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

Mild-to-Moderate

PSORIASISJohn Y. M. Koo

University of California San Francisco Medical CenterSan Francisco, California, U.S.A.

Mark G. LebwohlMount Sinai School of Medicine

New York, New York, U.S.A.

Chai Sue LeeUniversity of California Davis Medical Center

Sacramento, California, U.S.A.

New York London

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Informa Healthcare USA, Inc.270 Madison AvenueNew York, NY 10016

© 2006 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business

No claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 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.

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Visit the Informa Web site atwww.informa.com

and the Informa Healthcare Web site atwww.informahealthcare.com

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Preface

Preface

The goal of this book is to provide guidance on state-of-the-art clinicalmanagement of mild-to-moderate psoriasis, utilizing the experiences of agroup of experts well known in the psoriasis field. The treatments coveredinclude topical corticosteroids, calcipotriene, tazarotene, tar, anthralin,salicyclic acid, phototherapy, and lasers. There is a chapter highlightingrecent advances in combination therapy. We have also included chapterson palmar plantar psoriasis, scalp psoriasis, inverse psoriasis, and nail pso-riasis because these are areas of the body that are frequently resistant toordinary forms of therapy. The editors are hopeful that the comprehensiveyet practical and problem-focused approach to the management of mild-to-moderate psoriasis makes this a reference that dermatologists, primary carephysicians, residents, medical students, and other health care professionalscan turn to again and again for the most updated guidance in taking careof patients with mild-to-moderate psoriasis.

John Y. M. KooMark G. Lebwohl

Chai Sue Lee

iii

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Contents

Preface . . . . iiiContributors . . . . xiii

1. Therapy of Mild-to-Moderate Psoriasis—Introduction . . . . . 1Mark G. Lebwohl

2. General Approach to Psoriasis Treatment . . . . . . . . . . . . . . 3Steven R. FeldmanIntroduction . . . . 3General Considerations in Treatment of

Localized Psoriasis . . . . 5Conclusions . . . . 6Reference . . . . 7

3. The Koo–Menter Psoriasis Instrument for IdentifyingCandidate Patients for Systemic Therapy . . . . . . . . . . . . . . 9John Y. M. Koo, Jonathan W. Kowalski, Mark G. Lebwohl,Chris M. Kozma, and Alan MenterIntroduction . . . . 9Overview . . . . 10Components of the Koo–Menter Psoriasis

Instrument . . . . 10Background on the PQOL-12 . . . . 14Application of the Original PQOL . . . . 14Development of the PQOL-12 . . . . 15

v

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Study 1: Multicentered Office-Based Study . . . . 15Study 2: Using Data from the Randomized

Clinical Trial . . . . 24Minimally Important Difference . . . . 26Test–Retest Reliability of the PQOL-12 . . . . 26Calculating the PQOL-12 Score Within the KMPI . . . . 26Discussion on KMPI . . . . 27Conclusion . . . . 27References . . . . 28

4. General Guidelines for Administration of Topical Agentsin the Treatment of Mild-to-Moderate Psoriasis . . . . . . . . 29Jashin J. Wu and Gerald D. WeinsteinFactors of Psoriasis . . . . 30Medications . . . . 32References . . . . 38

5. Topical Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . 41Jason Givan, Daniel Pearce, and Steven R. FeldmanIntroduction . . . . 41Rationale for Psoriasis Therapy . . . . 42Mechanism of Action and Biologic Potency . . . . 42Delivery and Physiologic Potency . . . . 44Adherence . . . . 46Lessons from Skin Cap1 . . . . 48Efficacy . . . . 49Safety . . . . 50Safer Topical Corticosteroids: Are They Possible? . . . . 51Cost Considerations . . . . 52Practical Use of Topical Corticosteroids . . . . 52Steroid Alternatives: Complementary, Not Really

Alternatives . . . . 53Summary . . . . 54References . . . . 55

6. Vitamin D3 Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59Chai Sue Lee and John Y. M. KooChemistry and Mechanism of Action . . . . 60Calcipotriene Monotherapy . . . . 61Calcipotriene in Children . . . . 61

vi Contents

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Calcipotriene vs. Other Topical Agents . . . . 62Combination Therapy . . . . 63Calcipotriene and Topical Steroids . . . . 63Calcipotriene and Tazarotene . . . . 64Calcipotriene and Phototherapy . . . . 64Calcipotriene and Systemic Agents . . . . 65Adverse Effects . . . . 66Calcipotriene Application in Psoriasis . . . . 69Conclusions . . . . 70References . . . . 70

7. Fixed-Dose Corticosteroid/CalcipotrieneCombination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 75Chai Sue Lee and John Y. M. KooCombination Corticosteroid/Calcipotriene Therapy . . . . 76Clinical Trials and Analyses of Fixed-Combination

Formulation of BetamethasoneDipropionate/Calcipotriene . . . . 77

The Fixed-Dose Combination Is More Effective ThanSteroid or Calcipotriene Monotherapy . . . . 77

The Fixed-Dose Combination b.i.d. Achieves GreaterPASI Reduction Within One Week vs. SteroidMonotherapy . . . . 77

Once-Daily Fixed-Dose CombinationIs Safe and Effective . . . . 78

Once-Daily Fixed-Dose Combination Is as Safeand Effective as b.i.d. Therapy . . . . 80

Once-Daily Fixed-Dose Therapy Achieves Higher Clearanceand Fewer Adverse Events vs. Monotherapy . . . . 81

Once-Daily Fixed-Dose Therapy Is Effective for Patientswith Mild, Moderate, and Severe Psoriasis . . . . 81

Investigators and Patients’ Assessments of Once-DailyFixed-Dosed Therapy Agree . . . . 82

Long-Term, Once-Daily Fixed-Dose TherapyIs Safe and Effective . . . . 83

Potential Benefits of Fixed-DoseCombination Therapy . . . . 84

In Combination with Biologics . . . . 86In Combination with Other Systemic Agents . . . . 87Potential Effects on Compliance . . . . 87

Contents vii

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Conclusions . . . . 87References . . . . 88

8. Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91Chai Sue Lee and John Y. M. KooChemistry and Mechanism of Action . . . . 91Tazarotene Monotherapy . . . . 93Tazarotene vs. Topical Steroids . . . . 93Combination Therapy . . . . 94Tazarotene and Topical Steroids . . . . 94Tazarotene and Topical Steroid-Induced

Skin Atrophy . . . . 96Tazarotene Chemical Compatibility with

a Topical Steroid . . . . 96Tazarotene and Calcipotriene . . . . 97Tazarotene and UVB Phototherapy . . . . 97Tazarotene and PUVA Phototherapy . . . . 98Tazarotene and Nail Psoriasis . . . . 99Tazarotene Application in Psoriasis . . . . 99Side Effects . . . . 100Conclusions . . . . 101References . . . . 101

9. Topical Calcineurin Inhibitors . . . . . . . . . . . . . . . . . . . . 105Patricia Tinio and Mark G. LebwohlMechanism of Action . . . . 107Clinical Properties . . . . 107References . . . . 111

10. Treatment of Mild-to-Moderate Psoriasis with Coal Tar,

Anthralin, Salicylic Acid, and Lactic Acid . . . . . . . . . . . 115Priya Sivanesan and John Y. M. KooCoal Tar . . . . 115Anthralin . . . . 119Salicylic Acid . . . . 121Lactic Acid . . . . 122Conclusion . . . . 122References . . . . 122

viii Contents

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

12. Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 147Wendy Myers, Jennifer Tan, and Alice B. GottliebThe Rationale for Combination Therapy . . . . 147Phototherapy Combinations . . . . 148UV Phototherapy and Topical Medications . . . . 150Combining Systemic Agents with Topical Therapies in the

Treatment of Mild-to-Moderate Psoriasis . . . . 154Future Therapies for the Combination Treatment

of Mild-to-Moderate Psoriasis . . . . 158References . . . . 159

13. Topical Sequential Therapy of Psoriasis . . . . . . . . . . . . . 163John Y. M. Koo and Shanthi M. ColacoIntroduction . . . . 163Topical Sequential Therapy: Calcipotriene and

Halobetasol Propionate . . . . 164Optimal Timing to Proceed Down Sequential

Therapy Scheme . . . . 167Sequential Therapy as a Flexible Therapeutic

Strategy . . . . 168Sequential Therapy with New Topical Steroid

Formulations . . . . 168Topical Sequential Therapy Possibilities Beyond

Calcipotriene . . . . 169References . . . . 170

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

Contents ix

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Clobetasol Propionate Spray (Clobex Spray) . . . . 174Clobetasol Propionate Shampoo (Clobex Shampoo) . . . . 175Clobetasol Proprionate Lotion (Clobex Lotion) . . . . 176Hydrogel Patch . . . . 176Conclusions . . . . 181References . . . . 181

15. Palmoplantar Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . 183Brian Bonish and Kenneth B. GordonTreatment . . . . 185Topical Therapy . . . . 185Phototherapy . . . . 188Systemic Therapy . . . . 189Biologic Therapies . . . . 190Summary: A Treatment Approach for Therapy

of Palmoplantar Psoriasis . . . . 190Conclusion . . . . 192References . . . . 192

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

x Contents

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

18. Psoriasis of the Nails . . . . . . . . . . . . . . . . . . . . . . . . . . 221Maithily A. Nandedkar-Thomas and Richard K. ScherIntroduction . . . . 221Manifestations of Nail Psoriasis . . . . 222Association with Psoriatic Arthritis . . . . 226Associated Genetic Haplotypes . . . . 228Nail Psoriasis: Childhood vs. Adult Onset . . . . 228Diagnostic Challenge: Isolated Nail Psoriasis and Its

Impersonators . . . . 229Diagnostic Procedure: The Nail Biopsy . . . . 231Measurement of Severity: The Nail Psoriasis

Severity Index . . . . 231Treatment Options and Complications

from Therapy . . . . 231References . . . . 237

19. Summary of Therapeutic Options forMild-to-Moderate Psoriasis . . . . . . . . . . . . . . . . . . . . . 243Cindy Berthelot, Jennifer Clay Cather, and Alan MenterIntroduction . . . . 243Topical Therapies . . . . 245Phototherapy . . . . 256Summary . . . . 257References . . . . 257

Index . . . . 263

Contents xi

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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 UniversityMedical Center, Dallas, Texas, U.S.A.

Shanthi M. Colaco Department of Dermatology, Psoriasis and SkinTreatment Center, University of California San Francisco Medical Center,San Francisco, California, U.S.A.

Steven R. Feldman Department of Dermatology, Center for DermatologyResearch, Wake Forest University School of Medicine, Winston-Salem,North Carolina, U.S.A.

Rianne M. J. P. Gerritsen Department of Dermatology, RadboudUniversity Medical Center, Nijmegen, The Netherlands

Jason Givan Department of Dermatology, Center for DermatologyResearch, Wake Forest University School of Medicine, Winston-Salem,North Carolina, U.S.A.

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

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Alice B. Gottlieb Department of Dermatology, Tuffs-New EnglandMedical 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, RadboudUniversity Medical Center, Nijmegen, The Netherlands

John Y. M. Koo Department of Dermatology, Psoriasis and SkinTreatment 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 ofMedicine, New York, New York, U.S.A.

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

Robert A. Lee Department of Dermatology, Hospital of the University ofPennsylvania, 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 ClinicalPharmacology, Robert Wood Johnson Medical School, New Brunswick,New Jersey, U.S.A.

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

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

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Richard K. Scher Department of Dermatology, Columbia UniversityMedical Center, New York, New York, U.S.A.

Priya Sivanesan Department of Dermatology, University of CaliforniaSan Francisco, San Francisco, California, U.S.A.

Jennifer Tan Department of Medicine, Division of ClinicalPharmacology, Robert Wood Johnson Medical School, New Brunswick,New Jersey, U.S.A.

Patricia Tinio Department of Dermatology, Mount Sinai School ofMedicine, 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, RadboudUniversity Medical Center, Nijmegen, The Netherlands

Abby S. van Voorhees Department of Dermatology, Hospital of theUniversity of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

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

Jashin J. Wu Department of Dermatology, University of California,Irvine, California, U.S.A.

Contributors xv

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1

Therapy of Mild-to-ModeratePsoriasis—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 thedays of tar and anthralin, though the latter treatments are still occasionallyused. The introduction of topical corticosteroids in the latter third of the20th century had a dramatic impact on the topical therapy of psoriasis,and topical corticosteroids remain one of the most important treatmentsavailable for mild to moderate disease. Because superpotent corticosteroidsare associated with hypothalamic–pituitary–adrenal axis suppression, recentinnovations in topical corticosteroid development have emphasized morecosmetically elegant vehicles rather than more potent medications. Mostrecently, the superpotent corticosteroid clobetasol propionate has beendeveloped in foam, spray, lotion, and shampoo vehicles. Corticosteroidsare also available in creams, emollient creams, ointments, solutions, gels,and even tapes. Therefore it should not be surprising that corticosteroids areextensively covered in this book and controversies such as tachyphylaxis aswell as issues such as compliance with therapy are raised by experts in the field.

A major breakthrough in the treatment of mild to moderate psoriasisoccurred with the introduction of vitamin D analogs. Calcipotriene, alsoknown as calcipotriol, was the first agent approved and it was followedby additional vitamin D analogs including tacalcitol, calcitriol, and others.

1

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Tazarotene, a retinoid developed for psoriasis, was the next class of agentto be developed for this disease. Other topical agents include the topical immu-nomodulators, pimecrolimus, and tacrolimus. These agents are not veryeffective on thick plaques of the elbows and knees, but are highly effectiveon facial and intertriginous skin, precisely those areas where use of topicalcorticosteroids is associated with the development of cutaneous atrophy andformation of striae and telangiectasia. All of the above agents are reviewedcomprehensively in chapters written by leading authorities.

What can the clinician do when monotherapy with topical agents isnot sufficiently effective but the disease is not severe enough to justifysystemic therapy? Combination therapy has proven to be more effectivethan monotherapy with selected agents. Moreover, combination therapyoften eliminates the side effects of monotherapy. For example, the combina-tion of topical corticosteroids and tazarotene is not only more effective thaneither treatment alone, but tazarotene protects against the atrophy of thecorticosteroid while the corticosteroid minimizes the irritation caused bytazarotene. Likewise, the combination of calcipotriene with topical cortico-steroids is more effective than either agent alone, allowing reduced use ofthe corticosteroid and less irritation caused by the calcipotriene. The useof combination therapy has led to the development of yet another new agentthat combines calcipotriene with betamethasone dipropionate.

When combination therapy is not adequate, use of intralesionalcorticosteroids may be effective, and when the latter is not sufficient, photo-therapy may be warranted. New forms of phototherapy including narrow-band ultraviolet B (UVB) and localized targeted high output phototherapysuch as that afforded by the excimer laser are often effective for localizedrefractory plaques of psoriasis.

Finally, unique body sites such as the nails or scalp may require differ-ent vehicles and approaches to achieve good results. All of these challengesare addressed by experts in Therapy of Mild-to-Moderate Psoriasis with thehope that our patients will benefit from this book.

2 Lebwohl

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2

General Approach to Psoriasis Treatment

Steven R. Feldman

Department of Dermatology, Center for Dermatology Research,Wake Forest University School of Medicine, Winston-Salem,

North Carolina, U.S.A.

INTRODUCTION

Psoriasis is a complex disease to manage. It may present with wide rangingseverity affecting vastly different parts of the body. Very limited areas tovery diffuse generalized disease can be present, and the character of thelesions may vary from minimal redness to thick scaly red plaques. The var-ious presentations add to the complexity in choosing treatment.

Adding to the complexity of the treatment is the availability of a host ofdifferent topical, phototherapy, and systemic treatment options. Matchingthe 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 thatare being treated, but a patient, and patients’ responses to the lesions also varyconsiderably. Patients also differ in their concern about side effects and the waythey tolerate different topical preparations. These variations can be dramatic.In nearly all patients, psoriasis impacts quality of life, including social interac-tions. The overall impact of psoriasis on quality of life—particularly the effectof 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 theirpsychosocial needs. This is fundamental to effective psoriasis treatment.

3

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Addressing psychosocial issues helps to establish a strong working relation-ship between the physician and the patient. By doing so, patients are likely tobe more compliant with treatment and should have better health outcomes.

The first step to managing psychosocial needs is to sit within touchingdistance of the patient. While examining the lesions and talking to the patient,the physician should palpate lesions. While doing so the physician canremark, ‘‘Wow, these lesions are really thick.’’ The purpose of the palpationis not to determine the thickness of the lesions; the purpose of touching thelesions is to communicate to patients that they are not untouchable. Patientswith psoriasis feel isolated from others because of their disease and by touch-ing the lesions the physician communicates to the patient that they shouldnot be afraid of having contact with other people. Dr. J. Lamar Calloway,long-time dermatologist at Duke University, would actually rub his own faceafter palpating the psoriasis to help communicate to patients that psoriasis isnot an infectious condition.

