily application of placebo cream, low-potency corticosteroid (0.01% ﬂuocinolone acetonide cream), mid-potency corticosteroid (0.1% mometasone furoate cream), or high-potency corticosteroid (0.05% ﬂuocinonide cream) (16). Patients underwent 12 weeks of treatment, followed by four weeks of post-treatment observation. It took two weeks for the tazarotene plus mid-potency corticosteroid and three weeks for the tazarotene plus high-potency corticosteroid versus four weeks for the tazarotene plus lowpotency corticosteroid and tazarotene plus placebo groups to obtain at least 50% improvement. At the end of 12 weeks, 91% in the tazarotene/ mid-potency corticosteroid group, and 95% in the tazarotene/high-potency corticosteroid group, versus 80% in the tazarotene 0.1% gel/placebo group, obtained at least 50% improvement. The results with tazarotene/lowpotency corticosteroid group were not statistically superior to the tazarotene 0.1% gel/placebo group. Local skin irritation was less frequent in the groups treated with tazarotene plus a mid- or high-potency corticosteroid. Tazarotene plus high-potency corticosteroid had rates of burning that were almost half of those of tazarotene plus placebo (12% vs. 23%, respectively). During the post-treatment observation, rebound effect, often seen after discontinuation of corticosteroid monotherapy, was not observed in any of the combination tazarotene and topical steroid groups. Similarly, other studies have also conﬁrmed that the use of a mid- or high-potency corticosteroid enhances the efﬁcacy and tolerability of tazarotene (17,18). In addition, the efﬁcacy and tolerability of tazarotene with a midpotency topical steroid have been further studied. The combination of 0.1%

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tazarotene gel once daily with 0.1% mometasone furoate cream once daily was compared to monotherapy 0.1% mometasone furoate cream applied twice daily (14). A total of 73 psoriasis patients were treated for 12 weeks, followed by 12 weeks of post-treatment observation. At the end of 12 weeks, 74% of the patients treated with combination therapy of tazarotene with mometasone cream versus 58% of the patients treated with twice-daily mometasone furoate monotherapy achieved at least 50% global improvement in their psoriasis. During post-treatment observation, 68% (15 of 22) of the mometasone furoate monotherapy group dropped out from the study during the ﬁrst four weeks post-therapy due to recurrence and rebound, as compared to only 12% (three of 26) from the combination therapy group. Thus, the studies above show that the combination of mid- or highpotency steroid with tazarotene achieves faster and greater therapeutic effects, with fewer side effects and longer remission time than tazarotene monotherapy or topical corticosteroid monotherapy. Three different mid-potency topical steroids [i.e., betamethasone dipropionate 0.05% cream (Diprosone1), ﬂuticasone propionate 0.005% ointment (Cutivate1), or diﬂorasone diacetate 0.05% cream (Maxiﬂor1)] and three different high-potency steroid ointments [i.e., ﬂuocinonide 0.05% ointment (Lidex1), mometasone furoate 0.1% ointment (Elocon1), or diﬂorasone diacetate 0.05% ointment (Maxiﬂor1)] were compared in terms of efﬁcacy and tolerability in combination with tazarotene in a 12-week, multicenter, investigator-masked, randomized, parallel-group study involving 200 patients (19). Topical corticosteroid was applied in the morning and 0.1% tazarotene gel in the evening. The best-performing steroid was betamethasone dipropionate 0.05% cream (a mid–high-potency steroid), followed by mometasone furoate 0.1% ointment (a high-potency steroid) and diﬂorasone diacetate 0.05% ointment (a high-potency steroid). The best-tolerated regimen, however, was tazarotene plus mometasone furoate 0.1% ointment, and the optimal balance between efﬁcacy and tolerability was achieved with this regimen. The combination of betamethasone valerate foam 0.12% (Luxiq1) and 0.1% tazarotene cream was shown to be effective in a case series of 10 psoriasis patients (20). Two patients were clear of their psoriasis by week 4 and four were clear at week 8. More importantly, no adverse events, including irritation, were reported. The authors report that the use of the corticosteroid foam may protect against tazarotene-induced skin irritation, and the cosmetic appeal of a nongreasy corticosteroid foam improved patient compliance with the resultant high efﬁcacy that was seen. A double-blind, randomized, vehicle-controlled study examined the efﬁcacy of a combination of tazarotene and clobetasol both for initial efﬁcacy and for maintenance use (15). A total of 50 psoriasis patients were treated with a combination of 0.1% tazarotene gel and clobetasol ointment for an initial six-week ‘‘induction’’ phase. For the ﬁrst two weeks, 0.1% tazarotene

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gel was applied every morning and clobetasol ointment was applied every evening. During week 3 and 4, 0.1% tazarotene gel was applied every morning and clobetasol ointment was applied on Tuesday, Thursday, and Saturday evenings. During the last two weeks, 0.1% tazarotene gel was applied on Monday, Wednesday, and Friday mornings and clobetasol ointment was applied on Tuesday and Thursday evenings. After the six-week ‘‘induction’’ phase, patients with at least 50% improvement were randomized into one of the following three maintenance treatment groups for ﬁve months: combination therapy with 0.1% tazarotene gel applied on Monday, Wednesday, and Friday and clobetasol ointment applied on Tuesday and Thursday; 0.1% tazarotene gel applied on Monday, Wednesday, and Friday and white petrolatum applied on Tuesday and Thursday; and tazarotene gel vehicle applied on Monday, Wednesday, and Friday and white petrolatum applied on Tuesday and Thursday. At the end of the ﬁve-month maintenance therapy, 73% on tazarotene and clobetasol combination therapy, 47% on tazarotene thrice weekly, and 19% on vehicle retained at least 50% improvement relative to baseline. Similarly, other studies have also conﬁrmed lengthy remissions when tazarotene is used in combination with topical steroid (21). TAZAROTENE AND TOPICAL STEROID-INDUCED SKIN ATROPHY Not only do tazarotene and topical steroid act synergistically but tazarotene also reduces the degree of topical steroid-induced skin atrophy (22). In a study involving 24 healthy volunteers, subjects were randomized to apply 0.1% tazarotene gel, 0.05% diﬂorasone diacetate (Psorcon1), and 0.1% tazarotene gel combined with 0.05% diﬂorasone diacetate six days per week for four weeks (22). The subjects who applied 0.1% tazarotene gel had a mean epidermal thickness increase of 62%. The subjects who applied 0.05% diﬂorasone diacetate experienced a 43% reduction in the mean epidermal thickness. However, in the subjects who used tazarotene in combination with 0.05% diﬂorasone diacetate, there was only a reduction of 28% in the epidermal thickness. Thus, tazarotene signiﬁcantly reduced epidermal atrophy induced by topical steroid. TAZAROTENE CHEMICAL COMPATIBILITY WITH A TOPICAL STEROID Tazarotene and a range of topical corticosteroids (i.e., mometasone furoate 0.1% cream; ﬂuocinonide 0.05% ointment and cream; betamethasone dipropionate 0.05% gel, ointment, cream, and lotion; clobetasol propionate 0.05% gel, ointment, cream, and scalp solution; diﬂorasone diacetate 0.05% ointment and cream; halobetasol propionate ointment and cream) may be applied at the same time without adversely affecting the chemical stability

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of either tazarotene or the corticosteroids (23). However, chemical stability past two weeks have not been studied, and therefore, tazarotene and topical corticosteroids should not be premixed in a jar. TAZAROTENE AND CALCIPOTRIENE Although tazarotene and calcipotriene might not be as potent as class I topical steroids when each is used as monotherapy, they appear to have synergistic effects when combined, with the same efﬁcacy and rapidity as a class I superpotent topical steroid (24). In a prospective, open-label, left–right comparison study, combination therapy of 0.1% tazarotene gel once daily with calcipotriene ointment twice daily was comparable to clobetasol ointment twice daily (24). The study consisted of 15 patients who underwent a twoweek treatment course, followed by a four-week post-treatment observation. At the end of the two weeks, lesions treated with tazarotene and calcipotriene had the same improvement in overall lesion severity, reduction in plaque elevation and scaling as the clobetasol-treated lesions. Not surprisingly, erythema improved more in the clobetasol-treated lesions than the combined tazarotene and calcipotriene-treated lesions. There does not seem to be any chemical incompatibility between calcipotriene ointment and tazarotene gel that is clinically signiﬁcant (24). In a multicenter, randomized, investigator-masked study involving 120 psoriasis patients, the combination of tazarotene gel once daily with mometasone furoate cream once daily was compared to calcipotriene ointment twice daily (25). A total of 45% of patients in the combined tazarotene and mometasone group achieved 75% global improvement after two weeks of treatment compared with only 26% of patients in the calcipotriene group (25). Furthermore, the combination tazarotene and mometasone group had a signiﬁcantly greater reduction in scaling, erythema, plaque elevation, and body surface area involvement than calcipotriene monotherapy at the end of the four-week post-treatment observation. TAZAROTENE AND UVB PHOTOTHERAPY Tazarotene has been successfully combined with both broadband UVB phototherapy (BB-UVB) and narrowband UVB phototherapy (NB-UVB) for more effective and rapid clearing of psoriasis compared with either treatment alone (26–28). Once daily treatment with tazarotene 0.1% gel for two weeks followed by three times a week BB-UVB and tazarotene 0.1% gel was superior to BB-UVB monotherapy (27). It took a median of 25 days for the tazarotene and BB-UVB group to reach at least 50% improvement versus 53 days with BB-UVB monotherapy. Combined tazarotene and BB-UVB therapy also resulted in greater improvement in plaque elevation and scaling than did

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BB-UVB monotherapy. In addition, tazarotene signiﬁcantly reduced the amount of UV radiation required to improve psoriasis. The median cumulative BB-UVB dose was 390 mJ/cm2 in the combined tazarotene and BB-UVB group, while it was approximately four times higher (i.e., 1644 mJ/cm2) in BB-UVB monotherapy. To evaluate the efﬁcacy of topical tazarotene in combination with NB-UVB, a total of 10 patients were treated with 0.05% tazarotene once daily to one side of the body and NB-UVB ﬁve times a week for four weeks (28). Greater reduction in the psoriasis area and severity index scores were noted in the tazarotene-treated side. Tazarotene and vitamin D analogs as adjuncts to NB-UVB therapy have also been evaluated. Schiener et al. (29) studied 10 patients with widespread psoriasis and compared the combination of tazarotene gel 0.05% plus NB-UVB to calcipotriol ointment plus NB-UVB. Patients received NB-UVB treatment four times weekly and applied either of the assigned topical treatments once every evening on different halves of the body. Results showed that both regimens had identical number of exposure days and identical cumulative NB-UVB dose. Calcipotriol was generally very well tolerated. One patient developed hyperpigmentation strictly limited to the area where calcipotriol ointment was applied. On the side that tazarotene 0.05% gel was applied, four patients complained of itching and dryness. Despite such complaints, a follow-up questionnaire showed that six out of 10 patients still preferred tazarotene gel over calcipotriol ointment because it was easier to spread and less greasy. To date, no trials have assessed efﬁcacy or safety of tazarotene use prior to UVB exposure. Therefore, if used in combination with UVB, tazarotene should be applied after light treatment. Since tazarotene has been shown to reduce epidermal thickness, concerns have been expressed regarding the increased risk of burning. It has been suggested that the UVB dosage be reduced by one-third if tazarotene is added during phototherapy (30). No signiﬁcant photosensitivity occurred when tazarotene was used with phototherapy in any of these phototherapy trials. In addition, the incidence of irritation was less than expected when tazarotene was used with phototherapy than without. Behrens et al. (28) postulated that this might be the result of an enhanced barrier since UVA- and UVB-treated skin is more resistant to irritants. TAZAROTENE AND PUVA PHOTOTHERAPY To determine whether administration of topical tazarotene can increase the efﬁcacy of systemic PUVA, Tzaneva et al. (31) compared the therapeutic response of tazarotene plus PUVA to PUVA monotherapy in 31 chronic plaque-type psoriasis patients. Patients received PUVA treatment four times a week and applied 0.1% tazarotene gel every evening. To achieve complete,

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or near complete, clearing the cumulative UVA dose and the number of UVA exposures were statistically lower in those receiving combined PUVA and tazarotene therapy than those with PUVA monotherapy. The median cumulative UVA number of exposures and dosage were 14 and 32.3 J/cm2 for tazarotene plus PUVA and 16 and 37.0 J/cm2 for PUVA monotherapy. There was no difference in the observed duration of remission.

TAZAROTENE AND NAIL PSORIASIS Nail psoriasis also responds to tazarotene gel. In a randomized, doubleblind, vehicle-controlled study, 31 patients with ﬁngernail psoriasis were randomized to either 0.1% tazarotene gel or vehicle gel once daily for 24 weeks (32). The treatment was applied to two ﬁngernails, one under occlusion and the other one unoccluded. Tazarotene treatment under occlusion resulted in signiﬁcant reduction of onycholysis at weeks 4 and 12 and significant reduction of pitting by week 24. Unoccluded tazarotene treatment resulted in signiﬁcant reduction in onycholysis by week 24 but no improvement in pitting was noted. Tazarotene was well tolerated except for few cases of mild-to-moderate adverse effects of irritation and erythema. Thus, although both occluded and unoccluded tazarotene gel therapies were effective in decreasing onycholysis, the occluded tazarotene gel achieved its goal much earlier than the unoccluded tazarotene gel.

TAZAROTENE APPLICATION IN PSORIASIS Proper patient instruction is essential when using tazarotene. Patients should be instructed to apply tazarotene directly on the thick and scaly psoriatic lesions, taking care to avoid surrounding unaffected skin. Once the skin has become ﬂat and nonscaly, tazarotene should be discontinued. The gel and cream should be allowed to dry before wearing clothes since wearing clothing immediately after application might inadvertently spread the product onto uninvolved skin and cause irritation. Only a small amount of tazarotene is required. Use of excessive amounts may result in irritation. Patients should be warned of the likelihood of irritation, particularly if the agent is used on the face and neck. Intertriginous regions and genitals should be avoided. The gel preparation is preferable for scalp and nail psoriasis. If signiﬁcant irritation occurs, the patient may beneﬁt from what is termed ‘‘short contact’’ therapy (Table 1) (33,34). Duration of application appears to be related to rate of improvement. For example, following a very short contact (e.g., ﬁve minutes), ﬁrst signs of improvement are seen about three weeks later; following a 20-minute application, improvement is seen 7–10 days later.

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Table 1 Short Contact Therapy Apply tazarotene to plaques for a short period of time (5–20 min) Wash medication off after prescribed time period with water Gradually increase application time by 1–5 min as tolerated

Withholding treatment until irritation subsides, then reintroducing therapy every other day or changing to the 0.05% cream formulation (if an alternate formulation is used) may also help to reduce irritation. For patients with sensitive skin who might be prone to irritation, treatment with tazarotene may begin with the 0.05% cream formulation and stepped up as tolerated. In addition, initiation of therapy with alternate-day application has been recommended by some authors as a method to maximize tolerability (35). Irritation is most common during the ﬁrst 1–2 weeks of therapy (36). With time, most patients seem to be able to tolerate nightly treatment, but may occasionally need to skip a night because of irritation. Tazarotene may be most efﬁcacious and best tolerated when used in combination with a mid- or high-potency topical corticosteroid, calcipotriene, UVB phototherapy, or PUVA. One of the authors’ favorite topical regimens for treating recalcitrant thick psoriatic lesions is with triple combination therapy (Table 2). SIDE EFFECTS The most common side effects are skin irritation, including itching, burning, and erythema. These occurred in 10% to 23% of patients using the cream formulation and 10% to 30% of patients using the gel formulation, with 1–5 percentage points higher incidence correlated with the 0.1% concentration than the 0.05% concentration (37). No other treatment-related serious adverse effects were reported. Although the medication is not phototoxic or photoallergenic, the Food and Drug Administration (FDA)-approved package insert cautions against sunlight and sunlamp exposure. When combined with UVB, thinning

Table 2 Triple Combination Therapy Step 1: Apply a combination of superpotent topical steroid and calcipotriene in the morning Step 2: Apply a combination of superpotent topical steroid, calcipotriene, and tazarotene to plaques in the evening Or Apply a combination of superpotent topical steroid and calcipotriene after short contact therapy with tazarotene

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of the stratum corneum has been demonstrated, predisposing patients to burn more easily (30). If tazarotene is added to an ongoing phototherapy regimen, once there is evidence of decreased scaling and induration from the application of tazarotene, it may be prudent to lower the UVB dose by 30% to 50% or UVA dose (for PUVA) by 2 J/cm2 (35). The FDA has classiﬁed topical tazarotene as pregnancy category X. Tazarotene should not be used in pregnancy or in women who are not practicing adequate contraception. CONCLUSIONS Topical tazarotene is the only topical retinoid indicated for the treatment of psoriasis in the United States. Rather than using tazarotene as a monotherapy, tazarotene should be used in combination with mid- or high-potency topical corticosteroids, calcipotriene, UVB phototherapy, or PUVA as part of a long-term maintenance regimen. REFERENCES 1. Tang-Liu DD, Matsumoto RM, Usansky JL. Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis. Clin Pharmacokinet 1999; 37:273–287. 2. Nagpal S, Chandraratna RA. Recent developments in receptor-selective retinoids. Curr Pharm Des 2000; 6:919–931. 3. Fisher GJ, Talwar HS, Yiao JH, et al. Immunological identiﬁcation and functional quantiﬁcation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem 1994; 269:20,269–635. 4. Lefebvre P. Molecular basis for designing selective modulators of retinoic acid receptor transcriptional activities. Curr Drug Targets Immune Endocr Metabol Disord 2001; 1:153–164. 5. Nagpal S, Athanikar J, Chandraratna RA. Separation of transactivation and AP1 antagonism functions of retinoic acid receptor alpha. J Biol Chem 1995; 270:923–927. 6. Roeder A, Schaller M, Scha¨fer-Korting M, et al. Tazarotene: therapeutic strategies in the treatment of psoriasis, acne and photoaging. Skin Pharmacol Physiol 2004; 17:111–118. 7. Esgleyes-Ribot T, Chandraratna RA, LewKaya DA, et al. Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol 1994; 30:581–590. 8. Nonomura K, Yamanishi K, Yasuno H, et al. Up-regulation of elaﬁn/SKALP gene expression in psoriatic epidermis. J Invest Dermatol 1994; 103:88–91. 9. Krueger GC, Drake LA, Elias PM, et al. The safety and efﬁcacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis. Arch Dermatol 1998; 134:57–60. 10. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efﬁcacy and duration of therapeutic effects. J Am Acad Dermatol 1997; 37:29–85.

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11. Weinstein GD, Koo JY, Krueger GG, et al. Tazarotene Cream Clinical Study Group: tazarotene cream in the treatment of psoriasis: two multi-center, double-blind, randomized, vehicle-controlled studies of the safety and efﬁcacy of tazarotene creams 0.05% and 0.1% applied once daily for 12 weeks. J Am Acad Dermatol 2003; 48:760–767. 12. Lebwohl M, Aste E, Callen J, et al. Once-daily tazarotene gel versus twice-daily ﬂoucinonide cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998; 38:705–711. 13. Lebwohl M. Strategies to optimize efﬁcacy, duration of remission and safety in the treatment of plaque psoriasis by using tazarotene in combination with corticosteroid. J Am Acad Dermatol 2000; 43(2 Pt 3):S43–S46. 14. Koo JY, Martin D. Investigator-masked comparison of tazarotene gel q.d. plus mometasone furoate cream q.d. vs. mometasone furoate cream b.i.d. in the treatment of plaque psoriasis. Int J Dermatol 2001; 40(3):210–212. 15. Lebwohl M, Lombardi K, Tan MH. Duration of improvement in psoriasis after treatment with tazarotene 0.1% gel plus clobetasol propionate 0.05% ointment: comparison of maintenance treatment. Int J Dermatol 2001; 40(1):64–66. 16. Lebwohl M, Breneman D, Goffe B, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol 1998; 39: 590–596. 17. Tanghetti EA. The Tazarotene Stable Plaque Psoriasis Trial Study Group. An observation study evaluating the efﬁcacy of tazarotene plus corticosteroid in treating plaque psoriasis in patients switched from treatment with calcipotriene þ/ corticosteroid. Curtis 2000; 66(suppl 6):12–18. 18. Gollnick H, Menter A. Combination therapy with tazarotene plus a topical corticosteroid for the treatment of plaque psoriasis. Br J Dermatol 1999; 140(suppl 54):18–23. 19. Green L, Sadoff W, The Tazarotene Plus High-Potency or Mid-Potency Steroid Study Group. A clinical evaluation of tazarotene 0.1% gel, with and without a high-or mid-high-potency corticosteroid, in patients with stable plaque psoriasis. J Cutan Med Surg 2002; 6(2):95–102. 20. Dhawan S, Blyumin M, Pearce D, et al. Case reports: tazarotene cream (0.1%) in combination with betamethasone valerate foam (0.12%) for plaque-type psoriasis. J Drug Dermatol 2005; 4(2):228–230. 21. Poulin YP. Tazarotene 0.01% gel in combination with mometasone furoate in plaque psoriasis: a photographic tracking study. Cutis 1999; 63:41–48. 22. Kaiddbey K, Kopper SC, Sefton J, et al. A pilot study to determine the effect of tazarotene 0.1% gel on steroid-induced epidermal atrophy. Int J Dermatol 2001; 40:468–471. 23. Hecker D, Worsley J, Yueh G, et al. In vitro compatibility of tazarotene with other topical treatments of psoriasis. J Am Acad Dermatol 2000; 42:1008–1011. 24. Bowman P, Maloney J, Koo J. Combination of calcipotriene (Dovonex) ointment and tazarotene (Tazorac) gel versus clobetasol ointment in the treatment of plaque psoriasis: a pilot study. J Am Acad Dermatol 2002; 46(6):907–913. 25. Guenther LC, Poulin YP, Prasier DM. A comparison of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream daily versus calcipotriene

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0.005% ointment twice daily in the treatment of plaque psoriasis. Clin Ther 2000; 22(10):1225–1238. Lowe NJ. Optimizing therapy: tazarotene in combination with phototherapy. Br J Dermatol 1999; 140(suppl 54):8–11. Koo JY, Lowe NJ, Lew-Kaya DA. Tazarotene plus UVB phototherapy in the treatment of psoriasis. J Am Acad Dermatol 2000; 43:821–828. Behrens S, Grundmann-Kollamn M, Schiener R, et al. Combination phototherapy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel. J Am Acad Dermatol 2000; 42(3):493–495. Schiener R, Behrens-Williams SC, Pillekamp H, et al. Calcipotriol versus tazarotene as combination therapy with narrowband ultraviolet B (311 nm): efﬁcacy in patients with severe psoriasis. Br J Dermatol 2000; 143:1275–1278. Hecker D, Worsley J, Yueh G, et al. Interactions between tazarotene and ultraviolet light. J Am Acad Dermatol 1999; 41(6):927–930. Tzaneva S, Seebar A, Honigsmann A. A comparison of psoralen plus ultraviolet A (PUVA) monotherapy, tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis. Br J Dermatol 2002; 147:748–753. Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of ﬁngernail psoriasis: a double-blind, randomized, vehicle-controlled study. Cutis 2000; 68(5):355–358. Veraldi S, Schianchi R. Short-contact therapy with tazarotene in psoriasis vulgaris. Dermatol 2003; 206:347–348. Persaud A, Bershad S, Lamba S, et al. Poster Presentation, Short-Contact Tazarotene Therapy for Psoriasis. Nashville, TN.: American Academy of Dermatology, 2000. Koo JYM, Lebwohl MG, Lowe NJ, et al. Blueprints for optimizing topical retinoid treatment of psoriasis using creative therapeutic regimens. Skin Allergy News, February 16, 2002. Guenther L. Optimizing treatment with topical tazarotene. Am J Clin Dermatol 2003; 4(3):197–202. Allergan, Inc. Tazorac1 (tazarotene) package insert. Irvine, CA., USA: Allergen, Inc.

9 Topical Calcineurin Inhibitors Patricia Tinio and Mark G. Lebwohl Department of Dermatology, Mount Sinai School of Medicine, New York, New York, U.S.A.

The calcineurin inhibitors were developed as an alternative to topical and systemic glucocorticoids for immunosuppressive therapy. They were primarily used for the prevention of organ transplant rejection. These drugs include cyclosporin and the macrolides tacrolimus (FK 506) and, most recently, pimecrolimus (SDZ ASM 981), which are known to modify immune function by inhibition of calcineurin-dependent reactions critical in the production of inﬂammatory cytokines (1). Cyclosporin is effective in and approved for the treatment of inﬂammatory dermatoses including psoriasis, but is limited by systemic side effects such as renal toxicity and hypertension, and topical cyclosporin has almost negligible skin penetration (2,3). Tacrolimus and pimecrolimus have smaller molecular weights giving them the advantage of better skin penetration, which led to the development of topical formulations. Both topical tacrolimus and pimecrolimus do not cause skin atrophy mainly because calcineurin is not needed for collagen synthesis (1,4). This is in contrast to topical corticosteroids, which are associated with telangiectasia (Fig. 1), atrophogenicity, striae (Fig. 2), and other local cutaneous adverse effects when used over a long period of time (5,6). Both tacrolimus and pimecrolimus belong to the group of macrolide immunosuppressants, which are xenobiotics possessing a complex structure. They are derived from several strains of Streptomyces. The ﬁrst macrolide to be developed was tacrolimus, which is produced by Streptomyces 105

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Figure 1 (See color insert) Telangectasia, ear.

tsukubaensis (1). Several controlled trials have shown systemic tacrolimus to be effective in the treatment of psoriasis (7,8). Pimecrolimus is an ascomycin derivative, which is produced by another strain of Streptomyces, Streptomyces hygropicus var. ascomyceticus (1). One study has shown that systemic pimecrolimus is clinically highly effective in psoriasis and is well tolerated (9).

Figure 2 (See color insert) Striae distensae.

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MECHANISM OF ACTION Tacrolimus and pimecrolimus achieve their immunosuppressive function primarily through preventing T-cell activation; these drugs form complexes with a speciﬁc binding protein named the tacrolimus binding protein (FK-BP), which is their intracellular receptor (1,2). Once bound together, the complex will inhibit calcineurin leading to the prevention of cytokine expression. More speciﬁcally, when T lymphocytes are activated through antigenic stimulation, calcium levels in the cells rise and bind to calmodulin, which may in turn activate calcineurin. Calcineurin is a calcium-dependent phosphorylase enzyme that functions by dephosphorylating the cytoplasmic component of the nuclear factor of activated T cell (NF-ATc) allowing it to enter the nucleus and combine with its nuclear component NF-ATn. This crucial step then leads to the transcription of cytokines including interleukin (IL)-1, -2, -3, -4, transforming growth factor beta, and tumor necrosis factor alpha. When tacrolimus and pimecrolimus combine with their intracellular receptors, they are able to bind calcineurin and prevent the dephosphorylation of NF-ATc, thus blocking the production of proinﬂammatory cytokines (1–3,10). One study found increased IL-8 and IL-8 receptor (IL-8R) levels in psoriatic epidermis and tacrolimus in particular was shown to target the keratinocyte IL-8R by inhibiting its function and expression in vitro (11).

CLINICAL PROPERTIES Accumulating evidence has revealed psoriasis to be a genetically directed immunogenic inﬂammatory disease based on a self-reactive T-helper-1 (Th-1) response (12). Because of their chemical characteristics, tacrolimus and pimecrolimus can be effective for the topical treatment of inﬂammatory skin disorders wherein T cells may play a crucial role in development (13). Mrowietz et al. (13) demonstrated that pimecrolimus (1%) is similar in efﬁcacy to clobetasol-17-propionate (0.05%) in plaque-type psoriasis when applied topically under occlusion for two weeks using the microplaque assay, and no adverse drug effects were seen in any of the patients who participated in the study (13). Recently, a study that combined pimecrolimus ointment 0.1% in a formulation with 10% urea demonstrated that even without any occlusion, the pimecrolimus ointment 0.1%, in its experimental formulation, was effective in treating psoriasis plaques (14). A pilot study by Zonneveld et al. (15) in 1998 did not show similar efﬁcacy for 0.3% tacrolimus ointment in chronic plaque-type psoriasis. Their study compared calcipotriol ointment applied twice daily, and tacrolimus ointment and placebo ointment applied once daily on psoriatic plaques.

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An important and main difference from the earlier topical pimecrolimus study is that Zonneveld et al. did not use occlusion. Topical tacrolimus 0.3% was also applied under occlusion on descaled psoriatic skin in microplaques, and in this model topical tacrolimus showed efﬁcacy (16). The psoriatic plaques were ﬁrst descaled by overnight treatment with 2% salicylic acid in petrolatum before the medications were applied. No adverse events at the site of application or systemic side effects were observed. An eight-week, randomized, double-blind, vehicle-controlled, multicenter trial demonstrated that 0.1% tacrolimus ointment was effective in the treatment of facial and intertriginous psoriasis (Fig. 3A and B). A signiﬁcant difference was observed between the 0.1% tacrolimus ointment group and the vehicle group, with 62.5% of the 0.1% tacrolimus ointment group showing clearing or almost total clearing compared to 31.5% in the vehicle group at the end of eight weeks. Itching, hyperesthesia, and burning were adverse events reported for both treatment groups, but no systemic side effects were noted (17). Pimecrolimus cream 1% was also shown to be safe and effective for the treatment of inverse psoriasis in a multicenter, double-blind, randomized study involving 57 patients. At the conclusion of the study, 82% of the patients in the pimecrolimus group considered their disease well or completely controlled compared to 41% in the vehicle group. Adverse events were minimal and similar for both groups of patients (18). Topical corticosteroids and calcipotriol are not ideally used in areas of skin that are particularly thin and sensitive, such as the intertriginous areas and the face. These areas are more prone to skin atrophy from corticosteroid use, and calcipotriol causes signiﬁcant local irritation. It seems logical to conclude that because topical tacrolimus is effective on descaled psoriatic skin, it would probably work well on the thinner areas such as the face and ﬂexural regions. Several articles reported that 0.1% tacrolimus ointment was highly effective in the treatment of facial psoriasis and psoriasis of intertriginous areas (Fig. 4A and B) (5,19,20). There has also been one case report of generalized pustular psoriasis, which cleared almost completely after seven days of applying topical tacrolimus ointment (21). Approximately 10 g/day of tacrolimus was applied on the entire body and the patient’s liver and renal functions were not affected. The authors attribute part of the efﬁcacy of tacrolimus to the change in barrier function and less hyperkeratotic skin seen in generalized pustular psoriasis compared to chronic plaque-type psoriasis. It is evident that the type of formulation and method of application are important factors to consider in the use of topical tacrolimus and pimecrolimus in psoriasis (16). Also, because the skin of most patients with psoriasis is hyperkeratotic, ways to improve drug penetration and the speciﬁc area of the body affected with psoriasis should be taken into account.

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Figure 3 (See color insert) Psoriasis plaques on face (A) before therapy; (B) after therapy. Source: From Ref. 5.

The most common reported adverse effects of topical tacrolimus therapy include a sensation of skin burning, pruritus, and erythema (5,22). Recently, there was one report of deep dermatophytosis developing during topical tacrolimus therapy for facial psoriasis (23). Therapy of eyelid psoriasis can be problematic because topical corticosteroids are associated with the development of cataracts and glaucoma (24–27). Tacrolimus 0.1% ointment has been used safely to treat eyelid dermatitis twice daily for eight weeks without any effect on intraocular pressure (28). Irritation was noted to occur in 60% of patients.

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Figure 4 (See color insert) Psoriasis plaques on intertriginous areas (A) before therapy; (B) after therapy. Source: From Ref. 5.

Although they are relatively new, topical calcineurin inhibitors have provided clinicians with an effective and promising alternative to topical corticosteroids for the treatment of psoriasis, with the added beneﬁt of an excellent local and systemic side effect proﬁle. On March 10, 2005, the U.S. Food and Drug Administration (FDA) decided to add a ‘‘black box’’ warning for the use of topical tacrolimus (Protopic) and topical pimecrolimus (Elidel1). This decision was based on the ﬁnding of a theoretical risk of lymphoma or nonmelanoma skin cancer from these medications based on animal models. The animal subjects were

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given large doses of the drugs orally or the drugs were applied topically in a vehicle that enhances penetration (29). Human studies have not substantiated an association between topical tacrolimus or pimecrolimus and malignancies. Although deﬁnitive causation has not been established between topical use of tacrolimus and pimecrolimus and the development of cancer, several cases of lymphoma and cutaneous tumors (sarcoma, squamous cell carcinoma, and malignant melanoma) were noted to occur after the use of these drugs (30). Of note, there have been several reports of cutaneous T-cell lymphoma, a malignancy not associated with immunosuppressive therapy. The latter lymphoma is often mistaken for eczema, and it is possible that patients treated with tacrolimus or pimecrolimus had cutaneous T-cell lymphoma rather than eczema at the time the topical medications were prescribed. The American Academy of Dermatology strongly believes that these drugs are safe with proper use, and acknowledges that it is the physician’s responsibility to inform and educate patients regarding the beneﬁts and risks involved, and to monitor the patients accordingly. REFERENCES 1. Marsland AM, Grifﬁths CE. The macrolide immunosuppressants in dermatology: mechanisms of action. Eur J Dermatol 2002; 12(6):618–622. 2. Al-Daraji WI, Grant KR, Ryan K, Saxton A, Reynolds NJ. Localization of calcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/ NFAT activation in human keratinocytes by cyclosporin A. J Invest Dermatol 2002; 118(5):779–788. 3. Nghiem P, Pearson G, Langley R. Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol 2002; 46(2):228–230. 4. Nghiem P. ‘‘Topical Immunomodulators?’’: introducing old friends and a new ally, tacrolimus. J Am Acad Dermatol 2001; 44(1):111–113. 5. Freeman AK, Linowski GJ, Brady C, et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 2003; 48(4):564–568. 6. Meingassner JG, Grassberger M, Fahrngruber H, Moore HD, Schuurman H, Stutz A. A novel anti-inﬂammatory drug, SDZ ASM 981, for the topical and oral treatment of skin diseases: in vivo pharmacology. Br J Dermatol 1997; 137:568–576. 7. The European FK 506 Multicentre Psoriasis Study Group. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a double-blind, placebocontrolled study. Arch Dermatol 1996; 132(4):419–423. 8. Jegasothy BV, Ackerman CD, Todo S, Fung JJ, Abu-Elmagd K, Starzl TE. Tacrolimus (FK 506)—a new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128(6):781–785. 9. Rapperberger K, Komar M, Ebelin ME, et al. Pimecrolimus identiﬁes a common genomic anti-inﬂammatory proﬁle, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 2002; 119(4):876–887.

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10. Lemster B, Rilo HR, Carroll PB, Nalesnik MA, Thomson AW. FK 506 inhibits cytokine gene and adhesion molecule expression in psoriatic skin lesions. Ann N Y Acad Sci 1993; 696:250–256. 11. Schulz BS, Michel G, Wagner S, et al. Increased expression of epidermal IL-8 receptor in psoriasis. Down-regulation by FK 506 in vitro. J Immunol 1993; 151(8):4399–4406. 12. Ortiz-Urda S, Rappersberger K. New immunosuppressive agents for treating psoriasis. Hautarzt 2003; 54(3):230–236. 13. Mrowietz U, Graeber M, Brautigam M, et al. The novel ascomycin derivative SDZ ASM 981 is effective for psoriasis when used topically under occlusion. Br J Dermatol 1998; 139(6):992–996. 14. Mrowietz U, Wustlich S, Hoexter G, Graeber M, Brautigam M, Luger T. An experimental ointment formulation of pimecrolimus is effective in psoriasis without occlusion. Acta Derm Venereol 2003; 83:351–353. 15. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study. Arch Dermatol 1998; 134(9): 1101–1102. 16. Remitz A, Reitamo S, Erkko P, Granlund H, Lauerma AI. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999; 141(1): 103–107. 17. Lehwohl M, Freeman AK, Chapman MS, Feldman Sr, Hartle JE, Henning A. Tacronimus Ointment Study Group. Tacrolimus ointment is effective for facial and intertriginious psoriasis. J Am Acad Dermatol 2004; 51:723–730. 18. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol 2004; 51(5):731–738. 19. Yamamoto T, Nishioka K. Topical tacrolimus is effective for facial lesions of psoriasis. Acta Derm Venereol 2000; 80(6):451. 20. Clayton TH, Harrison PV, Nicholls R, Delap M. Topical tacrolimus for facial psoriasis. Br J Dermatol 2003; 149(2):419–420. 21. Ishiko A, Yokoyama T, Tanikawa A, Amagai M, Nagao K. A case of generalized pustular psoriasis treated with topical tacrolimus. Arch Dermatol 2003; 139(9):1219. 22. Soter NA, Fleisher AB Jr, Webster GF, Monroe EM, Lawrence I. The Tacrolimus Ointment Study Group. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: Part II, safety. J Am Acad Dermatol 2001; 44: S39–S46. 23. Yamamoto T, Nishioka K. Deep dermatophytosis during topical tacrolimus therapy for psoriasis. Acta Derm Venereol 2003; 83(4):291–320. 24. Tan MH, Lebwohl M, Esser AC, Wei H. The penetration of 0.005% ﬂuticasone propionate ointment in eyelid skin. J Am Acad Dermatol 2001; 45(3):392–396. 25. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin 1992; 10(3):505–512. 26. Eisenlohr J. Glaucoma following the prolonged use of topical steroid medication to the eyelids. J Am Acad Dermatol 1983; 8(6):878–881. 27. Costagliola C, Cati-Giovannelli B, Piccirillo A, Delﬁno M. Cataracts associated with long-term topical steroids. Br J Dermatol 1989; 120(3):472–473.