While sitting close to the patient, the physician should also proactivelyask patients a few questions about their disease. These questions are notlikely to change what the physician will prescribe, but they may changehow the patient views the doctor and the prescription and ultimately howadherent the patient will be to the treatment recommendations. There aremany things about psoriasis that are bothersome to patients and askingquestions about a few of these helps communicate to the patient that thedermatologist understands the disease and what the patient is goingthrough. One might ask if the itching has been bothersome, if past treat-ments have been messy or ineffective, or if psychosocial concerns have beenan issue. Simply asking a few questions (and listening intently) helps furtherthe bond between the physician and the patient.

No healthcare provider has enough time to explain to patients every-thing they would like to know about psoriasis. All of us, however, have thetime to encourage patients to join the National Psoriasis Foundation.The Psoriasis Foundation provides numerous benefits to patients. First, ithelps patients feel a part of a group, reducing their sense of isolation dueto the disease. Second, the Foundation helps educate patients about avail-able treatment options. Third, the Foundation encourages patients to becompliant with their dermatologists’ recommendations. Fourth, the Psoria-sis Foundation empowers patients to work towards a cure for the disease.

The Psoriasis Foundation offers a variety of brochures that are veryuseful for educating patients about specific treatment options. The PsoriasisFoundation periodical for patients entitled ‘‘Psoriasis Advance’’ helpspatients answer many of the psychosocial issues that physicians may not feelcomfortable addressing; for example, what to do if the lifeguard says youcannot go in the pool, what to do when people point and ask questions,or other social situations. Communication among members is very support-ive. 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 canjoin, 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 depen-dent on determining whether patients have relatively localized diseasesuitable for topical therapy or more extensive disease where phototherapy orsystemic treatments will be used. This book focuses on the treatment of peoplewith relatively localized disease. Formerly, the common categorization schemeof mild, moderate, and severe psoriasis has been used. These three categories donot correspond well to treatment decision making, however. Typically, onewould hear categorizations of mild-to-moderate versus moderate-to-severepsoriasis for treatment purposes. Mild-to-moderate psoriasis tends to refer topatients with relatively localized psoriasis. The moderate-to-severe categorytends to refer to the patient with more generalized disease or disease that isotherwise disabling. Treatment of this latter group has been covered in an excel-lent textbook entitled ‘‘Therapy of Moderate to Severe Psoriasis’’ by Weinsteinand Gottlieb (1). This chapter and this book focus on the treatment of thepatient with mild-to-moderate or localized psoriasis.

GENERAL CONSIDERATIONS IN TREATMENTOF LOCALIZED PSORIASIS

The treatment of localized psoriasis focuses on local treatments, predomi-nately topical treatments, although certainly localized phototherapy is alsoused. When it comes to topical treatments, multiple agents are availableincluding tar, anthralin, topical corticosteroids, topical vitamin D andVitamin A analogues, topical immunomodulators (tacrolimus and pimecro-limus), and keratolytics (such as salicylic acid). Whichever of these agentsare chosen, a primary consideration determining patients’ outcomes will bepatients’ compliance with the topical treatment regimen.

When patients with psoriasis have been asked about their compliancewith topical therapy, approximately 40% reported noncompliance. In aclinical trial that assessed compliance using both patient diaries and elec-tronic monitors, patients vastly overstated their true compliance. It is clearthat patients are not truthful with their doctors about their compliance withtopical therapy. Topical therapy is time consuming and messy, and overtime, compliance to topical therapy decreases. Indeed, chronic diseases like

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

General Approach to Psoriasis Treatment 5

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psoriasis—as well as treatment of the chronic condition—are frustrating andwear on people over time.

Outcomes of localized psoriasis treatment can be improved by encourag-ing patients to be compliant. There are a number of things that physicians cando to improve a patient’s compliance. First, as discussed above, physiciansshould establish a strong working relationship with the patient. They shouldinvolve the patient in the treatment-making decision. Vehicles which thepatients do not mind applying should be chosen. While it was commonlythought that ointments are more effective, new non-ointment, less messyvehicles may be able to deliver active drugs just as well as traditionalointments, and better compliance with a non-messy product may actually leadto greater efficacy than is seen with ointments.

Patients are also reluctant to apply topical therapy for long periods oftime before they see improvement. Fast acting agents should be used, especiallyinitially. The sequential therapy approach consists of using stronger, fasteracting but potentially more risky treatments early in the course of therapyand then transitioning to lower acting but safer treatments for the long-termmaintenance of the disease. This approach has the advantage of helpingpatients see early in the course of therapy that treatments work, therebyimproving patients’ compliance. Other approaches are to use the strongertopical agents such as clobetasol-containing topical corticosteroid productsinitially and then using them intermittently as needed to control the disease.

Another way to help improve compliance is to encourage patients toreturn to the office or at least contact the physician shortly after treatmenthas begun, for example in one to two weeks. A long interval before a returnvisit may lead to poor compliance if the patient feels that it will be impos-sible to be compliant for that length of time. By seeing patients back in justa week, patients are more likely to comply with therapy over that week,thereby seeing the potential benefits the treatment offers. Once they haveseen that the treatment actually works, they will use the treatment intermit-tently knowing that it will be effective for them. This short interval betweentreatment and the return visit may be especially important for patients withscalp psoriasis, as compliance with topical scalp treatment regimens isexceedingly time consuming and difficult.

CONCLUSIONS

Treating mild-to-moderate psoriasis (relatively localized psoriasis) can befrustrating for both the patient and the physician. Much of this frustrationcan be elevated by addressing patients’ psychosocial concerns up front. Allpatients with psoriasis should be encouraged to join the National PsoriasisFoundation. This helps reduce patients in isolation and increase theirknowledge about treatments, ultimately resulting in approved compliancewith the physician-recommended treatment regimens.

6 Feldman

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Topical treatments are proven for most patients with mild-to-moderatepsoriasis. Getting patients to actually use the treatment is a criticalcomponent in maximizing topical treatment efficacy. Patients should beencouraged to participate in the treatment planning process, choosing vehi-cles and other treatment characteristics (such as dosing) that fit the patient’slifestyle. Using rapidly acting agents initially and encouraging patients tocome in for an early follow-up visit or other factors may help improve thecompliance. The resulting improvement should help reduce the frustrationof psoriasis on both the patient and the physician.

ACKNOWLEDGMENTS

Center for Dermatology Research is funded by a grant from GaldermaLaboratories, 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: revisedand expanded. 2d ed. New York, NY: Marcel Dekker, 2003.

General Approach to Psoriasis Treatment 7

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3

The Koo–Menter Psoriasis Instrument forIdentifying Candidate Patients

for Systemic Therapy

John Y. M. Koo

Department of Dermatology, Psoriasis and Skin Treatment Center, University ofCalifornia 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 withsevere psoriasis reported frustration with the efficacy of their currenttreatment and 32% indicated that the treatment they are receiving is notaggressive enough (1). In addition, 87% of all psoriasis patients were receiving

9

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only topical medications for their psoriasis and only 26% of patients were verysatisfied with their treatments.

Several highly effective systemic therapies for psoriasis already existand other potential new systemic therapies are in development for patientswith psoriasis. Most psoriasis opinion leaders feel that a greater percentageof 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 ofwhether therapy that is more aggressive may be needed or not.

There has been no convenient tool that can assist dermatologists inidentifying patients who would benefit from systemic therapy for psoriasisand at the same time justify these decisions to third-party payers. However,tools such as these exist for other chronic diseases treated by rheumatolo-gists (e.g., for rheumatoid arthritis) and urologists (e.g., for benign prostatichyperplasia). Such a tool for psoriasis would need to incorporate both theassessments of health-related quality-of-life and the other measures ofdisease severity and associated joint disorder (2).

The Koo–Menter Psoriasis Instrument (KMPI) has been designed tobe a practical assessment tool, which dermatologists can quickly and easilyuse in their daily practice to help guide them in identifying patients withpsoriasis 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 awaitingevaluation by the physician. The topics of these sections include: validatedpsoriasis-specific quality-of-life, parts of body currently affected by psoria-sis, and psoriatic arthritis/joint symptomatology.

The physician then completes the reverse side of the instrument duringthe physical examination. The quality-of-life score is easily totaled from thefront page; body surface area (BSA) involvement is assessed using the ‘‘ruleof nines,’’ and a series of simple ‘‘yes’’ or ‘‘no’’ questions allows the physi-cian to quickly characterize the patient’s disease and treatment history. Thephysician uses the psoriasis-specific quality-of-life score, the total percentageof BSA involvement, and the overall clinical assessment of the patient’spsoriasis to determine the need for systemic therapy.

COMPONENTS OF THE KOO–MENTERPSORIASIS INSTRUMENT

Patient Self Assessment

Part 1. Health-Related Quality of Life

The patient completes the 12-item Psoriasis Quality-of-Life Questionnaire(PQOL-12).

10 Koo et al.

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

Koo–Menter Psoriasis Instrument 11

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Figure 2 Koo-Menter psoriasis instrument; physician assessment.

12 Koo et al.

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Developed from the original 41-item PQOL (which was created adecade ago based on literature review, patient focus groups and pilot testingin 505 patients with psoriasis), the items from the PQOL-12 were identifiedusing new data from 474 patients with psoriasis and determined to be validand reliable in assessing the impact of psoriasis on patients across thespectrum of psoriasis severity. In addition, the items of the PQOL-12 areresponsive and sensitive in measuring clinically meaningful change andimprovement following treatment.

The PQOL-12 was chosen as the quality-of-life measure for the KMPIbecause of its brevity, broad applicability across disease severity, the rigor ofits development and psychometric validation, and its psoriasis-specificfocus. The validation data for PQOL-12 will be described later under thesection ‘‘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’sindication of psoriasis sites helps facilitate the physician’s evaluation of thearea of psoriatic involvement in the patient.

Part 3. Joint Symptoms

The patient answers four questions about joint symptoms and psoriaticarthritis. These items, developed based on feedback from leading arthritisexperts, are included to facilitate early detection of this important associatedcondition while ensuring that the decision for systemic therapy is also basedon 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 ofnines or by the estimation using the area of open hand as approximately1% of the total body surface.

Part 3. Assessment of Psoriasis Severity

The following severity criteria are then assessed by the physician using sim-ple ‘‘yes’’ or ‘‘no’’ options:

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

� Guttate psoriasis

Koo–Menter Psoriasis Instrument 13

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� Localized psoriasis (less than 10% BSA involvement) that is resis-tant 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., gener-alized pustular or erythrodermic psoriasis), or

� Clinical evidence of psoriatic joint disease as assessed by thepatient and physician.

Part 4. Feasibility of Phototherapy

Lastly, the feasibility and clinical appropriateness of phototherapy is rapidlyevaluated 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 ofthe Physician Assessment, the candidacy for systemic therapy is determined.

If the physician has checked at least one of the shaded boxes in bothPart 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 1991by John Koo, M.D.(3–5). The questionnaire items were generated throughfocus groups in which patients discussed their experiences with psoriasis. Anationwide, population-based, demographically balanced sample of 50,000households was then used to identify 599 psoriasis patients in the UnitedStates for item testing. The 41-item PQOL was qualitatively divided intotwo domains: psychosocial and physical. The psychosocial domain consistedof 22 items requiring patients to characterize the impact of psoriasis on theirinteractions with friends and family and on their feelings and self-percep-tion. The physical domain consisted of 19 items requesting that patients ratethe impact of their psoriasis symptoms on their daily activities. PQOL itemswere rated on an 11-point Likert-type scale where 0¼ ‘‘not at all,’’5¼ ‘‘somewhat,’’ and 10¼ ‘‘very much.’’

APPLICATION OF THE ORIGINAL PQOL

The 41-item PQOL was utilized in a clinical study of 71 patients with stableplaque psoriasis on up to 20% of their total BSA, and plaque elevationof at least moderate severity (6). Psychometric analysis of the 41-itemPQOL showed satisfactory reliability, validity, and responsiveness to change(3). Items within each domain had approximately equal variances and

14 Koo et al.

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contributed equally to the total score and were, therefore, summed withoutweighting. The 41-item PQOL was scored by computing the mean scorefor 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, andthe assumption of two domains (psychosocial and physical) was not entirelyappropriate as analyses following its development had shown overlapamong these domains. A shorter instrument measuring unique constructswas needed for clinicians and researchers who were interested in assessingpsoriasis-specific Health-Related Quality-of-Life (HRQOL) in clinicalresearch or daily practice. Factor analysis techniques were used to refinethe 41-item PQOL. The resulting questionnaire (PQOL-12) consisted of 12items measured on one domain. Psychometric properties of the PQOL-12were 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 froman office-based study of 483 patients stratified by physician-rated psoriasisseverity 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. Physicianscompleted several different symptom severity assessment questionnaires:global assessment of severity ranging from mild, moderate, and severe basedon the BSA affected, PASI, overall lesional assessment (OLA) and severityof symptoms experienced by patients. In addition, each patient was asked tocomplete a demographic questionnaire, the PQOL, the Dermatology LifeQuality Index (DLQI) and a disease severity assessment. Patient-rated sever-ity was defined as mild, moderate, or severe with the question ‘‘How wouldyou 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 con-tacts and relationships?] in the psychosocial domain was divided into twoquestions, creating a 42-item instrument. A combination of qualitativereview and factor analysis was used to refine the questionnaire. Observa-tions were randomly assigned to an exploratory or confirmatory data set.The exploratory data set (n¼ 301) was used to reduce and refine the existingPQOL instrument and the confirmatory data set (n¼ 182) was used to testthe reliability of the findings from the exploratory analysis. Each PQOL

Koo–Menter Psoriasis Instrument 15

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item was evaluated for missing values, mean scores, floor/ceiling effects,reading level, translatability, and applicability to all patients. Qualitativecriteria were applied by assessing items for redundancy, wording, andmeaning/conceptual characteristics. Factor analysis was used to assessthe factor structure and item loadings on factors. An item-retention gridconsisting of all analytical parameters was created to evaluate all item para-meter estimates simultaneously and to facilitate the item-reduction decisionprocess. Once reduced, all analyses performed on the exploratory data set(i.e., descriptive and factor analysis) were repeated on the revised question-naire (i.e., PQOL-12) using the confirmatory dataset. The confirmatoryanalyses yielded results consistent with the exploratory analyses.

Validity and Reliability

Following the confirmatory analysis, the psychometric properties of thePQOL-12 were assessed using Multitrait Analysis Program-Revisedfor Windows1PC-SAS1–based software7 (9) and the pooled data set(n¼ 482). The PQOL-12 demonstrated desirable psychometric properties.Ninety-nine percent of respondents completed the survey providing evidenceof appropriate item responses of the PQOL-12. The PQOL-12 also exhibitedsupport for the assumptions of summated scales. The PQOL-12 items hadapproximately equal variances (so they could be summed) and contributedequally to total score (i.e., no weighting needed). All items demonstrated desir-able item internal consistency by exceeding the criteria of 0.40 correlation withthe total score. The instrument also demonstrated good potential for respon-siveness. 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 questionnairecould have been reduced even further, some questions that have been deemedimportant in clinical practice were retained. Investigation of construct validityindicated that the mean PQOL-12 score was moderately correlated with clin-ical measures, and highly correlated with patient-rated psoriasis severity(r¼ 0.61) and with the DLQI (r¼ 0.78) (Table 3).

Individual item correlations with overall patient-rated severity rangedfrom 0.40 (‘‘how helpless do you feel with regard to your psoriasis?’’) to0.61 (physical irritation). There were low to moderate correlations withphysician-rated severity. A probable explanation for the more modest correla-tions with physician-rated severity was that physicians based their severityassessment on BSA using an ordinal scale (mild<5%, moderate 5–10%, severe>10%) and lesion morphology that focused strictly on physical characteristicsof the patient’s condition. The correlations between individual PQOL-12items and the DLQI items ranged from 0.50 to 0.69. The total PQOL-12 scorewas 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 levelby both patients and physicians (Table 4). All pairwise comparisons of

16 Koo et al.

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Tab

le1

Item

Des

crip

tiv

eS

tati

stic

sfo

rth

eP

QO

L-1

2fr

om

an

Offi

ce-B

ase

dS

tud

y(S

tud

y1

)a

nd

the

Cli

nic

al

Tri

al

at

Ba

seli

ne

(Stu

dy

2)

Stu

dy

1(n¼

48

2)

Stu

dy

2(n¼

71

)

Item

Mea

nS

DR

an

ge

Mea

nS

DR

an

ge

Ov

erth

ep

ast

mo

nth

...

Ho

wse

lf-c

on

scio

us

do

yo

ufe

elw

ith

reg

ard

toy

ou

rp

sori

asi

s?6

.10

3.2

80

–1

06

.56

2.7

10

–1

0

Ho

wh

elp

less

do

yo

ufe

elw

ith

reg

ard

toy

ou

rp

sori

asi

s?5

.60

3.3

90

–1

06

.51

2.9

70

–1

0

Ho

wem

ba

rra

ssed

do

yo

ufe

elw

ith

reg

ard

toy

ou

rp

sori

asi

s?5

.76

3.4

50

–1

06

.42

3.0

30

–1

0

Ho

wa

ng

ryo

rfr

ust

rate

dd

oy

ou

feel

wit

hre

ga

rdto

yo

ur

pso

ria

sis?

5.9

33

.48

0–

10

5.9

92

.91

0–

10

To

wh

at

exte

nt

do

esy

ou

rp

sori

asi

sm

ak

ey

ou

ra

pp

eara

nce

un

sig

htl

y?

5.0

93

.25

0–

10

5.3

12

.71

0–

10

Ho

wd

isfi

gu

rin

gis

yo

ur

pso

ria

sis?

4.2

43

.25

0–

10

4.2

12

.95

0–

10

Ho

wm

uch

do

esy

ou

rp

sori

asi

sim

pa

cty

ou

ro

ver

all

emo

tio

na

lw

ell-

bei

ng

?4

.39

3.2

90

–1

04

.07

3.1

10

–1

0

Ov

era

ll,

tow

ha

tex

ten

td

oes

yo

ur

pso

ria

sis

inte

rfer

ew

ith

yo

ur

cap

aci

tyto

enjo

yli

fe?

4.1

13

.39

0–

10

3.6

33

.21

0–

9

Du

rin

gth

ep

ast

mo

nth

,h

ow

mu

chh

av

eea

cho

fth

efo

llo

win

gb

een

aff

ecte

db

yy

ou

rp

sori

asi

s?It

chin

g?

5.3

23

.41

0–

10

6.5

82

.76

0–

10

Ph

ysi

cal

irri

tati

on

?4

.98

3.4

00

–1

05

.77

3.0

70

–1

0P

hy

sica

lp

ain

or

sore

nes

s?3

.84

3.4

00

–1

04

.23

3.4

00

–1

0C

ho

ice

of

clo

thin

gto

con

cea

lp

sori

asi

s?5

.04

3.8

40

–1

06

.15

3.4

80

–1

0M

ean

PQ

OL

-12

Sco

re5

.03

2.7

60

–1

05

.45

2.1

30

.58

–9

.42

Ab

bre

viat

ion

s:P

QO

L-1

2;

12

-Ite

mP

sori

asis

Qu

ali

ty-o

f-L

ife

Qu

esti

on

nai

re;

SD

,st

an

da

rdd

evia

tio

n.

Koo–Menter Psoriasis Instrument 17

Page 35: Koo o 0849337232

Tab

le2

Su

mm

ary

of

the

Psy

cho

met

ric

Pro

per

ties

of

the

12

-Ite

mP

QO

Lin

Tw

oS

tud

ies

Pro

per

tyD

escr

ipti

on

/ra

tio

na

le(c

rite

rio

n)

Stu

dy

1(n¼

48

3)

Stu

dy

2(n¼

71

)

Rel

iab

ilit

yIn

tern

al

item

con

sist

ency

Ex

ten

tto

wh

ich

each

item

corr

ela

tes

wit

hth

eto

tal

sco

re(�

0.4

0;

�0

.30

ifd

om

ain

con

tain

sm

an

yit

ems)

Co

rrel

ati

on

sra

nged

fro

m0

.70

to0

.83

Co

rrel

ati

on

sra

ng

edfr

om

0.4

2to

0.7

8

Inte

rna

lco

nsi

sten

cyre

lia

bil

ity

Ho

mo

gen

eity

of

ad

om

ain

an

dex

ten

tto

wh

ich

do

ma

inis

free

of

ran

do

mer

ror

(Cro

nb

ach

’sa¼

0.7

0–

0.9

5)

Cro

nb

ach

’sa¼

0.9

5C

ron

ba

ch’s

0.9

1

Va

lid

ity

Item

mea

ns

an

dv

ari

an

ces

Inte

rch

an

gea

bil

ity

of

item

sw

ith

inea

chd

om

ain

(sim

ila

rm

ean

sa

nd

va

ria

nce

s,so

sco

res

can

be

sum

med

wit

ho

ut

ad

just

men

t)

Mea

ns

of

the

item

sw

ere

3.8

4–

6.1

0(S

D,

3.2

5–

3.8

4)

Mea

ns

of

the

item

sw

ere

3.6

3–

6.5

8(S

D,

2.7

1–

3.4

8)

Co

nst

ruct

vali

dit

yR

elati

on

ship

of

item

tod

om

ain

,ass

esse

db

yit

em/

do

main

corr

elati

on

sco

rrec

ted

for

ov

erla

p(s

imil

ar,

mo

der

ate

item

/d

om

ain

corr

ela

tio

ns.

Item

ssh

ou

ldco

ntr

ibu

teeq

ua

lly

tod

om

ain

sco

reso

tha

tit

emw

eig

hti

ng

isu

nn

eces

sary

)

Co

rrel

ati

on

of

item

sw

ith

tota

lsc

ore

ran

ged

fro

m0

.70

to0

.83

Co

rrel

ati

on

of

item

sw

ith

tota

lsc

ore

ran

ged

fro

m0

.42

to0

.78

Ex

tern

al

va

lid

ity

Rel

ati

on

ship

of

item

sto

exte

rna

l,o

ften

clin

ica

l,en

dp

oin

ts(a

tle

ast

mo

der

ate

Sp

earm

an

corr

ela

tio

ns)

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OL

-12

sco

rea

tb

ase

lin

eco

rrel

ate

dsi

gn

ifica

ntl

y(p<

0.0

5)

wit

hp

hy

sici

an

rate

dse

ver

ity

(0.3

8),

pa

ten

tra

ted

sev

erit

y(0

.61

),o

ver

all

lesi

on

al

ass

essm

ent

(0.3

8),

BS

A

PQ

OL

-12

sco

rea

tb

ase

lin

eco

rrel

ate

dsi

gn

ifica

ntl

y(p<

0.0

5)

wit

ho

ver

all

dis

com

fort

(0.4

9),

per

cen

tB

SA

18 Koo et al.

Page 36: Koo o 0849337232

(0.3

3),

PA

SI

(0.3

6)

an

dth

eD

LQ

I(0

.78

)a

ffec

ted

(0.4

2),

pru

riti

s(0

.41

),a

nd

ov

era

lld

isea

sese

ver

ity

(0.3

4);

PQ

OL

-12

wa

sn

ot

sig

nifi

can

tly

corr

ela

ted

wit

hp

hy

sici

an

ass

essm

ent

of

pla

qu

eel

eva

tio

n,

sca

lin

g,

or

ery

them

a

Res

po

nsi

ven

ess

Dis

trib

uti

on

of

resp

on

ses

Item

acc

epta

bil

ity

an

dco

mp

reh

ensi

on

of

mea

nin

gb

yre

spo

nd

ents

(res

po

nse

ssh

ou

ldsp

an

the

ma

jori

tyo

fth

esc

ale

)

Mea

nP

QO

L-1

2to

tal

sco

re¼

5.0

3,

SD¼

2.7

6,

Ra

ng

0–

10

Mea

nP

QO

L-1

2to

tal

sco

re¼

5.4

5,

SD¼

2.1

3,

Ra

ng

0.5

8–

9.4

2

La

cko

ffl

oo

ro

rce

ilin

gef

fect

sP

osi

tio

no

fin

itia

lsc

ore

(in

itia

lsc

ore

ssh

ou

ldn

ot

be

too

clo

seto

the

min

imu

mo

rm

ax

imu

mv

alu

es;

sca

les

sho

uld

ha

ve

suffi

cien

tra

ng

eo

nei

ther

sid

eo

fth

ein

itia

lsc

ore

tosh

ow

imp

rov

emen

to

rd

eter

iora

tio

n)

No

sig

nifi

can

tfl

oo

r(1

.5%

)o

rce

ilin

g(1

.0%

)ef

fect

sN

osi

gn

ifica

nt

flo

or

(0.0

%)

or

ceil

ing

(0.0

%)

effe

cts

Res

po

nsi

ve

tod

isea

sese

ver

ity

Sco

res

sho

uld

va

rysy

stem

ati

call

ya

cro

ssd

isea

sese

ver

ity

cate

go

ries

soth

at

mil

der

sev

erit

yis

ass

oci

ate

dw

ith

low

ersc

ore

sth

an

mo

rese

ver

ed

isea

se

Fo

rp

hy

sici

an

rati

ng

so

fse

ver

ity

,m

ean

PQ

OL

-12

sco

res

wer

e3

.9fo

rm

ild

,5

.0fo

rm

od

era

te,

an

d6

.4fo

rse

ver

ed

isea

se;

pa

irw

ise

com

pa

riso

ns

of

PQ

OL

-12

mea

ns

by

ph

ysi

cia

n-r

ate

dse

ver

ity

gro

up

sw

ere

Fo

rp

hy

sici

an

rati

ng

so

fse

ver

ity

,th

ere

wa

s1

to1

.5p

oin

td

iffe

ren

cein

sco

res

bet

wee

nm

ild

an

dse

ver

e(p¼

0.0

09

),m

ild

an

dm

od

era

te

(Co

nti

nu

ed)

Koo–Menter Psoriasis Instrument 19

Page 37: Koo o 0849337232

Tab

le2

Su

mm

ary

of

the

Psy

cho

met

ric

Pro

per

ties

of

the

12

-Ite

mP

QO

Lin

Tw

oS

tud

ies

(Co

nti

nu

ed)

Pro

per

tyD

escr

ipti

on

/ra

tio

na

le(c

rite

rio

n)

Stu

dy

1(n¼

48

3)

Stu

dy

2(n¼

71

)

sig

nifi

can

tly

dif

fere

nt

(p<

0.0

00

2)

(p¼

0.0

8)

mo

der

ate

,a

nd

sev

ere

dis

ease

cate

go

ries

(p¼

0.0

8)

at

ba

seli

ne

Fo

rp

ati

ent-

rate

dse

ver

ity

,m

ean

PQ

OL

-12

sco

res

wer

e3

.2fo

rm

ild

,5

.2fo

rm

od

era

te,

an

d7

.6fo

rse

ver

ed

isea

se;

pair

wis

eco

mp

ari

son

sw

ere

sta

tist

ica

lly

sig

nifi

can

t(p

<0

.00

01

)

Fo

rp

ati

ent-

rate

dse

ver

ity

,th

ere

wa

s1

to3

po

int

dif

fere

nce

inm

ean

PQ

OL

-12

sco

res

bet

wee

nm

ild

an

dm

od

era

te(p¼

0.0

03

),m

ild

an

dse

ver

e(p¼

0.0

01

)a

nd

mo

der

ate

an

dse

ver

e(p¼

0.0

3)

at

ba

seli

ne

Res

po

nsi

ve

totr

eatm

ent

Sco

res

cha

ng

ed

ue

totr

eatm

ent-

rela

ted

imp

rov

emen

tN

ot

ass

esse

dW

ith

ing

rou

pch

an

ge

fro

mb

ase

lin

esc

ore

sw

ere

sig

nifi

can

tly

dif

fere

nt

wit

htr

eatm

ent

(p<

0.0

01

)

Min

ima

lly

imp

ort

an

td

iffe

ren

ceD

iffe

ren

cein

sco

res

bet

wee

nim

pro

ver

sv

s.th

ose

wh

od

idn

ot

cha

ng

eo

nm

easu

res

of

sev

erit

y

Th

eM

IDd

efin

eda

sth

ed

iffe

ren

cein

mea

nch

an

ge

fro

mb

ase

lin

eP

QO

L-1

2sc

ore

for

pa

tien

tsw

ho

imp

rov

edb

ya

tle

ast

on

ep

oin

to

nth

ep

ati

ent

or

ph

ysi

cia

nra

ted

sev

erit

ysc

ale

,v

s.th

e

No

ta

sses

sed

Dif

fere

nce

for

imp

rov

ers

vs.

tho

sew

ho

sho

wed

no

cha

ng

ew

as

1.2

4(p

<0

.05

)o

nth

ep

ati

ent-

rate

dse

ver

ity

sca

lea

nd

20 Koo et al.

Page 38: Koo o 0849337232

mea

nch

an

ge

fro

mb

ase

lin

efo

rth

ose

wh

osh

ow

edn

och

an

ge

0.3

9(p¼

0.4

5)

on

the

ph

ysi

cia

n-r

ate

dse

ver

ity

sca

leD

iffe

ren

cein

sco

res

bet

wee

nim

pro

ver

sv

s.th

ose

wh

od

idn

ot

cha

ng

eo

ng

lob

al

eva

lua

tio

no

fre

spo

nse

totr

eatm

ent

Th

eM

IDd

efin

eda

sth

ed

iffe

ren

cein

mea

nch

an

ge

fro

mb

ase

lin

eP

QO

L-1

2sc

ore

for

pa

tien

tsw

ho

sho

wed

at

lea

stm

od

era

tere

spo

nse

totr

eatm

ent,

vs.

the

mea

nch

an

ge

fro

mb

ase

lin

efo

rth

ose

wh

osh

ow

edo

nly

slig

ht

resp

on

se(s

om

eim

pro

vem

ent—

ab

ou

t2

5%

;h

ow

ever

,si

gn

ifica

nt

evid

ence

of

stu

dy

con

dit

ion

rem

ain

s)o

rn

ore

spo

nse

totr

eatm

ent

(stu

dy

con

dit

ion

ha

sn

ot

cha

ng

ed)

No

ta

sses

sed

Dif

fere

nce

for

tho

sew

ho

sho

wed

mo

der

ate

imp

rov

emen

tv

s.th

ose

wh

osh

ow

edn

och

an

ge

or

on

lysl

igh

tim

pro

vem

ent

on

the

ph

ysi

cia

ns’

ass

essm

ent

of

the

glo

ba

lre

spo

nse

totr

eatm

ent

wa

s1

.14

(p¼

0.1

8)

Ab

bre

viat

ion

s:P

QO

L-1

2,

12-I

tem

Pso

rias

isQ

ual

ity-o

f-L

ife

Qu

esti

on

nai

re;

BS

A,

bo

dy

surf

ace

are

a;M

ID,

min

imall

yim

po

rtan

td

iffe

ren

ce;

SD

,st

an

dard

dev

iati

on

;S

E,

stan

dard

erro

r;D

erm

ato

logy

Lif

eQ

uali

tyIn

dex

;P

AS

I,p

sori

asi

sare

ase

ver

ity

ind

ex.

Koo–Menter Psoriasis Instrument 21

Page 39: Koo o 0849337232

Tab

le3

Co

rrel

ati

on

saB

etw

een

Fin

al

PQ

OL

-12

an

dC

lin

ica

lo

rO

ther

Pa

tien

t-R

epo

rted

Mea

sure

s(S

tud

y1

)

Qu

esti

on

Ph

ysi

cia

nR

S(n¼

47

4)

Pa

tien

tR

S(n¼

48

1)

OL

A(n¼

48

0)

BS

A(n¼

48

1)

PA

SI

(n¼

48

2)

DL

QI

(n¼

48

2)

Inth

ep

ast

fou

rw

eek

s..

.H

ow

self

-co

nsc

iou

sd

oy

ou

feel

wit

hre

ga

rdto

yo

ur

pso

ria

sis?

0.2

6s

0.4

80

.25

0.2

00

.22

0.6

4

Ho

wh

elp

less

do

yo

ufe

elw

ith

reg

ard

toy

ou

rp

sori

asi

s?0

.20

0.4

00

.26

0.2

00

.22

0.5

0

Ho

wem

ba

rra

ssed

do

yo

ufe

elw

ith

reg

ard

toy

ou

rp

sori

asi

s?0

.23

0.4

40

.23

0.2

00

.22

0.6

4

Ho

wa

ng

ryo

rfr

ust

rate

dd

oy

ou

feel

wit

hre

ga

rdto

yo

ur

pso

ria

sis?

0.2

50

.46

0.2

90

.21

0.2

40

.58

To

wh

at

exte

nt

do

esy

ou

rp

sori

asi

sm

ak

ey

ou

ra

pp

eara

nce

un

sig

htl

y?

0.3

50

.51

0.2

80

.30

0.3

00

.66

Ho

wd

isfi

gu

rin

gis

yo

ur

pso

ria

sis?

0.4

10

.54

0.3

60

.38

0.4

00

.66

Ho

wm

uch

do

esy

ou

rp

sori

asi

sim

pa

cty

ou

ro

ver

all

emo

tio

na

lw

ell-

bei

ng

?0

.26

0.4

40

.23

0.2

60

.26

0.6

4

Ov

era

ll,

tow

ha

tex

ten

td

oes

yo

ur

pso

ria

sis

inte

rfer

ew

ith

yo

ur

cap

aci

tyto

enjo

yli

fe?

0.2

70

.42

0.2

50

.25

0.2

60

.69

Du

rin

gth

ep

ast

fou

rw

eek

s,h

ow

mu

chh

av

eea

cho

fth

efo

llo

win

gb

een

aff

ecte

db

yy

ou

rp

sori

asi

s?It

chin

g?