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28. Freeman AK, Serle J, VanVeldhuisen P, et al. Tacrolimus ointment in the treatment of eyelid dermatitis. Cutis 2004; 73(4):267–271. 29. Niwa Y, Terashima T, Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol 2003; 149: 960–967. 30. Wooltorton E. Eczema drugs tacrolimus (Protopic) and pimecrolimus (Elidel): cancer concerns. CMAJ 2005; 172(9):1179–1180.

10 Treatment of Mild-to-Moderate Psoriasis with Coal Tar, Anthralin, Salicylic Acid, and Lactic Acid Priya Sivanesan Department of Dermatology, University of California San Francisco, San Francisco, California, U.S.A.

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.

Topical agents for the treatment of psoriasis are indicated for patients with any amount of affected body surface area, but are the mainstay of therapy for patients whose affected area is less than 10% of their body surface area. Among the traditional options of topical therapies for mild to moderate psoriasis are coal tar, anthralin, salicylic acid, and lactic acid. All four topical therapies have been used for many years and are proven safe and effective. However, recently newer topical agents such as calcipotriol and tazoratene have reduced the use of these older agents. This chapter will give an overview of the use of these four agents in the treatment of mild to moderate psoriasis. COAL TAR There are several types of tar including wood tar, shale tar, and coal tar used in the treatment of skin conditions. Coal tar is the liquid byproduct of the distillation of bituminous coal and has a pungent smell (1). Use of coal 115

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tar for skin conditions has been ongoing for over millenniums. Present day preparations closely resemble the coal tar that Dioscorides described and called ‘‘asphalt’’ almost 2000 years ago (2). Mechanism of action is still unknown in part due to the over 10,000 ingredients contained in coal tar. However, its antipruritic, anti-inﬂammatory, and antipsoriatic effects have been clinically evidenced since ancient times (3). Coal tar’s low cost, efﬁcacy, and safety proﬁle have made it one of the mainstays of mild to moderate psoriasis therapy during the decades preceding and following World War II. Coal tar is available in several preparations including ointment, cream, lotion, shampoo, gel, solutions, and soaps. These products are available in multiple concentrations. Crude coal tar is often available in three concentrations, 2%, 5%, and 10%, and is mainly used in Goeckerman therapy. Goeckerman therapy is named after the man who ﬁrst used this treatment regimen for psoriasis in 1925 (4). Goeckerman therapy involves the application of crude coal tar to the entire body including unaffected areas for several hours a day along with ultraviolet B (UVB) phototherapy. Because Goeckerman therapy involves the use of ‘‘black’’ tar as opposed to the more elegant but less effective ‘‘brown’’ tar such as liquor carbonis detergens (LCD), this previously was an inpatient treatment, but the modern modiﬁed version involves a more convenient Monday through Friday outpatient regimen conducted in psoriasis ‘‘day treatment centers.’’ LCD, an alcohol extract of crude coal tar, is one of the most widely used reﬁned preparations of coal tar, which is more cosmetically acceptable and available in a solution form. The solution vehicle makes it ideal for its primary use for scalp psoriasis, but is not as effective as ‘‘black’’ coal tar. LCD can also be compounded by specialty pharmacies in an aquaphor base that is suitable for use on body lesions. Most preparations of topical tar are designed for once daily application at night, but may be used more often if the patient is willing. Coal tar efﬁcacy has been investigated in several trials. Goeckerman therapy efﬁcacy was investigated in an open-label study by Lee and Koo. This study examined 25 consecutive Goeckerman patients admitted to University of California, San Francisco (UCSF) Psoriasis Treatment Center and showed that 100% reached psoriasis area severity index (PASI) 75 by 12 weeks of treatment and 95% reached it by eight weeks (Figs. 1 and 2) (5). This is a remarkable efﬁcacy considering the fact that, in the years 2003–2004 when this study was conducted, only the most recalcitrant psoriasis patients, most of whom have failed many other, more convenient treatment options such as entanercept, alefacept, efaluzimab, methotrexate, actretin, outpatient phototherapy, and of course topicals, were usually the ones referred to Goeckerman therapy. Another study by Menter and Cram evaluated the efﬁcacy and remission time following Goeckerman treatment. In this study, 300 patients treated with the Goeckerman regimen were followed for one or more years. Average time to reach 90% clearing of the skin was 18 treatment days.

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Figure 1 (See color insert) Psoriasis area severity index (PASI) scores of 25 consecutive Goeckerman patients treated at the University of California, San Francisco (UCSF) Psoriasis Treatment Center. Source: From Ref. 5.

% of Patients Reaching PASI 75

Ninety percent of the patients remained clear for a minimum of eight months and 73% were clear for one year or longer (6). It should be noted that this two-center (Dallas, Texas and San Francisco, California) study was carried out in the early 1980s before the advent of Health Maintenance Organizations (HMOs) and managed care when patients with generalized 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

96%

100%

8 weeks

12 weeks

56%

4 weeks

Weeks After Starting Goeckerman Therapy

Figure 2 Percent of patients achieving psoriasis area severity index (PASI) 75 with 4, 8, and 12 weeks Goeckerman therapy. Source: From Ref. 5.

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psoriasis had ready access to Goeckerman therapy. In today’s practice almost two decades later, Goeckerman therapy is primarily being utilized by psoriasis patients who have failed multiple other treatment methods that require less commitment in time and energy. The remission time seen today can be as good as was documented by Menter and Cram, but primarily in those with na€ve generalized psoriasis who have good insurance and gain access to Goeckerman therapy. The remission time of the more typical recalcitrant psoriasis patients referred for Goeckerman therapy today are generally shorter but still observed by the authors to be better than outpatient phototherapy and most biologics. Efﬁcacy of coal tar lotion has also been studied. A study by Goodﬁeld et al. compares efﬁcacy of a new 1% coal tar lotion preparation (Exorex) to conventional 5% coal tar lotion (Alphosyl) in mild to moderate psoriasis. One hundred and ﬁfty-eight patients received 1% proprietary coal tar lotion and 166 patients received conventional 5% coal tar lotion applied to skin three times a day for 12 weeks. The mean PASI decreased by 2.4 with 1% proprietary coal tar lotion and 1.5 with 5% conventional coal tar lotion (7). Interestingly, there was some controversy about the effectiveness of coal tar in the mid-1980s. A study by Stern et al. in 1986 concluded that coal tar did not provide any added beneﬁt to outpatient UVB phototherapy. This study compared 22 outpatients who treated one side of their body with tar oil and the other side of their body with oil vehicle twice daily and also received outpatient suberythemogenic doses of UVB phototherapy three times per week. This study evidenced no signiﬁcant difference between the tar oil half and the oil vehicle half of the body, with only a 9% reduction in the average UVB dose required for clearing on the tar oil half (8). However, it should be noted that both the tar oil and oil vehicle were applied just prior to phototherapy. Tar has been shown to block UVB and this most likely was the reason for lack of beneﬁt of tar with suberythemogenic doses of UVB witnessed in this study. A study by Lebwohl et al. (9) conﬁrms tar’s ability to block UVB light. For this very reason, in Goeckerman therapy, especially with ‘‘black’’ tar (as opposed to brown tar or LCD), UVB phototherapy is always given prior to the application of ‘‘black’’ tar. Since this controversial publication, there have been studies to validate the usefulness of coal tar with UVB. A study by Lowe et al. indicates that tar is a beneﬁcial addition to suberythemogenic doses of UVB. In this study, tar was not applied prior to phototherapy. More rapid improvement was evidenced in the group treated with topical tar and suberythemogenic UVB than in the group with oil base and suberythemogenic UVB—effectively reducing the exposure to UVB in the patients treated with topical tar. This same article also examined the combination of tar extract in oil and erythemogenic doses of UVB in hairless mice. Erythemogenic dosages of UVB produced almost maximal inhibition of DNA synthesis with or without coal tar (10). In general, for the ordinary psoriasis patient erythemogenic UVB is

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as effective with or without tar, and suberythemogenic UVB shows enhanced effectiveness with the addition of reﬁned tar products like LCD. However, from the authors’ experience, for the rare patient with extraordinarily resistant psoriasis, Goeckerman therapy (‘‘black’’ tar plus UVB) is much more effective than outpatient erythemogenic UVB alone. In our experience, the patient who has not cleared with maximal and optimal outpatient UVB with erythemogenic doses clears while on Goeckerman therapy. Coal tar is a safe agent to use in mild to moderate psoriasis but does have some obvious disadvantages and side effects. Among the side effects and disadvantages are staining of clothes and furniture, messy application, unpleasant odor, contact sensitivity (surprisingly rare despite its appearance), burning sensation, photosensitivity (although therapeutic in a controlled treatment setting), and tar folliculitis (2). Generally, the higher the concentration the more likely to cause skin irritation. Despite many decades of use, so far there seems to be no systemic side effects of the topical application of coal tar ever documented. In addition, the risk of skin cancer seems to be either very small or not demonstrably different from the general population. A 25-year follow-up study by Muller and Perry (11) found no difference in cancer rates between those treated with coal tar at the Mayo Clinic and the general population. A lawsuit in 2000 claiming that tar products are carcinogenic has made tar products hard to ﬁnd in California. In response to this lawsuit, the Food and Drug Administration (FDA) reviewed all available data and concluded that the therapeutic use of coal tar in concentrations and formulations used in over-the-counter drug products does not pose a risk of carcinogenicity; despite this FDA ruling, in January 2002, the state of California, which has strict antitoxic laws, ruled that over-the-counter coal tar products that contain more than 0.5% coal tar are required to be labeled with cancer warnings. Due to this requirement, many companies have chosen to either change the active ingredient in their products sold in California or simply discontinued sale of their tar products in California (12,13). Although coal tar can be inconvenient and messy, its demonstrated efﬁcacy, low cost, and its relatively minimal side effect proﬁle compared to other topicals and oral medications make it a reasonable option for long-term maintenance and treatment of mild–moderate psoriasis. ANTHRALIN Another option for treatment of mild to moderate psoriasis is anthralin. Anthralin, also known as dithranol (the most commonly used form of anthralin), was initially used mistakenly as a folk remedy for fungus infections such as mycoses of the skin when it was discovered to have therapeutic effects for psoriasis in 1877. It is an antipsoriatic medication derived from a tree extract known as Goa powder. The exact mechanism of action is still unknown today, but it has been shown to promote kerotinocyte differentiation,

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decrease cell respiration, and inhibit inﬂammation (14). Anthralin is commercially available in the United States in cream, ointment, and paste form in multiple concentrations from 0.05% to 1%. Anthralin can also be compounded by specialty pharmacies up to a concentration of 10%. There are several anthralin treatment regimens used for the management of plaque psoriasis. The Ingram method is designed for inpatient therapy and involves application of anthralin to the affected area followed by covering of the area with talcum powder and then gauze or stockinette. The anthralin is then wiped off after some time and the patient takes a tar bath. Finally, ultraviolet light therapy follows (15). Anthralin can also be used in a more convenient outpatient setting. Although no optimal treatment regimen has been established, the ‘‘need of quick results and no time’’ mentality of Americans has prompted development of a more convenient method of anthralin use. A study by Runne and Kunze indicates that application of higher concentrations of anthralin (1%, 2%, and 3%) using short contact anthralin therapy for 10–20 minutes at a time is more effective than a longer exposure of three hours at a lower concentration (0.1%, 0.25%, 0.5%, 1%, 2%). Short contact therapy (10–20 minutes) reduced clearing time by 6.8 days compared to longer exposure (three hours) (16). Another treatment regimen is application of anthralin overnight starting at low concentrations with weekly increases in concentration. A new formulation of anthralin, Psoriatec1, has been developed in an attempt to decrease the staining and inﬂammation associated with anthralin. Psoriatec is a 1% formulation of anthralin in a temperature-sensitive vehicle. The vehicle is deliberately designed to release anthralin only at skin temperatures. This temperaturesensitive activation decreases the risk of staining furniture and fabrics (17). The efﬁcacy of anthralin has been investigated in several trials. A retrospective study by Yamamoto et al. examined 70 patients who were treated with 0.1% to 2% anthralin. This study showed a mean improvement in PASI of 15.9 after three months of treatment (18). Another study compared short contact dithranol therapy with the Ingram regimen. The Ingram regimen showed a faster rate of improvement than the short contact method, but more irritation than with the short contact regimen (19). In general, the authors concluded that anthralin is most useful for thinning the plaques and is associated with a remission time of 3.9–6 months (20). One of the most important disadvantages associated with anthralin is purple staining of skin and other objects (clothing, furniture, etc.) and skin irritation. Careful application to only the affected areas is important, as surrounding normal skin may become more easily irritated with anthralin contact. Irritation typically improves after several days even with the same anthralin concentration (14). A possible way to decrease this irritation was studied by Schulze et al. This study showed that patients receiving combination therapy with 5% tar and anthralin had reduced rates of irritation than patients receiving only anthralin therapy (21). Topical corticosteroids may

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also be used for more severe erythema and inﬂammation of uninvolved, perilesional skin. In addition, application of zinc oxide paste perilesionally can reduce risk of irritating surrounding uninvolved skin. Staining and inﬂammation can be reduced with application of triethanolamine, a neutralizing agent, before the removal of anthralin. CuraStain, a brand name for triethanolamine, is a prescription drug available at most pharmacies. Other side effects of anthralin include burning, stinging, and dryness of skin (22). There are no systemic or long-term side effects reported in humans. Anthralin has been used safely for many years, but the staining remains a major limitation of this treatment. Newer formulations such as Psoriatec have tried to address this with some success. SALICYLIC ACID Salicylic acid is a keratolytic agent that is useful in the treatment of mild to moderate psoriasis. It is a good adjunct to other topical medications, but generally not used as monotherapy because it only removes scales. It is available in concentrations from 2% to 10% and in different vehicles including gels, creams, and shampoos. A commonly used preparation is Keralyt gel1, a 6% salicylic acid preparation that is readily available. Salicylic acid reduces scales and therefore enhances penetration of other topical agents such as topical steroids. A study by Koo et al. shows that a combination of mometasone furoate and salicylic acid ointment is more effective in treating moderate to severe psoriasis than mometasone furoate alone. In this study, 408 patients were randomized to either the treatment group with mometasone furoate alone or a treatment group with combination therapy with mometasone furoate and salicylic acid applied to target lesions twice daily for 21 days. The combination therapy of mometasone furoate and salicylic acid was signiﬁcantly more effective than mometasone furoate alone beginning at day 8. Combination therapy improvement continued through the end of the study with a more signiﬁcant difference between the two study groups at day 22 than at day 8 (23). Salicylic acid has also been used in combination with anthralin with success. However, salicylic acid should not be used in combination with calcipotriol (Dovonex1), as calcipotriol is inactivated upon contact with salicylic acid. Salicylic acid also blocks UVB and should not be applied prior to phototherapy. Salicylic acid may cause salicylate toxicity with application to a large body surface area (generally greater than 20% body surface area). Early signs of salicylate toxicity such as tinnitus and fatigue should be monitored during therapy with salicylic acid with some vigilance, as symptoms are reversible with discontinuation of salicylic acid. Over the past decades, there have been several case reports of acute hypoglycemia in diabetic patients treated with salicylic acid over a large body surface area. At the University of California San Francisco, there was one case of a diabetic patient who became comatose after being treated with salicylic acid over a

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large body surface area (24). This patient’s laboratory tests showed high serum salicylate levels and low blood glucose levels and the patient’s comatose state was reversed with IV glucose. Due to this rare reported side effect for diabetic patients, salicylic acid should be avoided in the diabetic patient (24). Alternate keratolytic agents such as lactic acid or urea should be considered instead. LACTIC ACID Lactic acid is another less common topical keratolytic agent used in the treatment of psoriasis. Lactic acid is a type of alpha-hydroxy acid mainly used as a second-line keratolytic agent when salicylate toxicity is a concern such as in diabetic patients. Lactic acid is effective and has proven keratolytic properties as evidenced by a study on hairless mice that shows that mice treated with lactic acid show enhanced desquamation of normal skin (25). Lactic acid also can be used on a larger surface area, as risk of salicylism is not a concern. In short, lactic acid is a beneﬁcial second-line keratolytic agent when salicylic acid is not an option. CONCLUSION The initial approach with most cases of mild to moderate psoriasis is topical therapy. Topical agents for psoriasis are usually well tolerated without serious systemic side effects. It is important not to forget the ‘‘tried and true’’ inexpensive agents such as coal tar, anthralin, or keratolytics such as salicylic acid and lactic acid. REFERENCES 1. Thami GP, Sarkar R. Coal tar: past, present and future. Clin Exp Dermatol 2002; 27(2):99–103. 2. Arnold WP. Tar. Clin Dermatol 1997; 15(5):739–744. 3. Federman DG, Froelich CW, Kirsner RS. Topical psoriasis therapy. Am Fam Phys 1999; 59(4):957–962, 964. 4. Gibson LE, Harold P. Goeckerman therapy. In: Psoriasis. Henry R, Howard M, eds. 3rd ed, revised and expanded. New York: Marcel Dekker Inc., 1998:469– 477. 5. Lee E, Koo J. Modern modiﬁed ‘‘ultra’’ Goeckerman therapy: a PASI assessment of a very effective therapy for psoriasis resistant to both prebiologic and biologic therapies. J Dermatol Treat 2005; 16(2):102–107. 6. Menter A, Cram DL. The Goeckerman regimen in two psoriasis day care centers. J Am Acad Dermatol 1983; 9(1):59–65. 7. Goodﬁeld M, Kownacki S, Berth-Jones J. Double-blind, randomized, multicentre, parallel group study comparing a 1% coal tar preparation (Exorex) with a 5% coal tar preparation (Alphosyl) in chronic plaque psoriasis. J Dermatol Treat 2004; 15(1):14–22.

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8. Stern RS, Gange RW, Parrish JA, Tang SV, Arndt KA. Contribution of topical tar oil to ultraviolet B phototherapy for psoriasis. J Am Acad Dermatol 1986; 14(5 Pt 1):742–747. 9. Lebwohl M, Martinez J, Weber P, DeLuca R. Effects of topical preparations on the erythemogenicity of UVB: implications for psoriasis phototherapy. J Am Acad Dermatol 1995; 32(3):469–471. 10. Lowe NJ, Wortzman MS, Breeding J, Koudsi H, Taylor L. Coal tar phototherapy for psoriasis reevaluated: erythemogenic versus suberythemogenic ultraviolet with a tar extract in oil and crude coal tar. J Am Acad Dermatol 1983; 8(6):781–789. 11. Muller SA, Perry HO. The Goeckerman treatment in psoriasis: six decades of experience at the Mayo Clinic. Cutis 1984; 34(3):265–268, 270. 12. National Psoriasis Foundation. Report on Internet. c2005. (Available from: http://www.psoriasis.org/treatment/psoriasis/topicals/tar.php.) 13. Margulies JB, Fulbright, Jaworski LLP. Calprop 65 [posting on Internet]. C1996–2004. Cited January 14, 2002. (Available from: http://www.calprop65. com/coaltar.html.) 14. Kraft S, Maibach HI, Shroot B. Dithranol. In: Henry R, Howard M, eds. Psoriasis. 3rd ed. New York: Marcel Dekker Inc., 1998:435–452. 15. Ingram JT. Approaches to psoriasis. Br Med J 1953; 2:591–594. 16. Runne U, Kunze J. Short-duration (‘minutes’) therapy with dithranol for psoriasis: a new out-patient regimen. Br J Dermatol 1982; 106(2):135–139. 17. Thune P, Brolund L. Short- and long-contact therapy using a new dithranol formulation in individually adjusted dosages in the management of psoriasis. Acta Derm Venereol Suppl (Stockh) 1992; 172:28–29. 18. Yamamoto T, Matsuuchi M, Irimajiri J, Otoyama K, Nishioka K. Topical anthralin for psoriasis vulgaris: evaluation of 70 Japanese patients. J Dermatol 2000; 27(7):482–485. 19. Statham BN, Ryatt KS, Rowell NR. Short-contact dithranol therapy—a comparison with the Ingram regime. Br J Dermatol 1984; 110(6):703–708. 20. Lebwohl M. A clinician’s paradigm in the treatment of psoriasis. J Am Acad Dermatol 2005; 53(1 suppl 1):S59–S69. 21. Schulze HJ, Schauder S, Mahrle G, Steigleder GK. Combined tar–anthralin versus anthralin treatment lowers irritancy with unchanged antipsoriatic efﬁcacy. Modiﬁcations of short-contact therapy and Ingram therapy. J Am Acad Dermatol 1987; 17(1):19–24. 22. Tremblay JF, Bissonnette R. Topical agents for the treatment of psoriasis, past, present and future. J Cutan Med Surg 2002; 6(3 suppl):8–11. Epub Apr 30, 2002. 23. Koo J, Cufﬁe CA, Tanner DJ, et al. Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis: a multicenter study. Clin Ther 1998; 20(2):283–291. 24. Maurer TA, Winter ME, Koo J, Berger TG. Refractory hypoglycemia: a complication of topical salicylate therapy. Arch Dermatol 1994; 130(11):1455–1457. 25. Kim TH, Choi EH, Kang YC, Lee SH, Ahn SK. The effects of topical alphahydroxyacids on the normal skin barrier of hairless mice. Br J Dermatol 2001; 144(2):267–273.

11 Phototherapy and Laser for the Treatment of Mild-to-Moderate Psoriasis Holly A. Kerr and Henry W. Lim Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, U.S.A.

Jennifer Trepte Department of Dermatology, Wayne State University, Detroit, Michigan, U.S.A.

INTRODUCTION Phototherapy has long been a mainstay therapy for psoriasis. In the last 5 to 10 years, there have been exciting new light sources developed for the treatment of psoriasis. These newer technologies have allowed us to increase our efﬁcacy and hopefully will decrease the long-term adverse events. The ultraviolet (UV) spectrum is divided into three categories: UVC, ultraviolet B (UVB), and UVA. UVC (200–290 nm) is rarely present on earth, as it is absorbed by the ozone layer. UVB (290–320 nm) is a mainstay in the treatment of psoriasis; it is known as the sunburn spectrum. UVA (320–400 nm) is divided into UVA1 (340–400 nm) and UVA2 (320–340 nm). Compared to UVA1, UVA2, being of shorter wavelength range, has biologic property that is closer to that of UVB. UVA1 has only recently been evaluated for the treatment of psoriasis. The combination of psoralen and UVA (PUVA) is a well-established psoriasis therapy. Ideal phototherapy for localized psoriasis would be localized treatment, sparing the healthy skin from the side effects of UV radiation. There are

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now a few targeted phototherapy devices that deliver UVB and/or UVA. In addition, an excimer laser light source, delivering 308 nm radiation to targeted psoriatic lesions, has been shown to be another effective therapeutic modality for psoriasis. Although phototherapy is generally not used as ﬁrst-line therapy for the treatment of localized psoriasis, it is a safe and effective secondline therapy, either as a monotherapy, or as a combination therapy for many patients. MECHANISM OF ACTION T cells play a central role in the pathophysiology of psoriasis. The induction of T-cell apoptosis is felt to be the main mechanism by which phototherapy is effective in the treatment of psoriasis. T-cell apoptosis has been shown with the treatment of broadband UVB (BB-UVB), narrowband UVB (NB-UVB), PUVA, the 308 nm excimer laser, and UVA1 (1–5). In one study, excimer laser was shown to be more effective than NB-UVB in inducing apoptosis of T cells (6). Other effects of UV include suppression of DNA synthesis, and generation of prostaglandins and cytokines. The cutaneous immunomodulation induced by phototherapy is an effective mode of treatment, without systemic immunosuppression and its associated side effects. With PUVA, an additional mechanism of action is the formation of cross-links between psoralen and the pyrimidine bases in the DNA, inhibiting DNA replication. ULTRAVIOLET B UVB phototherapy as monotherapy, or in combination with other therapies, is an effective therapy for the treatment of psoriasis. Clearance rates with UVB can be as high as 80% or greater in combination with topical therapy. The potential to induce remission is also an attractive feature. BB-UVB has been one of the mainstay therapies in the past for psoriasis. In 1981, Parrish and Jaenicke (7) identiﬁed that the 313 nm wavelength is the most effective one for the treatment of psoriasis; this lead to the development of NB-UVB (which emits 311–312 nm), which is becoming the new standard of care. Both booth and hand and foot phototherapy machines are available. Efficacy Numerous studies have compared BB-UVB to NB-UVB for the treatment of psoriasis, all of which demonstrate superiority of NB-UVB (8). Several studies have compared the efﬁcacy of NB-UVB with PUVA. In a randomized comparison of 100 patients with chronic plaque psoriasis, 84% of patients receiving twice-weekly oral PUVA achieved clearance, compared to 63% of

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the twice-weekly NB-UVB group (9). The PUVA-treated group also required signiﬁcantly fewer treatments to achieve clearance, and they remained in remission longer than the NB-UVB–treated group. A comparison of NB-UVB to systemic PUVA for the treatment of chronic plaque psoriasis revealed a reduction in the psoriasis area sensitivity index of 84% and 89%, respectively (10). There was a trend towards increased efﬁcacy and maintenance of clearance with PUVA. A report of 45 patients who completed a comparison study between three times per week of NB-UVB and oral PUVA showed that there was no statistically signiﬁcant difference in the number of days to clear, or the number of days in remission; however, the PUVA group required fewer treatments to clear (11). A randomized controlled trial compared the efﬁcacy of NB-UVB and trimethoxypsoralen (TMP) bath PUVA for chronic plaque psoriasis in 28 patients (skin phototypes I–III). Each body half was treated with either NB-UVB or bath PUVA. The NB-UVB–treated half achieved clearance a median of 11 days more quickly than PUVA (12). Remission durations did not differ. In practice, NB-UVB should be considered as the ﬁrst-line UV-based therapy, especially in Caucasians. However, in patients with skin type V or VI, or in those with very thick or large psoriatic lesions, PUVA may offer an advantage over NB-UVB due to the deeper penetration of UVA radiation. Combination Therapy NB-UVB in combination with anthralin or topical tazarotene has been shown to be more effective than monotherapy (13,14). There are conﬂicting reports of the efﬁcacy of the combination of NB-UVB and calcipotriol; however, it appears to have some added beneﬁt (15–18). Addition of topical corticosteroids to BB-UVB has not shown any added beneﬁt as compared to BB-UVB monotherapy, and may even induce a higher relapse rate (19). Systemic retinoids in combination with NB-UVB is more effective than NB-UVB alone (20); with the added anticarcinogenic effects of retinoids, this combination is a very useful treatment option. Acitretin in combination with NB-UVB results in faster improvement even in difﬁcult-to-treat patients. The combination of the two treatments appears to have synergistic effects (21). The combination of methotrexate and UVB resulted in clearing in 26 subjects with extensive psoriasis (22). Methotrexate was initiated three weeks before UVB phototherapy, and methotrexate was stopped when signiﬁcant clearing occurred. This combination resulted in low total cumulative doses of methotrexate, thus minimizing the risk of hepatotoxicity. However, in view of the potentiating effect of methotrexate in PUVA-induced photocarcinogenesis (23), the combination of methotrexate and NB-UVB should be used with caution. In cultured keratinocytes, calcineurin inhibitors (cyclosporine, tacrolimus, and pimecrolimus) have been shown to decrease apoptosis and to

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decrease DNA repair following exposure to UVB radiation (24). As such, until additional long-term studies are complete, it is prudent not to combine UVB phototherapy with topical calcineurin inhibitors. Indications The indications for UVB therapy include stable plaque psoriasis, history of rapid clearance with exposure to sunlight, resistant plaques to topical therapy, the ability of the patient to comply with treatment regimen, and patient preference. UVB is safe in patients who are pregnant, breast-feeding, or planning to become pregnant when topical agents, such as retinoids, are not a treatment option. In patients with skin type I or II, or a past history of X-ray therapy, arsenic exposure, or the use of immunosuppressive agents, UVB would be a better phototherapy option than PUVA. Should it be necessary, it is generally considered safer to treat patients with known history of non-melanoma skin cancer, or melanoma, with UVB compared to treatment with PUVA. Patient preference for avoiding oral medications is also an important factor in the decision-making process. As compared to PUVA, NB-UVB does not use photosensitizing agents; therefore, it is better tolerated and is more cost effective. Contraindications There are very few absolute contraindications to UVB phototherapy; these include patients with xeroderma pigmentosum, and those with basal cell nevus syndrome. Relative contraindications include photosensitive disorders, use of photosensitizing medications with an action spectrum in the UVB range, and history of skin cancer. Photodermatoses whose action spectrum may include the UVB range include polymorphous light eruption, chronic actinic dermatitis, and solar urticaria. It should be noted that the action spectrum of the vast majority of drug-induced photosensitivity is UVA; because NB-UVB emits at 311–312 nm, it is a safe light source to use. Due to the thin skin in the genital region and the increased risk of cutaneous malignancies, it is preferable not to treat this area with phototherapy. In a study involving a small number of subjects, UVB irradiation was shown to result in activation of HIV in the skin (25). However, multiple other studies showed effectiveness of UVB for many HIV-related dermatoses without any adverse side effects (26). Advantages and Disadvantages The advantages of NB-UVB are ease of administration and potential to induce remission. It is well tolerated, and hand and foot units are available for localized disease. The major disadvantage of NB-UVB phototherapy, which can be generalized to all forms of ofﬁce-based phototherapy, is the time commitment for three times a week of treatment. In addition, both

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BB-UVB and NB-UVB generally require more frequent maintenance treatments as compared to PUVA; this obviously needs to be balanced with the apparently higher photocarcinogenicity of PUVA, especially in fair-skinned individuals. If the patient is responsive to UVB, home phototherapy units can be considered as an option. Dose and Administration The initial dose of UVB can be determined by minimal erythema dose (MED) testing or by skin type. MED is the dose of UVB that produces minimally perceptible erythema covering the entire irradiated area. The guideline that we use for MED testing at Henry Ford Hospital is shown in Table 1. The initial ﬂuence is usually 70% of the patient’s MED. An alternate method of starting NB-UVB is based on skin type. The guideline for this method is shown in Table 2. In both methods, the dose is increased by 10–15% at each visit, guided by the patient’s side effects of the previous dose. NB-UVB three times per week has been shown to clear psoriasis significantly faster than twice-weekly treatment, and therefore is preferable for most patients (27). Once satisfactory clearing of the psoriatic lesions has occurred, at our institution, the frequency of therapy is usually decreased to twice a week for four weeks, and ﬁnally maintained once a week for a few weeks and then stopped if the patient remains clear. Some patients may require long-term treatment with UVB therapy, since their psoriasis will relapse if phototherapy treatments are discontinued. Goggles for eye protection are routinely used during the treatment session. In addition, as discussed previously, male genitalia should be shielded during treatment (28). Thick application of creams and ointments can actually block the transmission of UVB. Several topical treatments for psoriasis have been shown to block UVB. Anthralin can be found in a base containing salicylic acid; the latter absorbs UVB, hence limiting UVB transmission. Tar should also be removed before phototherapy because it physically blocks UV transmission. Clear liquid emollients such as mineral oil can be applied prior to phototherapy. Topical and systemic retinoids can decrease the MED due to their property of thinning the epidermis; therefore, if a retinoid is added to a treatment regime, at our center, we decrease the UVB dose by 30%. Table 1 Guideline for Determination of NB-UVB MED Using MED testing template, exposed 5 sites to 100, 200, 400, 600, and 800 mJ/cm2 Read at 24 hr MED is deﬁned as the minimal dose of NB-UVB that produces perceptible erythema covering the entire irradiated area Abbreviations: NB-UVB, narrowband-ultraviolet B; MED, minimal erythema dose.

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Table 2 Guidelines for Narrowband Ultraviolet B (NB-UVB Phototherapy) for the Treatment of Psoriasis Based on Skin Type Skin type

Initial dose (mJ/cm2)

Suggested maximum dose (mJ/cm2)

150 150 250 250 400 400

3000 3000 3000 3000 3000 3000

I II III IV V VI

Note: The dose is increased by 10% to 15% as tolerated. If the skin is light pink, the dose should be kept the same as the previous treatment. If the skin is red or tender the treatment is usually held. The recommended maximum dose on the face is 1000 mJ/cm2. This is the protocol for NB-UVB therapy with the Ultralite phototherapy unit used at Henry Ford Hospital. The protocol for different NB-UVB light boxes may differ.

If the patient’s psoriasis is limited to a few areas of the body, one should consider shielding the unaffected skin from UV radiation. The articles that are used to shield healthy tissue should be kept consistent to prevent UV-induced erythema in previously shielded sites. Adverse Effects The acute side effect of UVB is erythema, which appears four to six hours after radiation and peaks at 12–24 hours. If the ﬂuence is too high, blistering can occur. Patients will become tanned. UVB can induce a keratitis if proper eyewear is not used. The long-term side effects of UVB include photoaging. Animal studies show that the carcinogenicity of NB-UVB is approximately twice that of BBUVB at equivalent doses. Extrapolation of these data suggests that NB-UVB is two to three times more carcinogenic than BB-UVB per MED. However, the MED equivalent of NB-UVB required to clear psoriasis is around onethird of that for BB-UVB; therefore, there should be no greater risk for NB-UVB compared to BB-UVB (29). The role of BB-UVB or NB-UVB therapy in skin carcinogenesis of humans with psoriasis is not clear. The incidence of skin tumors in 195 psoriasis patients, receiving BB- or NB-UVB phototherapy with up to nine years of follow-up, did not provide evidence for an increased skin cancer risk (30). In a recent review of the literature, treatment with UVB phototherapy did not show an increased skin cancer risk in all studies reviewed but one, which showed an increased risk of genital tumors with UVB (28). A study of 1908 patients treated with NB-UVB in

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Dundee, Scotland, with a mean follow-up period of four years, did not detect any increased incidence of basal cell carcinoma (BCC) or melanoma; there was an increased incidence of BCC, which the authors felt could be explained by a number of other factors (31). Therefore, based on currently available data, both BB- and NB-UVB are safe treatment modalities. PSORALEN AND UVA PUVA photochemotherapy can be considered the gold standard of UVbased therapy for the treatment of psoriasis. The absorption spectrum of 8-methoxypsoralen (8-MOP) is 315–350 nm, with the maximum absorption occurring at 330–335 nm. The spectral output of the UVA light bulb used in PUVA ranges from 320 to 400 nm, with a peak emission at 352 nm. The efﬁcacy of PUVA is likely due to a few mechanisms. Psoralens intercalate into double-stranded DNA; with the absorption of a photon in the UVA range, 3,4- or 40 ,50 -cyclobutane monoadducts with pyrimidine bases are formed. When a second photon of light is absorbed by either of these two monoadducts, a bifunctional adduct is formed, which cross-links the DNA double helix. This inhibits DNA replication and ultimately causes arrest of the cell cycle. This is likely the main mechanism of action in the treatment of psoriasis. Psoralens in an excited state can also react with molecular oxygen, resulting in reactive oxygen species and cell damage. PUVA can also cause apoptosis of cutaneous lymphocytes. Psoralen can be administered orally, or topically. 8-MOP is the only form of psoralen available in the United States; it is used for systemic and topical therapy. 5-Methoxypsoralen (5-MOP) is used primarily in Europe. 4,5,8-TMP, 8-MOP, and 5-MOP can be used for bath PUVA. UVA can be administered by booth phototherapy or hand and foot units. Efficacy Patients treated with PUVA are able to achieve long remissions without requiring maintenance therapies (32). After 20–30 treatments twice or three times per week, almost 90% of patients achieve marked improvement or clearing (33,34). Combination Therapy PUVA can be combined with other therapies to improve its efﬁcacy, to decrease the cumulative dose of UVA, and, ultimately, to minimize its adverse effects. Topical therapies such as anthralin, tar, calcipotriol, and tazarotene can be effectively used in combination with PUVA (35,36). Tar, with an action spectrum in the UVA range, is not widely used in combination with PUVA due to its photosensitizing potential. Studies on

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efﬁcacy of topical corticosteroids in combination with PUVA have yielded conﬂicting results. Five studies comparing PUVA alone with PUVA and topical corticosteroids showed more rapid rates of clearing with the combination regimen; however, one of the ﬁve studies showed a more rapid relapse rate in the combination group (19). In a recent study of 40 patients, there was no signiﬁcant difference in clinical improvement of psoriasis treated either by PUVA plus topical steroids or PUVA plus bland emollients (37). PUVA combined with systemic retinoids is one of the most effective combination therapies. In a randomized, double-blind study, patients with severe, widespread psoriasis were treated either with PUVA as monotherapy or in combination with acitretin. Eighty percent of patients achieved marked or complete clearance with PUVA monotherapy, as compared to 96% of the patients with adjunctive acitretin administration. The cumulative UVA dose in the acitretin-PUVA group was 42% less than the PUVA-only group (38). Similar results have been seen in other studies. In a study performed by Lauharanta and Geiger (39), 34 patients with plaque psoriasis were treated with either acitretin or etretinate and bath PUVA; all patients achieved remission. There were no differences in the clinical response of the two groups, suggesting that acitretin is as effective as etretinate in combination with bath PUVA for the treatment of psoriasis. The combination of methotrexate and PUVA can be an effective treatment; however, due to the immunosuppressive properties of both treatment modalities, this combination should only be considered after the use of retinoids. Retinoids or methotrexate should be started one to three weeks prior to the initiation of PUVA, and continued until the psoriasis is almost clear. The retinoids or methotrexate can be tapered and then stopped, and PUVA should be continued as maintenance therapy; the latter is then tapered as appropriate. The combination of NB-UVB whole-body irradiation, followed by topical PUVA therapy utilizing cream preparation of psoralen for selected psoriatic plaques, has been shown to have signiﬁcantly higher efﬁcacy compared with either monotherapy (40). The cumulative UV doses were signiﬁcantly lower in the combination therapy group. It should be noted that this study, which was performed in Germany, used 0.001% 8-MOP in a cream base; whether the 0.1% 8-MOP lotion commonly used in the United States would have the same synergistic effect with NB-UVB remains to be evaluated. Indications PUVA has been shown to be more effective in clearing psoriasis in darker skin types, likely due to the longer wavelength, which results in deeper UV penetration. As well, thick plaques or involvement of hands and soles are generally more effectively treated with PUVA. Additional indications include failure to respond to UVB phototherapy and aggressive disease such as pustular psoriasis.