0.3

50

.58

0.4

10

.32

0.3

60

.62

Ph

ysi

cal

irri

tati

on

?0

.40

0.6

10

.44

0.3

40

.38

0.6

5P

hy

sica

lp

ain

or

sore

nes

s?0

.33

0.5

70

.40

0.3

10

.36

0.6

6C

ho

ice

of

clo

thin

gto

con

cea

lp

sori

asi

s?0

.37

0.4

90

.33

0.2

90

.32

0.6

8M

ean

PQ

OL

-12

Sco

re0

.38

0.6

10

.38

0.3

30

.36

0.7

8

aS

pea

rman

corr

elati

on

sfo

ro

rdin

al

mea

sure

men

tsc

ale

s(p

hysi

cian

-an

dp

ati

ent-

rate

dse

ver

ity)

an

dP

ears

on

corr

elati

on

sfo

rin

terv

al

mea

sure

men

tsc

ale

s

(OL

A,

BS

A,

PA

SI,

DL

QI)

.

Ab

bre

via

tion

s:P

QO

L-1

2,

12

-Ite

mP

sori

asi

sQ

ual

ity

-of-

Lif

eQ

ues

tio

nn

air

e;B

SA

,b

od

ysu

rfac

ea

rea

;D

LQ

I,d

erm

ato

log

yli

feq

ua

lity

ind

ex;

OL

A,

ov

era

ll

lesi

on

al

ass

essm

ent;

RS

,ra

ted

sever

ity;

PA

SI,

pso

riasi

sare

aan

dse

ver

ity

ind

ex.

22 Koo et al.

Page 40: Koo o 0849337232

Tab

le4

Mea

nP

QO

L-1

2S

core

sa

tB

ase

lin

ea

nd

En

d-o

f-T

rea

tmen

t,b

yP

hy

sici

an

-a

nd

Pa

tien

t-R

ate

dS

ever

ity

Cli

nic

al

tria

l(S

tud

y2

)

Offi

ce-b

ase

dst

ud

y(S

tud

y1

)B

ase

lin

eE

nd

of

trea

tmen

t

Ra

ter

Sev

erit

yn

Mea

n(S

D)

nM

ean

(SD

)n

Mea

n(S

D)

Ph

ysi

cia

nC

lea

red

0N

A0

0(0

)8

3.3

5(1

.92

)M

ild

16

83

.9(2

.6)

73

.90

(2.1

9)

38

3.1

3(2

.21

)

Mo

der

ate

15

15

.0(2

.8)

47

5.3

6(1

.89

)2

44

.89

(2.7

2)

Sev

ere

15

56

.4(2

.3)

17

6.3

6(2

.41

)1

8.0

0(N

A)

Pa

tien

tC

lea

red

0N

A0

0(0

)1

2.2

5(N

A)

Mil

d1

85

3.2

(2.3

)1

73

.59

(1.4

2)

26

2.3

8(1

.42

)

Mo

der

ate

17

85

.2(2

.3)

35

5.6

4(1

.99

)1

54

.74

(2.2

6)

Sev

ere

11

87

.6(1

.8)

18

6.8

0(1

.81

)5

6.1

8(2

.35

)

No

te:

To

tal

n<

48

3(o

ffice

-ba

sed

stu

dy

)o

r<

71

(cli

nic

al

tria

l)d

ue

tom

issi

ng

ph

ysi

cian

-o

rp

ati

ent-

rate

dse

ver

ity

data

.

Koo–Menter Psoriasis Instrument 23

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PQOL-12 means for both physician and patient ratings of severity in theoffice-based study were statistically significant (p< 0.001), providing evi-dence of discriminant validity.

Responsiveness

The potential for responsiveness was assessed in this office-based cross-sectional study (Study 1) using the PQOL-12. The mean score for thePQOL-12 was 5.03 (SD, 2.76). Only 1.5% of the responses were at the floorand 1% of responses were at the ceiling, indicating that the scale has thecapability to assess both extremes and that the instrument would be capableof detecting changes during a clinical trial. Responsiveness was furtherassessed with the following clinical trial data (Study 2).

STUDY 2: USING DATA FROM THE RANDOMIZEDCLINICAL TRIAL

In Study 2, data from the clinical trial on the 41-item PQOL was used toevaluate psychometric properties of the PQOL-12. Disease severity wasmeasured from both physician and patient perspectives. Physicians wereasked to evaluate overall patient discomfort, overall disease severity definedas mild, moderate, or severe, percent BSA involvement, signs and symptomsof disease (e.g., pruritis), and overall response to treatment. Patients wereasked to complete the 41-item PQOL and an overall evaluation of their dis-ease 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 theneed for a change in therapy). The PQOL-12 demonstrated validity andreliability. Item-to-total correlations were moderate to high, and Cronbach’sa was 0.91. Correlations of the total PQOL-12 score and the individualPQOL-12 items with the clinical measures were moderate for all measures(Table 5). The PQOL-12 also discriminated among physician and patient-rated severity at baseline and at end of treatment (Table 4).

Responsiveness

In Study 2 (using the clinical trial data retrospectively), the responsivenessassessment included examination of floor and ceiling effects, differences inseverity levels, and treatment effects. There were no floor or ceiling effectsobserved for the PQOL-12, indicating that it has the capability to detectimprovement and decline in this patient population. Mean PQOL-12 scores

24 Koo et al.

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were calculated for each disease severity level by both patients and physi-cians. Both at the baseline and at the end of treatment, differences betweenseverity levels were generally 1 or 2 points for both physician and patientratings (Table 4).

Table 5 Spearman Correlations Between PQOL-12 Items and Clinical Measures(Study 2)

QuestionDisease

discomfortDiseaseseverity

PercentageBSA Pruritis

In the past four weeks . . .How self-conscious do you feel

with regard to your psoriasis?0.34a 0.29a 0.43a 0.30a

How helpless do you feel withregard to your psoriasis?

0.32a 0.14 0.25a 0.25a

How embarrassed do youfeel with regard to yourpsoriasis?

0.35a 0.13 0.30a 0.25a

How angry or frustrated do youfeel with regard to yourpsoriasis?

0.44a 0.19 0.28a 0.28a

To what extent does yourpsoriasis make yourappearance unsightly?

0.37a 0.36a 0.36a 0.22

How disfiguring is yourpsoriasis?

0.31a 0.34a 0.59a 0.18

How much does your psoriasisimpact your overall emotionalwell-being?

0.50a 0.32a 0.29a 0.22

Overall, to what extent doesyour psoriasis interfere withyour capacity to enjoy life?

0.31a 0.23 0.28a 0.04

During the past four weeks, howmuch have each of thefollowing been affected byyour psoriasis?

Itching? 0.38a 0.22 0.16 0.67a

Physical irritation? 0.36a 0.31a 0.25a 0.60a

Physical pain or soreness? 0.31a 0.28a 0.17 0.33a

Choice of clothing to concealpsoriasis?

0.22 0.15 0.35a 0.22

Mean PQOL-12 Score 0.49a 0.34a 0.42a 0.41a

aSignificant at the a¼ 0.05 level.

Abbreviations: PQOL-12, 12-Item Psoriasis Quality-of-Life Questionnaire; BSA, body surface

area.

Koo–Menter Psoriasis Instrument 25

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MINIMALLY IMPORTANT DIFFERENCE

The MID was assessed using an anchor-based approach. The MID is thesmallest (or minimal) change in an HRQOL measure that is consideredmeaningful (or important) by either a clinician or a patient (8). A techniqueadapted from Juniper et al. was used to calculate the MID using data fromStudy 2 (8). Three anchors or measures of improvement were investigatedincluding: patient-rated disease severity, physician-rated disease severity,and physician-evaluated global response to treatment. A difference of 1.24points was observed between those who improved and those who reportedno change in the patient-rated severity. The difference in the means of thesetwo groups was statistically significant, indicating an important and statis-tically significant difference between these two groups. Differences betweenthose who improved and those who did not experience a change was calcu-lated as 1.14 using the physician rating of global response to treatment,although the means were not statistically significant between these twogroups. In contrast, differences between physician ratings of severity weresmaller (0.39) and the means of improvers and patients who did not experi-ence change were not statistically significant. This finding suggests that a0.4-point change may be sufficient to distinguish these groups on this mea-sure. In summary, these results suggest that the MID for PQOL-12 score isabout 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–retestreliability of PQOL-12, preliminary analyses from subsequent researchindicate that the test–retest correlation of PQOL-12 exceeds 0.80 whenconducted 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 usedtool within clinical practice, the calculation of the PQOL-12 score for usewithin 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) andis calculated by taking the mean of the item scores, the scoring for thePQOL-12 within the KMPI does not involve calculating mean item scorebut rather uses a simple sum of the item scores for a score that ranges from0 (best) to 120 (worst).

As the burden of psoriasis on a patient’s health-related and psoriasis-specific quality-of-life is determined by a range of variables unique to eachpatient’s disease symptoms and life-circumstances, a comprehensive andpractical approach was employed to determine a PQOL-12 score criterion

26 Koo et al.

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for use within Part 3 of the KMPI. Qualitative review of the data fromStudy 1 and Study 2 along with quantitative analyses (i.e., exploratory clus-ter analysis) was conducted to identify if there was a natural ‘‘cut-point’’between patients with mild and moderate psoriasis that was relativelystable over the various patient- and physician-rated severity measures. Inaddition, we sought to balance this with a cut-off point where a therapeuticintervention might be expected to have an impact on psoriasis-specificquality-of-life, while also accounting for the minimum important differenceon the PQOL-12, which is approximately 1 to 2 points. Analysis results indi-cated that such a cut-off point might be as low as a score of 25 using thescoring method for the PQOL-12 within the KMPI, however, clinicalopinion suggested the use of a more conservative 50 points for the finalinstrument. Further research is needed to better understand the minimumpoint where treatment might positively impact psoriasis patients based ontheir PQOL-12 score.

DISCUSSION ON KMPI

The KMPI provides a quick and easy way to identify and document patientswith psoriasis who require systemic therapy.

The KMPI is short enough to be completed during a routine visit to adermatologist. It takes approximately five minutes for the patient to com-plete the front page of the instrument while waiting in the reception areaor the examination room prior to being seen by the physician. Similarly,the physician assessment takes approximately five to seven minutes to com-plete and the resulting instrument can become part of the patient’s medicalrecord for reference at subsequent patient visits.

The KMPI is unique in providing a complete evaluation of the patient’sdisease status-incorporating assessments of psoriasis-specific quality-of-lifewith a validated questionnaire (PQOL-12), psoriasis severity and psoriaticjoint disease.

The KMPI alerts the physician and patient of the need to assesshealth-related quality-of-life and joint-related symptoms in the clinical eva-luation of psoriasis and determines the suitability (or otherwise) for systemictherapy in individual patients.

The KMPI has the potential to improve physician–patient communi-cation by involving the patient in characterizing their disease and its impacton their lives.

CONCLUSION

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

Koo–Menter Psoriasis Instrument 27

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patients with psoriasis who may be candidates for systemic therapy, as wellas 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 withpsoriasis 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 question-naire to assess the quality of life for psoriasis patients: an analysis of the reliability,validity, and responsiveness of the psoriasis quality of life questionnaire. Derma-tologie Psychosomatik 2002; 3:171–179.

4. Feldman S, Koo J, Menter A, Bagel J. Decision points for the initiation of sys-temic treatment for psoriasis. JAAD 2005; 53(1):101–107.

5. Koo J. Population-based epidemiologic study of psoriasis with emphasis onquality of life assessment. Dermatol Clin 1996; 14:485–496.

6. Koo JY, Martin D. Investigator-masked comparison of tazarotene gel q.d. plusmometasone furoate cream q.d. vs. mometasone furoate cream b.i.d. in the treat-ment of plaque psoriasis. Int J Dermatol 2001; 40:210–212.

7. Koo J, Menter A, Lebwohl M, et al. The relationship between quality of lifeand disease severity: results from a large cohort of mild, moderate, and severepsoriasis patients [abstr]. Br J Dermatol 2002; 147:1078.

8. Koo J, Kozma CM, Menter A, et al. Development of a disease-specific quality oflife 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 impor-tant change in a disease-specific quality of life questionnaire. J Clin Epidemiol1994; 47(1):81–87.

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4

General Guidelines for Administrationof 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% ofthe world (1). It is one of the more commonly seen and treated diseasesfor the general dermatologist, amounting to approximately 2.3% to 10%of the office practice (2,3). In a survey of dermatologists who belong tothe American Academy of Dermatology, approximately 70% of psoriasispatients were treated with topical therapies and 30% with phototherapy/systemic therapy (4). In another report, it is estimated that 75% of psoriasispatients have mild-to-moderate disease [as measured by <20% of body sur-face 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 byprimary care physicians), safe and effective, easy to administer, and cost effec-tive. However, it is not a realistic expectation that topical therapy will result intotal clearance of psoriatic lesions (6). Nevertheless, medical advances in the last30 years, particularly systemic therapy and phototherapy, have given manypsoriasis patients temporary partial to total clearance of their disease and relieffrom their symptoms.

In this chapter, we will discuss the various factors to consider whenchoosing whether to use topical agents versus systemic therapies. We will

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then discuss the different factors to consider before prescribing topical agentsfor psoriasis. We hope these general guidelines for the use of topical therapieswill 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 deter-mining the severity of psoriasis. Generally, the experienced dermatologistcan estimate in a brief examination the extent of disease and likely severity.To be more quantitative as measured in clinical trials, the patient’spalm including the fingers and the thumb (i.e., from the wrist to the tip ofthe fingers) constitutes approximately 1% of the total BSA. According to theNational Psoriasis Foundation, up to 3% BSA is considered mild psoriasis,and it can typically be managed with topical therapies alone. Between3% and 10% BSA is considered moderate psoriasis, and greater than 10%BSA is considered severe psoriasis. However, it remains controversial wherethe 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 toall the affected areas. Further, it would become difficult to obtain anadequate supply of topical therapy for sufficient coverage. Some topicalmedications such as topical steroids and calcipotriene have safety limitationson the amount of drug that is absorbed per unit of time as described else-where. Moderate-to-severe psoriasis usually requires systemic medicationsor phototherapy supplemented by topical therapies or systemic retinoids.

Psoriasis Area Severity Index

The PASI is a quantitative instrument that allows the dermatologist to makea specified measurement of disease severity combining BSA with the degreeof erythema, scaling, and thickness (induration). However, the actual prac-tice of calculating the PASI is generally too cumbersome in the clinical practicesetting. 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 scoreis 72.0, which represents 100% BSA and a score of four (or severe) forerythema, scaling, and thickness. It has been recently suggested that PASI<7.0 should correspond to mild plaque psoriasis, PASI 7.0–12.0 to moder-ate disease, and PASI >12.0 to severe disease (11).

PASI is also used to measure relative clinical changes, and thesechanges are often endpoints measured in clinical trials and published in theliterature. 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 PASIscore. For example, if a patient starts with a PASI score of 40, and two monthslater has a PASI score of 20, it means that there is a 50% improvement or aPASI50 improvement. PASI50 and PASI75 are the most commonly measuredendpoints for efficacy (12).

Location on Body and Types of Psoriasis

Aside from extent of BSA, other important factors include location of pso-riasis, 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, somore aggressive topical therapies would be warranted. Further, a personwho may appear in public may also wish to have exposed areas to be moreaggressively treated such as the hands and forearms. However, topical ste-roids should be used carefully and sparingly on the face since the skin isrelatively thin, and side effects such as acne/rosacea may occur. The eyelidsare 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 inconstant contact with each other, such as the axilla and groin. With a nat-ural occlusion caused by two skin planes, the potency of topical steroidsmay increase 10–100 times (13). Potent topical steroids should be avoidedin these self-occluded areas since the risk of skin atrophy is significantlyincreased. Calcipotriene, pimecrolimus, tacrolimus, or less potent topicalsteroids are safer therapies for inverse psoriasis.

In palmar-plantar psoriasis, the thickness of the skin of the palms andsoles diminishes the ability of topical therapies to penetrate the skin.Although these areas may have a small BSA, lesions on palms or solesmay be disabling, and topical therapies in combination with systemic ther-apy or phototherapy may be necessary.

Response to Therapy

Phototherapy and/or systemic therapy should be considered in even mildpsoriasis if the lesions are unresponsive to topical therapies. Sometimes thelocalized involvement is in an area that is physically, socially, emotionally,or occupationally disabling to the patient. As mentioned above, the face andhands are particular areas of concern, and appropriate aggressive treatment ofthese areas with phototherapy and/or systemic therapy in combination withtopical 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 arthri-tis (14). Patients with mild psoriasis are much less likely than patients withmoderate-to-severe psoriasis to be subsequently affected by psoriatic arthri-tis. 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 bepossible to tell that the patient had psoriasis in the first place. However, pso-riatic arthritis causes permanent bony changes that are irreversible, even ifthe patient is treated with disease-modifying systemic therapy.

None of the topical therapies have been shown to have any efficacy inresolving the pain or slowing joint destruction caused by psoriatic arthritis.If the patient does have mild psoriasis but with psoriatic arthritis that isadversely affecting everyday life or work, the patient should be consideredfor disease-modifying systemic therapies such as etanercept, infliximab, ormethotrexate. These medications have been shown to improve clinical fea-tures of the disease and slow radiographic progression of joint damage(15,16). Psoriatic arthritis may have a crippling effect on the patient, andit 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 overviewis presented here. When choosing a topical agent, it is best to understand theside effect profile, appropriate patient selection, efficacy, and expectedresults, and otherwise to master the use of a few therapies rather than touse all available topical therapies. In fact, topical therapies for psoriasisare fewer in number than the phototherapy and systemic treatmentsnow available. The main topical therapies used are topical steroids, calcipo-triene, and tazarotene, each of which has quantitative data on efficacy.Tacrolimus and pimecrolimus, which are topical immunomodulators, havebeen tested particularly for inverse psoriasis, but they are only moderatelyeffective. They are now used occasionally as off-label medications for psoriasis.

Anthralin and coal tar preparations are older therapies that are lesseffective, difficult to obtain, and significantly messy. Thus, they are infre-quently used today.

Table 1 The Major Topical Therapies Used to Treat Psoriasis

Topical steroidsCalcipotrieneTazaroteneAnthralinCrude coal tarLactic acidSalicylic acidPimecrolimusTacrolimusNonmedicated moisturizers

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Keratolytics such as lactic acid, salicylic acid, and the numerous avail-able nonmedicated moisturizers are complementary therapies that help toimprove quality of life symptoms. The keratolytics are useful for thickscaling areas, as on palms and soles. The moisturizers (lotions, creams,and ointments) are helpful in general for dry, scaly skin disease and dry cli-mates. Lotion preparations are more useful for scalp and intertriginousareas, while thick creams to ointments are superior for trunk and extremi-ties. Fissured psoriatic lesions that appear on palms and soles may benefitwith thick ointments or petrolatum. Patients with psoriasis should beencouraged 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 ofchoice, 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 loca-tion of disease:

� Range of potencies from weak to moderate to potent to super-potent (seven classes of potency).

� It is the authors’ suggestion that physicians new to the use oftopical corticosteroids select one steroid from one of the weak,moderate, and potent classes to learn what formulations areavailable (lotion, cream, ointment, etc.), packaging sizes [30 g(1 oz), 60 g, 120 g tubes, etc.], and generic/brand names. This willfacilitate writing prescriptions and providing an adequateamount 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 skinatrophy.

� 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 describedwith the term tachyphylaxis, which implies the developmentof resistance or loss of effectiveness over a period of two to

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four months. Early clinical trials with topical steroids lastedonly about one month during which time a good therapeuticresponse was obtained leading to the approval of these drugs.Subsequent experience and few studies suggest a loss of effi-cacy over the next several months (17). If discontinued, topicalsteroids 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 in0.05% 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 combi-nation with either calcipotriene or tazarotene preparations willproduce a higher response level approximating 70–90% insome clinical trials (18–21).

� These combinations may be most useful in patients with diffi-cult but limited lesions of psoriasis. Combinations producesignificantly higher costs. Depending on amount of skin beingtreated these costs can begin to approach those of systemictherapy (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 areainvolved and the frequency of applications. A rule of thumb is that approxi-mately 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 needa prescription for 180 g or 6 oz of medication in one prescription. Unfortu-nately, the prescribed amount of topical agents is frequently too little for theamount 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 vehicledepends on the location of the lesions, the patient’s symptoms, and thepatient’s preference. Patient preference often takes precedence as long asthere are no safety concerns.

Thicker (ointment) vehicles are generally more effective and moremoisturizing based on a quasiocclusion effect produced by the ointmentssuch as a Vaseline base. Thus, based on the same active ingredients, oint-ments are stronger than creams, which are stronger than lotions. Creamsspread across the skin easily and quickly, are more quickly absorbed thanointments, and do not produce a greasy effect on clothes. Thus, creamsmay have better compliance in the morning when the patient is wearingdress clothes for work or school. Ointments are more acceptable in theevenings when patients have more time to apply the medicine and are lessworried about staining their clothing. Patients usually appreciate a prescrip-tion for both a cream and an ointment of the same therapy.

The symptoms may also guide the vehicle choice. Dry or itchy skinmay benefit from an ointment or cream, which are better for moisturizing.Fissured psoriatic lesions that appear on palms and soles may benefit fromthick ointment or petrolatum. Gels and foams are particularly drying andmay be better suited for those who have oily skin or dislike the greasinessof ointments and creams. Patients with fissures or cracked lesions will com-plain of stinging pain if an alcohol-based vehicle such as a liquid solution orfoam is prescribed.

The location of the psoriasis may guide which vehicle to use. The scalp isan area of therapeutic challenge since the hair blocks the direct application tothe lesions and prevents patients from using cosmetically unsuitable vehiclessuch as ointments and creams. Gels, foams, liquid solutions, and lotions aretypically the best vehicles for the scalp. However, some African-Americanpatients with scalp psoriasis may prefer ointments. In the intertriginous areasof the body, such as axillae, groin or inframammary folds, a lotion or creamwill be more comfortable than an ointment.

Weather or environmental conditions may suggest the appropriatetype of vehicle/medication. For example, in a warm and moist climate,lotions and creams will be better tolerated than ointments. The opposite wouldbe true for dry or cold climates.

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Patients should be instructed on the correct use of these agents. Mosttherapies can be applied either on a damp scalp after towel drying or on adry scalp. It is imperative to instruct the patient on appropriate applicationso that the agent reaches the scalp lesions and not just the hair. Demonstrat-ing the application in the office may help with compliance. Patients shouldalso be taught that these medicines must be left on the scalp and thus usedafter a shampoo rather than before. Active medications to the scalp areoften applied at night and shampooed out in the morning with standard hairpreparations and conditioners as desired.

Patients should be instructed in the quantity of topical medicationsapplied to the skin. Basically, one should be rubbing in a thin film to theskin without leaving a thick or visible coating on the surface. That is waste-ful and expensive since the excessive medication will be rubbed off by theclothes. Keep in mind that in optimal conditions, only about 1% ofthe active ingredient, e.g., corticosteroid, applied to the skin actually pene-trates into the skin. Indeed, topical therapy is less than a wonderful way toget a drug into the skin. However, it does have the obvious advantage oflimiting the drug to only the skin in contrast to taking a drug orally, e.g.,oral prednisone versus topical steroids. There are vasoconstriction assayswith topical steroids that show penetration into the stratum corneum‘‘reservoir.’’ Plastic film occlusion several days after steroid application willproduce 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 witha particular vehicle for practical reasons is much less likely to use the agentas directed and may report that the therapy is ineffective when it actuallywould be effective if used correctly. This may limit the doctor’s therapeuticoptions and force the use of stronger medications. It is best to encourage thepatients to use their therapies as directed and to ask their opinion and feed-back about the prescribed medicine.

Strength of the Agent

The strength of the agent applies mostly to topical steroids, so we leave thatdetailed discussion to Chapter 4. However, it is very important to considerthe age of the patient. Due to their thinner skin, pediatric and elderlypatients 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 numberof 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 likelyto 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 thefeet, hands, and extremities, the patient can apply a low- to medium-classtopical 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 baggieor thin plastic glove over the feet or hands. One can use a sock or thin cottonglove to keep the plastic in place. Application of steroids under occlusion isonly done for a few hours or in the evening. Occlusion produces a greaterpenetration of the steroid into the skin lesions.

Extensive use of steroids under occlusion can produce side effectsincluding atrophy of the skin leading to fragility of the skin and purpura.In past years for severe psoriasis, steroids and occlusion were used exten-sively or even to the entire body leading to risks of systemic steroid effectsincluding damage involving the hypothalamus–pituitary–adrenal gland axisor the eventual development of pustular psoriasis in some patients. Fortu-nately, with the advent of many more treatments for moderate-to-severepsoriasis, extensive steroid/occlusion is rarely used today.

For patients with small 1–4 in lesions on the trunk and extremities, aquasitopical approach would be an intralesional technique utilizing theinjection of small doses of corticosteroids, mainly triamcinolone in anaqueous formulation. The most typical injection formulation is in a vial witha concentration of 10 mg/mL. Using dilutions with normal saline, a concen-tration of 2.5 mg/mL is prepared in the vial or syringe and injectedintradermally and superficially into the upper dermis. As concentrationsare increased to 5 or 10 mg/mL, the risk of atrophy in the injection site isincreased. The injection approach is often very effective for small, scatteredlesions 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, rota-tional, or sequential therapy. These techniques will be further discussed inlater chapters, but we will present the general rationale behind each one.Combination therapy works on the premise of two medications that actby different mechanisms to maximize clinical results and to minimize sideeffects of each individual agent. A treatment with a rapid onset of actionbut unfavorable side effect profile, such as a topical steroid, can be effec-tively combined with a slower-acting agent but more favorable side effectprofile, such as calcipotriene or tazarotene. However, this combinationeffect has a greater expense by using two different medications. A newcombination of calcipotriol/betamethasone dipropionate ointment, whichhas 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 usedcombinations 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 betweenmedications with differing toxicity profiles. This technique is more com-monly used with systemic therapies than with topical therapies (27).

Sequential therapy is when medications are used in a set sequence tomaximize the initial speed of improvement while minimizing long-termtoxicity. The three phases of this technique are the clearing phase, the transi-tional phase, and the maintenance phase. Although the classic example ishalobetasol propionate and calcipotriene, sequential therapy can be per-formed with any combination of a rapid-acting therapy and a maintenancemedication that is safe to use long term.

REFERENCES

1. Koo J. Population-based epidemiologic study of psoriasis with emphasis onquality of life assessment. Dermatol Clin 1996; 14:485–496.

2. Fleischer AB Jr., Feldman SR, Bradham DD. Office-based physician servicesprovided by dermatologists in the United States in 1990. J Invest Dermatol1994; 102:93–97.

3. Thompson TT, Feldman SR, Fleischer AB Jr. Only 33% of visits for skin diseasein the U.S. in 1995 were to dermatologists: is decreasing the number of derma-tologists 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 systematicreview 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 InvestDermatol 1994; 102:967–969.

8. Langley RG, Ellis CN. Evaluating psoriasis with psoriasis area and severityindex, Psoriasis Global Assessment, and Lattice System Physician’s GlobalAssessment. J Am Acad Dermatol 2004; 51:563–569.

9. Jacobson CC, Kimball AB. Rethinking the psoriasis area and severity index: theimpact 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 pso-riasis 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 criter-ion 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% reductionin the psoriasis area and severity index (PASI 50) is a clinically significant end-point 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 inthe treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet2000; 356:385–390.

16. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximabtherapy 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 fluocino-nide creams in psoriasis and eczema. Int J Dermatol 1985; 24:461–465.

18. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobe-tasol ointment in the long-term treatment of psoriasis: effects on the duration ofimprovement. J Am Acad Dermatol 1998; 39:447–450.

19. Kragballe K, Barnes L, Hamberg KJ, et al. Calcipotriol cream with or with-out concurrent topical corticosteroid in psoriasis: tolerability and efficacy. Br JDermatol 1998; 139:649–654.

20. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus cortico-steroid 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 cor-ticosteroid 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/betamethasoneformulation with rapid onset of action was superior to monotherapy withbetamethasone dipropionate or calcipotriol in psoriasis vulgaris. Acta DermVenereol 2002; 82:131–135.

23. Parslew R, Traulsen J. Efficacy and local safety of a calcipotriol/betamethasonedipropionate ointment in elderly patients with psoriasis vulgaris. Eur J Dermatol2005; 15:37–39.

24. Kragballe K, Noerrelund KL, Lui H, et al. Efficacy of once-daily treatment regi-mens with calcipotriol/betamethasone dipropionate ointment and calcipotriolointment 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 combina-tions. Clin Exp Dermatol 2001; 26:356–361.

27. Weinstein GD, White GM. An approach to the treatment of moderate to severepsoriasis with rotational therapy. J Am Acad Dermatol 1993; 28:454–459.

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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 thegeneral population, the majority of these individuals suffer from limited dis-ease, with lesions that encompass a relatively small portion of their totalbody surface area (1,2). Accordingly, most patients with psoriasis can betreated with topical medications. Topical corticosteroids, either exclusivelyor in combination with other treatments, remain the mainstay of treatmentin the United States. Approximately 50% of all patients with psoriasis aretreated exclusively with topical corticosteroids. An additional 26% ofpatients seeking medical care for psoriasis treatment are prescribed topicalcorticosteroids in combination with another medication (1).

Topical corticosteroids are a cornerstone of dermatologic treatmentfor many inflammatory skin conditions. There is seemingly an infinitenumber of topical corticosteroid agents available; they may be categorizedby potency and/or formulation (the latter including creams, ointments,lotions, sprays, foams, shampoos, oils, tape, etc.). Understanding thenuances of topical corticosteroid vehicles and potency is a critical aspectof dermatologic care in general and psoriasis treatment in particular. Eachformulation has advantages and disadvantages, and the wide variety offormulations provides the clinician great flexibility when prescribing

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these medications. This chapter will address many aspects of topicalcorticosteroid use, challenging existing paradigms and offering newapproaches to optimize topical corticosteroid treatment.

RATIONALE FOR PSORIASIS THERAPY

Psoriasis is a complex immune-mediated disease where inflammation andhyperproliferation are key features. A current model for psoriasis involvespresentation of an unknown antigen by an antigen presentation cell topatrolling na€��ve T-cells. Following complex intercellular signaling andrecruitment of memory T-cells to the psoriasis lesion, there is extensiveinflammation that is propagated by cytokines and growth factors that arenecessary for immune response. Several of these cytokines function both asinflammatory mediators and growth factors and help to explain the clinicalcharacteristics of plaque psoriasis.

Topical corticosteroids work by modulating complex intracellularsignaling of the immune system and by limiting vascular permeability thatpropagate the immune-mediated inflammatory response. A reduction inthe local production of cytokines and vasodilatory substances in lesionalskin 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 awoman with severe rheumatoid arthritis was successfully treated with anoral preparation of corticosteroid. Two years later, in 1950, the Nobel Prizewas awarded for the discovery of this new class of anti-inflammatory med-ication. Sulzberger and Witten’s description of ‘‘compound F’’ in 1952 is thefirst documented account of topical corticosteroid use.

The biological and pharmacological activity of the corticosteroidmolecule primarily stems from its ability to alter gene transcription and,ultimately, protein expression. For this to occur, the corticosteroid moleculemust first pass through the cell wall where it reversibly binds to a corticosteroidreceptor in the cellular cytoplasm. This newly formed corticosteroid–corticos-teroid receptor complex, with increased DNA binding capacity via an allos-teric change in configuration, then diffuses into the cell nucleus where it bindsto the cell’s DNA. Once bound to the cell’s DNA, the corticosteroid complexmodulates the transcription of messenger RNA (mRNA) (3). One down-stream 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 vasoconstrictiveabilities by decreasing the production of key vasodilatory proteins using thissame mechanism (4). Though the efficacy of a given topical corticosteroid isdetermined by several factors, the first key element is the quantitative abilityof the active molecule to bind corticosteroid receptors and subsequent tran-scriptional modulation.

Almost immediately following the discovery and first descriptions ofhydrocortisone, attempts to increase its potency were initiated. One wayto increase potency is halogenation (with fluoride or chlorine) at the C-6alpha or C-9 alpha structural positions (Fig. 1). Additionally, fluorinationin part produces a molecule with superior potency via protection of the ste-roid ring backbone structure from routine metabolic breakdown (5). Asmore potent corticosteroids were developed, side effects of corticosteroid

Figure 1 Functional effects of changing corticosteroid structural elements. The ster-oid base contains four rings. Corticosteroids have a dihydroxyacetone side chainattached to the carbon atom at position 17. The addition of a double bond betweenthe C-1 and C-2 atoms of the cholesterol backbone (A) increases potency by increas-ing the lipophilicity of the molecule. Halogenation (with fluoride or chlorine) at theC-6 or C-9 structural positions (B) increases corticosteroid potency through interac-tions with the corticosteroid receptor. Reduced polarity of the molecule (andtherefore greater lipophilicity) can also be achieved by removal of the (C) C-16 alphahydroxyl group or (D) the C-17 dihydroxyacetone side chain or (E) by maskinghydrophilic side groups, via esterification of the C-17 or C-21 positions.

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treatment became evident. Historically, more potent corticosteroids werecreated by fluorination; thus, fluorinated products became associated withhigher risk of adverse events. But clearly, it is not fluorination (or halogena-tion) per se that results in corticosteroid side effects. To the extent that agiven compound is able to activate the corticosteroid receptor, so too willbe its capacity to produce unwanted and detrimental side effects, irrespectiveof the potency-enhancing mechanism. It is an incorrect assumption border-ing on myth that nonhalogenated corticosteroids are in any way safer thanhalogenated ones; we can expect that corticosteroids of similar potency willhave similar side effect profiles.

DELIVERY AND PHYSIOLOGIC POTENCY

As with systemic corticosteroid therapy, topical corticosteroid therapy andefficacy relies upon activation of the cytoplasmic corticosteroid receptor.However, unlike systemic corticosteroids, which are ingested or injectedintramuscularly, topical corticosteroids must reach their target cells by firstdiffusing across the stratum corneum. Therefore, it is essential to realize thattopical corticosteroid potency is a function of not only the agent’s physio-logic potency to activate its cellular receptor but also the ability of thatagent to first gain access to the intended area.