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Contraindications Absolute contraindications to PUVA include xeroderma pigmentosum, basal cell nevus syndrome, personal history of melanoma, and photosensitive or photoaggravated disorders such as lupus erythematosus and dermatomyositis. Other absolute contraindications include young age (<10 years, because of the known chronic side effects of PUVA), and nursing mothers (because of the presence of 8-MOP in breast milk). Although psoralens are not considered to be teratogenic, it is not advisable to use PUVA in pregnant patients. Relative contraindications include family history of melanoma, history of non-melanoma skin cancer or dysplastic nevi, ingestion of photosensitizing medications, signiﬁcant solar damage, and previous treatment with ionizing radiation, arsenic, methotrexate, cyclosporine, or tacrolimus. PUVA should be used with caution in patients between 10 and 18 years of age, due to its long-term side effects. Caution should be used in patients with hepatic insufﬁciency as the metabolism of systemic psoralen may be delayed, resulting in prolonged photosensitivity. Renal insufﬁciency can slow down psoralen excretion. Advantages and Disadvantages In light-skinned individuals with thinner psoriatic plaques, PUVA has a role as a second-line light-based therapy, after NB-UVB. PUVA is preferable over NB-UVB in dark-skinned patients, and for thick lesions. The disadvantages of oral PUVA are its acute and chronic side effects (see side effects later). Bath PUVA provides uniform psoralen distribution to the skin with low plasma levels, and it results in a shortened duration of photosensitivity to approximately hours. Moreover, available data so far have shown no evidence for increased risk of skin cancer of any type with bath PUVA. However, to administer this treatment, one needs to have a bathtub, and because of the rapid decline of phototoxicity, the patient has to be exposed to UVA within 10–15 minutes after soaking in psoralen-containing bath water; the latter needs to be freshly prepared for each patient. It is, therefore, a resource-intensive therapy to administer. Topical psoralens in the form of creams or lotions avoid most of the systemic side effects of psoralens, and are convenient to administer; however, their nonuniform distribution can result in unpredictable phototoxicity. Furthermore, topical PUVA has a narrow therapeutic window, namely, with a slight increase in UVA, there could be a signiﬁcant increase in phototoxicity. The areas that receive localized topical PUVA may become quite tanned and the uneven pigmentation may be of cosmetic concern. Dose and Administration With the newer Oxsoralen Ultra formulation, 8-MOP is taken 1–1.5 hours prior to phototherapy, at a dose of 0.4–0.6 mg/kg, with a maximum of

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70 mg. Following oral administration, there are signiﬁcant inter- and intraindividual variations in the absorption of 8-MOP. Therefore, it is very important that the psoralen dose, type and amount of food intake, and timing of phototherapy after ingestion of psoralen are kept constant. Psoralen is preferable to be taken on an empty stomach, as food intake slows absorption and reduces the peak blood levels. However, due to gastrointestinal side effects, especially with 8-MOP, non-fat small meals may be taken to alleviate some of these symptoms. In some patients, the capsules may have to be ingested 10 minutes apart to minimize the gastrointestinal side effects. Antiemetics may have to be given to some patients. In patients who are unable to tolerate systemic PUVA, psoralen can be administered in a bath or cream/lotion, avoiding the gastrointestinal tract. In our institution, topical PUVA is administered using 0.1% 8-MOP solution in Lubriderm1 lotion, applied 20 minutes prior to exposure to UVA. The UVA dose protocol is shown in Table 3. Bath PUVA is only performed in very few centers in the United States because of the need for a bathtub. A bath containing 0.5–5.0 mg/L of 8-MOP, or 0.33 mg/L of TMP, needs to be freshly prepared; the patient will then soak in it for 15 to 30 minutes. At some phototherapy facilities [e.g., University of California, San Francisco (UCSF)], effective bath PUVA is being conducted simply by dissolving 50 mg of Oxsoralen Ultra in a hot cup of water ﬁrst and then adding it to 100 L of bath water. Exposure to the UVA needs to be performed within 30 minutes after the patient steps out of the bathtub. In Europe, oral 5-MOP is commonly used. It is less phototoxic than 8-MOP, therefore requiring a higher cumulative UVA dose. The dose range used is 1.2–1.8 mg/kg. It has less of a gastrointestinal side effect, hence is better tolerated. It is not available in the United States. Avoidance of prolonged sun exposure and wearing UVA-absorbing sunscreens on the days of PUVA therapy are necessary to prevent signiﬁcant phototoxicity. Unlike UVB-induced erythema, PUVA-induced phototoxicity begins approximately 24 hours after exposure and peaks at 48–72 hours after exposure. This is the reason that PUVA should not be administered two days in a row. If PUVA is administered on consecutive days, a treatment Table 3 Topical Psoralen and Ultraviolet A Protocol 0.1% methoxypsoralen in Lubriderm1 lotion is applied to the affected areas 20–30 min prior to treatment. This is only applied in the medical ofﬁce The initial dose of UVA is 0.25–0.5 J/cm2 The dose increase is based on side effects. If tolerated, increase by 0.25–0.5 J/cm2 Photochemotherapy is given three times per week The maximum dose is 8 J/cm2 Once the condition has improved, treatment frequency can be decreased to twice per week for 4–8 weeks and then once per week for 4–8 weeks, then discontinued

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protocol more often used in Europe, the dose is kept constant on the ﬁrst two days of the week, followed by a nontreatment third day; an increased but identical dose may be given on the fourth and ﬁfth day of the week (34). The initial dose of UVA can either be determined by minimal phototoxicity dose (MPD) or more commonly by Fitzpatrick skin type. The MPD is the minimal dose of PUVA that produces well-deﬁned erythema. These readings are performed at 48–72 hours. The skin-type–based protocol used at our institution is shown in Table 4. The dose of UVA should be adjusted, usually decreased by 25%, if patients are taking photosensitizing medications. UVA doses should also be decreased if topical or systemic retinoids are used during a course of PUVA because they thin the stratum corneum, reducing the amount of light required for phototoxicity. During the UVA exposure, protective eyewear should be used. Male genitalia are particularly sensitive to the development of squamous cell carcinomas (SCCs) (41); male genitals should be shielded during all of the UVA exposure. If PUVA is required for limited disease, careful shielding of unaffected skin is recommended. Therapy is usually administered twice to three times per week until the psoriasis is well controlled; it then can be decreased to twice and eventually once a week. Maintenance therapy has been shown to decrease the probability of remission; however, it will increase the patient’s cumulative dose of UVA. The British Phototherapy Group recommends that long-term PUVA therapy should only be considered in patients with a history of rapid relapses (42). However, whether this applies to non-Caucasians is not clear. To better deﬁne the frequency of PUVA therapy, a prospective, randomized, half-side study was performed in Austria, using 18 patients with chronic plaque psoriasis who received paired PUVA regimens (43). It was shown that reducing the number of treatments while maintaining the same UVA dose per week did not reduce efﬁcacy. Reducing the number of treatments from four times per week to twice a week and reducing the UVA dose from 1 to 0.75 or 0.5 MPD per treatment only slightly affected Table 4 Guideline for Psoralen and Ultraviolet A Photochemotherapy for the Treatment of Psoriasis Based on Skin Type

Skin type I II III IV V VI

Initial dose (J/cm2)

Dose increase per treatment (J/cm2)

Maximum dose (J/cm2)

0.5 1.0 1.5 2.0 2.5 3.0

0.5 0.5 1.0 1.0 1.5 1.5

8 (4-face) 8 (4-face) 12 (4-face) 12 (4-face) 20 (4-face) 20 (4-face)

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intermediate therapeutic efﬁcacy, and had no effect on ﬁnal clearance rates or time to complete clearance. The mean cumulative UVA dose was signiﬁcantly lower for the least intensive dose regimen (0.5 MPD twice/wk) than for the more intensive regimens. Due to the increased development of cutaneous malignancies with PUVA therapy, one should strongly consider the combination with other drugs such as retinoids or in rotation with other treatments to minimize total cumulative dose of PUVA. Adverse Effects The acute side effects can be due to either the psoralen or the UVA radiation. Systemic psoralen causes nausea and occasionally vomiting in up to 30% of patients taking 8-MOP. 5-MOP has fewer gastrointestinal symptoms and is better tolerated. Most drug-induced photosensitivities are due to UVA; therefore, a careful medication history will help prevent this adverse event. PUVA-induced phototoxic reactions, such as erythema and vesiculation, appear at 24–36 hours and peak at 48–72 hours; they can persist for a week or longer. Other known side effects include photo-onycholysis, melanonychia, and friction blisters. Subacute side effects can be an intractable pruritus known as ‘‘PUVA itch.’’ In some patients, therapy may have to be stopped until the pruritus resolves, and one can then consider restarting the treatment with a lower UVA dose. Tanning is a constant feature, especially in patients with darker skin. Long-term side effects include photoaging, the development of small brown to black macules in PUVA-exposed sites, known as PUVA lentigines, and photocarcinogenesis. Many of these long-term side effects have been reported by the PUVA follow-up study, a 16-center prospective cohort study of 1380 patients ﬁrst treated with PUVA in 1975–1976 in the United States (44). In a study on photoaging, actinic damage was observed in the hands of 61% of patients, and in the buttocks of 21%. Pigmentary changes were seen in the hands of 59% of patients, and in the buttocks of 25% (45). Increased risk of SCCs is a well-documented dose-dependent adverse effect in Caucasians. In the U.S. 16-center study, there was no increase in non-melanoma skin cancer in the ﬁrst 15 years of the study. However, after 25 years, 50% of patients who had received greater than 400 treatments had SCC, and 33% of patients who had received greater than 200 treatments had BCC (44). A Swedish study followed 4799 patients who had received PUVA between 1974 and 1985 with an average follow-up period of 15.9 years for men and 16.2 for women; increase in the risk for SCC was also observed: the relative risk for SCC was 5.6 for men and 3.6 for women (46). In contrast, a meta-analysis of all available long-term data on non-Caucasians with respect to non-melanoma skin cancer so far revealed no increase in risk in non-melanoma skin cancer in non-Caucasians (47).

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There is a signiﬁcant dose-dependent increase in SCC in the genitals of PUVA-treated male patients. The incidence of invasive penile and scrotal SCCs was increased by 52.6-fold. This dose-dependent increase in the risk of genital tumors is persistent long after PUVA therapy has been stopped, especially among those with high-dose exposures to both PUVA and tar or UVB (41). There are conﬂicting results on long-term studies on the incidence of melanoma after PUVA therapy. The PUVA follow-up study reported an increased risk of melanoma, greatest in patients exposed to high doses of PUVA (250 treatments), beginning 15 years after ﬁrst exposure to PUVA. The incidence rate ratio was 8.4 (48). In contrast, the Swedish follow-up study of 4799 patients who had received PUVA between 1974 and 1985 with an average follow-up period of 15.9 years for men and 16.2 for women did not ﬁnd an increased risk for melanoma, nor in a subcohort comprising 1867 patients followed for 15–21 years (46). In another study by the U.S. PUVA follow-up group of over 1000 patients treated with PUVA, UVB exposure (300 treatments vs. <300 treatments) was associated with a modest but signiﬁcant increase in SCC and BCC risk (49). These occurred on body sites typically exposed to UVB therapy, but not on chronically sun-exposed sites typically covered during therapy. Using the U.S. PUVA follow-up database, 135 patients who had used oral retinoids for greater than 26 weeks in one year were studied. The development of SCC and BCC for each patient during the retinoid use year was compared to the non-retinoid use years. It was found that oral retinoids reduced the risk of SCC but did not signiﬁcantly alter BCC incidence (50). TARGETED (LOCALIZED) PHOTOTHERAPY The appeal of targeted, or localized, phototherapy is its ability to spare healthy skin from the side effects of UV radiation. In addition, the affected areas can usually tolerate a higher dose than unaffected skin, as the ratedetermining factor for generalized phototherapy is usually erythema of uninvolved skin. It is known that normal skin can be exposed to up to three MEDs without blistering, while psoriatic skin may be exposed to up to three times this dose (nine MEDs) without blistering (51,52). The recent commercial introduction of ﬁber-coupled UVB phototherapy systems facilitates the use of this treatment modality for localized psoriasis plaques. The mechanism of action of targeted phototherapy is similar to that of the other UV-based therapy, namely by inducing T-cell apoptosis, suppression of DNA synthesis, and generation of prostaglandins and cytokines. It has been reported that the 308 nm excimer laser is more effective in the induction of T-cell apoptosis compared to NB-UVB (6). At the time of this writing, there are several targeted phototherapy systems available (Table 5): XTrac excimer laser system (PhotoMedex,

Daavlin National Biological

UV type

UVB, UVA, and visible UVA and UVB UVB

UVB

Xenon chloride laser UVB UVB and UVA

Abbreviations: UVA, ultraviolet A; UVB, ultraviolet B.

T 500x Excilite-mTM

MultiClear

CureLight Ltd.

MSQ Ltd.

Lovely IITM

TM

PhotoMedex LumenisTM TheralightTM, Inc.

Company

XtracTM BClearTM DuaLightTM

Phototherapy unit

295–315; 360–370; 405–450 290–330; 330–400 Peak: 308

300–380

308 290–320 290–330; 330–400

Wavelength (nm)

Table 5 Targeted Ultraviolet A and Ultraviolet B Phototherapy Units

Portable Compact, portable Portable

1.5 1.5 square 30 cm square

Portable Can switch from UVB to UVA, compact

Other features

2.3 2.3

4.0 1.6

1.8 1.8 circular 1.6 1.6 square 1.9 1.9 square

Spot size (cm)

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Montgomeryville, Pennsylvania, U.S.A.), BClear targeted photoclearing system (Lumenis, Santa Clara, California, U.S.A.), DuaLight UVA/UVB phototherapy system (TheraLight Inc., Carlsbad, California, U.S.A.), Lovely II (MSq Ltd., Caesarea, Israel), MultiClear (Curelight Ltd., Margate, Florida, U.S.A.), T-500x (Daavlin, Bryan, Ohio, U.S.A.), Excilite-m (National Biological Corporation, Twinsburg, Ohio, U.S.A.). XTrac is the only lasertargeted phototherapy system; the rest are non-laser light sources. Efficacy Most of the published studies on targeted phototherapy have been performed with the 308 nm excimer laser system, which will be the focus of the discussion in this section. There are not a lot of published studies on the other UV phototherapy machines; however, because their wavelengths are similar to that of BB-UVB, NB-UVB, or UVA, theoretically they should be as efﬁcacious as booth phototherapy. Initial case reports and subsequent larger studies (53) have shown signiﬁcant improvement and even remission of psoriatic lesions following exposure to the 308 nm excimer laser. In a multicenter study of 80 patients, stable mild to moderate plaque-type psoriasis was treated twice per week for a total of 10 treatments or clear disease (54). The initial dose was based on MED testing and the following treatments were based on plaque response. Seventy-two percent achieved at least 75% clearing in an average of 6.2 treatments. Eighty-four percent of patients reached improvement of at least 75% after 10 or fewer treatments. Fifty percent reached improvement of at least 90% after 10 or fewer treatments. In a follow-up study, 55% of patients reported an overall satisfaction with their treatments and 25% reported that their treatment was better than other therapies they had tried for localized disease (55). Higher doses can be used on psoriatic plaques with faster clearing and decreased cumulative dose as compared to conventional booth phototherapy (56). A dose-response study showed clearance of psoriasis with high ﬂuences (8–16 times MED) in as little as one treatment (52). Koebner reactions were not observed despite the side effects of transient painful blistering. Treatment with higher ﬂuences was more effective than with low and medium ﬂuences. In addition, the lesions treated with high ﬂuences remained in remission longer. The four-month relapse-free outcome is comparable or better than the standard topical or systemic therapy for psoriasis (52). In a study with four children with psoriasis, mean age 11, the excimer laser was found to be a safe and effective treatment for localized psoriasis in these children (57). Two studies have compared the excimer laser to incoherent UVB phototherapy with similar outcomes. Tanghetti and Gillis (58) compared the clinical outcome of treatment with the excimer laser to a continuouswave, incoherent UVB light source. Both systems cleared the treated psoriasis plaques equivalently, requiring no more than two to ﬁve weeks

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of treatment. When used at equally erythemogenic high doses, both systems produced rapid plaque clearance with minimal side effects. Ko¨llner et al. (59) treated 15 patients with plaque psoriasis. Three different psoriatic lesions were treated with either the xenon chloride 308 nm excimer laser, the 308 nm excimer lamp, or 311 nm NB-UVB three times per week. UVB doses were increased slowly and stepwise. There was no statistically signiﬁcant difference among the three groups after 10 weeks. The mean number of treatments needed to achieve clearance was 24. Both 308 nm light sources treated psoriasis with a similar efﬁcacy to standard NB-UVB phototherapy. Combination Therapy To date, there are no published studies on the combination of targeted phototherapy with adjunctive treatment. Indications Targeted phototherapy is ideal for localized mild to moderate psoriasis, including lesions on palms and soles, and on scalp. Contraindications There are no absolute contraindications. Contraindications are related to the corresponding wavelength. Advantages and Disadvantages The advantages of targeted phototherapy include sparing healthy tissue from UV radiation and ability to deliver high ﬂuences to affected areas. This could result in faster rate of response, and probably less cumulative dose. However, the time to administer therapy is greatly increased as compared to booth phototherapy. One can spend up to 20 minutes per session twice to three times per week. Under appropriate supervision, the therapy can be delivered by an experienced nurse, phototherapy technician, or physician. Dosage and Administration This topic has been studied most extensively with the 308 nm excimer laser. There are various treatment regimes reported and this is still an area of active investigation. Treatments are usually delivered twice or three times per week. The initial dosing is usually based on a predetermined MED as well as plaque thickness and location. Fluences should be adjusted according to symptoms and response to treatment. The initial dose is usually maintained until the plaques ﬂatten, at which point the dose is decreased. Likewise, if there is no improvement with the initial dose, the ﬂuence should be increased.

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Housman et al. (60), have found that twice-weekly excimer laser treatments promote clearance of psoriatic plaques and tapering the treatments may be beneﬁcial in maintaining the level of plaque clearance obtained from biweekly laser treatments. Ko¨llner et al. (59) treated 16 patients with the 308 nm excimer laser or with the 308 nm lamp with an accelerated scheme three times per week. They compared this with UVB therapy in which the dose was increased every second treatment. With the accelerated scheme, clearance was achieved with fewer treatments and with half the cumulative dose of a slow and stepwise regime. The side effects such as blistering and crusting were also increased. Adverse Effects The adverse effects of targeted phototherapy are related to the wavelength administered. The lesional and perilesional skin can develop erythema, tanning, vesiculation, erosion, or crusting. This may result in an uneven skin tone and may be a cosmetic concern for some patients. This dyspigmentation fades gradually with time once phototherapy is stopped. Interestingly, koebnerization has not been reported with vesiculation. In fact, just the opposite, faster clearance in the vesiculated areas or a ‘‘reverse’’ Koebner phenomenon has been reported. There are no long-term studies on carcinogenesis. ULTRAVIOLET A1 UVA1 is a relatively new type of phototherapy in the United States; however, it has been used since the early 1990s in Europe. Its main indications are for the treatment of atopic dermatitis and sclerosing disorders. Efficacy There are two small studies published on the use of UVA1 for the treatment of psoriasis. Kowalzick et al. (61) performed a paired controlled trial in three patients using medium dose UVA1 and BB-UVB for three weeks. Both the UVA1- and BB-UVB–treated lesions improved. A review cited three HIVpositive psoriatic patients who beneﬁted from UVA1 phototherapy (62). However, in a review of Mang and Krutmann’s (63) personal experience, there is little to no efﬁcacy of UVA1 for the treatment of psoriasis. It has been suggested that UVA1 is the phototherapy of choice for HIV-positive patients with psoriasis (63). Three HIV patients with psoriasis were treated with high dose (130 J/cm2) UVA1 with beneﬁt. A quantitative polymerase chain reaction (PCR)-based assay was performed in both lesional and nonlesional skin after one UVB or UVA1 exposure. The UVB-treated skin showed a 6–15-fold increase in the HIV copy number, whereas the UVA1-treated skin did not show any increase (62). Further studies are clearly needed.

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Combination Therapy To our knowledge, there have been no published studies looking at the combination of UVA1 with other therapies. Indications The indications for UVA1 for psoriasis are not clear, as further investigations are necessary to determine its efﬁcacy. Contraindications Contraindications include photodermatoses with action spectrum in the UVA1 range. In patients taking photosensitizing medications, UVA1 needs to be used with caution. Advantages and Disadvantages Further studies are necessary. Dosage and Administration Until further study with psoriasis shows good efﬁcacy, there is no established dose for this treatment. For atopic dermatitis and localized scleroderma, studies have been done using low dose (20 J/cm2), medium dose (50–60 J/cm2), and high dose (120 J/cm2). The low and medium doses are the more commonly used regimen at the present time. Adverse Effects UVA1 is generally well tolerated. Exposed skin will become tanned. There is a signiﬁcant amount of heat generated by the equipment throughout the treatment. Other possible side effects include xerosis, pruritus, and rarely skin burning. The long-term side effects are not known. In animal models, UVA1 has induced squamous cell cancers (64). CONCLUSION Phototherapy and photochemotherapy have a role in the treatment of localized and generalized psoriasis. Patient compliance and the ability for the patient to come to the ofﬁce regularly for the treatment are factors that need to be considered. Targeted phototherapy sparing uninvolved skin is a new development that is beneﬁcial for selected patients. The side effects of PUVA are well established. UVB, when judiciously administered, has minimal side effects.

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REFERENCES 1. Krueger JG, Wolfe JT, Nabeya RT, et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocytes pathology and by selective depletion of intraepidermal T cells. J Exp Med 1995; 182(6):2057–2068. 2. Ozawa M, Ferenczi K, Kikuchi T, et al. 312-nanometer ultraviolet B light (narrow-band UVB) induces apoptosis of T cells within psoriatic lesions. J Exp Med 1999; 189(4):711–718. 3. Johnson R, Staiano-Coico L, Austin L, et al. PUVA treatment selectively induces a cell cycle block and subsequent apoptosis in human lymphocytes. Photochem Photobiol 1996; 63(5):566–571. 4. Bianchi B, Campolmi P, Mavilia L, et al. Monochromatic excimer light (308 nm): an immunohistochemical study of cutaneous T cells and apoptosis-related molecules in psoriasis. J Eur Acad Dermatol Venereol 2003; 17(4):408–413. 5. Morita A, Werfel T, Stege H, et al. Evidence that singlet oxygen-induced human T helper cell apoptosis is the basic mechanism of ultraviolet-A radiation phototherapy. J Exp Med 1997; 186(10):1763–1768. 6. Novak Z, Bonis B, Baltas E, et al. Xenon chloride ultraviolet B laser is more effective in treating psoriasis and in inducing T cell apoptosis than narrow-band ultraviolet B. J Photochem Photobiol B 2002; 67(1):32–38. 7. Parrish JA, Jaenicke KF. Action spectrum for phototherapy of psoriasis. J Invest Dermatol 1981; 76(5):359–362. 8. Coven TR, Burack LH, Gilleaudeau R, et al. Narrowband UV-B produced superior clinical and histopathological resolution of moderate-to-severe psoriasis in patients compared with broadband UV-B. Arch Dermatol 1997; 133(12): 1514–1522. 9. Gordon PM, Diffey BL, Matthews JNS, et al. A randomized comparison of narrow-band TL-01 phototherapy and PUVA chemotherapy for psoriasis. J Am Acad Dermatol 1999; 41:728–732. 10. Tanew A, Radakovic-Fijan S, Schemper M, et al. Narrowband UV-B phototherapy vs photochemotherapy in the treatment of chronic plaque-type psoriasis: a paired comparison study. Arch Dermatol 1999; 135(5):519–524. 11. Markham T, Rogers S, Collins P. Narrowband UV-B (TL-01) phototherapy vs 8-methoxypsoralen psoralen-UV-A for the treatment of chronic plaque psoriasis. Arch Dermatol 2003; 139(3):325–328. 12. Dawe RS, Cameron H, Yule S, et al. A randomized controlled trial of narrowband ultraviolet B vs bath-psoralen plus ultraviolet A photochemotherapy for psoriasis. Br J Dermatol 2003; 148(6):1194–1204. 13. Storbeck K, Holzle E, Schurer N, et al. Narrow-band UVB (311nm) versus conventional broad band UVB with and without dithranol in phototherapy for psoriasis. J Am Acad Dermatol 1993; 28(2 Pt 1):227–231. 14. Behrens S, Grundmann-Kollmann M, Schiener R, et al. Combination phototherapy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel. J Am Acad Dermatol 2000; 42(3):493–495. 15. Bourke JF, Iqbal SJ, Hutchinson PE. The effects of UVB plus calcipotriol on systemic calcium homeostasis in patients with chronic plaque psoriasis. Clin Exp Dermatol 1997; 22(6):259–261.

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16. Rim JH, Choe YB, Youn JI. Positive effect of using calcipotriol ointment with narrow-band ultraviolet B phototherapy in psoriatic patients. Photodermatol Photoimmunol Photomed 2002; 18(3):131–134. 17. Woo WK, McKenna KE. Combination TL01 ultraviolet B phototherapy and topical calcipotriol for psoriasis: a prospective randomized placebo-controlled clinical trial. Br J Dermatol 2003; 149(1):146–150. 18. Brands S, Brakman M, Bos JD, et al. No additional effect of calcipotriol ointment on low-dose narrow-band UVB phototherapy in psoriasis. J Am Acad Dermatol 1999; 41(6):991–995. 19. Meola T Jr., Soter NA, Lim HW. Are topical corticosteroids useful adjunctive therapy for the treatment of psoriasis with ultraviolet radiation? Arch Dermatol 1991; 127(11):1708–1713. 20. Green C, Lakshmipathi T, Johnson BE, et al. A comparison of the efﬁcacy and relapse rates of narrowband UVB (TL-01) monotherapy vs. etretinate (re-TL-01) vs. etretinate-PUVA (re-PUVA) in the treatment of psoriasis patients. Br J Dermatol 1992; 127(1):5–9. 21. Spuls PI, Rozenblit M, Lebwohl M. Retrospective study of the efﬁcacy of narrowband UVB and acitretin. J Dermatol Treat 2003; 14(suppl 2):17–20. 22. Paul BS, Momtaz K, Stern RS, et al. Combined methotrexate–ultraviolet B therapy in the treatment of psoriasis. J Am Acad Dermatol 1982; 7(6):758–762. 23. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy follow-up study. Cancer 1994; 73(11):2759–2764. 24. Canning MT, Nay SL, Pena AV, et al. Immunosuppressive drugs that inhibit calcineurin decrease DNA repair and reduce apoptosis after UVB exposure in human keratinocytes. J Invest Dermatol 2005; 124:A19. 25. Breuer-McHam J, Simpson E, Dougherty I, et al. Activation of HIV in human skin by ultraviolet B radiation and its inhibition by NFkappaB blocking agents. Photochem Photobiol 2001; 74(6):805–810. 26. Akaraphanth R, Lim HW. HIV, UV and immunosuppression. Photodermatol Photoimmunol Photomed 1999; 15(1):28–31. 27. Cameron H, Dawe RS, Yule S, et al. A randomized, observer-blinded trial of twice vs. three times weekly narrowband ultraviolet B phototherapy for chronic plaque psoriasis. Br J Dermatol 2002; 147(5):973–978. 28. Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J Dermatol 2005; 44(5):355–360. 29. Young AR. Carcinogenicity of UVB phototherapy assessed. Lancet 1995; 345(8962):1431–1432. 30. Weischer M, Blum A, Eberhard F, et al. No evidence for increased skin cancer risk in psoriasis patients treated with broadband or narrowband UVB phototherapy: a ﬁrst retrospective study. Acta Derm Venereol 2004; 84(5): 370–374. 31. Man I, Crombie IK, Dawe RS, et al. The photocarcinogenic risk of narrowband UVB (TL-01) phototherapy: early follow-up data. Br J Dermatol 2005; 152(5):755–757. 32. Koo J, Lebwohl M. Duration of remission of psoriasis therapies. J Am Acad Dermatol 1999; 41(1):51–59.

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33. Melski JW, Tanenbaum L, Parrish JA, et al. Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial. J Invest Dermatol 1977; 68(6):328–335. 34. Henseler T, Hoenigsmann H, Wolff K, et al. Oral 8-methoxypsoralen photochemotherapy of psoriasis: the European PUVA study: a cooperative study among 18 European centers. Lancet 1981; 317(8225):853–857. 35. Torras H, Aliaga A, Lopez-Estebaranz JL, et al. A combination therapy of calcipotriol cream and PUVA reduces the UVA dose and improves the response of psoriasis vulgaris. J Dermatol Treat 2004; 15(2):98–103. 36. Behrens S, Grundmann-Kollmann M, Peter RU, et al. Combination treatment of psoriasis with photochemotherapy and tazarotene gel, a receptor-selective topical retinoid. Br J Dermatol 1999; 141(1):177. 37. Tahir R, Mujtaba G. Comparison of psoralen ultraviolet A (PUVA) photochemotherapy plus topical corticosteroids with PUVA plus bland emollients in the treatment of psoriasis. J Ayub Med Coll Abbottabad 2005; 17(1):34–36. 38. Tanew A, Guggenbichler A, Honigsmann H, et al. Photochemotherapy for severe psoriasis without or in combination with acitretin: a randomized, double-blind comparison study. J Am Acad Dermatol 1991; 25(4): 682–684. 39. Lauharanta J, Geiger JM. A double-blind comparison of acitretin and etretinate in combination with bath PUVA in the treatment of extensive psoriasis. Br J Dermatol 1989; 121(1):107–112. 40. Grundmann-Kollmann M, Ludwig R, Zollner TM, et al. Narrowband UVB and cream psoralen-UVA combination therapy for plaque-type psoriasis. J Am Acad Dermatol 2004; 50(5):734–739. 41. Stern RS, Bagheri S, Nichols K. PUVA follow up study. The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis. J Am Acad Dermatol 2002; 47(1):33–39. 42. Anonymous. British Photodermatology Group guidelines for PUVA. Br J Dermatol 1994; 130(2):246–255. 43. Legat FJ, Hofer A, Quehenberger F, et al. Reduction of treatment frequency and UVA dose does not substantially compromise the antipsoriatic effect of oral psoralen-UVA. J Am Acad Dermatol 2004; 51(5):746–754. 44. Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discontinuation of psoralen þ ultraviolet A: a cohort study. J Invest Dermatol 2003; 121(2):252–258. 45. Stern RS. Actinic degeneration and pigmentary change in association with psoralen and UVA treatment: a 20-year prospective study. J Am Acad Dermatol 2003; 48(1):61–67. 46. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol 1999; 141(1):108–112. 47. Murase JE, Lee EE, Koo J. Effect of ethnicity on the risk of developing nonmelanoma skin cancer following long-term PUVA therapy. Online Int J Dermatol 2005; 44(12):1016–1021. 48. Stern RS. PUVA follow up study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44(5):755–761.

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49. Lim JL, Stern RS. High levels of ultraviolet B exposure increase the risk of nonmelanoma skin cancer in psoralen and ultraviolet A-treated patients. J Invest Dermatol 2005; 124(3):505–513. 50. Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous squamous cell carcinoma risk in patients with psoriasis treated with psoralen-UVA: a nested cohort study. J Am Acad Dermatol 2003; 49(4):644–650. 51. Bonis B, Kemeny L, Dobozy A, et al. 308 nm UVB excimer laser for psoriasis. Lancet 1997; 350(9090):1522. 52. Asawanonda P, Anderson RR, Chang Y, et al. 308-nm excimer laser for the treatment of psoriasis: a dose-response study. Arch Dermatol 2000; 136(5):619–624. 53. Gerber W, Arheilger B, Ha TA, et al. Ultraviolet B 308-nm excimer laser treatment of psoriasis: a new phototherapeutic approach. Br J Dermatol 2003; 149(6):1250–1258. 54. Feldman SR, Mellen BG, Housman TS, et al. Efﬁcacy of the 308-nm excimer laser for the treatment of psoriasis: results of a multicenter study. J Am Acad Dermatol 2002; 46:900–906. 55. Rodewald EJ, Housman TS, Mellen BG, et al. Follow-up survey of 308-nm laser treatment of psoriasis. Lasers Surg Med 2002; 31(3):202–206. 56. Trehan M, Taylor CR. High-dose 308-nm excimer laser for the treatment of psoriasis. J Am Acad Dermatol 2002; 46(5):732–737. 57. Pahlajani N, Katz BJ, Lozano AM, et al. Comparison of the efﬁcacy and safety of the 308 nm excimer laser for the treatment of localized psoriasis in adults and in children: a pilot study. Pediatr Dermatol 2005; 22(2):161–165. 58. Tanghetti E, Gillis PR. Photometric and clinical assessment of localized UVB phototherapy systems for the high-dosage treatment of stable plaque psoriasis. J Cosmet Laser Ther 2003; 5(2):101–106. 59. Kollner K, Wimmershoff MB, Hintz C, et al. Comparison of the 308-nm excimer laser and a 308-nm excimer lamp with 311-nm narrowband ultraviolet B in the treatment of psoriasis. Br J Dermatol 2005; 152(4):750–754. 60. Housman TS, Pearce DJ, Feldman SR. A maintenance protocol for psoriasis plaques cleared by the 308 nm excimer laser. J Dermatol Treat 2004; 15(2):94–97. 61. Kowalzick L, Suckow M, Waldmann T, et al. Mitteldosis-UV-A1 versus UV-BTherapie bei Psoriasis. Z Dermatol 1999; 185:92–94. 62. Krutmann J, Stege H, Morita A. Ultraviolet-A1 phototherapy: indications and mode of action. In: Krutmann J, Ho¨nigsmann H, Elmets CA, Bergstresser PR, eds. Dermatological phototherapy and photodiagnostic methods. Berlin: Springer-Verlag, 2001:261–276. 63. Mang R, Krutmann J. UVA-1 phototherapy. Photodermatol Photoimmunol Photomed 2005; 21(2):103–108. 64. Sterenborg HJ, van der Leun JC. Tumorigenesis by a long wavelength UV-A source. Photochem Photobiol 1990; 51(3):325–330.

12 Combination Therapy Wendy Myers and Jennifer Tan Department of Medicine, Division of Clinical Pharmacology, Robert Wood Johnson Medical School, New Brunswick, New Jersey, U.S.A.

Alice B. Gottlieb Department of Dermatology, Tuffs-New England Medical Center, Boston, Massachusetts, U.S.A.