The ability of a given corticosteroid compound to traverse the stratumcorneum involves complex physical chemistry. Furthermore, the ability of aformulation to deliver a corticosteroid cannot be predicted and must beassessed, or measured, clinically. A key concept of the potency of a formula-tion is the ability of the active agent to separate from the vehicle and diffuseacross 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 sitson water in Italian dressing). How much drug reaches the targeted skin isdetermined in large part by how the drug partitions between the vehicle andstratum corneum phases. A corticosteroid that partitions from the vehicleinto the skin will have a greater potency than a comparable corticosteroidagent that tends to stay in the vehicle despite equal inherent receptor activatingability. Vehicles that drive the corticosteroid into the skin because of goodpartitioning—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 corneummay affect partitioning. For instance, polar, hydrophilic molecules movepoorly through the stratum corneum and lipophilic, nonpolar moleculesdiffuse through this barrier well (6–8). There are several methods by whichthe lipophilicity, and thus the diffusion capacity, of the active corticosteroidmay be enhanced. These include the removal of the C-17 dihydroxyacetoneside chain or the C-16 alpha hydroxyl group and the addition of a doublebond 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 theC-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 gen-erally (but not always) tends to increase the delivery of the active drug fromthe vehicle to the skin. Propylene glycol is often present in topical cortico-steroid vehicles. This large molecule binds water, increasing the effectiveconcentration of the active drug, diffusion of the drug into skin, andpotency. Contrary to what one might think, however, changing the concen-tration of the corticosteroid compound does not always lead to predictableeffects on potency. If one increases the concentration to the point that adrug crystallizes out of solution, the drug may lose all potency. Acompound’s partition coefficient may also be affected by concentration;increasing the concentration of a corticosteroid may increase potency, butit may not. Indeed, when 0.1% triamcinolone cream is diluted 1:1 withanother base, the resulting 0.05% concentration may have similar, higher,or lower potency compared to the original 0.1% cream. The potency effectsof changes to a formulation (such as dilution with another vehicle or com-bined use with other agents) cannot be predicted. The only way to know isto test the actual preparation in clinical studies.

Alteration of the stratum corneum by increasing its permeability gen-erally enhances the delivery of the agent to the targeted skin. Pretreatmentwith catalytic or fat solvents, removal of scale by chemical or physicalmodalities, increased hydration, and temperature elevation all tend to resultin a more permeable stratum corneum (5,6).

Given the multitude of variables that affect the potency of a given topi-cal corticosteroid, the clinical potency of a compound is unpredictable untilclinical testing is done. The standard modality of objectively measuring cor-ticosteroid potency is the vasoconstrictor assay, introduced by McKenzie andStoughton in 1962 (9,10). Topical corticosteroid application results invasoconstriction of the dermal blood supply via the alteration of genetranscription and subsequent vasoactive mediator production. The vasocon-strictor assay assesses the blanching properties of a given compound overtime. Thus, by measuring objective data produced by corticosteroid receptoractivation, the vasoconstrictor assay provides information regarding not onlythe compound’s inherent ability to activate its receptors but also the abilityof the topical corticosteroid vehicle to deliver the active drug. The vasocon-strictor assay is a good guide to how compounds will perform in clinicalpractice, although because this assay is performed on normal skin, it maynot fully reflect the potency of drugs used on diseased skin. The vasoconstric-tor assay is used to place a formulation into one of seven potency classes.

The potency of topical drugs is dependent on characteristics of thevehicle, but the specifics of which vehicles are more potent are not alwayspredictable. Many clinicians have been taught that ointments, primarily

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due to their occlusive properties and superior hydration of the stratum cor-neum, are inherently more potent than creams (as an aside, there are nostrict definitions of what is an ointment vs. a cream; these names are appliedby manufacturers). Though some ointments may be more potent thancreams, lotions, liquids, and so on, this concept does not necessarily holdacross all topical corticosteroids (11). ‘‘Approved clobetasol propionatefoam (Olux1, Connetics Corporation; Palo Alto CA), lotion and spray(both Clobex1, Galderma Laboratories, L.P.; Forth worth, Texas) prepara-tions are similar in potency to ointment preparations as demonstrated bycomparable vasoconstriction scores and by roughly similar efficacy ratesin clinical trials (11a).’’

ADHERENCE

Discussing the biologic properties and factors that affect the delivery of atopical corticosteroid to target skin may overlook the key determinant ofefficacy, adherence. A corticosteroid that partitions through the stratumcorneum easily and strongly activates corticosteroid receptors may not bevery 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 apatient’s willingness to adhere to a given prescribed regimen of topicalcorticosteroids. Among the most prevalent of these factors is patient appre-hension regarding possible adverse effects related to topical corticosteroidapplication. In a questionnaire-based study of 200 dermatology outpatientswith atopic eczema, nearly 75% of patients expressed concern over the pos-sibility of experiencing adverse effects related to topical corticosteroid usage.Overall, 24% of the 200 patients questioned admitted to noncompliance atsome point secondary to this concern. Of most concern to patients werethe possibilities of skin thinning and nonspecific long-term effects (12).

Vehicle preference is also a key component that is thought to affectcompliance. Several factors influence a patient’s preference with regard tothe vehicle utilized to deliver the corticosteroid agent. Among these are prod-uct characteristics such as subjective greasiness, messiness, and the degree towhich the product stains clothing. As a general rule, patients prefer non-messy preparations, such as solution and foam vehicles, to others (13).Nevertheless, individual patient preference with regard to desirable vehiclecharacteristics may be difficult to predict. For instance, some patients withpsoriasis prefer ointment-based agents. This is perhaps partially due to theimmediate ‘‘disappearance’’ (we use the word ‘‘disappearance’’ literally) ofscale that results from ointment application (14). While the scale is nolonger 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 patientsatisfaction and compliance. Another patient may prefer a less messy vehicleon exposed areas. It may not be possible to predict patients’ preferences fordifferent vehicles. We suggest that clinicians discuss the options withpatients 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 effortto maximize patient compliance, integrate their patients’ individual prefer-ences with regard to each of the characteristics when prescribing a topicalcorticosteroid regimen.

Measuring compliance as it pertains to the ‘‘real-world’’ practice ofmedicine is difficult, even more so in dermatology where often an arbitraryamount of a topical is applied to a skin region. Self-reported compliancemeasures are not to be trusted; electronic monitoring permits a more accu-rate account of patient compliance. In a trial of 30 patients treated withtopical 6% salicylic acid gel twice daily, adherence rates were consistentlylower when measured by electronic monitoring caps than when calculatedbased upon patient medication logs or medication weights, the traditionalmethods of determining patient compliance. In addition, there was a suddeninitial decrease in compliance within five days following the clinical encoun-ter with a continued gradual decrease over subsequent weeks. Compliancerates measured by electronic monitors declined from 85% to 51% overthe course of the eight-week trial (15). Considering that this study was donewith presumably highly motivated individuals who were paid to participatein a clinical trial, it is not unrealistic to predict that compliance rates in prac-tice may be even lower.

Another interesting feature of the salicylic acid gel trials was an inter-mittent increase in compliance, which appeared related to study visits attwo-week intervals. An increase in compliance shortly before visits shouldnot be unexpected, especially by those of us who floss more often beforethey see the dentist (we therefore term this effect the ‘‘dental floss effect’’).Frequent return visits are common in clinical trials and may explain in partthe tendency for clinical trials of a topical agent to show greater efficacythan the same topical agent in clinic populations. Thus, clinicians may beable to improve patients’ compliance by offering a return visit in one totwo weeks. We believe that compliance over the first one to two weeksmay be improved by this early return visit. Psychologically, it is far easierto comply with a request for daily application for one week than for aneight-week or longer period. Setting such short-term goals may help fostercompliance 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 drugor 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 withtwice-daily application of betamethasone dipropionate 0.05% ointment (16).The authors suggested that perhaps tachyphylaxis was more frequentlyobserved in clinical practice because of greater noncompliance in the clinic set-ting compared to the clinical trial setting. The observation of a steady reductionin the use of the 6% topical salicylic acid gel over an eight-week study also sug-gests that—with regard to topical corticosteroid treatment—a better definitionof tachyphylaxis is ‘‘a decreased response to topical corticosteroids duringchronic administration as the patient gradually stops putting it on because theyare tired of doing it.’’ In medicine, it is appreciated that adherence is an impor-tant concept, though it may clash with paternalism. One goal of dermatology ishow to better intervene and improve compliance, which will ideally improveoutcomes and lower long-term costs of psoriasis therapy.

LESSONS FROM SKIN CAP1

Skin Cap1, an over-the-counter spray marketed as a psoriasis treatment, wasintroduced in North America in 1995 (17). It was marketed as having zinc pyr-ithione as its active ingredient. Skin Cap1 quickly became a popular treatmentoption; patients, as well as dermatologists, enjoyed the remarkable efficacy theproduct offered to even the most therapeutically challenging psoriatic patient.The formulation provided for easy and nonmessy application, and no adverseeffects were expected for a zinc pyrithione spray. It was so effective that it wassuggested that psoriasis patients no longer needed corticosteroid injections,methotrexate, or psoralen and ultraviolet A (PUVA). Resistant scalp psoriasiscleared in as little as four days (18).

At the height of the clinical success of Skin Cap1 spray, however, reportsbegan to surface in Europe that the product contained potent corticosteroids. In1997, the Food and Drug Administration (FDA) removed Skin Cap1 from theU.S. market when several independent laboratories discovered that it containedclobetasol propionate. Some clinicians noted, though, that Skin Cap1 seemedfar more effective than topical clobetasol propionate ointment. Some suggestedthe possibility of a synergistic effect existing between the zinc and thecorticosteroid (17). The cytoplasmic corticosteroid receptor contains ‘‘zincfingers,’’ giving a basis for this synergistic hypothesis (19). A left/right compar-ison trial was performed in which clobetasol propionate was applied to alllesions and zinc pyrithione to half the body and zinc pyrithione vehicle to theother half. The zinc-treated side did no better than the control side (indeed,the side that got zinc did marginally worse—though not statistically signifi-cantly worse—than the side that did not get zinc) (20).

Three factors probably accounted for the dramatic efficacy of SkinCap1 compared to other clobetasol propionate preparations: compliance,

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compliance, and compliance! As discussed above, ointment vehicles are notinherently more potent than other vehicles and could be less potent if patientsdo not apply them (for many dermatologists, the efficacy of Skin Cap1 maybe the best clinical evidence that a drying spray can be as effective or moreeffective than an ointment containing the same active ingredient!). BecauseSkin Cap1 is easily applied, compliance is likely improved. Secondly, patientsare concerned about potential adverse effects with regard to the use of topicalcorticosteroids (12). When patients are told to apply clobetasol, they arewarned about cutaneous and internal risks. When doctors recommended SkinCap1, it was without these warnings (and without the many other scarywarnings in topical corticosteroid package inserts), also likely enhancing com-pliance. Finally, because patients paid for Skin Cap1 themselves, they wereprobably more invested in the product and more likely to use it.

The Skin Cap1 story provides us important guidance to success withtopical corticosteroids for psoriasis. High levels of efficacy can be expected ifwe can improve our patients’ adherence to the treatment regimen. Patientsshould be involved in the choice of treatment, vehicles and application fre-quencies should be chosen that fit patients’ lifestyles, and potential sideeffects of treatment should not be overstated.

EFFICACY

The clinical effectiveness of topical corticosteroids in treating inflammatorydermatoses has been documented in numerous clinical studies. From vasocon-strictor assays and clinical trials, it is known that superpotent, or class I, topicalcorticosteroids are most effective at treating plaque-type psoriasis. Severalstudies using traditional ointment/cream vehicles for class I agents demon-strate marked rapid improvement in approximately 80% of subjects (21–23).

More recently, formulations of the superpotent corticosteroid clobeta-sol in a more elegant foam vehicle have produced ‘‘clear or almost clear’’ in68% of subjects (24).

Less potent topical corticosteroids may also be effective at treatingpsoriasis. All other factors being equal, it can be expected that for the sametype of psoriasis plaque, class I medications, if an option, will provide fasterclearing/improvement relative to class II–VI drugs. Lower class prepara-tions are extremely helpful in situations where class I agents are to beavoided or minimized. For relatively thin plaque psoriasis, a mid-potencysteroid is often appropriate, as it can be expected that penetration of the cor-ticosteroid molecule is enhanced relative to thick plaques. Areas of the bodywhere the stratum corneum is relatively thin, such as the face, intertriginousareas, and genitals, are excellent areas to institute therapy with a relativelylow-strength topical corticosteroid; there are also several noncorticosteroidtopicals now available. Prudent use of lower-potency topical corticosteroidshelps to ensure that adverse events are minimized.

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Also, there are additional vehicles available when prescribing class II to VIIagents including oils, gels, tape, and injectable preparations. It is the opinion ofthis chapter’s authors that flurandrenolide-impregnated tape (Cordran1) is aninvaluable resource for small to medium or stubborn plaques; the appli-cation of the tape one to three times weekly helps to avoid problems withpoor compliance. It is difficult to classify flurandrenolide tape in the tradi-tional class system. Flurandrenolide is a class V corticosteroid, but whenused in the occlusive tape, it is expected that the bioavailability below tothe dermis and epidermis is enhanced; monitoring for adverse events isimportant. The efficacy of many corticosteroids may be enhanced whencombined with certain noncorticosteroid topical agents, a practice that iscommonplace in dermatology.

SAFETY

Fear of adverse effects from the use of topical corticosteroids is widespreadamong patients and physicians alike and may represent a significant barrierto effective treatment of inflammatory skin diseases like psoriasis. Nearly75% of patients prescribed with topical corticosteroids have some degreeof concern regarding the potential adverse affects related to their use; thegreatest concerns are skin atrophy, or thinning, and the fear of absorption(25). As the patients from the aforementioned study highlight, adverseevents from corticosteroid use are best grouped into local, or cutaneous,and systemic. It should also be noted that most adverse events that engenderfear are those associated with chronic therapy with the exception of sequelaefrom direct injection of psoriasis plaques and transient irritation.

Numerous studies have been reported regarding local skin atrophyand striae formation at the site of topical corticosteroid application. Histori-cally, these investigations have varied with regard to the atrophogenicpotential of this medication category, at least partially due to difficultiesrelated to the histological evaluation of sample tissue (26,27). Recently,improved ultrasound techniques have provided objective evidence of skinthinning by potent and very potent topical corticosteroids within six weeksof treatment onset (12,28–31). However, the precise degree of skin thinningrequired for clinical significance has yet to be determined. Other cutaneousand systemic side effects are summarized in Table 1.

Perhaps the most worrisome aspect of therapy with topical cortico-steroids is the potential for systemic absorption and subsequent metabolicderangements. Disturbance of the hypothalamic–pituitary axis, iatrogenicCushing’s syndrome, adrenal insufficiency, and necrosis of the femoral headare a few reported examples of systemic effects from topical corticosteroids(32–35). Several reports have failed to demonstrate evidence of cortisolsuppression with the use of low, mid-level, or high-potency topical corti-costeroids (12,36–41). Other evidence supports mild, transient cortisol

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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 extensivepsoriasis are at the highest risk for systemic effects though the amountrequired to create systemic side effects is not well described. A reasonablerule of thumb is no more than 50 g of a class I agent or 100 g of a class IIagent each week should be used in appropriate regions.

SAFER TOPICAL CORTICOSTEROIDS: ARE THEY POSSIBLE?

Since Sulzberger and Witten’s description of ‘‘compound F,’’ there havebeen great strides in the development and formulation of topical corticoste-roids. The potency of today’s topical corticosteroids has reached a levelcapable of effectively treating challenging and recalcitrant inflammatorydermatoses. With greater potency comes a greater potential for adverseevents. Research and development have attempted to dissociate potencyfrom adverse events in order to create safer potent topical corticosteroids.

Improving the safety profile of topical corticosteroids has proven everybit as challenging as increasing their potency. Creating nonfluorinatedpotent corticosteroids is not the solution; it is the strength of the corticoste-roid, not the fluorine atom covalently bound in the molecule that contributesto adverse events. There is no reason whatsoever to expect that potent non-fluorinated corticosteroids will have any less side effects than fluorinated

Table 1 Potential Side Effects from Topical Corticosteroid Use

Cutaneous effectsAllergic/contact dermatitisIrritationAtrophyStriaeTelangectasiaEcchymoses/purpuraHypopigmentationSteroid rosaceaPerioral dermatitisFolliculitisRebound/pustular flare

Systemic effectsHypothalamus-pituitary axis suppressionIatrogenic Cushing’s syndromeIatrogenic adrenal suppressionAvascular necrosis of the femoral head

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corticosteroids of equal potency. Mometasone furoate uses chlorinationrather than fluorination to achieve potency. Some studies claim a reducedrisk of adverse effects with mometasone furoate (28,45). These studies, how-ever, were not adequately designed to demonstrate comparable potencywhile decreasing adverse event rates. For example, one study comparingmometasone to hydrocortisone found greater potency with mometasonebut not significantly greater adverse events; this study was powered tofind differences in efficacy but was not powered to identify the likely realdifferences in adverse event profiles (46). Studies of the nonfluorinated pred-nicarbate have also claimed a dissociation between benefit and risk. Whileboth a reduction in adverse effect rate and equal potency have been demon-strated independently (30,31,47,48), studies have not shown the occurrenceof both outcomes simultaneously under identical conditions. Therefore, weconclude that the existence of safer topical corticosteroids with equalpotency is elusive and has yet to be demonstrated.