THE RATIONALE FOR COMBINATION THERAPY Even in mild cases of psoriasis, therapy with a single topical agent often fails to provide patients with adequate disease control. Fortunately, valid alternatives are available, as topical agents can be used in conjunction with other topical medications, systemic therapies, and phototherapy through a combinational, sequential, or rotational approach to treatment. This translates into management plans that extend from the simultaneous use of two treatment entities to well-choreographed time courses featuring multiple therapeutic agents. Situations in the treatment of mild to moderate psoriasis that may warrant this approach include refractory disease, acute ﬂares, poor quality of life, or an upcoming major life event for which total clearance is desired. Diversifying treatment tends to reduce the required dosages and adverse effects associated with aggressive treatment modalities, as well as beneﬁt the patient through potential cost reduction, ease of administration, and improved quality of life. The concept of maximizing efﬁcacy and minimizing adverse effects through the combined use of multiple treatment modalities for psoriasis has been used extensively (1). Combination therapy is most useful to treat 147

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Table 1 Combination Therapy Guidelines Factors in considering the switch to combination therapy Monotherapy is not or no longer effective Cumulative and/or acute toxicity is projected to be less Side effects are projected to be fewer Improved therapeutic outcome (e.g., time, likelihood of clearing) Increased possibility of tailoring therapy to individual needs Factors in choosing a particular combination of agents Severity of disease Patient’s expectations and ease of use History, relative to use of agents in the combination Response Side Effects Reported efﬁcacy and cost Source: From Ref. 1.

patients who have failed monotherapy, are taking or may take a medication whose toxicity will decrease when used in combination, or require tapering from a single therapeutic agent (1). This approach frequently involves using smaller doses of each agent for a limited period of time, with the more potent agent discontinued as clinical improvement is attained. Just as there is no single topical agent that can be used to treat all patients with psoriasis, ﬂexibility with combinational therapeutics is also necessary to achieve disease control. Guidelines to diagnosing combination therapy can be found in Table 1. There is evidence that combination therapy is often superior to monotherapy. In a 2000 review investigating disease clearance rates associated with various treatments for psoriasis, phototherapy was associated with 63% to 86% clearing and systemic therapy (with a non-retinoid) with 65% to 81% clearing (2). This was in comparison to the 2% to 36% clearing rate for topical therapies. When a second topical agent was added to topical monotherapy, there was a higher likelihood of clearing. Combination therapies involving systemic agents or phototherapy, however, yielded even higher clearing rates with the pair of acitretin plus psoralen and ultraviolet A (PUVA) and the Goeckerman regimen reaching 100% clearance. Included among the most successful combinations were ultraviolet B (UVB) plus anthralin, PUVA plus anthralin, and PUVA plus topical calcipotriol, with reported clearance rates of greater than 90% (2). Combination therapies have been superior to monotherapy in many double-blind studies, particularly the pairs of calcipotriol with betamethasone valerate ointments, acitretin with PUVA, and calcipotriol ointment with PUVA. PHOTOTHERAPY COMBINATIONS The use of phototherapy combinations is very common and widely used. Many combinations exist including therapy with UVB and PUVA, as well

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as numerous combinations of ultraviolet phototherapy and topical and systemic medications. UVB and PUVA A study by Momtaz and Parrish (3) found that the simultaneous administration of UVB and PUVA in patients with psoriasis led to more rapid clearing than either therapy used alone. In the study, the investigators administered UVB and PUVA to patients who were previously unsuccessful with either PUVA or UVB. All 42 of the study subjects tolerated the treatments well and cleared in an average of 11.3 treatments, half the number of treatments usually required with either therapy alone. In addition, the cumulative UVB dose was 18% of that normally used with UVB. The mean cumulative PUVA dose was less than half normally required. Narrowband UVB and Bath PUVA In a more recent study by Calzavara-Pinton (4), the combined use of bath PUVA followed by narrowband UVB (NB-UVB) was examined. Twelve patients were treated with bath PUVA in addition to NB-UVB on the other side of the body. It was found that NB-UVB enhanced the effects of bath PUVA. In addition, it was found that bath PUVA–NB-UVB cleared the psoriatic lesions with fewer total exposures as well as lower cumulative ultraviolet A (UVA) doses. A major disadvantage of the study was the limited follow-up of study participants with regard to long-term side effects, especially carcinogenesis. Currently, there is limited information of the carcinogenic potential of simultaneous PUVA and NB-UVB. NB-UVB and Cream PUVA It is well known that the systemic absorption of oral psoralens is associated with many risks, including the risk of developing cutaneous malignancies after long-term or high-dose therapy (5). In order to reduce these side effects, bath PUVA was developed and has been associated with equal efﬁcacy and fewer side effects, although ease of use and economic burden are obvious limitations. Bath PUVA requires several visits a week to the physician’s ofﬁce, may have costly copayments, and may result in the loss of many hours from the workplace. In a study of 30 patients with moderate to plaque psoriasis, Grundmann-Kollman et al. (6) examined the use of cream PUVA, a newer and less burdensome and costly modality compared to bath PUVA, in combination with narrowband UVB. In the study, 8-methoxypsoralen in Dorithin cream at a concentration of 0.001% was applied four times a week in an even layer for 30 minutes on psoriatic lesions. After this time period, the remaining cream was removed and followed by UVA administration after 30 minutes. Although both therapies induced clearance in all patients within ﬁve to seven weeks, combination therapy induced complete clearance of

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lesions in all patients within three to four weeks. In addition, the cumulative UV doses were greatly reduced in the combination regimens versus either therapy alone. The study strongly suggests that cream PUVA in conjunction with NB-UVB would be useful in psoriasis, especially in individuals with more resistant lesions that tend to clear less quickly. Although the studies by Momtaz and Calzavara-Pinton demonstrated beneﬁts of dual UVB and PUVA therapy, a study by Park and colleagues (7) examining PUVA and UVB against PUVA alone in 19 patients with psoriasis was unable to show a difference in the mean number of treatments, the mean UVA dose at clearing, or the mean cumulative UVA dose.

UV PHOTOTHERAPY AND TOPICAL MEDICATIONS UVB and Topical Vitamin D The results regarding the beneﬁts of combination therapy with UVB and topical vitamin D analogues such as calcipotriol and calcipotriene are varied. In 1990, Kragbelle (8) performed a study of 20 patients using calcipotriol in combination with UVB phototherapy. After eight weeks, a difference, although not statistical, in lesion clearance was noted between lesions treated with UVB and calcipotriol and calcipotriol alone (39% vs. 17%, respectively). Molin (9) conducted a large multicenter trial that examined a total of 101 patients treated with both UVB and calcipotriol and UVB or calcipotriol alone over the course of eight weeks. By the end of the study, the combined therapy group had an 82% mean reduction in the psoriasis area severity index (PASI) score versus 70% in the calcipotriol-alone group of patients. In addition, it was noted during study follow-up that patients who had received combination calcipotriol and UVB had slower onset of new lesions. Another study performed by Hecker and Lebwohl (10) examined a total of 20 patients with symmetric plaque-type psoriasis. Patients were treated with a combination of calcipotriene ointment and UVB on one side of the body, and with UVB and mineral oil on the other half. Of the 20 patients, 11 or 55% showed a greater decrease in severity of their psoriasis with combined therapy versus UVB with mineral oil. These differences were found to be statistically signiﬁcant as early as week 1. Another study by Ramsay and colleagues (11) examining twice weekly UVB plus calcipotriene cream versus three times a week UVB plus placebo cream found that efﬁcacy was generally comparable, but patients with combination therapy required statistically signiﬁcantly fewer exposures and cumulative UVB therapy to achieve total clearance than those patients receiving UVB alone. A more recent study by Woo and McKenna (12) aimed to determine if the combination of NB-UVB and topical calcipotriol produced the same UVB-sparing effects that were seen in previous studies with broadband UVB. Fifty patients with psoriasis were randomized into two groups: one that would receive NB-UVB with calcipotriol and the other with NB-UVB

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and placebo topical emollient. The mean cumulative UVB dose for the NB-UVB–calcipotriol group was signiﬁcantly lower than the NB-UVB group, conﬁrming that NB-UVB with topical calcipotriol cream has a UVBsparing effect. UVA and Topical Vitamin D The ﬁrst study exploring calcipotriol with PUVA phototherapy involved 103 patients (13). The patients were randomized to receive pretreatment with calcipotriol or placebo, then PUVA with continued calcipotriol or placebo for a total of 10 weeks. At the study’s end, there was a mean reduction in PASI scores of 91.4% in those treated with calcipotriol and PUVA, and 75.7% for those with PUVA and placebo. In addition, it was found that the cumulative UVA dose for the combination group was statistically signiﬁcant compared to the PUVA and placebo group. A second study using the left–right body comparison method examined 11 patients with plaque psoriasis receiving calcipotriene with PUVA versus PUVA alone (14). It was found that the plaques treated with calcipotriene needed fewer treatments as well as lower cumulative doses of UVA to clear their lesions. Recommendations Regarding UVB and Topical Vitamin D In 1997, Lebwohl and colleagues (15) studied the interactions between calcipotriene and ultraviolet light. Minimal erythema doses (MEDs) were determined for UVB and immediate pigment darkening was measured for UVA. Calcipotriene was applied to a small patch of skin prior to UVB, PUVA, UVA, or no phototherapy. It was found that MEDs for UVB and immediate pigment darkening for UVA were not affected by calcipotriene. On the other hand, the thick application of calcipotriene resulted in an increased MED with UVA phototherapy. UVA phototherapy also resulted in a signiﬁcant decrease in the concentration of calcipotriene present in the ointment after therapy, as tested by high-performance liquid chromatography. Therefore, when using calcipotriene/calcipotriol with phototherapy, it should be applied after UVA light administration. In addition, calcipotriene should be applied more than two hours before UVB exposure to prevent a burning sensation in sensitive patients (16). UVB and Tazarotene Tazarotene is a topical retinoid that mediates cell differentiation and proliferation (17). Studies examining the use of tazarotene and light therapy suggest improved efﬁcacy and safety when combining these therapies. Behrens et al. (17) performed a whole-body right–left comparison of NB-UVB plus tazarotene compared to NB-UVB in 10 patients with plaque psoriasis. After two weeks, both treatments markedly reduced PASI scores,

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and after four weeks, the median PASI reduction with combination therapy was 64% versus 48% with NB-UVB alone. A study by Koo and colleagues (18) examined whether the addition of topical tazarotene to broadband UVB phototherapy improved efﬁcacy without causing adverse events including photosensitivity. A randomized, investigator-blinded study of 40 patients evaluated the outcomes of subjects treated with UVB alone or UVB in addition to 0.1% tazarotene gel applied three times per week. At the study’s end (81 days), it was found that tazarotene plus UVB phototherapy achieved faster and signiﬁcantly greater reductions in plaque severity. By day 81, 82% of the plaques treated with tazarotene and UVB showed a marked response (75% improvement or better), whereas only 68% of the plaques treated with UVB-placebo, and 50% in UVB alone responded. Plaques treated with tazarotene and UVB achieved 75% improvement or better a median of 28 days earlier than did lesions treated only with UVB. It was also found that the cumulative UVB dose was signiﬁcantly lower in those with tazarotene and UVB than those with UVB alone or UVB with vehicle. Tazarotene and PUVA Behrens and colleagues (19) evaluated the efﬁcacy of tazarotene in combination with PUVA bath therapy in a total of 12 patients with plaque psoriasis. This study was a left–right comparison, with plaques on one half of the body treated either with tazarotene or placebo once daily, as well as both sides of the body treated with PUVA bath therapy four times a week. After three weeks, the mean PASI reduction with combination therapy was 76%, whereas a mean reduction of only 58% was noted with PUVA bath therapy alone. Concerns Regarding the Use of Tazarotene and Phototherapy As the studies exemplify, combination therapy with tazarotene and phototherapy is beneﬁcial, allowing for improved efﬁcacy and fewer cumulative phototherapy doses. Applying tazarotene three times a week for two weeks does cause thinning of the stratum corneum, permitting patients to burn more readily. Due to the fact that thinning of this layer of skin can drop the erythema induction threshold nearly 25%, doses of UVB should be reduced approximately one-third when tazorotene is added in the middle of a course of phototherapy (20). It has also been recommended to initiate PUVA therapy at slightly lower doses than usual (21). UVB and Tar/Anthralin The Goeckerman regimen, in which coal tar is applied to the skin, followed by UVB phototherapy, is among one of the oldest treatments for patients with psoriasis. Although effective, as is the comparable Ingram method (anthralin and UVB), both are very time-consuming, messy, and expensive therapies that usually require a supervised medical setting.

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There have been a few studies examining modiﬁed variants of these methods in order to determine if similar effectiveness is possible with more amiability. A left–right comparison study by Lebwohl and colleagues (22) looked at short contact anthralin with UVB phototherapy versus no anthralin and UVB. Of the 11 study participants, two patients treated with anthralin had a more rapid response. Boer and Smeenk (23), who examined various concentrations of short-acting anthralin with UVB or UVB alone, performed a similar study. Of the 15 patients participating in the study, four showed moderately improved clearance of psoriasis with short-acting anthralin and UVB versus UVB alone. Another variation of the Goeckerman and Ingram methods was performed by Swinehart and Lowe (24) where high-pressure, high-output metal halide UVA–UVB lamps, along with short-contact tar and more potent shortcontact anthralin, were examined to see if time of therapy could be reduced while maintaining effectiveness. At the end of the study, there was a mean clearance of 89%, with about 75% of these patients maintaining clearance for six months without the need for further therapy. Compared to the more traditional methods, this technique required fewer hours in contact with the medications, as well as less cost, time, and UV exposure. PUVA and Tar/Anthralin Several years ago, a study by Morison and colleagues (25) examined combination therapy of PUVA with anthralin. Although it was found that the combination did clear the subjects’ lesions more readily than PUVA alone, the study participants largely disliked the therapy mainly due to staining. UVB and Topical Steroids Dover and colleagues (26) examined the effect of potent topical steroid cream used together with UVB phototherapy on clearing of psoriatic lesions as well as duration of remission. A randomized, double-blind, placebocontrolled study was performed with patients being treated with UVB three times a week, with approximately half the patients applying topical corticosteroids twice daily and the other half applying placebo. The study found that there was no statistical signiﬁcance between clearance rates. In addition, there were no statistically signiﬁcant differences in the number of treatments or dosages of UVB required in order to achieve clearance. This study is in agreement with other earlier studies that also found there to be no advantageous effects of combination UVB and topical steroids. PUVA and Topical Steroids Data regarding the use of topical steroids in combination with PUVA, in contrast to studies with UVB, have shown some beneﬁt. In a comparison of studies by Meola et al. (27), ﬁve studies examining PUVA alone versus

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PUVA with topical steroids showed more rapid rates of clearing and fewer quantitative UVA doses with the latter. One of the studies in the review did show a higher relapse rate with corticosteroid use (25). COMBINING SYSTEMIC AGENTS WITH TOPICAL THERAPIES IN THE TREATMENT OF MILD-TO-MODERATE PSORIASIS While systemic therapies are often reserved for patients with moderate to severe psoriasis, there are several capacities in which these potent medications may play a role in the management of mild to moderate disease. According to the American Academy of Dermatology Consensus Statement on psoriasis therapies, systemic therapy may be employed in the treatment of mild to moderate psoriasis when the disease is unresponsive to topical agents or if there is lifestyle and/or employment disturbance (28). Patients meeting these qualiﬁcations may still demonstrate a limited affected body surface area, since treatment decisions ultimately involve the combined consideration of lesion severity and the patient’s quality of life and comorbidities, as well as the cost, risks, and beneﬁts of treatment relative to the patient’s desires (29). Cases initially perceived as mild may have a substantial impact on a patient’s quality of life and may therefore merit the consideration of a more vigorous treatment plan than originally envisioned by the physician (30). Patients with mild to moderate disease who have not responded to topical monotherapy are typically introduced to a combination of topical agents or phototherapy. Systemic therapy is considered if a patient’s lesions continue to resist these therapeutic measures or an adverse reaction to phototherapy occurs. In some cases, systemic therapy may be indicated earlier due to widespread disease, involvement of areas severely impacting quality of life, frequent relapse, or joint involvement (28,31). Furthermore, patients with moderate disease may request systemic therapy in an effort to avoid the excessive usage of topical agents or to ease the administration of therapy. For these reasons, as well as to increase compliance, there is currently a demand to develop systemic medications for the treatment of moderate disease (31). The systemic medications traditionally used in the treatment of psoriasis are methotrexate, cyclosporin, and acitretin. Novel developments in the immunopathogenesis of psoriasis have led to the introduction of biologic therapies such as alefacept, etanercept, and efalizumab. Less conventional systemic treatments that are not Food and Drug Administration (FDA)-approved for the treatment of psoriasis include pimecrolimus, mycophenolate mofetil, hydroxyurea, and 6-thioguanine. Usage of these agents may either follow or accompany topical therapy. An approach to treatment is generally governed by the physical characteristics of lesions, the locations affected, relapse frequency, and convenience of treatment modality (32). While many systemic medications are oral, the newer biologics are dispensed

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intravenously or subcutaneously. Using topical therapy in combination with systemic agents often allows for a reduction in the amount of systemic therapy administered as well as a decrease in associated toxicities. Combining topical and systemic therapies is commonplace in the treatment of psoriasis. For instance, in a retrospective analysis of 650 patients treated for psoriasis in an academic setting, over one-third of the patients receiving systemic therapy were simultaneously treated with a class I steroid (33). While not used as ﬁrst-line agents in the treatment of mild to moderate disease, systemic therapy plays an integral role in general psoriatic therapy and therefore is important to all physicians treating patients with this disease. As this manuscript is not focused on the treatment of moderate to severe psoriasis, discussion of systemic therapy will be limited to the following questions:

What systemic therapies are available for use with topical medications? What are the advantages of their usage and what are the most effective combinations? How should systemic medications be used with topical treatment and what are the associated toxicities?

Not all combinations are effective and some are even associated with increased toxicity. It is important to recall that although several combination therapies may be presented here, therapy for psoriasis is designed on an individual basis. In addition, while combination therapy may sufﬁce for some patients, others will require rotational or sequential therapy. Introduced by Weinstein and White (34), rotational therapy was originally designed for the treatment of moderate to severe disease using rotations of UVB plus tar, PUVA, methotrexate, and etretinate. Now, with the introduction of safer systemics, such as acitretin and biologic therapies, and more effective topicals, such as calcipotriene and tazarotene, rotational therapy may play a larger role in patients with clinically unresponsive mild to moderate disease. Furthermore, as described in the subsequent chapter, sequential therapy involving various treatment modalities is also instrumental in treating the entire clinical spectrum of psoriatic disease. Methotrexate Methotrexate is an immunosuppressant well known for its hepatic and hematologic toxicities, which was approved by the FDA for psoriasis treatment in 1971. An antagonist of folic acid, methotrexate prevents the division of rapidly proliferating cells through its inhibition of amino acid and DNA synthesis. Although proliferating lymphocytes and keratinocytes associated with disease pathogenesis are targeted, multiple organ systems are also affected, which leads to toxicities. It is among the oldest and most effective systemic medications used in the treatment of psoriasis; however, its role in

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treating mild to moderate disease involves only those cases that are unresponsive to topical therapy (35). A decision to administer methotrexate to patients with mild to moderate disease should be carefully deliberated because of the associated immunosuppression, potential for multiorgan toxicity, and possible need for liver biopsies. Although methotrexate is useful in acute ﬂares of psoriasis, short-term usage is accompanied by the risk of bone marrow toxicity. Phototherapy and other systemic therapies such as retinoids should be considered prior to starting methotrexate (36). Combination therapy with topicals such as tars and vitamin D analogs is encouraged and methotrexate has also been used successfully in combination with anthralin (36,37). A study conducted in India demonstrated that disease could be adequately controlled with short-term methotrexate interspersed by topical therapy with coal tar, anthralin, or calcipotriene. In many patients, remission was facilitated by the application of aggressive topical therapy to residual lesions during the tapering of methotrexate (38). Methotrexate has also been used in combination with systemic agents for severe psoriasis; clinical improvement was noted in 13 out of 14 patients treated with methotrexate and hydroxyurea at doses that were half of those previously required for individual treatment with either agent. There was also no difference in laboratory measures such as serum transaminases, blood urea nitrogen, and creatinine (39). Cyclosporine As an inhibitor of the enzyme calcineurin, cyclosporine thwarts the production of nuclear factor of activated T cells (NF-AT), a nuclear transcription factor for interleukin-2 and other inﬂammatory genes, and thus inhibits the activation and proliferation of T cells. These ﬁndings have been conﬁrmed by in vivo observations in psoriatic skin (40). Cyclosporine was originally introduced in the 1970s as an immunosuppressant used to prevent organ rejection in kidney transplant patients. In the treatment of psoriasis, its use is generally limited to patients with moderate to severe disease due to associated side effects such as nephrotoxicity, immunosuppression, and multiple drug interactions. Indicated for patients with severe, recalcitrant plaque psoriasis, use of cyclosporine in patients with more mild disease should be considered only after the patient has been formally educated in regard to the drug’s toxicities and risks. The medication should only be contemplated for short-term use in those who have generally tried another agent ﬁrst or who require short-term treatment for a severe ﬂare (41). Short courses of cyclosporine as monotherapy have been shown to rapidly clear chronic plaque psoriasis over a range of severities with generally good tolerability (42). Combinational therapy with topical agents such as anthralin, corticosteroids, and vitamin D analogs result in a superior clinical outcome and frequently a lower required dosage of cyclosporine (28,43).

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There are generally two approaches to using cyclosporine in combination. First, cyclosporine can be used initially to rapidly clear psoriasis at a dosage of up to 5 mg/kg/day. Towards the end of therapy, topical preparations including tar, anthralin, retinoids, or calcipotriene can be used on the resistant areas. The immunosuppressive nature of the drug tends to diminish cutaneous irritation caused by these agents. When the same topical agents are applied at the onset of treatment, a dose of only 2 mg/kg/day is generally needed to obtain clinical efﬁcacy (28). A study of 12 patients with chronic, plaque-type psoriasis receiving cyclosporine in combination with topical anthralin showed a beneﬁcial effect in patients who were slow to initially respond to cyclosporine alone (44). While the local antiproliferative effects of anthralin on keratinocytes may work in conjunction with the systemic effects of cyclosporine, the addition of topical therapy made little clinical difference in patients who were considered to be rapid responders. However, the addition of cyclosporine to topical anthralin therapy yielded a response rate higher than that achieved by anthralin alone. The only adverse effect was a cutaneous hypersensitivity to anthralin noted in some patients after the discontinuation of cyclosporine (44). Observed relapses of psoriatic lesions upon withdrawal of cyclosporine led to trials investigating the use of the drug in combination with topical clobetasol propionate. The addition of clobetasol to a daily cyclosporine dose of 3 mg/kg cleared psoriasis in 3.5 weeks rather than in six weeks in patients treated with cyclosporine alone. There was no difference in the noted side effects between the groups; however, there was also no signiﬁcant difference in relapse rates. These data suggest that when used in combination with clobetasol, a lower cumulative dose of cyclosporine can be used to achieve clearance (45). Unlike methotrexate, cyclosporine is not associated with acute bone marrow toxicity and may be a safer alternative for short-term use. Interestingly, however, the combination of methotrexate and cyclosporine has been effective in the treatment of both psoriasis and psoriatic arthritis (46,47). Maintaining a dosage of less than 5 mg/kg/day will minimize the well-known nephrotoxicity associated with cyclosporine. Methotrexate in combination with cyclosporine has successfully cleared recalcitrant psoriasis with both agents administered at lower doses with decreased overall toxicities (47). Although cyclosporine is very effective at rapidly clearing psoriatic plaques, relapses often occur after the discontinuation of therapy. This reason, in addition to the risk of multiorgan system toxicity, limits the role of cyclosporine in the treatment to mild to moderate disease to the short-term treatment of ﬂares or to disease unresponsive to ﬁrst-line agents. Acitretin Acitretin, an oral retinoid, is an FDA-approved treatment for psoriasis that is most effective in treating pustular psoriasis. When combined with UVB or

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PUVA phototherapy, topical calcipotriene, cyclosporine, or methotrexate, acitretin has successfully improved other types of psoriasis as well (48). Acitretin is the metabolite of etretinate, a molecule that is approximately 50 times more lipophilic and thus accumulates in adipose tissue and exhibits an extended half-life. Both are highly teratogenic; however, the lengthy half-life of etretinate led to its replacement by acitretin in June 1997 (49). The ingestion of alcohol with acitretin leads to its enzymatic conversion to etretinate and subsequently to the clinically signiﬁcant accumulation of the teratogenic compound. It is therefore imperative that all women treated with acitretin are educated of the risks associated with concurrent alcohol ingestion and acitretin therapy (49,50). Also noteworthy for patient discussion is the ethanol content of various over-the-counter preparations, cold medications, and cooking supplies. As with all systemic medications, the use of acitretin is most often reserved for moderate to severe disease but may still have a role in combination with other agents in mild to moderate disease. As a class, oral retinoids are not as efﬁcacious as phototherapy or methotrexate (51). In plaque-type psoriasis, acitretin is used in combination with topical steroids, dithranol, or phototherapy (52). These regimens tend to decrease the dose of acitretin required for clinical improvement while also maximizing efﬁcacy and decreasing adverse effects. Combinations of oral retinoids with PUVA, anthralin, and topical steroids have been extensively studied, though clinical experience was largely gained using etretinate (53). A retinoid in combination with betamethasone valerate cream 0.1% applied twice daily was found to be more effective than either agent alone (54). The effectiveness of acitretin for plaque-type psoriasis is markedly improved with UVA or UVB treatment (55,56). Beneﬁts of using the two therapies in combination include lower ultraviolet and retinoid doses, reduction of retinoid-associated side effects, and the possible suppression of cutaneous malignancies associated with UVB and PUVA (57). Likewise, patients treated with a retinoid and topical anthralin have maintained remission for longer than those treated with monotherapy of either agent (53). From these studies, there is evidence that patients with mild to moderate disease may beneﬁt from maintenance therapy with topical agents or phototherapy with an oral retinoid available intermittently to treat relapses. FUTURE THERAPIES FOR THE COMBINATION TREATMENT OF MILD-TO-MODERATE PSORIASIS There are a variety of medications currently in clinical trials for the treatment of psoriasis, including inhibitors of angiogenesis, oral pimecrolimus, lasers, newer retinoids and vitamin derivatives, antidiabetic agents, and cytokine inhibitors. The development of targeted therapies in conjunction with a novel understanding of disease pathogenesis has created a promising future for our patients with psoriasis.

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ACKNOWLEDGMENT Disclosures: Dr. Alice Gottlieb: Sources of Funding for Research: Amgen Inc.; BiogenIdec, Inc.; Centocor, Inc.; Genetech, Inc; WH Conzen Chair in Clinical Pharmacology; Abbott Labs, Ligand Pharmaceuticals Inc.; Beiersdorf, Inc.; Fujisawa Healthcare, Inc.; Celgene Corp.; Synta, Bristol Myers Squibb, Inc. Speakers’ Bureau Memberships: Amgen Inc.; BiogenIdec, Inc.; Wyeth Pharmaceuticals. Current Consulting Agreements: Amgen Inc.; BiogenIdec, Inc.; CellGate, Inc.; Centocor, Inc; Genetech, Inc; Novartis AG; Wyeth Pharmaceuticals; Schering-Plough Corporation; Eisai; Celgene Corporation; Bristol Myers Squibb Co.; Beiersdorf, Inc.; Warner Chilcott; Abbott Labs; Allergan; Kemia; Roche; Sankyo; Advanced ImmuniT; Medarex; Celera. Dr. Wendy Myers is participating in a research fellowship partially funded by Amgen Inc. REFERENCES 1. Menter MA, See JA, Amend WJ, et al. Proceedings of the psoriasis combination and rotation therapy conference. Deer Valley, Utah, Oct. 7–9, 1994. J Am Acad Dermatol 1996; 34(2 Pt 1):315–321. 2. Al-Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of psoriasis treatment. J Am Acad Dermatol 2000; 42(5 Pt 1):796–802. 3. Momtaz KT, Parrish JA. Combination of psoralens and ultraviolet A and ultraviolet B in the treatment of psoriasis vulgaris: a bilateral comparison study. J Am Acad Dermatol 1984; 10:481–486. 4. Calzavara-Pinton P. Narrow band UVB (311 nm) phototherapy and PUVA photochemotherapy: a combination. J Am Acad Dermatol 1998; 38:687–690. 5. Morison WL. Systemic and topical PUVA. In: Treatment of moderate to severe psoriasis. 2d ed. New York, NY: Marcel Dekker, 2003:91–114. 6. Grundmann-Kollman M, Ludwig R, Zollner TM, et al. Narrowband UVB and cream psoralen-UVA combination therapy for plaque-type psoriasis. J Am Acad Dermatol 2004; 50:734–739. 7. Park YK, Kim HJ, Koh YJ. Combination of photochemotherapy (PUVA) and ultraviolet B (UVB) in the treatment of psoriasis vulgaris. J Dermatol 1988; 15:68–71. 8. Kragbelle K. Combination of topical calcipotriol (MC 903) and UVB radiation for psoriasis vulgaris. Dermatologica. 1990; 181(3):211–214. 9. Molin L. Topical calcipotriol combined with phototherapy for psoriasis. The results of two randomized trials and a review of the literature. CalipotriolUVB Study Group. Dermatology 1999; 198:375–381. 10. Hecker D, Lebwohl M. Topical calcipotriene in combination with UVB phototherapy for psoriasis. Int J Dermatol 1997; 36:302–303. 11. Ramsay CA, Schwartz BE, Lowson D, et al. Calcipotriol cream combined with twice weekly broad-band UVB phototherapy: a safe, effective, and UVB-sparing

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Myers et al. antipsoriatic combination treatment. The Canadian Calcipotriol and UVB Study Group. Dermatology 2000; 200(1):17–24. Woo WK, McKenna KE. Combination TL-01 ultraviolet B phototherapy and topical calcipotriol for psoriasis: a prospective randomized placebo-controlled clinical trial. Br J Dermatol 2003; 149:146–150. Frappaz A, Thivolet J. Calcipotriol in combination with PUVA: a randomized double blind placebo study in severe psoriasis. Eur J Dermatol 1993; 3:351–354. Speight EL, Farr PM. Calcipotriol improves the response of psoriasis to PUVA. Br J Dermatol 1994; 130:79–82. Lebwohl M, Hecker D, Martinez J, et al. Interactions between calcipotriene and ultraviolet light. J Am Acad Dermatol 1997; 37:93–95. Lebwohl M, Menter A, Koo J, et al. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol 2004; 50:416–430. Behrens S, Grundmann-Kollmann M, Schiener R, et al. Combination phototherapy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel. J Am Acad Dermatol 2000; 42:493–495. Koo JY, Lowe NJ, Lew-Kaya DA, et al. Tazarotene plus UVB phototherapy in the treatment of psoriasis. J Am Acad Dermatol 2000; 43:821–828. Behrens S, Grundmann-Kollmann M, Peter RU, et al. Combination treatment of psoriasis with phototherapy and tazarotene gel, a receptor-selective topical retinoid. Br J Dermatol 1999; 141:177. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and phototherapy. J Am Acad Dermatol 2001; 45:487–498. Hecker D, Worsley J, Yeuh G, et al. Interactions between tazarotene and ultraviolet light. J Am Acad Dermatol 1999; 41:927–930. Lebwohl M, Berman B, France DS. Addition of short-contact anthralin therapy to an ultraviolet B phototherapy regimen: assessment of efﬁcacy. J Am Acad Dermatol 1985; 13:780–784. Boer J, Smeenk G. Effect of short-contact anthralin therapy on ultraviolet B irradiation of psoriasis. J Am Acad Dermatol 1986; 15:198–204. Swinehart JM, Lowe NJ. UVABA therapy for psoriasis. Efﬁcacy with shortened treatment times with combined use of coal, tar, anthralin, and metal halide ultraviolet machines. J Am Acad Dermatol 1991; 24:594–597. Morison WL, Parrish JA, Fitzpatrick TB. Controlled study of PUVA and adjunctive topical therapy in the management of psoriasis. Br J Dermatol 1978; 98:125–132. Dover JS, McEvoy MT, Rosen CF, et al. Are topical steroids useful in phototherapy for psoriasis? J Am Acad Dermatol 1989; 20:748–754. Meola T Jr., Soter NA, Lim HW. Are topical steroids useful adjunctive therapy for the treatment of psoriasis with ultraviolet radiation? A review of the literature. Arch Dermatol 1991; 127:1708–1713. Callen JP, Krueger GG, Lebwohl M, et al. AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003; 49(5):897–899. Krueger GG, Feldman SR, Camisa C, et al. Two considerations for patients with psoriasis and their clinicians: what deﬁnes mild, moderate, and severe psoriasis? What constitutes a clinically signiﬁcant improvement when treating psoriasis? J Am Acad Dermatol 2000; 43(2 Pt 1):281–285.

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30. Choi J, Koo JY. Quality of life issues in psoriasis. J Am Acad Dermatol 2003; 49(suppl 2):S57–S61. 31. Mrowietz U. Advances in systemic therapy for psoriasis. Clin Exp Dermatol 2001; 26(4):362–367. 32. Marchetti A, Feldman SR, Kimball AB, et al. Treatments for mild-to-moderate recalcitrant plaque psoriasis: expected clinical and economic outcomes for ﬁrstline and second-line care. Dermatol Online J 2005; 11(1):1. 33. Pearce DJ, Spencer L, Hu J, et al. Class I topical corticosteroid use by psoriasis patients in an academic practice. J Dermatol Treat 2004; 15(4):235–238. 34. Weinstein GD, White GM. An approach to the treatment of moderate to severe psoriasis with rotational therapy. J Am Acad Dermatol 1993; 28(3):454–459. 35. Roenigk HH Jr., Auerbach R, Maibach HI, et al. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19(1 Pt 1):145–156. 36. Roenigk HH Jr., Auerbach R, Maibach HI, et al. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol 1998; 38(3):478–485. 37. van de Kerkhof PC, Mali JW. Methotrexate maintenance following Ingram therapy in ‘‘difﬁcult psoriasis.’’ Br J Dermatol 1982; 106:623–627. 38. Kumar B, Saraswat A, Kaur I, et al. Short-term methotrexate therapy in psoriasis: a study of 197 patients. Int J Dermatol 2002; 41(7):444–448. 39. Sauer GC. Combined methotrexate and hydroxyurea therapy for psoriasis. Arch Dermatol 1973; 107(3):369–370. 40. Gottlieb AB, Grossman RM, Khandke L, et al. Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J Invest Dermatol 1992; 98(3):302–309. 41. Lebwohl M, Ellis C, Gottlieb AB, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol 2001; 39(3): 464–475. 42. Berth-Jones J, Henderson CA, Munro CS, et al. Treatment of psoriasis with intermittent short course cyclosporin (Neoral). A multicentre study. Br J Dermatol 1997; 136(4):527–530. 43. Ellis C, Battu M. Cyclosporine. In: Treatment of moderate to severe psoriasis. 2d ed. New York, NY: Marcel Dekker, 2003:151–179. 44. Gottlieb SL, Heftler NS, Gilleaudeau P, et al. Short-contact anthralin treatment augments therapeutic efﬁcacy of cyclosporine in psoriasis: a clinical and pathologic study. J Am Acad Dermatol 1995; 33(4):637–645. 45. Grifﬁths CE, Powles AV, Baker BS, et al. Combination of cyclosporine A and topical corticosteroid in the treatment of psoriasis. Transplant Proc 1998; 20(3 suppl 4):50–52. 46. Mazzanti G, Coloni L, De Sabbata G, et al. Methotrexate and cyclosporin combined therapy in severe psoriatic arthritis. A pilot study. Acta Dermatol Venereol Suppl (Stockh) 1994; 186:116–117. 47. Clark CM, Kirby B, Morris AD, et al. Combination treatment with methotrexate and cyclosporin for severe recalcitrant psoriasis. Br J Dermatol 1999; 141(2): 279–282. 48. Winterﬁeld SL, Menter A, Gordon K, et al. Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis 2005; 64(suppl 2):ii87–ii90, discussion ii91–ii92.

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13 Topical Sequential Therapy of Psoriasis John Y. M. Koo and Shanthi M. Colaco Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A.

INTRODUCTION Optimal management of psoriasis, a chronically recurring disease, must include a strategy for initial rapid symptomatic relief as well as long-term maintenance therapy. Sequential therapy is a therapeutic approach that employs a deliberate sequence of speciﬁc therapies to maximize the rate of initial improvement and smooth transition to long-term maintenance therapy. The traditional therapeutic approach to psoriasis has been the initiation of a single treatment modality. If the chosen medication does not work effectively, it is discontinued and replaced by a new therapy and so on. A natural consequence of this simplistic monotherapy approach is the tendency to evaluate treatments predominantly based on the rate at which they result in initial symptomatic relief. In reality, there are other factors that should also guide treatment choice including long-term safety, duration of response, and propensity toward tachyphylaxis. The idea of sequential therapy is to optimize these factors by recognizing the advantages and disadvantages of each therapeutic option and then creating the most ideal pairs. Most psoriasis therapies can be categorized into ‘‘rabbits,’’ which are fast acting and very effective but have questionable long-term safety proﬁles, or ‘‘turtles,’’ which have a slower onset of action and are less effective

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Table 1 Sequential Therapy Phase 1: Clearing phase !Phase 2: Transition phase !Phase 3: Maintenance phase

but safer for long-term use. In sequential therapy, ‘‘rabbits’’ and ‘‘turtles’’ are paired in speciﬁc sequences to maximize both efﬁcacy and safety. Sequential therapy embraces the value of providing rapid symptomatic relief to suffering patients while also emphasizing the importance of providing a strategy for safe, long-term control of their disease. This is typically accomplished in three phases: the clearing phase (Phase 1), which employs a rapid-acting or ‘‘quick ﬁx’’ agent for fast relief; the transition phase (Phase 2), the most challenging phase in which one attempts carefully, patiently, and creatively to have the ‘‘turtle’’ successfully take over from the ‘‘rabbit’’ without inciting worsening of psoriasis; and the maintenance phase (Phase 3), the goal of which is long-term control with minimal side effects (Table 1). As the clearing phase agent is usually a superpotent topical steroid, there is a risk of rebound of psoriatic lesions while transitioning to the safer, less potent maintenance phase agent. The skillful combinational use of therapeutic agents and optimal timing of regimen changes during the transition phase can signiﬁcantly reduce this risk and is essential to a successful therapeutic course. With all of the therapeutic modalities currently available for psoriasis, the possibilities for sequential therapy schemes are endless and include systemic sequential therapy involving the newer biological agents as well as various phototherapy options. This chapter will only focus on the concept of sequential therapy using topical agents. The most common topical sequential therapy scheme in practice today will be described and used to illustrate the principles that guide clinicians in choosing among existing schemes as well as creating new schemes. The concept of sequential therapy using systemic or phototherapy modalities are addressed in other publications.