COST CONSIDERATIONS

Very recently, there has been increasing attention given to the economics ofpsoriasis care. Annual U.S. cost estimates of treating psoriasis range from$650 million to $2 billion (49). Topical corticosteroids are the most commonclass of medications used to treat psoriasis and there are economic considera-tions for their use as adjunctive or primary therapy. The first and mostobvious is the ability of the patient (plus or minus potential third partypayers) to pay for a certain medication. In today’s complex setting of co-paysand insurance caps, a discussion centered on a patient’s ability to afford amedication should be given. There is tremendous variation seen not onlyamong classes of topical steroids, but also within them as well, as seen inFigure 1 (50); there are generic alternatives regardless of the desired class.Also, on a macro-scale, the effect of corticosteroids on the cost of caringfor psoriasis patients needs to be considered. A recent analysis demonstratedthat the use of topical corticosteroids is a primary driver for reduced healthcare costs (51). This study highlights the concept of topical corticosteroids ascontroller 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 cor-ticosteroid is meaningless if the patient does not apply the product asinstructed. Therefore, maximization of patient compliance is crucial to thepractical use of topical corticosteroids, as well as all topical and oral medica-tions. There are numerous factors that influence an individual patient’smedication 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 psor-iasis patients. Greater compliance can be expected when clinicians touch thepsoriasis, and ask questions about the patient’s disease how it affectsthe patient’s life. Second, physicians should encourage patients to join theNational Psoriasis Foundation and make use of the Foundation’s educa-tional resources. The Foundation encourages patients to adhere to theirdermatologists’ treatment recommendations. Through increasing patients’understanding of psoriasis, the National Psoriasis Foundation also empowerspatients to take control of their disease and its treatments; such an approachlikely leads to greater adherence and better treatment outcomes.

Next, physicians should involve the patient in treatment planning andchoose treatment options that the patient finds acceptable. If less messyvehicles 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 influencepatient compliance. Duration of treatment has been documented to affectcompliance rates for those patients on chronic medication regimens, as isoften the circumstance with psoriasis patients. Compliance decreases astreatment duration lengthens in patients requiring chronic oral calcium chan-nel blocker therapy (52). Frequent office visits provide reinforcement ofbehaviors that will hopefully prevent discouragement, noncompliance, andtreatment failure. Patient compliance increases during the period surround-ing a clinical encounter with a physician or other health care provider.Compliance rates of 88% and 86% to epilepsy medications were observed fivedays before and after a clinical visit, respectively. However, compliance ratesfell to approximately 73% when measured one month following the patient’sclinical visit (53). Similarly, a clinical study of 30 patients on stable anti-epileptic drug regimens demonstrated a 33% increase in drug levels simplyby 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 ‘‘dentalfloss effect.’’ Irrespective of the terminology, the phenomenon is well estab-lished and should be exploited by the practitioner in an effort to maximizepatient compliance. A return visit one or two weeks after initiating topicaltreatment may be a strong incentive to adhere to the treatment.

STEROID ALTERNATIVES: COMPLEMENTARY, NOTREALLY ALTERNATIVES

The perceived and actual potential for adverse effects associated with long-term high-potency topical corticosteroid use propels a search for even safertopical therapies. Topical calcipotriene (Dovonex1) obtained FDA approvalin December of 1993. It is a synthetic vitamin D3 derivative indicated for

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the topical treatment of psoriasis. Topical calcipotriene quickly replacedanthralin and tars as the primary noncorticosteroid treatment for psoria-sis, and by 1996 it accounted for 71% of the noncorticosteroid medicationsused at psoriasis visits (1). While approved for monotherapy in the topicaltreatment of psoriasis, dermatologists swiftly realized the drug’s limitationsand the need to use it as an adjunct to topical corticosteroids rather than asa substitute for corticosteroids. In 1994, the drug’s inaugural year of FDAapproval, it was utilized as monotherapy in 44% of the patients to whomit was prescribed. By 1996, this number had fallen to only 16%. Conversely,cases in which the drug was utilized as an adjunct to topical corticosteroidsincreased from 17% to 84% between these same years (1). Central to calci-potriene’s decline as a monotherapy agent are the extended treatment periodprior to clinical response and the agent’s principal adverse effect, skin irrita-tion. Fortunately, both of these factors are lessened by combined use with atopical corticosteroid agent (56–58). Thus, calcipotriene exists today moreas a topical corticosteroid adjunct than as an alternative.

A second topical agent heralded as a corticosteroid alternative in thetreatment of psoriasis, topical tacrolimus (Protopic), is an immunosuppres-sant agent produced by Streptomyces tsukubaensis. Clinical studies of topicaltacrolimus for psoriasis are more limited than those concerning topical calci-potriene. One clinical trial found 0.03% topical tacrolimus, applied oncedaily, to be no more effective than placebo (59). However, 0.1% topical tacro-limus is effective in the treatment of facial and inverse psoriasis, with 81% ofpatients demonstrating complete clearing (60). The increased efficacy of topi-cal tacrolimus in the treatment of facial and inverse psoriasis is likely a directresult of the improved penetration of topical agents typically observed inthese regions. When topical tacrolimus is combined with salicylic acid, apenetration enhancing agent, it is efficacious for common plaque psoriasis(59). Topical tacrolimus may be an acceptable alternative to topical cortico-steroids in the treatment of facial and inverse psoriasis or it may be usedin combination with topical corticosteroids as has been done with topicalcalcipotriene. With regard to plaque psoriasis located elsewhere, topical tacro-limus may be used with penetration enhancers or perhaps new formulationswill help better deliver the product.

SUMMARY

Psoriasis is a common, chronic, inflammatory skin condition requiring long-term medical management. The vast majority of psoriasis patients have mildto moderate disease that can be managed with topical corticosteroids. Thechronicity of the disease and its treatment are major hurdles for patientsand their dermatologists. Chronic adherence to the use of any medicationis problematic, and chronic applications of time consuming, messy topicalpreparations are particularly difficult.

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Selection of the appropriate agent for a given patient is critical in orderto maximize compliance; no agent, regardless of biologic/physiologicpotency, can be effective if it is not applied. For the prescriber, this meanstaking 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 regardingadverse effects are common among patients prescribed topical corticoste-roids and are a frequent source of noncompliance. To maximize the benefitsof topical corticosteroids, physicians should seek to identify and minimizethese barriers.

When used well, how effective are topical corticosteroids for psoriasis?Clinical studies and clinical experience with Skin Cap1 demonstrate thehigh level of efficacy that can be achieved with topical corticosteroids whenpatients actually apply them. By paying attention to the factors that influ-ence patients’ adherence to topical agents, topical corticosteroids can beamong our most potent psoriasis treatment options.

ACKNOWLEDGMENTS

Center for Dermatology Research is funded by a grant from GaldermaLaboratories, LP. Dr. Feldman has also received support from Connetics,Astellas, Abbott, Amgen, Biogenidec, Centocor, Photomedex, and Genentech.

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12. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia inpatients with atopic eczema. Br J Dermatol 2000; 142(5):931–936.

13. Feldman S, Housman T. Patients’ vehicle preference for corticosteroid treat-ments of psoriasis. Am J Clin Dermatol 2003; 4(4):221–224.

14. Van de Kerkhof PC, Steegers-Theunissen RP, Kuipers MV. Evaluation of topi-cal drug treatment in psoriasis. Dermatology 1998; 197(1):31–36.

15. Carroll CL, Feldman SR, Camacho FT, Manuel JC, Balkrishnan R. Adherenceto topical therapy decreases during the course of an 8-week psoriasis clinicaltrial: commonly used methods of measuring adherence to topical therapy over-estimate actual use. J Am Acad Dermatol 2004; 51(2):212–216.

16. Miller JJ, Roling D, Margolis D, Guzzo C. Failure to demonstrate therapeutictachyphylaxis to topically applied steroids in patients with psoriasis. J Am AcadDermatol 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 thefirst zinc finger specify DNA response element activation by the glucocorticoidreceptor. 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 effi-cacy of clobetasol propionate 0.05% foam in the treatment of psoriasis. J AmAcad 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 psoria-sis. 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 inthe treatment of patients with chronic, localized plaque psoriasis. J Am AcadDermatol 1991; 25(6 Pt 2):1153–1156.

23. Katz HI, Gross E, Buxman M, Prawer SE, Schwartzel EH, Gibson JR. A double-blind, vehicle-controlled paired comparison of halobetasol propionate cream onpatients 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 clobetasolpropionate foam 0.05% in the treatment of mild to moderate plaque-type psor-iasis of nonscalp regions. J Cutan Med Surg 2003; 7:185–192.

25. Charman C, Chambers C, Williams H. Measuring atopic dermatitis severity inrandomized controlled clinical trials: what exactly are we measuring? J InvestDermatol 2003; 120(6):932–941.

26. Goa KL. Clinical pharmacology and pharmacokinetic properties of topicallyapplied 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 theatrophogenic potency of mometasone furoate, a newly developed chlorinatedpotent topical glucocorticoid as compared to other topical glucocorticoids oldand new. Int J Clin Pharmacol Ther 1995; 33(4):187–189.

29. Kerscher MJ, Korting HC. Comparative atrophogenicity potential of mediumand highly potent topical glucocorticoids in cream and ointment according toultrasound analysis. Skin Pharmacol 1992; 5(2):77–80.

30. Kerscher MJ, Korting HC. Topical glucocorticoids of the non-fluorinateddouble-ester type. Lack of atrophogenicity in normal skin as assessed by high-frequency ultrasound. Acta Derm Venereol 1992; 72(3):214–216.

31. Korting HC, Vieluf D, Kerscher M. 0.25% prednicarbate cream and the correspond-ing vehicle induce less skin atrophy than 0.1% betamethasone-17-valerate cream and0.05% clobetasol-17-propionate cream. Eur J Clin Pharmacol 1992; 42(2):159–161.

32. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insuffi-ciency: 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. Ost-eonecrosis of the femoral head that developed after long-term topical steroidapplication. J Orthop Sci 2001; 6(1):92–94.

35. Katz HI, Hien NT, Prawer SE, Mastbaum LI, Mooney JJ, Samson CR. Super-potent topical steroid treatment of psoriasis vulgaris—clinical efficacy andadrenal 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 Dermatol1976; 94(suppl 12):67–76.

37. Crespi HG. Topical corticosteroid therapy for children: alclometasone dipropio-nate 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 inchildren. Arch Dermatol 1978; 114(8):1165–1167.

40. Van Der Meer JB, Glazenburg EJ, Mulder PG, Eggink HF, Coenraads PJ. Themanagement of moderate to severe atopic dermatitis in adults with topical fluti-casone propionate. The Netherlands Adult Atopic Dermatitis Study Group. Br JDermatol 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 atopicdermatitis. 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 gluco-corticosteroids. Pediatrics 1980; 65(1):103–106.

43. Queille C, Pommarede R, Saurat JH. Efficacy versus systemic effects of sixtopical steroids in the treatment of atopic dermatitis of childhood. PediatrDermatol 1984; 1(3):246–253.

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44. Juhlin L. Comparison of fluticasone propionate cream, 0.05%, and hydrocortisone-17-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 mometa-sone furoate cream in the treatment of steroid responsive dermatoses. AustralasJ Dermatol 1991; 32(2):85–91.

46. Bhardwaj SS, Camacho F, Derrow A, Fleischer AB Jr, Feldman SR. Statisticalsignificance and clinical relevance: the importance of power in clinical trials indermatology. 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-strengthglucocorticoids. Skin Pharmacol Appl Skin Physiol 2002; 15(2):85–91.

48. Schafer-Korting M, Korting HC, Kerscher MJ, Lenhard S. Prednicarbate activityand benefit/risk ratio in relation to other topical glucocorticoids. Clin PharmacolTher 1993; 54(4):448–456.

49. Javitz HS, Ward MM, Farber E, Nail L, Vallow SG. The direct cost of care forpsoriasis 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 thera-pies: considerations for therapy selection. Dermatol Nurs 2004; 16(5):421–428, 432.

51. Kulkarni AS, Balkrishnan R, Richmond D, Pearce DJ, Feldman SR. Medication-related factors affecting health care outcomes and costs for patients with psoriasis inthe United States. J Am Acad Dermatol 2005; 52(1):27–31.

52. Farmer KC, Jacobs EW, Phillips CR. Long-term patient compliance with pre-scribed 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 inantiepileptic 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 combina-tion of calcipotriol and betamethasone valerate after 2 weeks’ treatment with cal-cipotriol 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 calcipotrieneointment and halobetasol ointment compared with either agent alone for thetreatment 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 halobe-tasol ointment in the long-term treatment of psoriasis: effects on the duration ofimprovement. J Am Acad Dermatol 1998; 39:447–450.

59. Carrol CL, Clarke J, Camacho F, Balkrishnan R, Feldman SR. Topical tacroli-mus 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 treat-ment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol2003; 48(4):564–568.

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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 approvedfor the treatment of plaque psoriasis in the United States. Calcipotriene isknown as calcipotriol (Daivonex1) outside of the United States, Canada,Japan, etc. It is the first elegant nonsteroidal topical alternative for the treat-ment of psoriasis and is available as an ointment, cream, or scalp solution.

Other topical vitamin D3 analogs are available outside of the UnitedStates for the treatment of psoriasis, such as calcitriol (Silkis1), tacalcitol(Bonalfa1), and maxacalcitol (Oxarol1). Calcipotriene ointment wasfound to be significantly more effective than calcitriol ointment in a random-ized, double-blind study (1). In another large multicenter, randomized,double-blind study, calcipotriene was found to be significantly more effectivethan tacalcitol when calcipotriene ointment was compared to tacalcitolointment based on their marketed treatment schedule of twice a day for cal-cipotriene and once daily for tacalcitol (2). Calcipotriene ointment once dailyand maxacalcitol ointment once daily was shown to have similar efficacy (3).However, acute renal failure associated with hypercalcemia has beenreported with maxacalcitol (4,5). In the package insert of maxacalcitol, the

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Japanese Food and Drug Administration (FDA) recommends checkingserum calcium and renal function tests periodically (once after the firsttwo to four weeks of treatment and as required thereafter). Furthermore,the Japanese FDA recommends close monitoring for patients with extensivepsoriasis or severe psoriasis using maxacalcitol with periodic serum calciumand renal function tests since the impaired skin barrier function can causeincreased transdermal absorption of maxacalcitol, and thus hypercalcemiais more likely to occur. Although hypercalcemia can also occur with calcipo-triene, the risk seems less, and there is no recommendation by the U.S. FDAto check serum calcium level or renal function tests periodically. Calcipo-triene is the only vitamin D3 analog available in the United States, sincemaxacalcitol was clinically tested in the United States and the final decisionwas 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 ofcombination, sequential, and in comparison with other topical agents, andit is probably one of the most favorable agents in terms of efficacy and sideeffect 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, whichis the most active metabolite of vitamin D3, improves psoriasis provided theimpetus for the development of analogs of this compound, including calci-potriene, which might prove useful for the treatment of psoriasis with muchless effect on calcium homeostasis (6). Figure 1 shows the chemical structureof calcipotriene and other vitamin D3 analogs. Calcipotriene is a syntheticanalog of 1a,25-dihydroxycholecalciferol (calcitriol).

At the molecular level, calcitriol and its analogs, including calci-potriene, elicit most of their biologic effects by binding to a specificintracellular receptor, the vitamin D receptor, and regulating gene transcrip-tion (7). Calcipotriene has been shown to have an affinity for vitamin Dreceptors similar to that of calcitriol (8–10). The beneficial effects of calci-potriene on psoriasis are similar to those of calcitriol and include, mostnotably, inhibition of proliferation of keratinocytes and increased terminaldifferentiation (11,12). However, calcipotriene is 100 times less potent in itseffects on calcium metabolism (13).

Flow cytometric analysis has shown significant decreases relative to pla-cebo in numbers of proliferating basal keratinocytes in psoriatic skin treatedwith topical calcitriol (14). In addition, application of calcipotriene ointmenttwice daily for up to eight weeks has been shown to result in partial recoveryof the stratum corneum, complete recovery of the stratum granulosum, andcorrection of intercellular spacing and number and structure of desmosomes(15,16). Furthermore, application of calcipotriene ointment for four weeks

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has been shown to be associated with suppression of epidermal T cell andpolymorphonuclear leukocyte accumulation in psoriatic skin (15).

CALCIPOTRIENE MONOTHERAPY

Multiple clinical trials have confirmed the efficacy and safety of all formula-tions (ointment, cream, and solutions) of calcipotriene in the treatment ofpsoriasis in adults (11,12,17). In addition, long-term studies have shownthat the benefits of calcipotriene therapy were maintained for up to oneyear (18–22).