TOPICAL SEQUENTIAL THERAPY: CALCIPOTRIENE AND HALOBETASOL PROPIONATE The most commonly practiced topical sequential therapy scheme for psoriasis in the United States involves halobetasol propionate (Ultravate1) ointment, a superpotent topical corticosteroid, and calcipotriene (Dovonex1) ointment, a vitamin D analog (Table 2). The sequence entails application of halobetasol propionate once daily in the morning and calcipotriene once daily at bedtime for approximately one month (Phase 1, clearing phase), then calcipotriene twice daily on weekdays and halobetasol propionate twice daily on weekends for one month or longer (Phase 2, transition phase), and ﬁnally, calcipotriene twice daily until psoriasis completely resolves, at which time therapy can be tapered off (Phase 3, maintenance phase). This particular

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Table 2 Example of Topical Sequential Therapy Phase 2: pulse therapy, Phase 1: halobetasol calcipotriene bid on propionate qam, ! ! weekdays, halobetasol calcipotriene qhs propionate bid on weekends Phase 2: pulse therapy, Phase 1: clobetasol calcipotriene bid on foam and weekdays, clobetasol calcipotriene bid foam and calcipotriene bid on weekends Approximately Approximately 1 month 1 month

Phase 3: calcipotriene bid, then taper off

Phase 3: calcipotriene bid, then taper off

Until psoriasis resolves completely

scheme has been chosen to illustrate the idea of topical sequential therapy because it is the only scheme in which the merit of each step has been validated by double-blind, randomized clinical trials directly comparing the various options. Calcipotriene has been shown through well-controlled studies to be a safe and effective treatment for psoriasis (1–5). For example, calcipotriene ointment was found in a double-blind, multicenter study to be superior to ﬂuocinonide (Lidex1) ointment, both in rate of improvement and degree of efﬁcacy (6). It is not surprising that the frequency of calcipotriene and other vitamin D analogs used in the treatment of psoriasis falls second only to higher-strength topical corticosteroids. However, there are a signiﬁcant number of dermatologists in the United States who question the effectiveness of calcipotriene after experiencing somewhat disappointing results with the medication when it was ﬁrst introduced. This less than expected ‘‘reallife’’ efﬁcacy of calcipotriene may stem from a few issues. First, it was not realized until years after introduction that the efﬁcacy of calcipotriene is essentially halved and it has an even slower onset of action when it is used only once daily instead of twice daily (7). Unfortunately, most patients were using calcipotriene once daily at bedtime, as it was initially only available in an ointment formulation, which is less conducive to morning application. Interestingly, the efﬁcacy of once-daily calcipotriene use approaches that of twice-daily use if it is continued for eight weeks. However, most patients (and their physicians) were disappointed by the slow onset of action, which is especially true of once daily use, and concluded that calcipotriene was not a useful medication long before eight weeks had passed. Second, a random string of calcipotriene nonresponders may have biased some dermatologists’ clinical impression of this medication. Third, calcipotriene could have caused disappointment when used to abruptly replace a superpotent topical steroid

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only to result in rebound of psoriatic lesions. Finally, the use of calcipotriene as monotherapy is associated with a 2% to 3% incidence of signiﬁcant lesional and perilesional irritation, which is bothersome enough to patients that they discontinue use (8,9). The sequential use of calcipotriene and halobetasol propionate as described previously provides a solution to many of the aforementioned concerns. While superpotent topical steroids such as halobetasol propionate work very well, the combined use of topical steroids and calcipotriene appears to work even better. In fact, the two medications seem to be ideal partners. A double-blind, randomized, multicenter study found that, after only 14 days of therapy, the use of calcipotriene ointment in the morning and halobetasol propionate ointment in the evening was signiﬁcantly more effective when compared to twice-daily monotherapy with either agent and also resulted in a lower incidence of irritation from calcipotriene (10). Additional double-blind, randomized studies have also supported the ﬁnding that calcipotriene and corticosteroids work synergistically to enhance efﬁcacy and result in fewer side effects than treatment with either agent alone (11). Moreover, the use of halobetasol propionate at the start of therapy can compensate for calcipotriene’s slow onset of action and cover patients who might be calcipotriene-slow or nonresponders. Finally, using calcipotriene in conjunction with halobetasol propionate may decrease the incidence of skin thinning from topical steroid use (12). Similar results were found using a combination of calcitriol, another vitamin D analog, and betamethasone valerate, another topical steroid (13). The side effect proﬁle of superpotent topical steroids makes them a poor choice for long-term control of psoriasis. This well-known fact is the rationale for the ‘‘weekday–weekend’’ regimen of the transition phase (Phase 2). The ﬁrst regimen of this kind was introduced in the late 1980s by which the patient applies a potent topical steroid daily until ﬂattening of the plaque occurs and then uses the steroid on weekends only (14). It has since been modiﬁed to include calcipotriene after Lebwohl et al. (15) found that the addition of calcipotriene ointment twice daily on weekdays to the use of halobetasol ointment twice daily on weekends resulted in nearly twice as many patients achieving a six-month remission and a decreased incidence of side effects associated with long-term topical steroid use. The use of this type of intermittent pulse dosing during Phase 2 allows clinicians to safely extend treatment of psoriasis with superpotent topical steroids. Pulse therapy also minimizes the risk of rebound by allowing superpotent topical steroids to be gradually tapered off rather than abruptly discontinued once psoriatic plaques have become macular. During the maintenance phase (Phase 3), the twice-daily application of calcipotriene alone (Phase 3) can be initiated once lesions have not only ﬂattened but also the degree of erythema has decreased from red to pink. This calcipotriene dose may be gradually decreased to once daily, then once

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every other day, and, ultimately, when psoriasis is no longer visible, all prescription medications can be discontinued. Of note, the calcipotriene molecule is relatively unstable and can be inactivated when combined with some topical medications, especially if an acidic environment is created (16). In the aforementioned study that demonstrated the superiority of using once-daily calcipotriene and halobetasol propionate to twice-daily monotherapy with either agent, the once-daily calcipotriene and halobetasol propionate ointments were applied separately, morning and night, in order to prevent inactivation of either agent (10). This is also true of the Phase 1 regimen presented in Table 2. Halobetasol propionate ointment and cream have since been found to be among the medications that are compatible with calcipotriene (17). Therefore, as calcipotriene and halobetasol propionate are individually known to have better efﬁcacy when applied twice a day compared to once a day, the best theoretical regimen would be to use both calcipotriene and halobetasol propionate twice daily. The author recommends mixing the agents in one palm just prior to each application instead of premixing agents, as inactivation can begin as soon as 50 hours after mixing (17). Similarly, calcipotriene can be continued on weekends during Phase 2 pulse therapy, with halobetasol propionate applied in addition to calcipotriene. From common clinical experience, the simultaneous use of the two medications appears to work well, although clinical studies have yet to be performed. Recommending that patients mix calcipotriene and halobetasol propionate creams for morning application and the two ointment formulations for nighttime application may increase compliance. OPTIMAL TIMING TO PROCEED DOWN SEQUENTIAL THERAPY SCHEME The issue of timing of each treatment phase can be approached in two different ways. The ﬁrst is to establish approximate timeframes for the individual treatment phases based on clinical experience and prior studies. Generally speaking, Phase 1 takes three to four weeks, Phase 2 takes another month, and Phase 3 goes on indeﬁnitely or until psoriasis has completely resolved. Needless to say, patients’ lesions need to be assessed intermittently to ensure that the majority of lesions are responding appropriately to treatment. If the patients’ lesions are improving faster or slower than the predicted timeframes, then transitioning between phases must be adjusted accordingly. For example, some patients with chronically active lesions may require indeﬁnite pulse therapy (Phase 2). Fortunately, this ‘‘weekday–weekend’’ regimen appears to be remarkably safe. In my experience, patients do not have any signiﬁcant skin atrophy on this regimen as long as superpotent topical steroids are not applied more than two days per week or to the patient’s face, axilla, groin, and other sensitive areas. Adrenal suppression should not be a concern when topical steroids are used only two days per week.

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The second approach to the issue of timing is more sophisticated but also seems to be more effective. Patients are instructed to transition therapy from Phase 1 to Phase 2 for plaques that have ﬂattened and from Phase 2 to Phase 3 for ﬂattened lesions in which the degree of erythema has decreased from red to pink. With this approach, treatment is individualized so that faster-responding lesions move quickly along the sequence and thick, recalcitrant plaques stay in Phase 1 for more time (where induration obviates the concern for skin atrophy). SEQUENTIAL THERAPY AS A FLEXIBLE THERAPEUTIC STRATEGY The activity of psoriatic lesions is often unpredictable and therapeutic goals range from maintenance of long-term remission, control of acute ﬂares, or even a period of treatment cessation if the severity of psoriasis decreases. Patients with this chronic disease can certainly beneﬁt from individualized treatment plans. The advantage of sequential therapy is that the intensity of treatment can be easily adjusted to the level of activity of psoriasis. As their psoriasis improves, patients transition to the next phase, or if their psoriasis worsens (for example, during winter months), they can regress to an earlier treatment phase. Not only do patients appear to have better clinical outcomes with this ﬂexible therapeutic strategy but they also appreciate the greater sense of control they feel over a disease that is known to unpredictably ﬂuctuate in severity during its chronic course. SEQUENTIAL THERAPY WITH NEW TOPICAL STEROID FORMULATIONS One of the new, innovative formulations of topical steroids uses a foam vehicle to deliver medication. Foam is thermolabile and breaks down on contact with human skin. The result is drug delivery with minimal residue, quick absorption, and increased convenience of application. Furthermore, several in vitro studies have indicated that the foam formulation is a more efﬁcient vehicle for topical drug delivery in comparison to traditional creams, ointments, and solutions (18–22). Clobetasol propionate (Olux1 foam) is one of the topical steroids now available in a foam formulation. Clobetasol propionate foam, like other foam formulations, is quickly absorbed and leaves minimal residue, which makes it ideal for use in combination with other topical agents, such as calcipotriene. The foam vehicle is absorbed so quickly that there is no theoretical concern for dilution or incompatibility when combined with other therapeutic agents. The efﬁcacy of clobetasol propionate foam and calcipotriene ointment when used in a topical sequential therapy scheme was recently evaluated in a clinical study (23,24). The ﬁrst part of the study evaluated the

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twice-daily use of clobetasol propionate foam and calcipotriene ointment as the clearing phase regimen (23). Eighty-six subjects were randomized to three groups: twice-daily monotherapy with clobetasol propionate foam, monotherapy with calcipotriene ointment, or combination therapy. Subjects in the combination group were directed to apply calcipotriene ointment immediately after the clobetasol propionate foam was absorbed. After two weeks of treatment, reductions in psoriasis severity scores for the target lesions were signiﬁcantly greater in the combination therapy group compared to either monotherapy group [clobetasol alone: p ¼ 0.0017 (trunk lesions) and p < 0.0001 (extremity lesions); calcipotriene alone: p < 0.0001 (both trunk and extremity lesions)]. With respect to the trunk psoriatic lesions, the combination therapy group achieved a 69.3% mean reduction in psoriasis severity scores, compared to 48.1% with clobetasol propionate foam alone and 36.6% with calcipotriene ointment alone. A similar pattern was seen with extremity lesions. The results also support in vitro data, as described earlier, suggesting that calcipotriene inactivation does not occur when it is applied immediately after a topical steroid foam (25). The results of the second phase of this sequential therapy study were reported at the 2005 Annual American Academy of Dermatology meeting (24). The second phase involved 38 subjects who achieved at least a 50% reduction in their target lesion severity score during part one. Patients were randomized to one of two groups: twice-daily calcipotriene ointment on weekdays plus twice-daily clobetasol propionate foam or placebo on weekends. Treatment groups were compared using intent-to-treat analysis. After six months of treatment, the combination therapy group showed a consistent trend toward longer maintenance of remission compared to the monotherapy group. Although the data were not found to be statistically signiﬁcant, this same trend continued throughout all study assessments. The data led the authors to suggest that there might be a positive effect associated with using clobetasol propionate foam and calcipotriene ointment in pulse therapy. Given the consistency of these trends, it is probable that the results would have been statistically signiﬁcant if a greater number of subjects were enrolled in the study. The above results strongly suggest that there is an advantage to using foam vehicles for drug delivery in combination sequential therapy. Once again, the foam vehicle is absorbed so quickly that calcipotriene can be applied soon thereafter without concern for dilution and incompatibility with other medications. TOPICAL SEQUENTIAL THERAPY POSSIBILITIES BEYOND CALCIPOTRIENE The idea of sequential therapy can be applied to the combined use of any topical agents with ‘‘rabbit’’ (quick ﬁx) characteristics and ‘‘turtle’’ (safe longterm) characteristics. For example, once-daily tazarotene (Tazorac1) 0.1%

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gel, used in combination with mometasone furoate (Elocon1) 0.1% cream, was recently shown in clinical trials to be more efﬁcacious than twice-daily treatment with either agent alone (26,27). These two medications appear to work synergistically and could possibly be used in a sequential mode. The more traditional topical agents such as tar or anthralin might also be more effective in combination with topical steroids in a sequential therapy scheme. The possibilities with respect to topical sequential therapy in the treatment of psoriasis are limited only by the skill and creativity of the dermatologist. Development of sequential therapy schemes using new agents such as combined calcipotriol and betamethasone dipropionate (Dovobet1) promises increased rate of initial improvement relative to calcipotriene alone and minimized long-term side effects if used in a sequential scheme, and may make the treatment of this chronic disease more convenient.

REFERENCES 1. Kragballe K, Gjertsen BT, de Hoop D, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337:193–196. 2. Cunliffe WJ, Berth-Jones J, Claudy A, et al. Comparative study of calcipotriol (MC 903) ointment and betamethasone 17-valerate ointment in patients with psoriasis vulgaris. J Am Acad Dermatol 1992; 26:736–743. 3. Berth-Jones J, Chu AC, Dodd WAH, et al. A multi-centre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Dermatol 1992; 127:266–271. 4. Ellis JP, Grifﬁths WAD, Klaber MR. Long-term treatment of chronic plaque psoriasis with calcipotriol ointment in patients unresponsive to short-contact dithranol. Eur J Clin Res 1995; 7:247–257. 5. Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipotriol in chronic plaque psoriasis. Dermatology 1994; 189:260–264. 6. Bruce S, Epinette W, Funicella T, Ison A, Johns EL, Loss R. Comparative study of calcipotriene (MC903) ointment and ﬂuocinonide ointment in the treatment of psoriasis. J Am Acad Dermatol 1994; 31:755–799. 7. In the ﬁles at Westwood-Squibb Pharmaceutical Corporation. 8. Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol 2002; 146:351–364. 9. Bruner CR, Feldman SR, Ventrapragada M, Fleischer AB. A systematic review of adverse effects associated with topical treatments for psoriasis. Dermatol Online J 2003; 9:2. 10. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment with halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol 1996; 35:268–269. 11. Lamba S, Lebwohl M. Combination therapy with vitamin D analogues. Br J Dermatol 2001; 144:27–32. 12. Lebwohl M. Topical application of calcipotriene and corticosteroids: combination regimens. J Am Acad Dermatol 1997; 37(3 Pt 2):S55–S58.

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13. Kowalzik L. Clinical experience with topical calcitriol (1,25 dihydroxyvitamin D3) in psoriasis. Br J Dermatol 2001; 144:21–25. 14. Katz HI, Hien NT, Prawer SE, et al. Betamethasone dipropionate in optimized vehicle: intermittent pulse dosing for extended maintenance treatment of psoriasis. Arch Dermatol 1987; 123:1308–1311. 15. Lebwohl M, Siskin SB, Epinette W, et al. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 1998; 39:447–450. 16. Kragballe K. Vitamin D3 analogues. Dermatol Clin 1995; 13:835–839. 17. Patel B, Siskin S, Krazmien R, et al. Compatibility of calcipotriene with other topical medications. J Am Acad Dermatol 1998; 38:1010–1011. 18. Lenn J, Tanojo H, Huang X. Anatomical region variations on the in vitro skin permeation of clobetasol propionate formulations. Presented at 62nd annual meeting of the Academy of Dermatology, Washington, D.C., 2004. 19. Huang X, Tanojo H, Lenn J, Deng CH, Krochmal L. A novel foam vehicle for delivery of topical corticosteroids. J Am Acad Dermatol 2005; 53(1 suppl 1): S26–S38. 20. Lenn J, Madlambayan L, Huang X, Tanojo H. Comparison of clobetasol propionate skin permeation and drug distribution in vitro from various topical drug delivery vehicles (foam, lotion, and wash-off shampoo). Presented at summer meeting of the American Academy of Dermatology, New York, NY, 2004–2005. 21. Deng H, Tanojo H, Lenn J, Cuesico C, Huang X. Foam as a novel vehicle in topical therapy. Presented at 62nd annual meeting of the American Academy of Dermatology, Washington, D.C., 2004. 22. Huang X, Tanojo H, Lenn J, Cuesico C, Deng H. Impact of vehicle on clobetasol propionate skin permeation and drug distribution in vitro. Presented at 62nd annual meeting of the American Academy of Dermatology, Washington, D.C., 2004. 23. Blum R, Stern D, Lebwohl M, Bandow G, Koo J, Cheplo K. A multi-center study of calcipotriene 0.005% ointment and clobetasol propionate 0.05% foam in the sequential treatment of localized plaque-type psoriasis. Presented at summer meeting of the American Academy of Dermatology, New York, NY, 2004. 24. Koo J, Blum R, Lebwohl M, Stern D, Bandow G, Cheplo K. A 2-part, multi-center study of calcipotriene ointment, 0.005% and clobetasol propionate foam 0.05% in the sequential treatment of localized plaque-type psoriasis: long-term outcomes. Presented at 63rd annual meeting of the American Academy of Dermatology, New Orleans, LA., 2005. 25. Franz T, Lehman P, Spellman M. Calcipotriene stability in the presence of steroid foam. Presented at 60th annual meeting of the American Academy of Dermatology, New Orleans, LA., 2002. 26. Green L, Sadoff W. A clinical evaluation of tazarotene 0.1% gel, with and without a high- or mid-high-potency corticosteroid, in patients with stable plaque psoriasis. J Cutan Med Surg 2002; 6(2):95–102. 27. Koo JY, Martin D. Investigator-masked comparison of tazarotene gel q.d. plus mometasone furoate cream q.d. vs. mometasone furoate cream b.i.d. in the treatment of plaque psoriasis. Int J Dermatol 2001; 40(3):210–212.

14 New Developments in Topical Psoriasis Therapy Chai Sue Lee Department of Dermatology, University of California Davis Medical Center, Sacramento, California, U.S.A.

John Y. M. Koo and Shanthi M. Colaco Department of Dermatology, Psoriasis and Skin Treatment Center, University of California San Francisco Medical Center, San Francisco, California, U.S.A.

INTRODUCTION There have not been many new developments in topical therapies for psoriasis in the past few years. One of the few new topical agents that was recently approved by the United States Food and Drug Administration is a ﬁxeddose formulation of 0.064% betamethasone dipropionate and 0.005% calcipotriene ointment (Taclonex). This ﬁxed-dose combination therapy is discussed separately in Chapter 7. In this chapter, we will discuss other new topical psoriatic therapies including a new spray formulation of clobetasol propionate 0.05% (Clobex Spray) and two other formulations of clobetasol propionate 0.05%, a shampoo (Clobex Shampoo), and lotion (Clobex Lotion) as well as Hydrogel patch.

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CLOBETASOL PROPIONATE SPRAY (CLOBEX SPRAY) Clobetasol propionate is the most common topical corticosteroid used to treat moderate to severe psoriasis in the United States and Europe (1). Various formulations of clobetasol propionate are available, including ointment, cream, emollient cream, gel, lotion, solution, foam, shampoo, and most recently spray. Treatment success with any therapy, including topical therapy, depends on patient compliance. One strategy employed by clinicians to increase patient compliance and patient satisfaction with treatment is to pick the formulation that is most pleasing for the particular patient. Although the ointment for mulation has traditionally been thought to be more effective than other formulations due to its occlusive property, many patients dislike using ointment because it is greasy and difﬁcult to apply on large areas. A new spray formulation of clobetasol propionate is now available that is effective, safe, well tolerated, and may be more acceptable for regular use by patients. Clobetasol propionate spray is indicated for the treatment of moderate to severe plaque psoriasis affecting up to 20% body surface area in 18-year old patients or older. The total dosage should not exceed 50 g/wk. Two multicenter, randomized, double-blind, vehicle-controlled phase III studies have shown consistent rapid reduction in overall disease severity with twice daily clobetasol propionate spray in patients aged 18 years and older with moderate to severe plaque psoriasis (2). In study 1, 55% of patients were completely clear or almost clear by week 2, and 78% were completely clear or almost clear at week 4. In study 2, 47% of patients were clear or almost clear by week 2, and 82% were clear or almost clear at week 4. Approximately 25% of patients were judged completely clear in study 1, and 30% were completely clear in study 2 by week 4. The same studies also suggested that patients who had it cleared during treatment with clobetasol propionate spray tended to remain clear for at least four weeks after treatment had ended. All patients who had disease that was judged clear, almost clear, or mild in the two phase III studies had a follow-up visit scheduled at four weeks after the end of treatment. During the four-week posttreatment period, patients were allowed to use only a moisturizer. Seventy-two percent of patients in study 1 and 76% of patients in study 2 were still clear, almost clear, or mild. Clobetasol propionate spray was very well tolerated during the phase III studies. The most common adverse event was application site burning. However, there were no signiﬁcant differences between adverse events in the treatment and control groups. In summary, clobetasol propionate spray is a new formulation that may be more cosmetically elegant and user-friendly than the traditional ointment or cream formulations. Patient compliance may therefore improve and hence better treatment results and increased patient satisfaction.

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CLOBETASOL PROPIONATE SHAMPOO (CLOBEX SHAMPOO) A novel short contact shampoo formulation of clobetasol propionate is a convenient, safe, well-tolerated, efﬁcacious treatment for moderate to severe scalp psoriasis. It is applied once daily on the dry scalp for 15 minutes before lathering and rinsing and can be used continuously for a period of four weeks. Many patients may ﬁnd the more traditional formulations of clobetasol propionate such as ointments and creams cosmetically unacceptable for treating the scalp location. The solution formulation can cause burning and stinging. The foam formulation of clobetasol propionate (Olux) offered several advantages compared to previous treatments. However, several factors may affect treatment compliance with the foam. The foam treatment requires twice a day application and contains 60% alcohol that may sting and dry the hair (3). In comparison, clobetasol propionate shampoo is to be applied once a day, contains only 10% alcohol, and can be used for a period of four weeks compared to just two weeks. In addition, this short contact formulation should minimize the systemic absorption of clobetasol propionate, and thus help to avoid the potentially harmful adverse effects of potent corticosteroids such as hypothalamic pituitary adrenal axis axis suppression (4). In a phase III study, the adverse event rate was similar between clobetasol propionate shampoo and vehicle groups (2). The most common adverse event was skin discomfort, which included stinging and burning (10.6% of shampoo subjects vs. 17% of vehicle subjects). All adverse events were transient and mild or moderate in intensity. None of these adverse events caused the subjects to discontinue treatment. In a multicenter, randomized, investigator-blinded study, the application of clobetasol propionate shampoo once daily was compared to the application of calcipotriene solution (Dovonex) twice daily for four weeks in the treatment of moderate to severe scalp psoriasis (5). Clobetasol propionate shampoo was signiﬁcantly more effective than calcipotriene solution. Furthermore, clobetasol propionate shampoo was better tolerated than calcipotriene solution. A burning sensation was signiﬁcantly more common in the calcipotriene solution group. In another multicenter, randomized, investigator-blinded study, clobetasol propionate shampoo once daily was compared to clobetasol propionate gel (Temovate Scalp Application) once daily for four weeks in the treatment of moderate to severe scalp psoriasis (2). Clobetasol propionate shampoo and Temovate Scalp Application were shown to have similar efﬁcacy and safety proﬁle. In summary, clobetasol propionate shampoo offers a convenient, effective, safe, well-tolerated treatment option for the treatment of moderate to severe scalp psoriasis. Since many patients wash their hair every day already, treatment with clobetasol propionate shampoo can be incorporated into the patient’s daily schedule without taking too much time. This can greatly increase patient compliance and therefore treatment success and patient satisfaction.

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CLOBETASOL PROPRIONATE LOTION (CLOBEX LOTION) An alcohol-free lotion containing clobetasol propionate has also been recently introduced. This lotion is unique from the standpoint of not containing alcohols and providing a more patient friendly application for more widespread body application. In clinical trials, the lotion was as effective as Temovate Cream in treating moderate to severe psoriasis. Interestingly, in these trials, four weeks posttherapy, statistically (p ¼ 0.044) 50% more patients who responded to therapy remained in remission from the Lotion cohort in comparison to those treated with Temovate cream (2). The clobetasol lotion has been shown in vitro to deliver twice as much clobetasol to the epidermal compartment (2). Hence the prevailing theory is that psoriatic lesions responsive to therapy are more thoroughly treated with the Lotion versus Temovate Cream resulting in a longer duration of response with the Lotion.

HYDROGEL PATCH One of the promising developments in topical therapy of psoriasis is the use of Hydrogel for occlusion of topical agents. It is a well-established fact that occlusion of a topical agent with an impermeable substance signiﬁcantly increases percutaneous absorption of the medication leading to enhanced efﬁcacy (6–8). However the cost and/or inconvenience of current available devices for occlusion has precluded the use of occlusion in the day-to-day clinical practice of dermatology. Accordingly, occlusion is generally considered only after other topical therapeutic options have proven to be inadequate. Once a dermatologist chooses to pursue occlusion as a therapeutic strategy; saran wrap or plastic food wrap is the most commonly used material. However, plastic wrap is notoriously difﬁcult to use for several reasons. Plastic wrap has no adhesive and needs to be secured in place with adhesive tape, which can irritate the skin. Signiﬁcant skin irritation or ‘‘tape burn’’ can sometimes result in koebnerization of the traumatized site. Furthermore, patients report that plastic wrap is unsightly, has no inherent elasticity, and does not allow skin to breathe, which results in excessive sweating and discomfort to the patient. Hydrocolloid dressings (e.g., Duoderm1) are a more convenient and aesthetically pleasing alternative to plastic wrap for occlusion of topical agents. Randomized, controlled trials have clearly demonstrated the beneﬁt of occlusive therapy using hydrocolloid dressings with and without the concomitant use of highpotency topical steroids in psoriasis (8). However, hydrocolloid dressings are much too expensive for use in enhancing topical therapy of psoriasis and are currently used mainly for the purpose of wound healing. Although dermatologists are well aware of the beneﬁt of occluding topical agents in psoriasis, the lack of a convenient and affordable material for occlusion precludes use of this valuable therapeutic option in real life.

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The technological developments taking place in Japan could change this current situation. In Japan and other parts of Asia, there is a long tradition of using medicated patches for muscular skeletal pain instead of oral nonsteroidal anti-inﬂammatory agents, as is more common in the United States. These medicated patches have evolved to become inexpensive, discrete, and ﬂexible with an extremely low incidence of skin irritation. One of the newest materials used to create these patches is Hydrogel, which is composed of more than 50% water. Hydrogel patches are quite versatile. They range from those that resembled human skin to those that are transparent or look like a thin slice of tofu. Hydrogel patches have many advantages when compared to other agents used for occlusion. They are signiﬁcantly more cost effective than hydrocolloid patches, have an extremely low incidence of skin irritation, and are highly ﬂexible and elastic so as to make them almost unnoticeable to patients once placed on their skin. Because Hydrogel is hydrophilic rather than hydrophobic, for optimally enhanced penetration of topical agents, it can be constructed in such a way that one side adheres to the skin and the other side is coated with a material that makes the Hydrogel virtually impermeable. Hydrogel occlusion as monotherapy for mild psoriasis has been shown to improve lesions in six to eight weeks. This is not surprising as several research studies have already demonstrated that occlusion alone can result in improvement, if not complete resolution of psoriasis (6,8–14). Moreover, this specially designed impermeable Hydrogel can also enhance the efﬁcacy of various available topical therapies ranging from steroids to nonsteroids (Figs. 1–6). Currently, there is an ongoing study evaluating the efﬁcacy of Hydrogel occlusion in combination with several topical medications and

Figure 1 (See color insert) Pretreatment Hydrogel alone.

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Figure 2 (See color insert) Posttreatment Hydrogel alone.

as a monotherapy for psoriasis. The preliminary results are promising in terms of patient acceptance, a low estimated production cost, and the capability of Hydrogel to enhance the treatment of psoriasis, both alone and in conjunction with topical agents. There are at least three potential uses of Hydrogel in the topical therapy of psoriasis. First, Hydrogel can be used as a ‘‘second line therapy.’’ It is well known by clinicians that all psoriatic plaques, even in the same individual, are not created equal—some plaques are responsive to therapy while

Figure 3 (See color insert) Pretreatment Hydrogel/TAC 0.1% cream versus TAC 0.1% cream alone.

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Figure 4 (See color insert) Posttreatment Hydrogel/TAC 0.1% cream versus TAC 0.1% cream alone.

others are recalcitrant. A certain treatment regimen will often clear 80% to 90% of a patient’s psoriatic lesions, leaving them with 5% to 20% of lesions that are resistant to treatment. Resistant plaques are commonly found on the elbows, knees, and shins, but can be located anywhere on the body. Because these plaques are resistant to even the most effective topical

Figure 5 (See color insert) Hydrogel/Protopic 0.1% ointment versus Protopic 0.1% ointment alone.

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Figure 6 (See color insert) Hydrogel/Ultravate 0.05% cream þ Dovonex 0.005% cream versus Ultravate 0.05% cream þ Dovonex 0.005% cream alone.

regimen, such as the combination of calcipotriol with a super-potent topical steroid, patients are often forced to live with their stubborn lesions. This is where Hydrogel occlusion can be used to enhance the efﬁcacy of the most effective topical treatments. Second, Hydrogel may be used to ‘‘jump start’’ topical therapy of select plaques with particularly severe morphology in terms of scaling, induration, and erythema. Once again, these lesions are typically located on elbows, knees, and shins. In addition to enhancing efﬁcacy of topical agents, application of Hydrogel in these locations can also conceal lesions and stop scales from shedding onto clothes, furniture, etc. The third potential use of Hydrogel in the treatment of psoriasis is as a ‘‘ﬁrst line therapy’’ by patients with mild psoriatic lesions. In these patients, Hydrogel occlusion may be effective in conjunction with a mild topical agent such as hydrocortisone 1% cream or even as monotherapy. Use of Hydrogel in this manner requires minimal physician supervision due to the relatively benign nature of the therapy. Finally, Hydrogel patches may be useful in the treatment of pruritic, licheniﬁed chronic psoriatic plaques. Lichen Simplex Chronicus is most commonly considered in the differential diagnosis of patients who present with this condition. However, patients with a pruritic variant of psoriasis can also develop licheniﬁed psoriatic plaques, which are notoriously difﬁcult to treat as long as patients continue to scratch. In addition to acting as a physical barrier to scratching, Hydrogel appears to have a cooling effect on the skin surface, which provides relief from pruritus. In summary, Hydrogel patches present an affordable, convenient alternative to current methods of occlusion in psoriasis and may signiﬁcantly enhance topical therapy of psoriasis.

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CONCLUSIONS Psoriasis is a chronic disease and therefore requires long-term treatment. However, only 60% of patients are compliant with their therapy (15). There are several reasons why psoriasis patients are not compliant with their treatments (16). The treatments may not work well or they are too toxic. Other reasons are the treatments are inconvenient or relapse occurs too quickly. The new topical treatment options discussed in this chapter should improve patient compliance and patient satisfaction. 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. Al Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of psoriasis treatment. J Am Acad Dermatol 2000; 42:796–802. 2. Data on ﬁle, Galderma Laboratories, L.P. 3. Connetics Corporation. Clobetasol propionate (foam) prescribing information. Palo Alto, (CA); Connetics Corporation, January 2003. 4. Stoughton RB, Wullich K. Relation of application time to bioactivity of a potent topical glucocorticoid formulation. J Am Acad Dermatol 1990; 22: 1038–1041. 5. 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. 6. 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. 7. Gottlieb AB, Staiano Coico L, Cohen SR, Varghese M, Carter DM. 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. 8. Grifﬁths CEM, Tranfaglia MG, Kang S. Prolonged occlusion in the treatment of psoriasis: a clinical and immunohistologic study. J Am Acad Dermatol 1995; 32:618–622. 9. Fry L, Almeyda J, McMinn RMH. Effects of plastic occlusive dressings on psoriatic epidermis. Br J Dermatol 1970; 82:458–462. 10. Halprin KM, Fukui K, Ohkawara A. Flurandrenolon (Cordran) tape and carbohydrate metabolizing enzyme. Arch Dermatol 1969; 100:336–341. 11. Baxter DL, Stoughton RB. Mitotic index of psoriatic lesions treated with anthralin, glucocorticosteroid and occlusion only. J Invest Dermatol 1970; 54:410–412. 12. Urabe H, Nishitani K, Kohda H. Hyperthermia in the treatment of psoriasis. Arch Dermatol 1981; 117:770–774. 13. Fisher LB, Maibach HI. Physical occlusion controlling epidermal mitosis. J Invest Dermatol 1972; 59:106–108. 14. Friedman SJ. Management of psoriasis vulgaris with a hydrocolloid occlusive dressing. Arch Dermatol 1987; 123:1046–1052.

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15. Zaghloul SS, Goodﬁeld JJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol 2004; 140(4):408–414. 16. 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.

15 Palmoplantar Psoriasis Brian Bonish Division of Dermatology, Stritch School of Medicine, Loyola University, Maywood, Illinois, U.S.A.

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

While patients with limited psoriasis may, in general, suffer from a signiﬁcant disease burden, those with involvement of the palms of the hands and soles of the feet, 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). The presence of plaques with ﬁssures and/or pustules on the hands and feet can be painful, debilitating, and socially stigmatizing. These plaques can greatly interfere with a patient’s daily activities, and their location makes it difﬁcult to avoid trauma and irritation. In a recent publication, a task force of the American Academy of Dermatology speciﬁcally pointed out that disease limited to the palms and soles can be severe even though the total body surface area involved may be small. 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 2% of the population, but the pattern and incidence of the palmoplantar disease is still unclear. In one study of 3065 Indian psoriatic patients, 92% had plantar involvement and 56% of manual laborers had hand involvement. Although usually a bilateral disease, in patients with a

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single hand involved it was their dominant hand, suggesting that this was the result of trauma to the hand resulting in the Koebner phenomena (2). Limited studies suggest that these lesions are not the result of dermatophyte infection or contact sensitivities (3). 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 generalized thickening and scaling (keratoderma). This thickened skin can develop deep ﬁssures that are quite painful and can interfere with patient’s ability to walk or use their hands. The plaques are usually sharply demarcated, with clinically apparent disease on the hands ending at the wrist ﬂexures with involvement of the ﬁnger pads but not their 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 on 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 is listed in Table 1. Most commonly, erythematous, hyperkeratotitic 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. Importantly, inﬂammatory fungal infection is an important aspect of the differential of plantar disease. The diagnosis of palmoplantar psoriasis is facilitated by the presence of psoriatic disease elsewhere on the body or by the presence of nail changes. However, in isolation, it can be more difﬁcult to differentiate from other diseases in the differential diagnosis. Though diagnosis of palmoplantar psoriasis is generally made on clinical appearance, a skin biopsy may be helpful. The histological appearance of palmoplantar psoriasis may be similar to typical psoriatic lesions but may have an increased number of 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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neutrophilic pustules in the epidermis. A potassium hydroxide preparation or fungal culture may be helpful in distinguishing palmoplantar psoriasis from a dermatophyte infection. All potential clues may be necessary in making the appropriate diagnosis and allow for effective therapy of the patient’s condition. One condition in the differential diagnosis deserves particular mention: palmoplantar pustulosis, including acrodermatitis of Hallapeau. This disease can appear clinically identical to palmoplantar psoriasis and is frequently categorized as a subset of palmoplantar psoriasis. Palmoplantar pustulosis is associated with previous smoking and patients frequently have autoimmune thyroid disease (4). While there is signiﬁcant clinical and histologic similarity between the two conditions, current studies have separated genetic susceptibility for these two diseases. Palmoplantar pustulosis, for example, is not associated with high-risk loci of the psoriasis susceptibility 1 (PSORS1) locus in the major histocompatibility (MHC) locus of the genome. Moreover, it may respond differently to treatment (5). Thus, data concerning the treatment of palmoplantar psoriasis may not be translatable to palmoplantar pustulosis. 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 disease. Studies of topical therapy, phototherapy, and systemic therapy for palmoplantar psoriasis are often performed after the primary investigations of 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 makes ﬁnding a consistent study population difﬁcult. Even more frustrating is that in studies of plaque psoriasis, data speciﬁc to palmoplantar disease are rarely captured. Thus, we are left with scattered studies and case reports to identify potential treatments, which could have a great impact on patient welfare. We will classify treatment of palmoplantar psoriasis into three basic areas that can be mixed if needed: topical therapy, phototherapy, and systemic therapy. TOPICAL THERAPY Protective Measures The most seemingly obvious intervention that can be of beneﬁt for patients who suffer from palmoplantar psoriasis is protection from exposures that can worsen the disease. Palmoplantar psoriasis patients have diminished

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cutaneous 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 instruction in avoiding irritation to their hands and feet. It is important that they avoid harsh cleansers and contact with chemicals and solvents. These patients should 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 frequently 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 used, but patients must be careful to avoid agents with additives that may aggravate their condition. In these cases, 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 can be an inconvenience to 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 may impact the dermal immune process may not be delivered to the appropriate layers of the skin in a sufﬁcient amount to have a 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. Conversely, the thickness of the skin in the palms and soles allows for class I and II high-potency topical corticosteroids to be used without fear

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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. Occlusion will increase the potency of the topical corticosteroid by about 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. The addition of keratolytic agents like salicylic acid, urea, or lactic acid can reduce the hyperkeratosis associated with palmoplantar psoriasis and increase the penetration of the corticosteroid agents. Topical Vitamin D Derivatives (Calcipotriene/Calcipotriol) Other topical agents in use for plaque psoriasis may also have a role in palmoplantar disease, but good data on their efﬁcacy are not readily available. Calcipotriene has been reported to have some efﬁcacy in a number of case reports and uncontrolled small series in the literature (7). There have, however, been no reported placebo-controlled trials. In one randomized trial, calcipotriol used twice weekly under occlusion was compared to twice a day application in a six-week period (8). 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 (9). Topical Retinoids Systemic retinoids have been used for the treatment of palmoplantar psoriasis for many years (see later). Thus, it has been assumed that topical application of antipsoriatic 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 clinical similarities to psoriasis, has been reported with a good response (10). Additionally, one large center has reported use of topical tazarotene with qualitatively good responses when used in

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combination with topical corticosteroids, though no objective response rates are reported (9). Clearly, further investigation is warranted. Topical Methotrexate Topical 0.25% methotrexate gel was shown not to be statistically signiﬁcantly effective for palmoplantar psoriasis (11). 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 a 50% improvement in 80% of palmar and 64% of 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 Ultraviolet B (UVB) phototherapy has been a standard therapy for psoriasis for decades. More recently, narrowband UVB (NB-UVB) treatment has come into common usage. Like other treatments for palmoplantar psoriasis, however, data on its effectiveness are limited. In one open-label prospective study of of NB-UVB therapy, 9 of 11 patients with refractory palmoplantar psoriasis responded to hand–foot UVB treatment. Additionally, one of three patients with palmoplantar pustulosis had a good response to this therapy (12). 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 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 through application of a cream or solution of psoralen or by soaking in a solution of the medication. This therapy avoids many of the complications and side effects associated with oral 8-methoxypsoralen. Topical psoralen and ultraviolet A (PUVA) therapy has probably been the most widely studied treatment for palmoplantar psoriasis and 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 (13–20). 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 non-laser varieties, has been reported. The 308 nm excimer laser has been suggested as an alternative to traditional phototherapy in one large center. This therapy can be administered with or without the addition of systemic retinoids. A recent pilot study has demonstrated efﬁcacy of a non-laser 308 nm light source in palmoplantar pustulosis in a very limited number of patients (21). Like all aspects of palmoplantar psoriasis, more study is required for any deﬁnitive understanding of directed phototherapy efﬁcacy in this disease. 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 (22–24). This effect is signiﬁcantly improved with the addition of photochemotherapy, a protocol that has been studied in controlled trials (25–27). Oral retinoids, with or without phototherapy, are frequently the ﬁrst oral medication chosen for palmoplantar psoriasis (9). Importantly, due to risks associated with teratogenicity, the U.S. Food and Drug Administration 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 on this subject. In a retrospective analysis, methotrexate has been reported to be used and effective in one large treatment center (9). The limitation of methotrexate use has been side effects associated with this medication. Before starting

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methotrexate, patients must be evaluated for baseline normal liver function, renal function, and bone marrow. Cyclosporin A Cyclosporin A (CsA) 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. CsA has been studied in a randomized placebocontrolled trial with a dose of 2.5 mg/kg/day demonstrating response in 17 out of 19 patients, 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 (28). Additional prospective analyses have veriﬁed the efﬁcacy of CsA (29). It has been used effectively in both the United States and Europe (9,30). Systemic toxicities are the limiting factor in the use of CsA. CsA is immunosuppressive and patients need to be evaluated for hepatitis B and C, human immunodeﬁciency virus, and tuberculosis prior to starting. Additionally, patients need regular monitoring of renal function and blood pressure while taking CsA (29,30). BIOLOGIC THERAPIES There have been limited case reports in the literature suggesting efﬁcacy of biologic immunotherapies in the treatment of palmoplantar psoriasis or palmoplantar pustulosis. Alefacept and etanercept have had published case reports suggesting efﬁcacy (31,32). Importantly, for patients who also suffer from psoriatic arthritis, anti-tumor necrosis factor (TNF-a) biologic therapies such as inﬂiximab, adalimumab, and etanercept have been shown to halt the progression of their disease. For these patients, anti-TNF-a therapies should be considered a ﬁrst-line therapy (33). 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 given based on the authors’ treatment protocol for palmoplantar psoriasis, which is used in their 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 in patients with extensive disease. In general, the authors begin with combination topical therapies, usually a potent topical corticosteroid used in combination with calicipotriol

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Figure 1 Possible treatment algorithm for palmoplantar psoriasis. Abbreviations: NB-UVB, narrowband ultraviolet B; PUVA, psoralen and ultraviolet A; TNF, tumor necrosis factor.

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 ensure 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 ﬁnd topical PUVA therapy to be more effective than NB-UVB, but many patients prefer the ease of avoiding the photosensitizing agent. They

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do not use systemic PUVA for localized palmoplantar disease, as application to these areas of 8-methoxypsoralen 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, they consider systemic treatment. In patients who are male or are female and postmenopausal, their 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, they 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, they 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. Though 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 are 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, Fleischer AB, Feldman SR. 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. Kumar B, Saraswat A, Kaur I. Palmoplantar lesions in psoriasis: a study of 3065 patients. Acta Derm Venereol 2002; 82(3):192–195. 3. 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. 4. Eriksson MO, Hagforsen E, Lundin IP, Michaelsson G. Palmoplantar pustulosis: a clinical and immunohistological study. Br J Dermatol 1998; 138(3): 390–398. 5. 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.

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6. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 1992; 72(1): 69–71. 7. Thiers BH. The use of topical calcipotriene/calcipotriol in conditions other than plaque-type psoriasis. J Am Acad Dermatol 1997; 37(3 Pt 2):S69–S71; 5. 8. Duweb GA, Abuzariba O, Rahim M, al Taweel M, al Alem S, Abdulla SA. Occlusive versus nonocclusive calcipotriol ointment treatment for palmoplantar psoriasis. Int J Tissue React 2001; 23(2):59–62; 3. 9. Spuls PI, Hadi S, Rivera L, Lebwohl M. Retrospective analysis of the treatment of psoriasis of the palms and soles. J Dermatol Treat 2003; 14(suppl 2):21–25. 10. 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. 11. 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. 12. Nordal EJ, Christensen OB. Treatment of chronic hand dermatoses with UVBTL01. Acta Derm Venereol 2004; 84(4):302–304. 13. Agren-Jonsson S, Tegner E. PUVA therapy for palmoplantar pustulosis. Acta Derm Venereol 1985; 65(6):531–535. 14. Behrens S, von Kobyletzki G, Gruss C, Reuther T, Altmeyer P, Kerscher M. PUVA-bath photochemotherapy (PUVA-soak therapy) of recalcitrant dermatoses of the palms and soles. Photodermatol Photoimmunol Photomed 1999; 15(2):47–51. 15. 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. 16. Grundmann-Kollmann M, Behrens S, Peter RU, Kerscher M. 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. 17. Hawk JL, Grice PL. The efﬁcacy of localized PUVA therapy for chronic hand and foot dermatoses. Clin Exp Dermatol 1994; 19(6):479–482. 18. 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. 19. 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. 20. 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. 21. 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. 22. Thune P. Treatment of palmoplantar pustulosis with Tigason. Dermatologica 1982; 164(1):67–72. 23. White SI, Marks JM, Shuster S. Etretinate in pustular psoriasis of palms and soles. Br J Dermatol 1985; 113(5):581–585.

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24. 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. 25. 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. 26. 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. 27. Lawrence CM, Marks J, Parker S, Shuster S. A comparison of PUVA-etretinate and PUVA-placebo for palmoplantar pustular psoriasis. Br J Dermatol 1984; 110(2):221–226. 28. Reitamo S, Erkko P, Remitz A, Lauerma AI, Montonen O, Harjula K. Cyclosporine in the treatment of palmoplantar pustulosis. A randomized, double-blind, placebo-controlled study. Arch Dermatol 1993; 129(10):1273–1279. 29. 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. 30. 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. 31. Myers W, Christiansen L, Gottlieb AB. Treatment of palmoplantar psoriasis with intramuscular alefacept. J Am Acad Dermatol 2005; 53(suppl 2):S127–S129. 32. Weinberg JM. Successful treatment of recalcitrant palmoplantar psoriasis with etanercept. Cutis 72(5):396–398. 33. Mease PJ. Recent advances in the management of psoriatic arthritis. Curr Opin Rheumatol 2004; 16(4):366–370.

16 Scalp Psoriasis Peter C. M. van de Kerkhof, Marloes M. Kleinpenning, and Rianne M. J. P. Gerritsen Department of Dermatology, Radboud University Medical Center, 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 epidemiological 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 manifestation 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, respectively, 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 psychological 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% of patients, respectively, 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 sleeves around the hair, which appearance is also described as ‘‘pseudoteigne amiantace´e.’’ 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 at least some episodes. It is the traditional view that scalp psoriasis is not characterized by hair loss or 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 hairs 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 (See color insert) 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 also is a papulosquamous condition, however with more yellow scale crusts 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; they underwent histological, bacteriological, 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, respectively. Therefore, in the case of pityriasis amiantacea, the differential diagnosis is broad, and in case the clinical picture is not conclusive, histological examination and cultures may be indicated (11). In psoriasis of the scalp, overgrowth of Malassezia species remains an important feature, which may be of therapeutical relevance.

GENERAL THERAPEUTIC ASPECTS A questionnaire mailed to patients of the Dutch Society for Psoriasis (n ¼ 922 responders) (3) revealed that 99.6% of patients used a topical corticosteroid for scalp psoriasis (Table 1). 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. Seventy-two percent of them indicated that they had used treatments for more than eight weeks. Of particular importance is the fact that the patients indicated that the formulation, allowing a cosmetically acceptable treatment, was of utmost importance.

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Table 1 Actual Frequency of Use of Various Treatments in Scalp Psoriasis (n ¼ 922 Patients) Treatment 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 Other treatments Calcipotriol ointment Coal tar shampoo UVB phototherapy Salicylic acid Other/unknowna

No. of patients 13 14 32 16 18 28 65 19 125 106 101 26 37 72 292 258 474 119 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 double-blind 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 might 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 doubleblind 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).

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More recently, clobetasol propionate shampoo 0.05% was reported to be a new option for the treatment of patients with moderate to severe scalp psoriasis (17). In a multicenter, randomized, vehicle-controlled, double-masked, and parallel group study, clobetasol propionate shampoo was compared with the corresponding vehicle shampoo in patients with moderate–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. DESCALING OF THE SCALP Debridement of the scalp by an automatized shampooing and debridement machine has been shown to markedly empower the response to antipsoriatic treatments (18). Salicylic acid 5% to 10% has been shown to have a marked keratolytic effect. Salicylic acid is formulated in an ointment that 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, which can be used in concentrations of up to 40% (19). 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 psoriasis area severity index (PASI) for the scalp during an eight-week treatment (20). 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, polyethylene glycol (PEG)-40, sorbitan peroleate, PEG-40 hydrogenated castor oil, trideceth-9, propylparaben, butylated hydroxytoluene (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 (21). IMIDAZOLE ANTIFUNGALS As scalp psoriasis is accompanied by an overgrowth of pityrosporon, an antifungal treatment seems to be a rational approach. The outcome of

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various studies on topical and systemic antifungal treatments is contradictory (22–25). 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 epidemiological 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 to an ointment, although an ointment provides better bioavailability. More recently, a foam vehicle became available. The advantage of the foam is that it spreads between the hairs 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 (26). In a comparative study against standard treatment (corticosteroid lotion or vitamin D3 treatments) betamethasone 17-valerate in foam was more effective, resulting in clearing or nearly clearing in 88% of the patients (27). In another study, it was shown that once-daily applications of betamethasone 17-valerate was as effective as twice-daily application (28). The average sign scores (erythema þ induration þ scaling) reduced from 8.1 to 3.9 and 7.7 to 3.0 during a four-week head to head study (28). In a comparative study of clobetasol propionate foam 0.05% against clobetasol cream and vehicle 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 (29). 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 and that the skin of the scalp is by far more permeable to topical corticosteroids than most other regions of the skin (30,31). The efﬁcacy and safety ratio of topical corticosteroids may be enhanced by applying corticosteroid preparations intermittently two to three days per week. Furthermore, the addition of salicylic acid may increase the bioavailability of topical corticosteroids considerably, enhancing efﬁcacy. Plastic occlusion (e.g., a shower cap) may be helpful in enhancing the efﬁcacy of corticosteroids. 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 (32). Combination treatments with vitamin D3 analog, the topical retinoid tazarotene (33), and ultraviolet B (UVB) phototherapy are important options for effective and safe control of scalp psoriasis.

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VITAMIN D3 ANALOGS 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, though less effective as compared to betamethasone lotion (34). In 73% to 75% of the patients treated with betamethasone, a marked improvement or clearing was observed and in 57% to 58% of the calcipotriol-treated 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, which 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 results in maximum efﬁcacy already after two to three weeks. In another comparative study (open-label) during six weeks both treatments were equally effective (35). 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 (36). 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 (37). In a multicenter prospective observational cohort consisting of 3396 patients treated with calcipotriol lotion twice daily over an eight-week period, the following observations were made (38). In the total cohort, the scalp severity index reduced from 18.4 to 5.6. In 80%, the improvement was rated as good to very good. 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 weeks’ 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 eight weeks’ treatment, the median sum score had decreased by 53% in the tacalcitol group with 80% of the patients showing marked improvement to clearing (39). 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 applications of a topical corticosteroid during weekend days and once or twice daily of a vitamin D3 analog during weekdays (40).

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PHOTOTHERAPY Phototherapy, although effective in plaque psoriasis, has limited applications in scalp psoriasis, as the hair prevents adequate UV exposition of the skin surface. The UVB/ﬁber optic comb has been shown in a pilot study of 14 patients to improve the treated sides well above the untreated sides (41). The 308 nm excimer laser also has been investigated with respect to efﬁcacy in the treatment of scalp psoriasis. In a study of 13 patients, excimer lasertreated sides improved well above untreated sides (42). A challenging development is photodynamic therapy (43). Application of aminolevulinic acid results in intracellular accumulation of protoporphyrin IX, which 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 the 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 outpatient 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 an ultrapotent topical corticosteroid in a vehicle that is well accepted by the patient for scalp treatment. If this approach is not effective after eight weeks or not appreciated for reason of intolerance, an ultrapotent topical corticosteroid may be combined with UVB therapy. In order to optimize phototherapy of the

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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 an outpatient 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 an ultrapotent 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. Kerkhof PCM van de, 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. Kerkhof PCM van de, Hoop D de, Korte J de, et al. Scalp psoriasis; clinical presentations and therapeutic management Dermatology 1998; 197:326–334. 4. Schoorl WJ, Baar HJ, Kerkhof PCM van de. The hair root pattern in psoriasis of the scalp. Acta Derm Venereol 1992; 72:141–142. 5. Plozzer C, Coletti C, Kokelj F, Trevisan G. Scanning electron microscopy study of hair shaft disorders in psoriasis. Acta Derm Venereol Suppl 2000:9–11. 6. Kerkhof PCM van de, 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. Prohic A. Identiﬁcation of Malassezia species isolated from scalp skin of patients with psoriasis and healthy subjects. Acta Dermatovenereol Croat 2003; 11: 10–16.

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11. 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. 12. Olansky S. Whole coal tar shampoo: a therapeutic hair repair system. Cutis 1980; 25:99–104. 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 1ozide 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. 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. 19. Shemer A, Nathansohn N, Kaplan B, et al. Treatment of scalp seborrhoeic dermatitis and psoriasis with a ointment of 40% urea and 1% bifonazole. Int J Dermatol 2000; 39:532–534. 20. Prins M, Swinkels OQJ, Bertholet B, Valk PGM van der. Dithranol short contact treatment of scalp psoriasis. J Derm Treat 1999; 10:13–17. 21. 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. 22. Farr PM, Krause LB, Marks JM, et al. Response of scalp psoriasis to oral ketoconazole. Lancet 1985; 8461(II):921–922. 23. Faergemann J. Treatment of sebopsoriasis with itraconaxole. Mykosen 1985; 28:612–618. 24. Rosenberg EW, Belew PW, Skinner RB. Treatment of psoriasis with antimicrobial agents. Semin Dermatol 1985; 4:307–311. 25. 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. 26. 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. 27. 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. 28. 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.

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29. Bergstrom KG, Arambula K, Kimball AB. Medication formulation affects quality of life: a randomized single-blind study of clobetasol propionate foam 0.05% comparison with a combined program of clobetasol cream 0.05% and solution 0.05% for the treatment of psoriasis. Cutis 2003; 72:407–411. 30. Robertson D, Maibach H. Topical corticosteroids. Semin Dermatol 1983; 2:238– 249. 31. Feldman RJ, Maibach HI. Penetration of 14C hydrocortisone through normal skin, the effect of stripping and occlusion. Arch Dermatol 1965; 91:661–666. 32. 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. 33. 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 (ZoracTM). Dermatology 1999; 199:40–46. 34. 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. 35. 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. 36. Kerkhof PCM van de, 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. 37. Barnes L, Altmeyer P, Forstrom L, Stenstrom MH. Long-term treatment of psoriasis with calcipotriol scalp solution and cream. Eur J Dermatol 2000; 10:199–204. 38. Thaci D, Daiber W, Boehncke WH, Kaufmann R. Calcipotriol solution for the treatment of scalp psoriasis: evaluation of efﬁcacy, safety and acceptance in 3,396 patients. Dermatology 2001; 203:153–156. 39. Ruzicka T, Trompke C. Treatment of scalp psoriasis. An effective and safe tacalcitol emulsion. Hautarzt 2004; 55:165–170. 40. Lebwohl M, Yoles A, Lombardi K, Lou W. 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. 41. Taneja A, Racette A, Gourgouliatos Z, Taylor CR. Broad-band UVB ﬁber-optic comb for the treatment of scalp psoriasis: a pilot study. Int J Dermatol 2004; 43:462–467. 42. Taylor CR, Racette AL. A 308 nm excimer laser for the treatment of scalp psoriasis. Lasers Surg Med 2004; 34:136–140. 43. Gupta AK, Ryder JE. Photodynamic therapy and topical aminolevulinic acid: an overview. Am J Clin Dermatol 2003; 4:699–708.

17 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, and 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

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onset has a bimodal distribution with the ﬁrst peak at 22.5 years of age and second peak at 55 years of age (6). Psoriasis appears to demonstrate a polygenic mode of inheritance. Approximately one-third of 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 histocompability complex types [human leukocyte antigen (HLA)-Cw6, HLA-B57, HLADR7] 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), and palmoplantar pustulosis (HLA-B8, HLABw35, HLA-Cw7, HLA-DR3) (7–9). 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. Nail pits and onycholysis at the proximal nail (oil spots) are common in inverse psoriasis. 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 psychological health of the person. Overall clinical severity of psoriasis, as assessed by the psoriasis area and severity index (PASI), and duration of psoriasis may not always be related directly to health-related quality-of-life measures (11). Patients with psoriasis often ascribe a substantial negative effect on their quality of life (12). The psychosocial

Figure 1 (See color insert) Patient with inverse psoriasis involving the intragluteal fold.

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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 functioning 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 psychological 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, topical steroidtreated, and control patients shows no evidence of Candida infection (18). 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 1 Drugs That Exacerbate Psoriasis Antimalarials Lithium b-Blockers NSAIDs Trazadone Interferon-alpha Terbeniﬁne ACE inhibitors Gemﬁbrizol Tetracycline Penicillin Abbreviations: NSAIDs, nonsteroidal anti-inﬂammatory drugs; ACE, angiotension converting enzyme.

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

(Table 2). The lesions are generally deep red, smooth, even glistening with a well-demarcated 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 superpotent class I steroids to the weaker class VII steroids. They are believed to reduce inﬂammation by reducing inﬂammatory cells and cytokines, including interleukin (IL)-1, IL-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage-colony stimulating factor (GM-CSF) (19–21). 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 occlusion in these areas, they are even more sensitive to topical corticosteroids. An open-label study of

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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 (22). 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 (23). Pulse therapy has been shown to prevent tachyphylaxis in psoriasis vulgaris but has not been studied for inverse psoriasis. Rarely, the hypothalamic–pituitary–adrenal axis can be suppressed in cases of widespread use rather than those observed in inverse psoriasis patients. 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-gamma, and GM-CSF by T cells. Because it is not associated with skin atrophy, calcipotriene has potential advantages when used in intertriginous areas (24). 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 ﬂuocinonidetreated subjects and continued to be signiﬁcantly lower through week 6 (25). Calcipotriene can also be used in conjunction with topical corticosteroids to extend the duration of remissions while minimizing the effects of chronic steroid use. In a randomized, double-blind 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 (26). 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 (27). 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 (28). Topical Retinoids Tazarotene has multiple effects on keratinocyte differentiation and proliferation, and inﬂammation processes that contribute to psoriasis. There are

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two classes of nuclear retinoid receptors that have been identiﬁed: the retinoic acid receptor (RAR) and retinoid X receptor (RXR) (29). Tazarotene selectively binds to RAR and RXR. The function of these RARs and RXRs 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. A randomized, double-blind, placebo-controlled study involving 324 plaque psoriasis patients using tazarotene gel 0.05% or 0.1% applied once a day for three months demonstrated clearance in 63% and 50% of cases, respectively, compared to 30% of the vehicle (30). 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 (31). 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 (32). Tacrolimus, a lipophilic agent produced by Streptomyces tsukubaensis, exhibits similar in vivo and in vitro biological characteristics to cyclosporin A. Furthermore, it is more potent than cyclosporin A. Inhibition of calcineurin blocks the activity of nuclear factor (NF) 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 epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, or IL-6 through inﬂuence on the keratinocyte cell cycle at G0/1 phases and dosedependent inhibition of IL-8, which is elevated in psoriatic plaques. Tacrolimus has a lower molecular weight and is therefore a much better skin penetrant than cyclosporine, and can thus be used topically. Adverse events include burning, heat sensation, itching, and erythema. In contrast to topically applied 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 (33). A randomized, doubleblind, vehicle-controlled study of inverse psoriasis with 167 patients using 0.1% tacrolimus showed 65.2% of the tacrolimus ointment group and 31.5%

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of the vehicle were 90% clear by eight weeks (34). None of the patients had skin atrophy, telangiectasias, or striae during the eight-week study. 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 randomized, double-blind, vehiclecontrolled trial involving 57 patients studying inverse psoriasis showed 82% of the pimecrolimus group and 41% of the vehicle were 90% clear by eight weeks (35). However, topical tacrolimus and pimecrolimus should be used with caution due to the rare but potentially severe adverse events (36–38). Use of systemic tacrolimus has been shown to be associated with both lymphoid and nonlymphoid malignancies in the post-transplant setting (39,40). Topical tacrolimus has been implicated in squamous cell carcinoma of the penis (41). Oral pimecrolimus has been associated with development of lymphoma in monkey models (42). In mouse models, topical tacrolimus has been shown to accelerate the development of squamous cell carcinomas (43). In March 2005, the Food and Drug Administration (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 (42). 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 (42). 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 (20). Light Therapy Ultraviolet (UV) light causes DNA damage to cutaneous tissue and thereby can inhibit cell proliferation (2). Speciﬁcally, it appears to target cutaneous immune cells and reduce the production of inﬂammatory cytokines important in psoriasis pathogenesis. It is widely used in the treatment of psoriasis vulgaris (20). Broadband ultraviolet B (BB-UVB) and narrowband UVB (NB-UVB) can be used to treat plaque psoriasis. NB-UVB maximizes psoriasis clearance compared with its erythrogenic potential but has the disadvantage of producing more severe and longer lasting burns than BB-UVB. The

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long-term effect of NB-UVB on carcinogenesis in plaque psoriasis remains unknown. Its overall safety is generally believed to be better than psoralen plus ultraviolet A (UVA) (PUVA) (44). 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. 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 NB-UVB (45). 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, basal cell carcinoma, and possibly malignant melanoma (46,47). 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 UV 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 lesions after three weeks of treatment (48). 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 analog of folic acid and a competitive inhibitor of the enzyme dihydrofolate reductase (49). The inhibition of thymidylate synthesis 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 (50,51). It is

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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-blind, 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 (52). 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 (53). 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 or not 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, nuclear factor of activated T cells (NFAT), which is important for inﬂammatory cytokine expression (54). Cyclosporine is indicated for the treatment of severe plaque psoriasis in patients who are not immunocompromised (55). 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% and 80% reduction at 8 and 12 weeks, respectively. Its use for inverse psoriasis has not been speciﬁcally studied (52,54). Nephrotoxicity is the main adverse effect of cyclosporine therapy (53). Acute renal toxicity is dose-dependent and reversible upon lowering the dosage or discontinuation of the drug. Other common side effects include

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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 in incidence of non-melanoma 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 be induced and maintained by a complex pattern of overexpressed Th1 cytokines such as IL-2, -6, -8 or IFN-gamma and TNFalpha (56). In particular, TNF-alpha is involved in the activation of NF-jB, a transcription factor that regulates the expression of cytokines such as IL-6, IL-8, and CSF. It also induces the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule type 1 on endothelial cells and keratinocytes, which are both involved in trafﬁcking lymphocytes to inﬂammatory lesions. TNF-alpha 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 (57). Etanercept is a recombinant soluble fusion protein consisting of two identical chains of the TNF-alpha receptor fused with the Fc portion of human immunoglobulin G1 (IgG1). It is functioning as a competitive inhibitor for binding of TNF-alpha at its receptor. Inﬂammatory cytokines such as TNF have been implicated in the pathogenesis of psoriasis. In a randomized, double-blind study, 672 plaque psoriasis patients either received placebo or received 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 (58). In another randomized, double-blind, placebo-controlled study, of 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 (59). Inﬂiximab is a human–mouse monoclonal chimeric antibody against the TNF-alpha molecules. Adalimumab is a humanized monoclonal antibody against the TNF-alpha 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, or inﬂiximab 10 mg/kg at weeks 0, 2, and 6. At 10 weeks, 82% of patients in the inﬂiximab 5 mg/kg group and 73% of patients in the inﬂiximab

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10 mg/kg group had a 75% improvement in the PASI scores compared to 18% of patients in the placebo group (60). Alefacept is a fusion protein composed of the leukocyte functionassociated antigen (LFA)-3 with the Fc portion of human IgG and binds to cluster of differentiation 2 (CD2) on T cells to block costimulation by antigen presenting cells. In a randomized, placebo-controlled, 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 (61). Two weeks after 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 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 demonstrated 75% response as compared with 5% of patients who received placebo (62). 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, chronically 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.

REFERENCES 1. Odom RB, James WD, Berger TG. Andrews’ Diseases of the Skin: Clinical Dermatology. 9th ed. Philadelphia: W. B. Saunders Co., 2000. 2. Fitzpatrick TB, Freedberg IM. Fitzpatrick’s Dermatology in General Medicine. 6th ed. New York: McGraw-Hill, Medical Pub. Division, 2003. 3. van de Kerkhof PCM. Textbook of Psoriasis. 2nd ed. Malden: Blackwell Science, 2003. 4. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin 1996; 14(3):485–496.

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5. Stern RS, Nijsten T, Feldman SR, et al. Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc 2004; 9(2):136–139. 6. Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica 1974; 148(1):1–18. 7. Watson W, Cann HM, Farber EM, et al. The genetics of psoriasis. Arch Dermatol 1972; 105(2):197–207. 8. Tiilikainen A, Lassus A, Karvonen J, et al. Psoriasis and HLA-Cw6. Br J Dermatol 1980; 102(2):179–184. 9. Zachariae H, Overgaard Petersen H, Kissmeyer Nielsen F, et al. HLA antigens in pustular psoriasis. Dermatologica 1977; 154(2):73–77. 10. Lever WF, Elder DE. Lever’s Histopathology of the Skin. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005. 11. Kirby B, Richards HL, Woo P, et al. Physical and psychologic measures are necessary to assess overall psoriasis severity. J Am Acad Dermatol 2001; 45(1):72–76. 12. Fortune DG, Richards HL, Grifﬁths CE, et al. Psychological stress, distress and disability in patients with psoriasis: consensus and variation in the contribution of illness perceptions, coping and alexithymia. Br J Clin Psychol 2002; 41(Pt 2):157–174. 13. Choi J, Koo JY. Quality of life issues in psoriasis. J Am Acad Dermatol 2003; 49(suppl 2):S57–S61. 14. Gupta MA, Gupta AK. Psoriasis and sex: a study of moderately to severely affected patients. Int J Dermatol 1997; 36(4):259–262. 15. Yosipovitch G, Tang MB. Practical management of psoriasis in the elderly: epidemiology, clinical aspects, quality of life, patient education and treatment options. Drugs Aging 2002; 19(11):847–863. 16. Pauluzzi P, Boccucci N. Inverse psoriasis induced by terbinaﬁne. Acta Derm Venereol 1999; 79(5):389. 17. Gilleaudeau P, Vallat VP, Carter DM, et al. Angiotensin-converting enzyme inhibitors as possible exacerbating drugs in psoriasis. J Am Acad Dermatol 1993; 28(3):490–492. 18. Flytstrom I, Bergbrant IM, Brared J, et al. Microorganisms in intertriginous psoriasis: no evidence of Candida. Acta Derm Venereol 2003; 83(2):121–123. 19. Wolverton SE. Comprehensive Dermatologic Drug Therapy. Philadelphia: Saunders, 2001. 20. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and phototherapy. J Am Acad Dermatol 2001; 45(4):487–498; Quiz 499–502. 21. Lebwohl M, Ting PT, Koo JY. Psoriasis treatment: traditional therapy. Ann Rheum Dis 2005; 64(suppl 2):ii83–ii86. 22. Lebwohl MG, Tan MH, Meador SL, et al. Limited application of ﬂuticasone propionate ointment, 0.005% in patients with psoriasis of the face and intertriginous areas. J Am Acad Dermatol 2001; 44(1):77–82. 23. du Vivier A, Stoughton RB. Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol 1975; 111(5):581–583. 24. Duweb GA, Eldebani S, Alhaddar J. Calcipotriol cream in the treatment of ﬂexural psoriasis. Int J Tissue React 2003; 25(4):127–130.

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25. Bruce S, Epinette WW, Funicella T, et al. Comparative study of calcipotriene (MC 903) ointment and ﬂuocinonide ointment in the treatment of psoriasis. J Am Acad Dermatol 1994; 31(5 Pt 1):755–759. 26. Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halobetasol ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 1998; 39(3):447–450. 27. Kienbaum S, Lehmann P, Ruzicka T. Topical calcipotriol in the treatment of intertriginous psoriasis. Br J Dermatol 1996; 135(4):647–650. 28. Russell S, Young MJ. Hypercalcaemia during treatment of psoriasis with calcipotriol. Br J Dermatol 1994; 130(6):795–796. 29. Duvic M, Nagpal S, Asano AT, et al. Molecular mechanisms of tazarotene action in psoriasis. J Am Acad Dermatol 1997; 37(2 Pt 3):S18–S24. 30. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, for topical therapy of psoriasis: vehicle-controlled study of safety, efﬁcacy, and duration of therapeutic effect. J Am Acad Dermatol 1997; 37(1):85–92. 31. Yamauchi PS, Rizk D, Lowe NJ. Retinoid therapy for psoriasis. Dermatol Clin 2004; 22(4):467–476. 32. Reynolds NJ, Al-Daraji WI. Calcineurin inhibitors and sirolimus: mechanisms of action and applications in dermatology. Clin Exp Dermatol 2002; 27(7): 555–561. 33. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study. Arch Dermatol 1998; 134(9):1101–1102. 34. Lebwohl M, Freeman AK, Chapman MS, et al. Tacrolimus ointment is effective for facial and intertriginous psoriasis. J Am Acad Dermatol 2004; 51(5):723–730. 35. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol 2004; 51(5):731–738. 36. Gupta AK, Adamiak A, Chow M. Tacrolimus: a review of its use for the management of dermatoses. J Eur Acad Dermatol Venereol 2002; 16(2):100–114. 37. Gupta AK, Chow M. Pimecrolimus: a review. J Eur Acad Dermatol Venereol 2003; 17(5):493–503. 38. Ashcroft DM, Dimmock P, Garside R, et al. Efﬁcacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: metaanalysis of randomised controlled trials. BMJ 2005; 330(7490):516. 39. Siddiqui MA, Sullivan S, al-Mofadhi AM. Lymphomatoid papulosis and FK 506. Int J Dermatol 1997; 36(3):202–205. 40. Jain AB, Yee LD, Nalesnik MA, et al. Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic end result data. Transplantation 1998; 66(9):1193–1200. 41. Langeland T, Engh V. Topical use of tacrolimus and squamous cell carcinoma on the penis. Br J Dermatol 2005; 152(1):183–185. 42. US Food and Drug Administration. FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. 2005. www.fda.gov/cder/ drug/advisory/elidel_protopic.htm. 43. Niwa Y, Terashima T, Sumi H. Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol 2003; 149(5):960–967.

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44. Weischer M, Blum A, Eberhard F, et al. No evidence for increased skin cancer risk in psoriasis patients treated with broadband or narrowband UVB phototherapy: a ﬁrst retrospective study. Acta Derm Venereol 2004; 84(5):370–374. 45. Gordon PM, Diffey BL, Matthews JN, et al. A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis. J Am Acad Dermatol 1999; 41(5 Pt 1):728–732. 46. Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol 1998; 134(12):1582–1585. 47. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA follow-up study. N Engl J Med 1997; 336(15):1041–1045. 48. Mafong EA, Friedman PM, Kauvar AN, et al. Treatment of inverse psoriasis with the 308 nm excimer laser. Dermatol Surg 2002; 28(6):530–532. 49. Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am 1997; 23(4):739–755. 50. Roenigk HH Jr., Auerbach R, Maibach H, et al. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol 1998; 38(3):478–485. 51. Naldi L, Grifﬁths CE. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the beneﬁts and risks. Br J Dermatol 2005; 152(4):597–615. 52. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003; 349(7): 658–665. 53. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001; 45(5):649–661; Quiz 662–664. 54. Ho VC. The use of ciclosporin in psoriasis: a clinical review. Br J Dermatol 2004; 150(suppl 67):1–10. 55. 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(3):366–375. 56. Krueger JG. The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002; 46(1):1–23; Quiz 23–26. 57. Kipnis CD, Myers WA, Opeola M, et al. Biologic treatments for psoriasis. J Am Acad Dermatol 2005; 52(4):671–682. 58. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349(21):2014–2022. 59. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol 2003; 139(12):1627–1632; Discussion 1632. 60. Chaudhari U, Romano P, Mulcahy LD, et al. Efﬁcacy and safety of inﬂiximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357(9271):1842–1847. 61. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345(4):248–255. 62. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349(21):2004–2013.

18 Psoriasis of the Nails Maithily A. Nandedkar-Thomas Professional Dermatology Care, PC, Reston, Virginia, U.S.A.

Richard K. Scher Department of Dermatology, Columbia University Medical Center, New York, New York, 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 seven 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. Nearly 90% of patients who develop psoriatic arthritis will have nail changes as the ﬁrst external indicator of joint disease. 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). 221

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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 their toenails under the safety of socks (7). This is especially true in patients who have concomitant onychomycosis due to psoriasisinduced nail injury (8). The various manifestations of nail psoriasis and its associations and mimics, as well as objective means of measuring nail alterations will be discussed in this chapter. 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) (9). The largest portion of the nail unit is the nail plate, which is derived from the nail matrix that 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

Figure 1 The nail unit.

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component of the nail unit is the distal phalanx beneath the nail structures. Changes in this joint element become evident as psoriatic arthritis (10). Alterations in nail unit organization occur in a limited number of sites: nail matrix, nail bed, proximal nail fold, and hyponychium (Table 1) (2,10). 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 (11). 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 buildup of parakeratotic proximal matrix cells pressing against the dorsal nail plate (10). Zaias’ landmark study demonstrated that as the nail plate grows out, the poorly adherent parakeratotic cells desquamate from the surface of the nail plate, leaving an indentation as clinical evidence of their former activity (10,12). 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 (10). Interestingly, nail pitting is infrequently seen on toenails (13). 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 toward 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. 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 trauma than ﬁngernails (10). However, the exact cause has yet to be elucidated. Beau’s lines are horizontal indentations in the nail plate due to temporary arrest of matrix growth during a period of inﬂammation (10). Onychomadesis is due to severe disease leading to separation of the nail plate from the proximal nail fold (10). Trachyonychia is due to proximal matrix disease that manifests as roughened or ‘‘sandpaper’’ nails (14). 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 (10). Red spots in the lunula are seen when the distal matrix is affected (2). When the nail bed alone is affected then ‘‘oil spots,’’ nail bed hyperkeratosis,

Nail bed, mid-distal matrix

Morphology due to pathologic change: Pitting—deep, Leukonychia irregular Red spots in the indentations in lunula the nail plate Crumbling (all Beau’s lines matrix) Onychomadesis Trachyonychia Crumbling (due to total matrix involvement for a long duration)

Nail matrix, proximal involvement Oil spots Hyperkeratosis Splinter hemorrhages

Nail bed only Onycholysis due to distal separation of the two structures progressing proximally

Nail bed and plate

Nail unit psoriasis location

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

Nail bed and hyponychium

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

Chronic paronychia Splinter hemorrhages Silvery classic plaques

Proximal nail fold

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Figure 2 (See color insert) Pitting in nail psoriasis. Source: Courtesy of Maithily Nandedkar-Thomas.

and splinter hemorrhages are common (15,16). Oil spots, also known as ‘‘salmon patches,’’ refer to a yellow-orange discoloration due to psoriasis of the nail bed (Fig. 3) (17). 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 toward the matrix. The plate appears whitish rather than yellow because air becomes trapped underneath it. It is usually surrounded by a reddish hue (10) and is distinguished from true leukonychia by location. Leukonychia is usually seen on the proximal

Figure 3 (See color insert) Oil spot in nail psoriasis. Source: Courtesy of Maithily Nandedkar-Thomas.

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Figure 4 (See color insert) Onycholysis in nail psoriasis. Source: Courtesy of Maithily Nandedkar-Thomas.

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 (10). Proximal nail fold plaques are marked by classic cutaneous psoriasis with silvery scales over a red base (2). This may appear as chronic paronychia (11). Nail bed psoriasis in conjunction with hyponychial involvement leads to subungual hyperkeratosis and ultimately crumbling of the nail plate (18). While there are numerous manifestations of nail psoriasis, very few are characteristic of psoriasis alone. The classic oil spot is the most diagnostic lesion, followed by random ﬁngernail pitting and subungual hyperkeratosis, respectively (12,17). 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 (19). 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 (13). Unfortunately, despite several treatment options described in the literature, successful eradication of the disorder prior to anonychia and scarring remains poor (20). ASSOCIATION WITH PSORIATIC ARTHRITIS The most common signs of ﬁngernail psoriasis are oil spots and pitting, with subungual hyperkeratosis being the most common sign associated with psoriatic

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arthritis (21). While subungual hyperkeratosis is also the most common form of toenail psoriasis, it is less often associated with arthritis. Many studies have established that patients with psoriatic distal interphalangeal (DIP) joint disease are highly likely to have associated psoriatic nail changes in the same digit (22,23). One study has also suggested that extent and duration of nail disease correlates with the severity of DIP joint disease. 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 (24). DIP joint inﬂammation is not the only form of psoriatic arthritis. Moll and Wright (25) originally classiﬁed psoriatic arthritis into ﬁve types based on clinical features. Type I refers to primarily 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 usually presents with ankylosing spondylitis. Of all the psoriatic arthritis types, this one has the least association with nail disease. The major distinguishing characteristic of psoriatic arthritis 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 (26). Enthesopathy speciﬁcally refers to inﬂammation occurring at the attachment site of tendons and ligaments to bone. Symptoms include joint pain, stiffness, and enthesitis with swelling at the tendon insertion points leading to ‘‘sausage digits’’ and joint deformation (27). It is classiﬁed as a seronegative, inﬂammatory arthropathy, meaning rheumatoid factor is usually negative. Much like cutaneous psoriasis, it waxes and wanes unpredictably (28). A recent study sought to determine if psoriatic nail alteration can be used as an independent predictor of psoriatic arthritis, regardless of the type (29). 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 directly correlated with the severity of the enthesitis and skin psoriasis. The arthritis also tended to be progressive and unremitting in those patients. However, dactylitis and axial disease was not associated with nail disease. In fact, the lesser the nail involvement, the more likely the patient was to have the human leukocyte

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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 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.

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

HLA-Cw6 negative

HLA-B13 and HLA-B57 (B17)

Stronger association with dystrophic nails than if Cw6 positive

If more severe skin disease, then joint or nail disease

antigen (HLA)-B27 genetic haplotype, which is associated with axial rather than DIP joint disease (28). 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) (28,30,31). However, genetic factors alone cannot account for the occurrence of psoriasis. Environmental and immunologic factors most certainly play a role in its inception. The simultaneous onset of skin and joint disease has been correlated with an increased frequency of disease eruptions (3). Although nail changes can be evident, the severity and extent of scalp involvement has been found to be an even better marker for psoriatic arthritis (3). Apparently, worsening of scalp psoriasis is directly correlated with an increase in the number of deformed and swollen joints, sausage digits, and DIP alterations. Therefore, while nail disease may forecast joint disease on the concomitantly affected digit, it is not likely to be the best predictor of psoriatic arthritis in other joints. NAIL PSORIASIS: CHILDHOOD VS. ADULT ONSET Characterizations of childhood psoriasis versus adult psoriasis are numerous and varied. A recent Asian study examining the epidemiology of childhood psoriasis in 419 patients found that boys tend to develop psoriasis at an earlier age than girls (32). Inﬂammatory nail changes were found in 31% of patients, with pitting being the most common ﬁnding, followed by ridging and discoloration. Interestingly, 2.3% of patients presented with nail disease as the initial

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presentation of their psoriasis. Various studies from around the world have had conﬂicting ﬁndings (33,34). This is likely based on varying genetic haplotypes and immunosusceptibility patterns to infectious disease that predispose to the development of psoriasis (35). A Denmark study found a female preponderance with childhood onset psoriasis (36). An Australian study found that the mean onset of psoriasis in children was less than ﬁve years of age, whereas most studies note onset to be between the ages of 5 and 14 (32–37). However, despite some contradictory data, certain generalities may be made regarding childhood versus adult onset nail psoriasis. When a familial history of psoriasis is found in association with juvenile-onset psoriasis, the disease course is inevitably more severe, more strongly associated with psoriatic arthritis, and more likely to display nail changes (6,38,39). Most patients, regardless of gender, develop psoriasis after the age of 20 (40). When childhood onset of nail psoriasis occurs, it is commonly precipitated by trauma or infectious disease (32,36,41). Also, the later the onset of cutaneous psoriasis, the less often concomitant ﬁngernail or toenail psoriasis occurs. This is especially true for toenail psoriasis (42). Although rare, when a child presents with nail alteration as the sole manifestation of psoriasis, an evaluation for juvenile psoriatic arthritis should be considered (43).

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. For this reason, it is prudent to perform a potassium hydroxide (KOH) wet mount, culture, or nail clipping for a periodic-acid–Schiff stain to ensure that 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 (44,45). This is often difﬁcult to eradicate. It is especially true if the superimposed infection is due to molds rather than dermatophytes (45). 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 or nail cosmetics (46,47). Like most diagnostic dilemmas, a thorough history and examination usually help to ascertain the correct diagnosis.

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Drug Reactions These are often seen in patients taking antibiotics such as minocycline or other phototoxic drugs (48). However, drug-induced onycholysis may occur with no associated cutaneous photosensitivity. Beau’s lines and onychomadesis are the most common abnormalities associated with drug reactions (49). When they are also associated with onycholysis, the clinical picture can clearly mimic psoriasis (50). 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. Linear Verrucous Epidermal Nevus Linear psoriasis is a rare entity whose existence has been questioned (51). 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 (52,53). Biopsy alone may not conﬁrm the diagnosis because histological features may overlap (54,55). 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 (56). 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 (57). 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 (11). Squamous Cell Carcinoma Albeit rare, there have been reports of squamous cell carcinoma (SCC) arising in psoriatic nails (58–60). There is only one report of SCC arising in a psoriatic nail bed (50). Interestingly, this man had an exophytic verrucous plaque arising from a psoriatic thumbnail that became progressively larger

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over a four-month period. Finally, pain prompted the patient to report it to the physician. Because it had progressed substantially, the terminal phalanx required amputation. Histological exam 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 There are numerous excellent textbooks that describe the appropriate method for punch biopsy of the nail bed versus the nail matrix (2,61–64). 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 nail abnormality. On occasion, both the nail bed and the matrix require biopsy simultaneously. In this case a longitudinal biopsy may be appropriate (65). 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 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 (66). 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 least complex (67). TREATMENT OPTIONS AND COMPLICATIONS FROM THERAPY There are numerous treatments for nail psoriasis. The drugs 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.

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Table 3 NAPSI Scoring System NAPSI scoring systema

Nail matrixb

0

None

None

0

1

Present in 1 quadrant

Present in 1 quadrant

Possible points: 1 or 2 Enter score:

2

Present in 2 quadrants

Present in 2 quadrants

Possible points: 2 or 4 Enter score:

3

Present in 3 quadrants

Present in 3 quadrants

Possible points: 3 or 6 Enter score:

4

Present in 4 quadrants

Present in 4 quadrants

Possible points: 4 or 8 Enter score:

Nail bedc

Total scored

a

For each nail, score the points as shown in the column. This 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 zero and a maximum of eight points awarded for each nail: four possible points for evidence of matrix disease and four possible points for evidence of nail bed disease. Abbreviation: NAPSI, nail psoriasis severity index. b

Steroids and Steroid-Like Drugs The high-potency topical steroids are likely the most utilized form of therapy for nail psoriasis. Although they are relatively inexpensive and readily available, tachyphylaxis occurs with prolonged use. The most effective of all steroids for nail matrix psoriasis appears to be the triamcinolone acetonide (2.5 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 (68). However, in our experience dilution of the triamcinolone acetonide with 1% lidocaine and application of anesthetic refrigerant spray prior to rapid injection minimizes patient discomfort and increases tolerability. Both authors utilize this technique on Table 4 NAPSI Scoring Table Nail scoring table—compile the score for each nail Nail 1________ Nail 2________ Nail 3________ Nail 5________ Nail 6________ Nail 7________ Nail 9________ Nail 10________ Final score total:_______________ Note: Minimum score is zero and maximum score is 80. Abbreviation: NAPSI, nail psoriasis severity index.

Nail 4________ Nail 8________

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a routine basis for psoriatic nails with good results. The major complications from this therapy are hemorrhage under the nail plate and steroidinduced atrophy of the skin and subcutaneous tissues (2,69). However, in our experience, careful injection at the inﬂammatory psoriatic site with small amounts 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 (DovonexTM) 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 (70). They appear to be just as effective in decreasing hyperkeratosis. However, the ideal use of calcipotriene appears to be in combination with other oral agents such as cyclosporine or even topical steroids (71,72). Combination therapies seem to be more effective at producing clinical improvement in nail psoriasis. 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 (73–75), 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-a) or T cells. TNF-a is required for cell-mediated inﬂammation (76). The key cell in the inﬂammatory milieu is the activated T cell (77). The induction of both cytokines is a normal host response required for the inﬂammatory cascade to occur. TNF-a overproduction and subsequent activation of T cells lead to pathologic disease states (76). Thus, the rationale for use of some of these therapies is that they are designed to diminish TNF-a, which, in turn, appears to decrease the inﬂammatory, destructive component of psoriasis resulting in clinical improvement in disease. They can be loosely grouped as TNF-a inhibitors (etanercept, adalimumab, and inﬂiximab) and T-cell modulators (alefacept and efalizumab). Etanercept is a TNF-a receptor antibody fusion protein, which acts like a soluble TNF-a receptor that competitively binds TNF-a (78). Thus, the bound TNF-a cannot bind to its native receptor on the target cell. This means that although the TNF-a molecule is still present, it becomes biologically inactive because it is bound to a receptor that impersonates its normal binding companion. Then the TNF-a bound etanercept is metabolized and eliminated via the liver and kidneys. Twice-weekly self-administered subcutaneous (SQ) injections are required initially and then decrease to once weekly. The human monoclonal antibody adalimumab is also SQ injectable, which is self-administered every two weeks (76). Inﬂiximab is a chimeric mouse/human monoclonal antibody that is administered intravenously (IV)

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once every two months (79). Rather than acting as a counterfeit receptor like etanercept, the other two TNF-a inhibitors are antibodies that actually bind circulating TNF-a, thus impairing its ability to bind to its receptor. 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-a, blocking its ability to bind to its receptor and thereby reducing localized inﬂammation (76). Alefacept is a fusion protein that binds to T cells and induces apoptosis. It provides targeted destruction of pathogenic T cells (80). Efalizumab is a human monoclonal antibody that binds to leukocyte function-associated antigen (LFA) on T cells. When LFA is bound, the T cells cannot bind to the intercellular adhesion molecule on the antigen presenting cell. Normally, the interaction of LFA to the intercellular adhesion molecule allows an activated T cell to migrate out of the circulation and into the skin. Thus, efalizumab binds to cluster of differentiation (CD)-11a, which is the alpha subunit of LFA-1. This leads to a sequestration of pathogenic T cells in the circulatory system, resulting in less evidence of psoriasis clinically (81). 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. So far, there are only three reports of nail psoriasis improvement using the biologic agents. Two are for alefacept and the other is for inﬂiximab (82–84). Given the mechanism of action of the biologic agents, improvement in nail psoriasis is a highly probable consequence with increased use. In one author’s experience (M.N.T.), etanercept appears to improve the amount of pitting present but does not alter oil spots. Alefacept appears to have no effect at all. The same author has treated multiple patients with alefacept and has seen remarkable clearing of all cutaneous plaques. Clinically, there is usually no remaining evidence that these patients ever had psoriasis except for the isolated persistent nail psoriasis. Of all the biologics, etanercept may be very effective for nail psoriasis, as it is the only agent speciﬁcally designed to prevent joint destruction, which is anatomically adjacent to the nail unit. Thus, it is not surprising that this agent appears to have improved psoriatic nails. However, this is anecdotal evidence. Clearly, more studies are required to ascertain whether biologic agents are effective for nail psoriasis and which ones. Retinoids Tazarotene 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-gamma is the predominate type of RAR in the epidermis (85). Topical tazarotene impairs keratinocyte proliferation and inﬂammation, which may be one of the mechanisms for

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onycholysis. One study from Columbia University demonstrated that tazarotene under occlusion appears to reduce onycholysis and also improve the appearance of pitting (86). A subsequent study has conﬁrmed this ﬁnding (87). Both studies found that the drug was well tolerated; repeated use caused minimal irritation. Acitretin and isotretinoin are systemic retinoids that are more effective when combined with phototherapy, either ultraviolet B (UVB) or psoralen and ultraviolet A (PUVA) (88,89). Acitretin is the treatment of choice for pustular psoriasis but is less effective against plaque psoriasis (90). There is one report of near total clearance of severe nail psoriasis with acitretin (91). While this report shows impressive results, it is not the best choice for isolated nail psoriasis given the systemic side effects such as hyperlipidemia and hyperostosis, and the localized side effects such as oral xerosis and periungual pyogenic granulomas (92). One major limitation of both the topical and systemic retinoid is that they are contraindicated in pregnancy. Both are category X. Chemotherapy and Keratolytic Agents Cyclosporine is well established as an effective oral immunosuppressive agent for the treatment of generalized psoriasis as well as nail psoriasis (93,94). However, 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 gastrointestinal (GI) tract that have lipid permeable membranes, the nail plate is actually more of a concentrated hydrogel (94). 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 water-based 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 (95). This method was effective in improving nail psoriasis. The key feature of this study is that an inappropriate vehicle can alter the efﬁcacy of a potentially good drug because it is unable to penetrate the nail plate. The oral form of the drug is pregnancy category C. Numerous studies have shown that daily topical 1% to 5% 5-ﬂuorouracil is effective for the treatment of psoriatic nails (96,97). Fluorouracil is a chemotherapeutic agent that inhibits the enzyme thymidylate synthetase, which leads to a decrease in cellular proliferation. It appears that using the lowdose formulation of the drug in a delayed nail penetration vehicle such as urea and propylene glycol enhances penetration (98). 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 use of topical 5-ﬂuorouracil (99).

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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 is a sulfonamide that is used to treat psoriatic arthritis. There is one case report of improvement in nail psoriasis with its use (100). 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. 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 (101). 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 (102,103). 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. Grenz ray therapy has been used with moderate success to treat psoriatic nails. In a Swedish study, 5 Gy of Grenz rays were applied once a week for 10 weeks (104). 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, and may result in temporary thinning of the nail plate (103). This perhaps could be used as a method for preparing the nails for one of the topical occlusive therapies, but the concern for radiations adverse effects renders 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 that have yet to be studied in full. No doubt the elusive deﬁnitive treatment has yet to be developed. Meanwhile, for isolated nail psoriasis, the best treatment remains simple intralesional corticosteroids.

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63. Krull EA, Zook EG, Baran R, Haneke E. Nail surgery, a text and atlas. New York: Lippincott, Williams and Wilkins, 2000. 64. Scher RK, Daniel CR III. Nails. Diagnosis, therapy, surgery 3rd ed. Philadelphia. Eselvier Saunders. 2005:1–324. 65. Grover C, Khandpur S, Reddy BSN, et al. Longitudinal nail biopsy: utility in 20-nail dystrophy. Dermatol Surg 2003; 29:1125–1129. 66. Rich P, Scher RK. Nail psoriasis severity index: a useful tool for evaluation of nail psoriasis. J Am Acad Dermatol 2003; 49(2):206–212. 67. Baran RL. A nail psoriasis severity index. Br J Dermatol 2004; 150:568–569. 68. DeBerker DAR, Lawrence CM. A simpliﬁed protocol of steroid injection for psoriatic nail dystrophy. Br J Dermatol 1998; 138:90–95. 69. Deffer TA, Goette K. Distal phalangeal atrophy secondary to topical steroid therapy. Arch Dermatol 1987; 123:521–522. 70. Tosti A, Piraccini BM, Cameli N, et al. Calcipotriol ointment in nail psoriasis: a controlled double-blind comparison with betamethasone diproprionate and salicylic acid. Br J Dermatol 1998; 139(4):655–659. 71. Feliciani C, Zampetti A, Forleo P, et al. Nail psoriasis: combined therapy with systemic cyclosporine and topical calcipotriol. J Cutan Med Surg 2004; 8(2):122–125. 72. Rigopoulos D, Ioannides D, Prastitis N, et al. Nail psoriasis: a combined treatment using calcipotriol cream and clobetasol proprionate cream. Acta Derm Venereol 2002; 82(2):140. 73. Goedkoop AY, De Rie MA, Picavet DI, et al. Alefacept therapy reduces the effector T-cell population in lesional psoriatic epidermis. Arch Dermatol Res 2004; 295(11):465–473. 74. Weinberg JM. An overview of inﬂiximab, etanercept, efalizumab and alefacept as biologic therapy for psoriasis. Clin Ther 2003; 25(10):2487–2505. 75. Weinberg JM, Saini R, Tutrone WD. Biologic therapy for psoriasis—the ﬁrst wave: inﬂiximab, etanercept, efalizumab, and alefacept. J Drugs Dermatol 2002; 1(3):303–310. 76. Saripalli YV, Gaspari AA. Focus on: biologics that affect therapeutic agents in dermatology. J Drugs Dermatol 2005; 4(2):233–245. 77. Mehlis Sl, Gordon KB. The immunology of psoriasis and biologic immunotherapy. J Am Acad Dermatol 2003; 49:S44–S50. 78. Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol 2003; 49:S105–S111. 79. Gottlieb AB. Inﬂiximab for psoriasis. J Am Acad Dermatol 2003; 49:S112–S117. 80. Krueger GG, Callis KP. Development and use of alefacept to treat psoriasis. J Am Acad Dermatol 2003; 49:S87–S97. 81. Leonardi CL. Efalizumab: an overview. J Am Acad Dermatol 2003; 49: S98–S104. 82. Sobera J, Parrish C, Elewski B. Improvement in nail psoriasis with alefacept. J Am Acad Dermatol 2004; 50:145. 83. Callen JP. Improvement of severe psoriatic nail involvement with alefacept therapy. J Am Acad Dermatol 2004; 50:145. 84. Bianchi l, Bergamin A, de Felice C, et al. Remission and time of resolution of nail psoriasis during inﬂiximab therapy. J Am Acad Dermatol 2005; 52(4):736–737.

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85. Van Laborde S, Scher RK. Developments in the treatment of nail psoriasis, melanonychia striata and onychomycosis. Dermatol Clin 2000; 18(1):37–46. 86. 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. 87. Bianchi L, Soda R, Diluvio L. Tazarotene 0.1% gel for psoriasis of the ﬁngernails and toenails: an open label prospective study. Br J Dermatol 2003; 149(1):207–209. 88. Roenigk RK, Gibstine C, Roenigk HH. Oral isotretinoin followed by psoralens and ultraviolet A or ultraviolet B for psoriasis. J Am Acad Dermatol 1985; 13:153–155. 89. Lebwohl M. Acitretin in combination with UVB or PUVA. J Am Acad Dermatol 1999; 41:S22–S24. 90. Moy RL, Kinston TP, Lowe NJ. Isotretinoin vs. etretinate therapy in generalized pustular and chronic psoriasis. Arch Dermatol 1985; 121:1297–1301. 91. 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. 92. Lebwohl M, Ali S. Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001; 45(5):649–661. 93. 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. 94. Murdan S. Drug delivery to the nail following topical application. Int J Pharm 2002; 236:1–26. 95. Cannavo SP, Guarneri F, Vaccaro M, et al. Treatment of psoriatic nails with topical cyclosporine: a prospective, randomized placebo-controlled study. Dermatol 2003; 206(2):153–156. 96. Schissel DJ, Elston DM. Topical 5-ﬂuorouracil treatment for psoriatic trachyonychia. Cutis 1998; 62(1):27–28. 97. Fredriksson T. Psoriatic nails and 5-ﬂuorouracil. J Am Acad Dermatol 1982; 6(1):117. 98. deJong EM, Menke HE, van Praag MC, et al. Dystrophic psoriatic ﬁngernails treated with 1% 5-ﬂuorouracil in a nail penetration-enhancing vehicle. Dermatology 1999; 199(4):313–318. 99. Schmied E, Levy PM. Transient rhabdomyolysis connected with topical use of 5-ﬂuorouracil in a patient with psoriasis of the nails. Dermatologica 1986; 173(5):257–258. 100. Gerster JC, Hohl D. Nail lesions in psoriatic arthritis: recovery with sulfasalazine treatment. Ann Rheum Dis 2002; 61:277. 101. Yamamoto Y, Katayama I, Nishioka K. Topical anthralin therapy for refractory nail psoriasis. J Dermatol 1998; 25:231–233. 102. Marx JL, Scher RK. Response of psoriatic nails to oral photochemotherapy. Arch Dermatol 1980; 116(9):1023–1024. 103. YU RC, King CM. A double-blind study of superﬁcial radiotherapy in psoriatic nail dystrophy. Acta Derm Venereol 1992; 72(2):134–136. 104. Lindelof B. Psoriasis of the nails treated with Grenz rays: a double blind bilateral trial. Acta Derm Venereol 1989; 69(1):80–82.

19 Summary of Therapeutic Options for Mild-to-Moderate Psoriasis Cindy Berthelot University of Texas Medical School Southwestern, Dallas, Texas, U.S.A.

Jennifer Clay Cather and Alan Menter Division of Dermatology, Baylor University Medical Center, Dallas, Texas, U.S.A.

INTRODUCTION Precise deﬁnitions of mild and moderate psoriasis remain an elusive goal. In general, patients with psoriasis limited to less than 5% body surface area (BSA) with no associated joint disease and little or no impact on their quality of life (QOL) are labeled as mild psoriasis and best managed with topical medications (Fig. 1) (1). Patients with moderate psoriasis have between 2% and 10% of involved BSA, with or without associated arthritis, with some alteration of the patient’s QOL (Fig. 2) (2). These patients frequently require phototherapy and/or systemic therapy in addition to topical therapy. Patients with severe psoriasis generally have greater than 10% BSA involvement, with or without associated arthritis, with a broad impact on health and QOL, and generally will require phototherapy and/or systemic therapy in addition to topical therapy. Psoriasis is a dynamic disease that responds to a wide range of therapies, including topical, light, and systemic therapies, each with varying degrees of success. The primary treatment goals for patients with psoriasis are to reduce the size, thickness, and extent of plaque involvement, prevent progressive joint destruction, and improve QOL (1). Several factors 243

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Figure 1 (See color insert) Localized mild psoriasis.

inﬂuence therapeutic selections for patients with mild-to-moderate psoriasis, including the nature (thick vs. thin plaques), anatomical location, and distribution of the lesions. Corticosteroids are the most frequently used topical therapy for psoriasis in the United States. Additional topical agents used include

Figure 2 (See color insert) Moderate psoriasis.

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calcipotriene, a vitamin D analog, a newly available combination of calcipotriene betamethasone dipropionate, tazarotene, the only retinoid approved for the treatment of psoriasis, derivatives of coal tar, and anthralin (Table 1). Each has varying degrees of effectiveness for mild-to-moderate psoriasis with unique safety and tolerability proﬁles. The majority of patients with psoriasis presenting to dermatologists have used a variety of topical medications in an attempt to limit the physical (itching, burning, redness, and scaling) and emotional impact of their disease. Certain patients with what may be considered mild disease by deﬁnition (< 5% BSA) are so anxious about the physical and emotional aspects of their limited disease, e.g., scalp, hands, and/or feet, that systemic treatment may be considered. Patient preference must also be considered, as some therapies are cosmetically unappealing, time consuming, and can stain skin, clothing, and bed linens. Hence, education of patients relating to the nuances of topical therapy, e.g., frequency, application techniques, and amount of drug required per body surface unit, is essential. Ultimately, treatment selection for each patient must take into account the patient’s disease severity, expectations for improvement, pregnancy consideration, and the risk–beneﬁt ratio associated with each potential topical, phototherapy, and systemic therapy. A summary of therapeutic options for the treatment of mild-tomoderate psoriasis will be presented based on our cumulative experiences in running a tertiary referral clinical and research psoriasis unit.

TOPICAL THERAPIES Corticosteroids Topical corticosteroids account for the vast majority of prescriptions written by dermatologists and primary care physicians for mild-to-moderate psoriasis. These agents act on nuclear hormone receptors to exert their antiinﬂammatory, antiproliferative, and immunosuppressive properties. Clinical efﬁcacy, which correlates to the Stoughton–Cornell classiﬁcation (an assay of a corticosteroid’s ability to cause vasoconstriction) is dictated by the potency of a particular molecule and the delivery vehicle (3). Steroid potencies range from class VII corticosteroids (weakest agents), including over the counter 1% hydrocortisone, to superpotent class I corticosteroids (strongest agents). Topical steroids are available in several vehicles, including lotions, creams, solutions, emollients, ointments, gels, sprays, and steroid-impregnated tapes (3). Application under occlusive surgical-type dressings, Unna Boot, or Saran Wrap1 maximizes potency of topical steroids (Figs. 3 and 4) (4). Novel delivery systems, such as the foam preparations of betamethasone valerate 0.1% and spray and shampoo formulations of clobetasol propionate 0.05%, may be associated with increased patient compliance (5).

Topical nuclear hormone receptor

Topical vitamin D analog Topical vitamin A derivative

Topical

Topical

Corticosteroid

Calcipotriene

Tazarotene

Anthralin

Coal tar

Regulator of cell differentiation and inhibitor of proliferation in keratinocytes Normalization of abnormal keratinocyte differentiation, reduces keratinocyte proliferation, and reduces inﬂammation Possible inhibition of DNA synthesis and proliferation, generation of free radicals, alter EGF receptor pathway, alter mitochondrial respiratory function Antipruritic, antibacterial, inhibits inappropriate epidermal proliferation

Hydration, softening, epidermal barrier Aids in exfoliation, improves absorption of other therapies Anti-inﬂammatory, antiproliferative, and immunosuppressive

Purpose

Abbreviations: HPA, hypothalamic–pituitary–adrenal; EGF, epidermal growth factor.

Topical Topical

Category

Emollients Keratolytics

Treatment

Table 1 Topical Treatments for Psoriasis

Irritation, acneiform eruptions, folliculitis

Irritation, staining

Irritation

Atrophy, striae, acne telangiectasias, rebound phenomenon, perioral dermatitis, tachyphylaxis, HPA axis suppression Irritation, potential hypercalcemia

None Salicylate toxicity

Adverse events

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Figure 3 (See color insert) Application of topical corticosteroid under Saran Wrap1 occlusion.

Class I corticosteroids are highly effective, with 75% of patients with localized plaque psoriasis achieving 75% improvement (6). Continuous application may, however, induce tachyphylaxis, a phenomenon whereby medications lose their efﬁcacy with prolonged use; however, a recent study has questioned this issue (7,8). A novel maintenance regimen involving the use of a less potent ointment application once daily for two consecutive days each week after an initial two-week treatment period maintained the improvement of psoriatic lesions for up to 10 weeks (9). A ‘‘weekend’’ or ‘‘pulse therapy’’ regimen developed to prevent cutaneous and systemic side

Figure 4 (See color insert) Lewis technique.

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effects uses a class I ointment applied three times over a 24-hour period each week with improvement of psoriasis maintained for up to six months in 60% of patients (10). Intermittent pulse dosing on the weekends or two consecutive days can be used to maintain response, either as monotherapy or in combination with nonsteroidal preparations used ﬁve days a week (11,12). Anatomical Considerations It is important to recognize that different regions of the body require varying steroid potencies to avoid cutaneous side effects, especially atrophy in areas of thin skin (e.g., ﬂexures) (Table 2). Safety Safety concerns are related predominately to local toxicity seen with improper use, for example using a class I preparation on a thin skin site, or overly prolonged duration of therapy. Side effects of topical corticosteroids, especially those of the superpotent category, include cutaneous atrophy, the development of striae, scar extension, formation of telangiectasias, acne/ folliculitis, and perioral dermatitis (Figs. 5 and 6) (13). While hypothalamic– pituitary–adrenal (HPA) axis suppression can occur with prolonged use of excessive amounts of topical corticosteroids, this is seldom an issue if the total weekly dosage limit does not exceed 50 g in an adult (3). Other manifestations of local toxicity may include hypopigmentation, especially in patients with skin types 3 and above, and masking of skin infections like tinea incognito (Fig. 7) (14). In addition, a rebound phenomenon may occur after discontinuation of prolonged use of topical corticosteroids (15,16). A ﬁnger-tip unit (FTU) is a practical and simple measure for patients to understand (Table 3). This unit is the amount of ointment expressed from a tube with a 5-mm diameter nozzle, applied from the distal skin crease to the tip of the index ﬁnger (17).

Table 2 Anatomical Considerations for Corticosteroid Application Anatomical area Face, intertriginous, and genital areas Thicker skin (elbow, knees, back) Scalp Extremities Palmar-plantar

Treatment options Class VI or VII corticosteroid, tacrolimus or pimecrolimus, topical antifungals High-potency corticosteroids with or without vitamin D3 or A preparations Gel, foam, shampoo, topical or intralesional corticosteroids, anthralin, tar, salicylic acid, or vitamin D3 Class I or II corticosteroid in an ointment, spray, or foam vehicle with or without occlusion Class I or II corticosteroids with or without occlusion

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Figure 5 (See color insert) Perioral dermatitis secondary to topical corticosteroid application.

Vitamin D Analogs Calcipotriene, also known as calcipotriol, is a synthetic vitamin D3 analog. Both calcipotriene and calcitriol (the biologically active form of vitamin D) act on nuclear hormone receptors to regulate cellular differentiation. However, calcipotriene has 100 to 200 times less effect on calcium metabolism when compared to calcitriol, and is thus far less likely to produce hypercalcemia (7). Calcipotriene can be combined with other treatment modalities to provide more rapid clearance of disease with potential dose-sparing effects. Calcipotriol ointment has comparable or slightly better efﬁcacy than class II corticosteroid ointments for the treatment of psoriasis (18). While less effective than superpotent corticosteroids, regimens utilizing a combination of calcipotriene and a class I corticosteroid have demonstrated greater effectiveness over each agent alone (19,20). Currently, corticosteroids are used

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Figure 6 Striae due to topical corticosteroid application.

in an induction regimen (twice a day for two weeks), due to their faster onset of action, followed by maintenance therapy with calcipotriene on the weekdays and corticosteroid on the weekends (19,20). In trials that compared calcipotriene and anthralin, calcipotriene was preferred by patients because of less staining, less irritation, and also improved QOL issues (21). The combination of calcipotriene and other therapeutic modalities have also been shown to be beneﬁcial. Two studies have shown greater clearing with the combination of calcipotriene and ultraviolet B (UVB) than with monotherapy with either treatment (22,23). This combination results in fewer UVB exposures and a lower cumulative dose, suggesting that patients may be able to achieve lesion clearing with less frequent UVB treatments. A recent study showed that the combination of the two were more effective in reducing the psoriasis area and severity index (PASI) early on in treatment, than narrow-band UVB (NB-UVB) alone (24,25). Combination therapy with calcipotriene and psoralen and ultraviolet A (PUVA) has also been shown to be beneﬁcial (26). A calcipotriol/betamethasone dipropionate combination is available in Europe and has recently been approved for use in the United States. In clinical trials, patients with a mean baseline PASI of 9.5 to 10.9 experienced a mean 65% to 74.4% PASI improvement within four weeks utilizing this combination preparation on a once daily basis signiﬁcantly better than placebo (27). Safety Regular twice-daily application of topical calcipotriene for extended periods of time as monotherapy is essential to maintain clinical responsiveness.

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Figure 7 (See color insert) Tinea incognito.

Table 3 The Number of FTU Required for Different Areas of the Body Area of body Face and neck Front of trunk Back of trunk Arm and forearm Hand Leg and thigh Foot

Number of FTU 2.5 6.7 6.8 3.3 1.2 5.8 1.8

(s.d. 0.8) (s.d. 1.7) (s.d. 1.2) (s.d. 1.0) (s.d. 0.4) (s.d. 1.7) (s.d. 0.6)

Abbreviations: FTU, ﬁnger-tip unit; s.d., standard deviation.

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If patients use calcipotriene intermittently, they may experience ﬂares of their psoriasis. The most common side effect is lesional or perilesional erythema, scaling, stinging, or burning, noted in up to 20% of patients, especially when used on the face and intertriginous areas (18,19). Reducing the frequency of applications using concomitant topical corticosteroids or diluting calcipotriene with petrolatum has been suggested to reduce the irritation (28,29). While hypercalcemia has been reported in patients who have applied excessive amounts over large surface areas, restricting the application to less than 100 g a week has shown no signiﬁcant alterations in calcium or bone metabolism (30,31). Calcipotriene should not be used where there is an increased risk of systemic absorption, such as in patients with inﬂammatory erythrodermic or pustular forms of psoriasis (7). Calcipotriene is pregnancy category C (safety for use during pregnancy has not been established), not teratogenic, and is not known whether the agent or its metabolite enters breast milk (32,33). The use of calcipotriol has been studied in children, showing a statistically signiﬁcant reduction in the PASI from 6.1 to 2.7 (34). Retinoids Tazarotene is the only retinoid approved for the topical therapy of psoriasis. It selectively binds retinoid receptor subtypes beta and gamma to regulate gene transcription, thereby normalizing keratinocyte differentiation and proliferation (35). The efﬁcacy of tazarotene compared to placebo has been established in randomized, double-blind trials and its therapeutic effects appear to be sustained after the cessation of treatment. In one study, 73% of patients were maintained in remission for at least ﬁve months with a regimen of tazarotene gel 0.1% applied Mondays, Wednesdays, and Fridays, and clobetasol ointment applied Tuesdays and Thursdays (36). Additionally, like calcipotriene, tazarotene avoids the side effects of corticosteroids including atrophy and tachyphylaxis (37). In one clinical study, the combination of calcipotriene and tazarotene was shown to have similar efﬁcacy when compared to clobetasol alone (38). The combination of tazarotene and UVB has also been studied. It is important to note that neither UVB nor UVA inactivates tazarotene, as compared to calcipotriene (39). Patients also responded more favorably when treated with a UVB and tazarotene combination than when treated with UVB alone (40,41). However, as application of tazarotene results in thinning of the stratum corneum, caution must be exercised by reducing the dose of UVB. Safety Tazarotene’s main concern is the development of local irritation, frequently seen in a perilesional distribution in light-skinned individuals (Fig. 8) (42). Numerous strategies have been developed to avoid this ‘‘retinoid dermatitis,’’

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Figure 8 (See color insert) Retinoid dermatitis.

including short contact therapy, intermittent therapy, and combination therapy with topical corticosteroids (3). When tazarotene is used once daily with mometasone furoate 0.1% cream or ﬂuocinonide 0.05% cream, improvement is enhanced and irritation diminished (43). In addition to the synergistic action of these two drugs, tazarotene has also been shown to counteract the atrophogenic effects of corticosteroids. While the 0.1% formulation is more effective than the 0.05%, it is also associated with a potential for irritation (44). Tazarotene should be used sparingly with a pea-sized amount generally sufﬁcient for a lesion of psoriasis the size of a palm (1% BSA) and the patients should be advised to anticipate a transient (four weeks) mild increase in erythema. Tazarotene is contraindicated in pregnancy (pregnancy class X). Following topical application of tazarotene gel or cream to the skin, systemic absorption of the active metabolite and the parent drug is negligible, provided the drug is used sparingly on less than 20% of the body surface area (44,45). The plasma elimination half-life of the drug is 15 to 17 hours and there is no systemic accumulation of the drug following multiple topical applications; therefore, if any were absorbed, we advise a two-week washout prior to pregnancy (46). Immunomodulators Tacrolimus and pimecrolimus are calcineurin inhibitors functioning as immunosuppressants and both are approved by the U.S. Food and Drug Administration for the treatment of atopic dermatitis (47). While topical corticosteroids are frequently utilized for psoriasis in the intertriginous

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and facial areas, their side effects may mitigate use in these areas. Topical tacrolimus offers the potential for an anti-inﬂammatory effect, while avoiding the atrophy and acneiform eruptions commonly associated with the use of topical corticosteroids (48). Several studies have shown the beneﬁts of tacrolimus for facial and intertriginous psoriasis (49,50). One study showed excellent improvement at the end of an eight-week treatment period, with 65.2% of the tacrolimus ointment group, versus 31.5% of the vehicle group, giving a clear or almost clear response (50). Adverse events were similar in the 0.1% tacrolimus ointment and vehicle groups. In a study of pimecrolimus in 57 patients with moderate to severe inverse psoriasis, 54% of the pimecrolimus group versus 21% of the placebo group had an Investigator’s Global Assessment score of 0 or 1 (clear or almost clear) at week 2 (51). By week 8, 71% of the pimecrolimus group had an Investigator’s Global Assessment score of 0 or 1. Pimecrolimus was safe and well-tolerated, with adverse events similar between groups. Topical tacrolimus and pimecrolimus are ineffective for standard plaque psoriasis. Safety Recently, concern has been raised due to the development of tumors associated with these agents. Nine cases of tumor adverse events and 21 cases of tumor adverse events with pimecrolimus and tacrolimus, respectively, have been reported to the U.S. Food and Drug Administration’s Adverse Event Reporting System (52). Although systemic tacrolimus used during pregnancy may result in fetal malformations and preterm deliveries, the bioavailability of topical tacrolimus is less than 5% of the orally administered form, making the potential for tumors with standard topical therapy extremely low indeed (53–55). Both topical and systemic tacrolimus preparations are pregnancy category C (56). Coal Tar This agent is messy, malodorous, and stains clothing and other fabrics, leading to poor patient compliance despite being inexpensive. Liquor carbonis detergens is better tolerated and may be compounded in various vehicles (57). We frequently use 10% to 20% liquor carbonis detergens with one-fourth strength betamethasone valerate in a hydrophilic emollient base at night for thin plaque psoriasis or as an adjunct to phototherapy. It is important to instruct patient not to apply tar preparations prior to their phototherapy to avoid ‘‘tar smarts.’’ Safety From a safety standpoint, skin irritation, acneiform eruptions, and folliculitis are common. The carcinogenicity of coal tar has clearly been

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demonstrated by in vitro and animal studies, and appears to be potentiated by concomitant use of UV radiation (58). In addition, cases of skin cancer have been linked with coal tar use, especially on the genitalia (59). Tar preparations are frequently used by dermatologists as shampoos for the treatment of scalp psoriasis. In addition, a vast array of over-the-counter tar-containing products are advertised and still used by psoriasis patients. Coal tar is safe to apply during pregnancy (pregnancy class A), and a retrospective study of 23 pregnant patients during which the dermatological use of tar was clear was not associated with any adverse outcomes (60). Anthralin Anthralin, or dithranol, has historically been used as part of the Ingram regimen (daily coal-tar bath, UVB, followed by application of an anthralin– salicylic acid paste) (3). Anthralin, like coal tar, commonly causes irritation, and also has a signiﬁcant problem with the staining of skin, fabric, and bathroom tile, and therefore it has largely been abandoned outside of phototherapy and outpatient regimens. Short contact regimens (minutes to 1–2 hours) and more cosmetically acceptable formulations are used in the outpatient setting as monotherapy or in combination with other agents to reduce these side effects. Short contact anthralin therapy, using concentrations of 1% or greater, entail application of ﬁve minutes on the ﬁrst day and then increasing by ﬁve minutes every other day until minimal irritation develops, after which the period of application is maintained until clearing (61). Staining of the skin and irritation may be lessened by application of triethanolamine before removal of the anthralin (62). Micanol1 is a 1% anthralin formulation in a temperature-sensitive vehicle that releases active medication at skin surface temperature (63). It is possibly more acceptable to patients because staining of household fabrics and furniture is minimized. Studies have demonstrated efﬁcacy of Micanol1 in shortand long-term regimens, as well as utility in scalp psoriasis refractory to other treatments. Safety Anthralin should be used with care because of potential for irritation and staining. Thus, it must be applied only to plaques and not to surrounding normal skin, as irritation and staining of the skin may develop. Anthralin is pregnancy category C and no reproduction studies, human or animal, or reports of adverse fetal effects have been published (59). While studies have shown that anthralins is a tumor promoter producing transient changes in the growth or differentiation of the epidermis, no signiﬁcant increase in pre-malignant or malignant skin tumors have been noted in over 50 years of usage (64).

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Emollients and Keratolytics These agents are recommended as concomitant therapy for the treatment of psoriasis. Hydration of the dysfunctional epidermal barrier helps decrease erythema, pruritus, and scaling within lesions (65). In general, while ointments are the most effective, patient preference and compliance is better with less greasy emollient bases (66). In addition, in certain body areas (e.g., legs) and patient populations (e.g., elderly), emollients should be used as an adjunct to topical steroid usage, especially after bathing. The only combination keratolytic creams commercially available in the United States are lactic acid/urea based (67). Outside the United States, a combination of 0.05% betamethasone dipropionate ointment and 3% salicylic acid is available (68). Salicylate-containing preparations should not be applied before light therapy given their photoprotective effects. We usually limit the use of these products for hands, feet, elbows, and knees to aid in exfoliation on the penetration of concomitant topical agents. Safety While keratolytics containing salicylic acid are generally regarded as safe, their use should be limited to less than 20% BSA to avoid salicylate toxicity, classically characterized by tinnitus, dizziness, gastrointestinal distress, and psychiatric disturbances (69). Keratolytics are pregnancy class C (safety for use during pregnancy has not been established) and application to the face, genitalia, and eyes should be avoided (70). PHOTOTHERAPY Although the majority of patients with mild-to-moderate psoriasis are treated successfully with topical agents, some may also require phototherapy. Because of its efﬁcacy and safety proﬁle, UVB continues to have widespread use in spite of the development of newer treatment modalities for psoriasis. Studies have shown that UVB in conjunction with other treatment modalities shows additional beneﬁts, and results in lesion clearing with less frequent UVB radiation treatments. UVB therapy with a lubricating base results in shorter treatment periods, which means the surrounding skin will be exposed to smaller doses of UVB, with a diminished risk of actinic damage (71). UVB combination with tazarotene 0.1% gel may be more beneﬁcial than UVB alone (40,41). Similarly, the addition of calcipotriene to UVB results in lesion clearing with less frequent UVB radiation treatments (22,23). UVB phototherapy combined with topical corticosteroids has shown no dose-sparing effect or therapeutic advantage, and may even shorten remission time. The use of broadband UVB has diminished in recent years with the introduction and widespread availability of narrow-band UVB, which has a quicker and more sustained onset of action. The excimer

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laser is a beam of 308 nm light and has been successfully used to treat localized plaques of psoriasis (‘‘targeted phototherapy’’), including those on the palms and soles (72). PUVA therapy is considered more durable than UVB, with some patients even achieving long-term remission without maintenance therapy. Methoxsalen is pregnancy category C and should be given to pregnant females only in cases where it is clearly needed. Because PUVA is mutagenic and induces sister chromatid exchanges, it should be considered a potential teratogen and women at risk of becoming pregnant who are treated with PUVA should consider using contraception (73).

SUMMARY Biologic systemic therapies for psoriasis have dominated the literature, meetings, and marketing efforts over the past three years. However, topical therapy is likely to remain an essential form of therapy for the majority of psoriasis patients, either as monotherapy for patients with limited disease, or as an adjunctive therapy to phototherapy and systemic agents for more severe psoriasis. While writing a prescription for a single topical preparation, or combination of agents, is relatively quick and easy, time must be spent in educating each individual patient on the nuances of topical therapy in order to optimize the positive effects of these preparations, while minimizing their side effects. As the majority of patients with psoriasis are part of the spectrum of mild-to-moderate disease, it is hoped that the practical points outlined in this chapter will be of value for the practicing dermatologist.

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Index

1a,25-Dihydroxycholecalciferol, 60 5-Methoxypsoralen (5-MOP), 131 8-Methoxypsoralen (8-MOP), 131 Absorption spectrum, 131 Acetonide side groups, 45 Acitretin, 157, 235 Adalimumab, 233 Adjunctive therapy, 256 Alefacept, T-cell-like, 234 Alopecia cicatricialis, 196 Anhydrous vehicle, 78–79 advantageous characteristics of, 84–85 Anthralin, 255 application of, 120 combination therapy of, 120 disadvantages of, 120 efﬁcacy of, 120 in psoriasis treatment, 119–121 side effects of, 121 topical, 236 Anthralin therapy, 255 short contact, 120 Anthralin treatment regimens, of plaque psoriasis, 120 Anti-inﬂammatory agents, nonsteroidal, 177 Antiemetics, 134

Antifungals imidazole, 199 treatment, 199 Antipsoriatic treatment, 202 Arthritis mutilans, 227 psoriatic, types of, 227 Asymmetric oligoarthritis, 227 Axial disease, 227

Basal cell carcinoma (BCC), 131 Beau’s lines, 223, 230 Betamethasone dipropionate b.i.d., 77 cream, 95 ointment, 76, 256 once-daily, 78, 80 Betamethasone dipropionate plus salicyclic acid, 62 Betamethasone dipropionate/ calcipotriene combination, 84–85 with biologics, 85–86 clinical trials and analyses of, 77 effectiveness of, 77 formulation of, 76 with other systemic agents, 86

263

264 [Betamethasone dipropionate/ calcipotriene combination] potential effects on compliance, 86 therapy, 77 Betamethasone valerate ointment, 62 Biologic therapies, 190 Biopsy, nail, 231 Black tar, 116 Blennorrhagicum, keratoderma, 187 Body surface area (BSA), 29, 243 Bonalfa1, 59 Brown tar, 116 Butylated hydroxytoluene (BHT), 199

Calcineurin, 107 inhibitors, 127, 253 topical, 110 Calcipotriene, 1, 30, 34, 59, 164, 187, 233 application of, 60 application in psoriasis, 68 beneﬁcial effects of, 60 chemical structure of, 61 in children, 61 combination of, 63 combined with UVB phototheraphy, 64 effectiveness of, 165 efﬁcacy of, 165 features of, 66 molecule, 167 monotherapy, 61 ointment, 76–77 b.i.d., 77, 80 and corticosteroids combination, 2 plus narrowband UVB, 64 for psoriasis treatment, 165 side effect of, 66 skin irritation from, 66–68 and systemic agents, 65–66 and tazarotene, 64 topical, 75–76 steroids, 63 versus other topical agents, 62 Calcipotriene and halobetasol propionate, use of, 166

Index Calcipotriol, 187 lotion, 201 ointment, 59 treatment, 197 Calcitriol, 59 Calcium metabolism, 251 Carcinogenesis, skin, 130 Carcinogenic potential, 149 Cellular proliferation, 235 Chemotherapeutic agent, 235 Chemotherapy, 235–236 Class I topical steroids, 64 Clear liquid emollients, 129 Clinical morphology, 196 Clobetasol, 157 containing topical corticosteroid products, 6 foam, 70 Clobetasol propionate, 174 foam, 46 efﬁcacy of, 168 twice-daily monotherapy with, 169 lotion, 176 shampoo, 175, 199 spray, 174 Clobex lotion, 176 Clobex shampoo. See Clobetasol propionate, shampoo Clobex spray. See Clobetasol propionate, spray Coal tar efﬁcacy of, 116 preparations of, 116 psoriasis treatment with, 115–119 therapeutic use of, 119 Coal tar in mild-to-moderate psoriasis, side effects and disadvantages, 119 Coal tar lotion, efﬁcacy of, 118 Combination therapy, 127, 131, 147, 255 rationale for, 147 Corticosteroid(s), 245 adherence of, 46–48 aspect of, 50 atrophogenic effects of, 252 biological activity of, 42–44 and calcipotriene combination, 2

Index [Corticosteroid(s)] cost considerations for, 52 delivery of, 44 effects of, 51 efﬁcacy of, 49–50 essential abilities of, 42 functional effects of changing, 43 high-potency, 94 intralesional, 2 mechanism action of, 42–44 mid-potency, 94 ointments, 251 physiologic potency, 44 practical use of, 52 preparation, 199 propylene glycol present in, 45 psoriasis treated with, 41 safety proﬁle of, 51–52 side effects from topical, 75 skin cap treatment for, 48–49 and tazarotene combination, 2 therapy, 76 topical, 1, 75–76, 96, 120–121 use of, 50 Corticosteroid/calcipotriene combination therapy beneﬁts of, 76 pitfalls of, 76 Corticosteroid/calcipotriene ointment, ﬁxed-dose, 76 Corticosteroid clobetasol propionate, 1 Cronbach’s a, 24 CsA. See Cyclosporin A Cutaneous immune cells, 213 Cutaneous lesions, presentation of, 207 Cutaneous psoriasis, 226 Cutaneous tumors, 111 Cutivate1, 95 Cyclosporin A (CsA), 105, 156, 190, 215, 235, 236 vitro biological characteristics, 212 Cyclosporine therapy, effect of, 215 Cytokine expression, prevention of, 107 Cytokines, 42 inﬂammatory, 214, 216 expression, 215 production of, 213

265 Daivobet1, 76 Daivonex1, 76 Demarcated erythematous plaques, 196 Dermatitis, retinoid, 252 Dermatology life quality index (DLQI), 15 Dermatophyte infection, 184 Dermatoses, inﬂammatory treatment of, 105 Diabetic patients, acute hypoglycemia in, 121 Diprosone1, 76, 95 Disease-modifying systemic therapies, 32 Distal interphalangeal (DIP) joint disease, 227 Dithranol therapy, short contact, 120, 199 Diversifying treatment, 147 Deoxyribonucleic acid (DNA)-binding proteins, 92 Deoxyribonucleic acid (DNA) synthesis, 155 inhibition of, 214 Dovobet1, 76, 170 Dovonex1, 59, 76, 164, 233 Drug reactions, 230 Drug, steroid-like, 232–233 Drug within vehicles, 45 Duoderm1, 176 Dysfunctional epidermal barrier, hydration of, 255

Ear telangectasia, 106 Efalizumab, 234 Elidel1, 111 Elocon1, 95 Emollients clear liquid, 129, 186 and keratolytics, 255 Endothelial cells, 216 Enthesopathy, 227 Epidermal growth factor (EGF), 212 Epidermal hyperproliferation, 212 Epidermal T cell, 61 Erythema, 64

266 Erythrodermic psoriasis, 207 Etanercept, 32, 233 Excimer laser, 126

Fissured psoriatic lesions, 35 Fixed-dose combination therapy, 77 clinical improvement in patient with, 85 corticosteroid/calcipotriene ointment, 76 effectiveness of, 77 once-daily, 78 b.i.d. therapy versus, 80 efﬁcacy of, 80, 83 higher clearance of, 81 investigators and patients’ assessments of, 82 monotherapy versus, 80 psoriasis activity with, 81–82 twice-daily versus, 77 potential beneﬁts of, 84 Flow cytometric analysis, 60 Fluocinonide cream, 93 ointment, 62 Fluorouracil, 235–236 Flurandrenolide-impregnated tape, 50 Follicular hyperkeratoses, 197 Food and Drug Administration (FDA), 30, 154, 213 Fungal culture, 185 Fungal infection, 207 inﬂammatory, 184 Fungal lesions, 197 Future therapies, 158

Gastrointestinal distress, 256 Gastrointestinal side effect, 134 Gastrointestinal symptoms, 216 General therapeutic aspects, 197–198 Genetic haplotypes, 228 Gene transcription, 252 Goa powder, 119

Index Goeckerman therapy, 116 with black tar, 117 study of, 118 Grenz ray therapy, 236

Halobetasol cream, 167 ointment, 63, 70, 167 propionate, 164 Haplotypes, genetic, 228 Hemorrhages, splinter, 223, 225 Histopathology, 207 HRQOL measure, 15, 26 Human immunoglobulin, 216 Human leukocyte antigen (HLA)-B27 genetic haplotype, 228 Human–mouse monoclonal chimeric antibody, 216, 233 Hydrocolloid dressings, 176 patches, 177 Hydrogel, 177 occlusion, 177, 180 patches, 176, 180 use of, 180 Hydrophilic emollient base, 253 Hypercalcemia and hypercalciuria, 60, 67, 252 Hyperkeratosis nail bed, 225 subungual, 223, 227 Hyponychial skin, 223 Hypothalamic pituitary–adrenal (HPA) axis suppression, 211, 248

Imidazole antifungals, 199 Immune cells, 207 Immunogenic inﬂammatory disease, 107 Immunomodulation, cautaneous, 126 Immunomodulators, topical, 32, 253 Immunopathogenesis, 216 Immunosuppression, 26 agent, 236 function of, 107 properties of, 132, 245

Index Inﬂammatory cytokines, 214, 216 expression, 215 production of, 213 Inﬂammatory dermatoses, treatment of, 105 Inﬂammatory fungal infection, 184 Inﬂammatory nail changes, 229 Inﬂiximab, 32, 233 Ingram method, for inpatient therapy, 120 Intercellular adhesion molecule interaction, 216–217 Interleukin (IL), 43, 107 Intertriginous psoriasis, 207, 211 Intracellular accumulation, 202 Irritation, 66–67 lesional, 66 perilesional, 66

Juvenile-onset psoriasis, 229

Keralyt1 gel, 121 Keratinocyte cell cycle, 212 differentiation, 252 proliferation, 212 retinoid effects on, 92 Keratoderma blennorrhagicum, 184, 187 Keratolytics agents of, 122, 188, 235–236 uses of, 33 Koebner phenomena, 184, 186, 233 Koebner reactions, 139 Koo–Menter Psoriasis Instrument (KMPI) components of, 10 discussions on, 27 PQOL-12 score calculation within, 26 quality-of-life measure for, 13 use in psoriasis, 27

Leukocyte function-associated antigen (LFA), 234 Leukonychia, 225, 226

267 Lichen planopilaris, 197 simplex chronicus, 180 striatus, 230 Lidex1, 95 Light therapy, 213 Likert-type scale, 14 Linear psoriasis, 230 Linear verrucous epidermal nevus, 230 Liquor carbonis detergens (LCD), 116, 253 Liver biopsy, 215 Lupus erythematodes, 197 Lymphoid malignancies, 213 Lymphoma, theoretical risk of, 111 Lymphoproliferative disorders, 216

Maxacalcitol, 59 Maxiﬂor1, 95 Messenger RNA (mRNA), transcription of, 42 Methotrexate, 32, 127, 155, 189, 214 therapy, 66, 215 topical, 188 Mid-matrix disease, 5–6, 154, 225 Minimal erythema dose (MED) testing, 129, 151 Minimally important difference (MID) of PQOL-12 score, 24, 26 Minimal phototoxicity dose (MPD), 135 Mometasone furoate and salicylic acid ointment, combination therapy of, 121 Mometasone furoate monotherapy, 95 Muscular skeletal pain, 177

Nail allergic contact dermatitis in, 229–230 bed hyperkeratosis, 225 psoriasis, 226 biopsy, 231 fold plaques, 226 growth center, 223 inﬂammatory changes, 229

268 [Nail] matrix, 222, 223 psoriasis, 232 penetration, 235 pitting, 184, 223 psoriatic changes, 222 sandpaper, 223 Nail psoriasis, 99 childhood versus adult onset, 228–229 clinical manifestations of, 224 diagnostic challenge, 229–231 diagnostic procedure, 231 manifestations of, 222–226 treatments for, 231–236 Nail psoriasis severity index (NAPSI), 231 scoring system, 232 scoring table, 232 uses of, 231 NAPSI. See Nail psoriasis severity index Narrowband ultraviolet B (NB-UVB) treatment, 188, 191 Nephrotoxicity, 215 Nonsteroidal anti-inﬂammatory agents, 177 Nonsteroidal preparations, 247 Nuclear factor of activated T cell (NF-ATc), 107, 156 Nuclear hormone receptors, 245, 251 Nuclear retinoid receptors, 212 Nuclear transcription factor, 156

Oil spots, 225, 226 Oily sebaceous glands, 66 Ointment betamethasone dipropionate, 76 betamethasone dipropionate/ calcipotriene, 77 betamethasone valerate, 62 calcipotriene, 76–77 calcipotriol, 59 corticosteroid/calcipotriene, 76 ﬂuocinonide, 62 halobetasol, 63, 70 Oligoarthritis, asymmetric, 227 OLUX1, 70 foam, 168

Index Onychodystrophy, extensive, 226 Onycholysis, 226 Onychomadesis, 223, 230 Onychomycosis, 229 Oral psoralens, 149 Oral retinoid, 157, 189 Oxarol1, 59

Palmoplantar psoriasis diagnosis of, 184 phototherapy, 188–189 systemic therapy, 189–190 topical therapy of, 185–188 treatment, 185 treatment algorithm for, 191 treatment approach for therapy of, 190–192 Palmoplantar pustulosis, 185 Parakeratosis pustulosa, 230 Parakeratotic cells, 223, 225 Paronychial skin, 184 Periodic-acid–Schiff stain, 229 Perioral dermatitis, 248 Photoaging, 136 Photocarcinogenesis, 136 Photochemotherapy, 189 Photodermatoses, 128 Photodynamic therapy, 202 Photoprotective effects, 256 Photosensitivity, 152 drug-induced, 128 Phototheraphy, 125, 188–189, 202, 236, 256 and calcipotriene, 64 combinations, 148 directed, 189 mechanism of, 126 narrowband ultraviolet B (UVB), 64 psoralen and ultraviolet A (PUVA), 64 targeted (localized), 137 advantages and disadvantages of, 140 adverse effects for, 141 combination therapy of, 140 contraindications of, 140 dose and administration for, 140

Index [Phototheraphy] efﬁcacy of, 139 indications for, 140 mechanism of action of, 137 ultraviolet 1 advantages and disadvantages of, 142 adverse effects of, 142 combination therapy for, 142 contraindications, 142 dose and administration of, 142 efﬁcacy of, 141 indications of, 142 ultraviolet A (UVA), 65 ultraviolet B (UVB) absolute contraindications for, 128 advantages and disadvantages of, 128 adverse effects for, 130 contraindications for, 128 dose and administration for, 129 indications of, 128 irradiation of, 128 as monotherapy, 126 relative contraindications of, 128 Phototoxic reactions, 136 Pimecrolimus an ascomycin derivative, 106 ointment, 107 Pityriasis amiantacea, 197 Placebo, 62, 65 Plaque psoriasis, 107, 187, 202, 247 anthralin treatment regimens of, 120 chronic, 207 treatment of, 91 ﬂuocinonide cream in, 93 Plaques, 184 chalky, 225 nail fold, 226 Polyarthritis, symmetric, 227 Potassium hydroxide preparation, 185 Potencies, range of, 33 Potential dose-sparing effects., 252 PQOL. See Psoriasis Quality-of-Life Questionnaire Protein mediators, 43

269 Protocol skin-type–based, 135 UVA dose, 134 Pseudoteigne amiantacee, 196 Psoralen and ultraviolet A (PUVA), 148, 235–236 absolute contraindications, 133 bath, 149 combination therapy for, 131 contraindications, 133 cream, 149 efﬁcacy of, 131 indications of, 132 photochemotherapy, 131 and Tar/Anthralin, 153 and topical steroids, 153 Psoralens, 131 Psoriasis arthritis, 13 calcipotriene application in, 68 candidacy for systemic therapy for, 14 categorization of, 5 chronic plaque, 207 combination, rotational, and sequential therapy for, 2, 37–38 cutaneous, 226 deﬁnition of, 29 effect of, 207 erythrodermic, 207 eyelid, therapy of, 110 facial and intertriginous, 108 factors of, 30 familial history of, 229 foundation, 4 general approach to, 3 inﬂammatory erythrodermic forms of, 252 intertriginous, 207, 211 joint symptoms of, 13 KMPI use in, 27 linear, 230 localized outcomes of, 6 treatment of, 5–6 measuring compliance in, 47 medications for, 30, 32 mild, 5

270 [Psoriasis] modalities for, 147 nail, 99, 224 nail bed, 226 nail matrix, 232 narrowband ultraviolet B (UVB) for, 2 palmar-plantar, 31 pathogenic causes of, 92 patients compliance in, 5–6, 47 indication of, 13 psychosocial needs of, 3–5 recalcitrant, remission time of, 118 self-assessment in, 10–13 phototherapy for, 2, 14, 31 physician assessment in, 13 physician’s approach to, 4 pimecrolimus, use of, 109 plaque, 91, 107, 109, 110, 202, 247 plaque evaluation of, 64 pustular, 108 scalp, 5, 116, 195, 228 severe, 5 severity, 13 strength of agent for, 36 tazarotene application in, 99–100 Temovate1, 176 therapies, categories of, 163 topical tacrolimus for, 54 use of, 109 topical therapies for, 1, 32, 115 algorithm of, 33 treatment of, 106, 116, 245 agents in, 5 anthralin in, 119–121 calcipotriene in, 1 with corticosteroids in, 1–2, 41 effective agents in, 1–2 inverse, 108 lactic acid in, 122 mild-to-moderate, 119–121 salicylic acid in, 121–122 tazarotene in, 1 treatment phase timing of, 167–168

Index [Psoriasis] types of, 31 vehicle for, 35 vitamin D analogs in, 1 and vitamin A analogues in, 5 Psoriasis Activity and Severity Index (PASI), 15, 30–31, 77, 116, 150, 199, 251 of Goeckerman patients, 117 reduction in, 78 Psoriasis plaques, 107 on face, 109 on intertriginous areas, 110 Psoriasis Quality-of-Life Questionnaire (PQOL) items, 10 41 items of, 14, 24 application of original, 14–15 conﬁrmatory analysis of, 15–16 rating of, 14 reﬁning and reducing to 12 item instrument, 15 12-item Psoriasis Quality-of-Life Questionnaire (PQOL-12), 10, 24 background on, 14 development of, 15 item descriptive statistics for, 17, 25 minimally important difference (MID) of, 24, 26 multicentered ofﬁce-based study of, 15 responsiveness of, 24 validity and reliability of, 16 psychometric properties of, 15, 18–22 responsiveness of, 24 score at baseline and end of treatment, 23–25 calculation within KMPI, 26 test–retest reliability of, 26 Psoriasis severity scores, 169 Psoriasis susceptibility 1 (PSORS1), 185 Psoriasis therapies, categories of, 163 Psoriatec1, 120 Psoriatic arthritis, 227–228 causes of, 32 characters of, 227 presence or absence of, 31

Index [Psoriatic arthritis] slowing joint destruction caused by, 32 types of, 227 Psoriatic lesions, 168, 207 rebound of, 166 risk of, 164 Psoriatic nail changes, 222 Psoriatic nail disease, misdiagnosis for, 229 Pulse therapy, 167 PUVA. See Psoralen and ultraviolet A

Renal function tests, 60 Retinoic acid receptors (RARs), 91–92, 212, 234 Retinoid, 189, 234–235, 252 dermatitis, 252 oral, 189 topical, 187–188, 211 Retinoid receptors, 252 types of, 91 Retinoid X receptors (RXRs), 91–92, 212 Rhabdomyolysis, transient, 235 Rheumatoid arthritis, 227

Salicylate toxicity, 256 signs of, 121 Salicylic acid applications of, 199 keratolytic agent, 121 Salicylic acid gel trials, feature of, 47 Salmon patches. See Oil spots. Sandpaper nails, 223 Scalp psoriasis, 5, 116, 195, 228 refractory, 255 treatment strategies, 202–203 Scanning electron microscopy, 196 SCC. See Squamous cell carcinoma Seborrheic dermatitis, 197, 210 Sequential therapy, 164, 168, 169 advantage of, 168 combination, drug delivery in, 169 factors of, 163

271 [Sequential therapy] as ﬂexible therapeutic strategy, 168 phases of, 164 second phase of, 169 topical, 164–167 Serum calcium level, 60 Shampoos, 198–199 clobetasol propionate, 175, 198 zinc pyrithion, 198 Short contact therapy, 100 Silkis1, 59 Skin cancer, risk of, 119 Skin cap spray, 48 Skin carcinogenesis, 130 Skin conditions, treatment of, coal tar used in, 115 Skin irritation, 176 incidence of, 177 Skin, paronychial, 184 Skin surface temperature, 255 Small blood vessels, vasoconstriction of, 210 Splinter hemorrhages, 223, 225 Squamous cell carcinomas (SCCs), 135, 213, 214, 230–231 Staphylococcus isolates, 197 Steroid, 30, 33–34, 232–233 applications of, 37 aspects of using, 33 chronic effect of, 211 class I topical, 64 mid–high-potency, 95 monotherapy, 77 side effect proﬁle of, 166 superpotent topical, 166 topical, 33 Steroid-like drugs, 232–233 Stoughton–Cornell classiﬁcation system, 210, 245 Stratum corneum, 60 thickness of, 186 Streptomyces hygropicus var. ascomyceticus, 106 Streptomyces tsukubaensis, 54, 105, 212 Striae distensae, 106 Subcutaneous (SQ) injections, 233 Subungual hyperkeratosis, 223, 227

272 Sulfasalazine, 236 Sunburn spectrum, 125 Superpotent corticosteroids, 251 Symmetric plaque-type psoriasis, 150 Symmetric polyarthritis, 227 Systemic antifungal treatment, 202 Systemic calcium metabolism, 201 Systemic tacrolimus, 213

T-cell, 42, 126, 233, 234 apoptosis, 126 inﬁltration, 212 like alefacept, 234 T-cell lymphoma, cutaneous, 111 T lymphocytes, 107 Tacalcitol, 59 Tachyphylaxis, 47, 76, 211 Taclonex1, 76 Tacrolimus ointment, 107–108 and pimecrolimus use, 111 topical, 54, 108 therapy, adverse effects of, 109 Tacrolimus binding protein (FK-BP), 107 Tar black, 116 brown, 116 coal, 115–119 types of, 115 Tazarotene, 34, 234 active metabolite of, 92 application, 99–100 and calcipotriene, 97 chemical compatibility with topical steroid, 96–97 chemical structure of, 92 and corticosteroids combination, 2 combination therapy of, 94–95 efﬁcacy and tolerability of, 94 gel, 93, 95–96 and clobetasol ointment, 95 combination therapy, 96 efﬁcacy and safety of, 93 treatment success rates for, 93 and mometasone group, 97

Index [Tazarotene] monotherapy, 93 and nail psoriasis, 99 in pregnancy, 101 and psoralen and ultraviolet A (PUVA) phototherapy, 98–99, 152 symptoms of, 93 topical, 187 and topical steroid, 94–96 and topical steroid-induced skin atrophy, 96 treatment side effects of, 100–101 and ultraviolet B (UVB) phototherapy, 97–98 use of, 93–94 versus topical steroids, 93 Tazarotene chemical compatibility, with topical steroid, 96–97 Tazarotene gel Tazarotenic acid, 92 Telangectasia, ear, 106 Temovate cream, 176 Temperature-sensitive vehicle, 255 Therapeutic effects, 252 Therapy combination, 34, 37 complications from, 231–236 Goeckerman, 116 methotrexate, 66 rotational, 37 sequential, 38 short contact, 100 topical, 31 amount of, 34 occlusion used to, 36 techniques to enhance, 36–37 triple combination, 100 Thymidylate synthesis, 214 TNF-a. See Tumor necrosis factor-alpha Toenails, 223 Tolypocladium inﬂatum gams, 215 advantages and disadvantages of, 133 adverse effects, 136 dose and administration fo, 133 relative contraindications, 133

Index Topical agents, 187 Topical anthralin, 236 Topical calcipotriene, application of, 251 Topical corticosteroids, 186–187, 200 Topical immunomodulators, 212 Topical methotrexate, 188 Topical psoralen and ultraviolet A (PUVA) therapy, 188–189, 191 Topical retinoids, 187–188, 211 Topical retinoid tazarotene, 200 Topical tazarotene, use of, 187 Topical vitamin D derivatives, 187 Trachyonychia, 223 Transforming growth factor (TGF), 212 Transient rhabdomyolysis, 235 Trimethoxypsoralen (TMP), 127 Tumor necrosis factor (TNF), 210 Tumor necrosis factor-alpha (TNF-a ), 233 bound etanercept, 233 inhibitors, 233, 234 molecule, 233 Tumors, cutaneous, 111

Ultravate1, 70, 164 Ultraviolet A (UVA) dose protocol, 134 and topical vitamin D, 151 Ultraviolet B (UVB) narrowband, 149 and Anthralin, 152

273 [Ultraviolet B (UVB)] and tazarotene, 151 and topical steroids, 153 and topical vitamin D, 150 radiation treatments, 256 sparing effect, 64 Ultraviolet B (UVB) phototherapy, 116, 188–189 suberythemogenic doses of, 117 and topical medications, 150 Ultraviolet (UV) spectrum, categories of, 125 UVA. See Ultraviolet A. UVB. See Ultraviolet B.

Vascular cell adhesion molecule, 216 Vasoconstriction, 36 Vasoconstrictor assay, uses of, 45 Vehicles, 44 types of, 35–36 Violaceous papules, 197 Vitamin D3 analog, 59 available in United States, 60 chemical structure of, 60–61 mechanism of action for, 60 Vitamin D derivatives, 187

Zinc pyrithione, 48 shampoos, 198 spray, 200 vehicle, 48

Figure 6.2 (See p. 67)

Skin irritation from calcipotriene. Figure 6.3 Skin irritation from calcipotriene. (See p. 68)

Figure 7.6 Rapid clinical improvement in patient treated with fixed dose combination therapy. (See p. 86)

Figure 9.1

Telangectasia, ear. (See p. 106)

Figure 9.2 Striae distensae. (See p. 106)

Figure 9.3

Psoriasis plaques on face (A) before therapy; (B) after therapy. (See p. 109)

Figure 9.4 Psoriasis plaques on intertriginous areas (A) before therapy; (B) after therapy. (See p. 110)

Figure 10.1 PASI scores of 25 consecutive Goeckerman patients treated at the UCSF Psoriasis Treatment Center. (See p. 117)

Figure 14.1 Pretreatment Hydrogel alone. (See p. 177)

Figure 14.2 Posttreatment Hydrogel alone. (See p. 178)

Figure 14.3 Pretreatment Hydrogel/TAC 0.1% cream versus TAC 0.1% cream alone. (See p. 178)

Figure 14.4 Posttreatment Hydrogel/TAC 0.1% cream versus TAC 0.1% cream alone. (See p. 179)

Figure 14.5 (See p. 179)

Hydrogel/Protopic 0.1% ointment versus Protopic 0.1% ointment alone.

Figure 14.6 Hydrogel/ Ultravate 0.05% cream + Dovonex 0.005% cream versus Ultravate 0.05% cream + Dovonex 0.005% cream alone. (See p. 180)

Figure 16.1 Classical manifestations of scalp psoriasis: (A) psoriasis of the scalp; (B) scarring psoriatic alopecia; (C) hairline psoriasis. (See p. 196)

Figure 17.1

Patient with inverse psoriasis involving the intragluteal fold. (See p. 208)

Figure 18.2

Pitting in nail psoriasis. (See p. 225)

Figure 18.3 Oil spot in nail psoriasis. (See p. 225)

Figure 18.4 (See p. 226)

Onycholysis in nail psoriasis.

Figure 19.1 Mild psoriasis. (See p. 244) Figure 19.2 (See p. 244)

Moderate psoriasis.

Figure 19.3 Application of topical corticosteroid under Saran Wrap® occlusion. (See p. 247)

Figure 19.4 Lewis technique. (See p. 247)

Figure 19.5 Perioral dermatitis secondary to topical corticosteroid application. (See p. 249)

Figure 19.7 Tinea incognito. (See p. 251)

Figure 19.8 Retinoid dermatitis. (See p. 253)

Herbs for Healthy Skin, Hair & Nails: Banish Eczema, Acne and Psoriasis With Healing Herbs That Cleanse and Tone to Body Inside and Out (Keats Good Herb Guide)

Management of psoriasis

Severe Psoriasis Market

Psoriasis: A Patient's Guide

Psoriasis Y Sida

Handbook of Psoriasis

Handbook of Psoriasis 2nd Ed

Textbook of Psoriasis, 2nd Edition

An Atlas of Psoriasis, Second Edition

100 Questions & Answers About Psoriasis

Psoriasis and Psoriatic Arthritis: An Integrated Approach

Conquering Psoriasis: An Illustrated Guide to the Understanding and Control of Psoriasis

Psoriasis and Psoriatic Arthritis An Integrated Approach