In a noncomparative study, 40 patients receiving twice daily calci-potriene ointment had a mean time to healing of 53.5 days (range 14–78days), with a mean time to relapse of 43.3 days (range 14–112 days) (23).At the time of relapse, patients recommenced treatment with calcipotrieneointment, with a mean time to healing following relapse of 44.6 days (range14–57 days). Furthermore, the time to heal following relapse significantlycorrelated with the duration of the first treatment period. Those treatedfor less than eight weeks initially healed after relapse in 40.6 days (range14–56 days) versus 69.6 days (range 63–78 days) in those requiring morethan eight weeks’ treatment during the initial phase. Therefore, there appearsto be faster and slower responders to calcipotriene therapy.

CALCIPOTRIENE IN CHILDREN

There are only limited data on the efficacy of calcipotriene in children. In amulticenter, randomized, double-blind, placebo-controlled study, significantly

Figure 1 Chemical structures of vitamin D3 analogs.

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more patients achieved a marked improvement or clearance of psoriasis in thecalcipotriene-treatment group than placebo after eight weeks of treatment inchildren aged 2 to 14 years according to investigator-assessed overall responses(60% vs. 44%), although patient- or guardian-assessed response rates did notdiffer significantly between the two groups (24). However, there was no signif-icant difference in the reduction in overall disease severity between twice-dailycalcipotriene ointment and placebo (52% vs. 37% reduction). A similarresponse with calcipotriene therapy was also observed in a noncomparative,nonblind study in 66 children aged 3 to 14 years (25). In a long-term noncom-parative study in 12 children aged 8 to 15 years, calcipotriene ointment twicedaily was shown to be effective in reducing disease severity (26). The meanoverall psoriasis area and severity index score was reduced by 65% followingcalcipotriene 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 efficacycompared to topical corticosteroids in several clinical studies. In three largemulticenter studies, subjective response rates after six weeks were signifi-cantly better with twice-daily calcipotriene ointment than with twice-dailybetamethasone valerate ointment (27–29). In addition, twice-daily calcipo-triene ointment was shown to have similar efficacy compared to twice-dailybetamethasone dipropionate plus salicyclic acid (dosages not reported) (30).Furthermore, twice-daily calcipotriene ointment was shown to be signifi-cantly better than twice-daily fluocinonide ointment (13).

Calcipotriene ointment twice daily was significantly more effectivethan twice-daily 5% coal tar plus 2% allantoin and 0.5% hydrocortisone (32).In addition, twice-daily calcipotriene ointment provided similar or superiorefficacy to once-daily short-contact 0.1% to 3% dithranol (33–35). Calci-potriene ointment also had a significantly greater cosmetic acceptability thanshort-contact dithranol cream (33).

A comparison of tazarotene 0.1% gel once daily plus mometasonefuroate 0.1% cream once daily versus calcipotriene ointment twice dailyfound similar efficacy after eight weeks of treatment (36). At the end of eightweeks, 59% of patients in the calcipotriene group versus 60% in the tazaro-tene plus mometasone group achieved a marked or �75% improvementin severity of psoriasis based on investigator assessment. In addition, therewere no differences in plaque elevation or scaling scores between thetwo treatment groups, although erythema scores were significantly betterin the tazarotene plus mometasone group. Calcipotriene was better toleratedthan tazarotene plus mometasone. Significantly fewer patients in the calci-potriene group experienced burning (8% vs. 42%), pruritus (13% vs. 32%),skin irritation (12% vs. 28%), or erythema (7% vs. 25%) than the tazaroteneplus mometasone group.

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COMBINATION THERAPY

Combination therapy is often used to increase the efficacy of treatmentsthrough additive/synergistic effects and/or to minimize adverse effects.Most dermatologists in the United States use calcipotriene not as mono-therapy but rather in combination with other treatments. Combination ofcalcipotriene with other treatments not only increases the rate of improve-ment and offers greater improvement but minimizes adverse effects insome cases; for instance in the case of topical steroids, the topical steroiddecreases the risk of skin irritation by calcipotriene, and calcipotrieneprevents skin atrophy by the topical steroid.

CALCIPOTRIENE AND TOPICAL STEROIDS

In a two-week study of 127 patients with moderate plaque psoriasis, thecombination of once-daily calcipotriene ointment (applied in the morning)and once-daily halobetasol ointment (applied in the evening) was signifi-cantly better than either twice-daily calcipotriene or twice-daily halobetasol(37). The study protocol required that one agent be applied in the morningand the other agent in the evening. It is possible that when both calcipo-triene and halobetasol are applied twice daily, their efficacy may be evenfurther improved since both calcipotriene and halobetasol are known tobe more effective when used twice a day instead of once a day (38). Oneof the authors’ favorite topical combination therapy for psoriasis is sequen-tial 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 oncedaily (weeks one and three) and calcipotriene ointment twice daily (weekstwo and four) was significantly better than betamethasone dipropionateonce daily for four weeks (39). Moreover, significantly more patients achieveda marked improvement or complete clearance with pulse therapy than withmonotherapy according to both physicians’ (96% vs. 41%) and patients’(96% vs. 37%) assessment.

A multicenter, randomized, double-blind six-month study investigatedthe duration of remission with topical combination therapy with twice-dailycalcipotriene ointment on weekdays and twice-daily halobetasol ointmenton weekends in 40 patients with plaque psoriasis (40). Significantly morepatients in the combination pulse therapy with calcipotriene ointment(applied twice daily on weekdays) plus halobetasol ointment (applied twicedaily during the weekend) remained in remission throughout the six-monthstudy period than patients receiving halobetasol ointment twice daily onweekends and placebo ointment twice daily during the week (76% vs.40%). Remission was defined as achieving or maintaining marked improve-ment (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 tazaro-tene might not be as potent as class I topical steroids when each is usedas 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, combinationtherapy of calcipotriene ointment twice daily with tazarotene 0.1% gel oncedaily was comparable to clobetasol ointment twice daily (41). The studyconsisted of 15 patients who underwent a two-week treatment course, fol-lowed by a four-week post-treatment observation. At the end of the twoweeks, lesions treated with calcipotriene and tazarotene had the sameimprovement in overall lesion severity, reduction in plaque elevation andscaling as the clobetasol-treated lesions. Not surprisingly, erythema improvedmore in the clobetasol-treated lesions. Adverse events were more frequentin calcipotriene–tazarotene-treated lesions than in those treated withclobetasol. The most common adverse effects related to treatment with cal-cipotriene and tazarotene were asymptomatic erythema and mild peeling.However, no patient had to withdraw or interrupt treatment because ofadverse events. The results of this study suggest that there does not appearto be any clinically relevant chemical incompatibility between calcipotrieneointment and tazarotene gel, as was shown by their apparently synergisticeffects on improving psoriasis.

CALCIPOTRIENE AND PHOTOTHERAPY

Outpatient ultraviolet B (UVB) phototherapy should be performed three tofive times a week. Twice-weekly UVB phototherapy is often inadequateto achieve satisfactory results. However, calcipotriene cream combined withtwice-weekly broadband UVB phototherapy has demonstrated efficacyequivalent to three times per week UVB with only the vehicle of calcipo-triene cream (42). The reduction in UVB therapy from three to two timesa week is a critical therapeutic improvement because one of the most chal-lenging aspects of successful phototherapy is getting a commitment frompatients for three visits per week.

In another study, calcipotriene plus narrowband UVB (NB-UVB)phototherapy was shown to have a UVB-sparing effect compared withNB-UVB alone (43). In contrast, Brands and colleagues (44) did not findsignificant improvement with combination calcipotriene and NBUVB versusNB-UVB alone. The authors suggest that differences in the comparisonswith UVB phototherapy may reflect differences in UVB phototherapy tech-niques, patient noncompliance in applying calcipotriene ointment, or a UVBblocking action of calcipotriene ointment.

Addition of calcipotriene ointment therapy to thrice-weekly psoralen andultraviolet A (PUVA) phototherapy significantly improved the response of

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patients to PUVA therapy, but in another study using twice-weekly PUVAtreatments the response in the two treatment groups was similar (45,46).

Frappaz and Thivolet (45) showed that the combination of twice-dailycalcipotriene ointment and PUVA phototherapy three times a week wasmore effective than PUVA alone. In contrast, in another study calcipotrieneointment plus twice-weekly PUVA phototherapy provided similar reduc-tions in overall disease severity scores to PUVA monotherapy (46). Bothstudies, however, showed a significant decrease in the duration of PUVAtherapy, in the cumulative ultraviolet A (UVA) dose, and number ofUVA irradiations when PUVA was used in combination with calcipotrienecompared with PUVA monotherapy (45,46). For example, in the larger studythe duration of PUVA therapy was reduced from 34 to 22 days, the cumulativeUVA dose reduced from 57 to 30 J/cm2, and the number of UVA irradiationsadministered reduced from 15 to 10 (45).

CALCIPOTRIENE AND SYSTEMIC AGENTS

In 1998, van de Kerkhof et al. (47) reported the addition of calcipotrieneointment twice daily to systemic treatment with acitretin was significantlymore effective than acitretin plus placebo ointment. All patients were treatedwith a starting dose of 20 mg/day of acitretin. The dose was increased everytwo weeks in increments of 10 mg/day until a maximum dose of 70 mg/daywas reached, clearance was achieved, or patients developed unacceptableside effects to acitretin. After 12 weeks, 67% of the patients in the calcipo-triene and acitretin group achieved clearance or marked improvementcompared to 41% of the patients in the acitretin plus placebo ointmentgroup (47). Furthermore, the median total dose of acitretin required toreach clearing or marked improvement was significantly reduced in the com-bination therapy group compared with acitretin alone (1680 vs. 2100 mg). Ina more recent study with a longer duration of treatment, the duration oftreatment and total dose of retinoid required to achieve clearance wereslightly lower in the calcipotriene and acitretin group; however, the differencewas not statistically significant (48). After 52 weeks, 60% in the calcipotrieneand acitretin combination therapy group and 40% in the acitretin monother-apy group achieved complete clearance. The addition of calcipotriene did notsignificantly reduce the total duration of treatment (82.8 vs. 92.8 days) andcumulative dose of acitretin required to reach clearance state (1613 vs.2205 mg). Even though the result of the second study did not reach statisticalsignificance, the consistent trend and the notable difference between thecalcipotriene and acitretin group compared with acitretin monotherapygroup may indicate that with a large enough number of subjects, statisticalsignificance might have been achieved.

Combination therapy with calcipotriene ointment twice daily and oralcyclosporine 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 clear-ing or 90% improvement in psoriasis area and severity index score occurredin 50% of patients in the calcipotriene and cyclosporine group compared to12% of the patients in the cyclosporine plus placebo ointment group (49).

De Jong et al. (50) has shown that when methotrexate therapy is dis-continued, topical therapy with calcipotriene ointment twice daily results inan extension of the remission time before a relapse of psoriasis occurs com-pared with maintenance treatment with the vehicle only (113 vs. 35 days).Furthermore, the weekly dose of methotrexate needed to treat psoriasis islower by combining methotrexate with calcipotriene than by combiningmethotrexate with the vehicle. The mean weekly dose of methotrexate was6.5 mg/wk in the patient group treated with calcipotriene versus 9.9 mg/wkin the patient group treated with the vehicle (50). This results in lower cumu-lative dosage and therefore in a substantial reduction of the risk of short- andlong-term side effects of methotrexate.

ADVERSE EFFECTS

One of the most important features of calcipotriene, which makes it an excel-lent agent for primary care physicians as well as for dermatologists, is itssafety profile. Calcipotriene is steroid free, and thus free from steroid sideeffects such as skin thinning, striae formation, and adrenal suppression. Itis generally well tolerated. There were no significant differences in the natureand incidence of adverse events with the different formulations (11,12).

Irritation

The only significant cutaneous side effect of calcipotriene is lesional andperilesional (around the lesion) irritation, which occurs in 12% to 20.1%of patients in clinical trials (27,31,33,51,52). Irritation from calcipotrieneusually presents with a red ring of inflamed skin surrounding the treatedlesions (Fig. 2). Patients usually report a mild stinging, itching, or burningsensation. This is usually mild to moderate in severity. It is usually transient,and patients quickly become accustomed to it. In clinical trials, only one of25 patients had to discontinue treatment because of skin irritation fromcalcipotriene (53).

Irritation from calcipotriene is more frequent on the face and intertri-ginous areas such as the axilla and groin. It appears to depend largely on thepenetration of calcipotriene through the skin. The skin-to-skin occlusioninherent in intertriginous areas enhances penetration of calcipotriene, whichis thought to account for the increased rate of irritation in these areas. Cal-cipotriene is lipophilic and more readily absorbed by skin containing oilysebaceous glands, such as the face, which also helps explain why it tendsto be more irritating on the face.

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Irritation from calcipotriene can usually be resolved by using smalleramounts and/or less frequent application (e.g., once a day or every otherday instead of twice a day). Once this regimen is tolerated, the frequencyand dose can again be increased carefully. Also, using the cream formu-lation instead of the ointment formulation can often minimize the risk ofirritation. Diluting calcipotriene with a lubricant, such as petroleum jellyor a moisturizer, is another method of reducing potency and irritation.

In rare patients, calcipotriene may cause excessive peeling and appar-ent expansion of erythema beyond the original border of the psoriasis(Fig. 3). If this peculiar perilesional peeling occurs, and if the sensation isnot bothersome, one can reassure the patient and encourage continueduse of calcipotriene until everything, including the expanded erythematousor peeling area, resolves. Another strategy used by most clinicians at theinitiation of therapy is combining calcipotriene with a class I topical steroid.The risk of developing irritation with calcipotriene is greatly reduced when itis used in conjunction with a topical steroid (37).

Hypercalcemia and Hypercalciuria

The systemic side effect to be aware of when using calcipotriene is hyper-calcemia and hypercalciuria. Although several studies have investigatedthe effects of calcipotriene twice daily (up to 100 g/wk) on serum and urine

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

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calcium levels in patients with psoriasis (54–59), only one study showed asmall but significant increase in urine calcium levels (55).

In clinical practice, however, there have been isolated case reports ofhypercalcemia and hypercalciuria (17). The majority of cases of hypercalce-mia have occurred in patients who exceeded the recommended maximumtopical dosage of 100 g/wk, although a few occurred in patients using<100 g/wk. All reported episodes of hypercalcemia and hypercalciuria haveresolved on discontinuation of calcipotriene.

A good guideline to follow is to limit total weekly use of calcipotrienein all formulations (ointment, cream, solution) to 100–120 g/wk to avoidthe 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.

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

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CALCIPOTRIENE APPLICATION IN PSORIASIS

Patients need to be well educated when they are given a prescription forcalcipotriene. If the patient is to use calcipotriene as monotherapy, it iscritical to communicate to the patient the importance of using it twice aday, and to warn the patient of possible skin irritation as well as possibleslow onset of action, especially if calcipotriene monotherapy is only usedonce a day.

In clinical practice, it is difficult to find patients who actually complywith the twice-daily recommended usage. To maximize the chance that a patientwill use it this way, it is best to prescribe calcipotriene cream as well as oint-ment so that the patient can use the more elegant but slightly less effectivecream in the morning, and more effective but less elegant ointment formula-tion at night.

Adult patients should also be instructed to use no more than100–120 g/wk of calcipotriene to avoid the risk of hypercalcemia. For exam-ple, if the patient is using calcipotriene cream in the morning andcalcipotriene ointment in the evening, then the patient should not use morethan 50–60 g/wk of calcipotriene cream and 50–60 g/wk of calcipotrieneointment. Currently, in the United States, there are no dosage recommenda-tions available for the use of calcipotriene in children, whereas in the UnitedKingdom, the maximum recommended dosage in children aged 6–12 yearsis 50 g/wk increasing to 75 g/wk in those aged over 12 years (17). No dosagerecommendations are available for children less than six years of age (17).

Calcipotriene is contraindicated in patients with known calciummetabolism disorders, evidence of vitamin D toxicity, or hypersensitivityto calcipotriene or any other constituents of the ointment. It is pregnancycategory C, and safety of calcipotriene in pregnancy has not yet been fullyestablished.

As hypercalcemia is extremely rare in patients applying calcipotrieneno more than 100–120 g/wk, serum and urine calcium levels do not needto be monitored, except possibly in those with generalized pustular or ery-throdermic psoriasis, who may be susceptible to hypercalcemia (60).

Calcipotriene is a relatively unstable molecule and is inactivated byacidic pH. It is not compatible and should not be mixed or applied in con-junction with salicylic acid, lactic acid, or ammonium lactate lotion unlessapplication times are separated by at least two hours. Significant degra-dation was found in combination with hydrocortisone-17-valerate 0.2%ointment but it was found to be compatible with halobetasol propionate0.05% ointment and cream, tazarotene gel, and Estargel (13). When com-bined with phototherapy, calcipotriene should be applied a minimum oftwo hours before light treatment to prevent inactivation by the UVA wave-lengths and rare burning sensations from UVB wavelengths.

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CONCLUSIONS

Calcipotriene is valuable as a first- or second-line therapy option for themanagement of mild to moderate psoriasis and in combination with otherantipsoriatic agents for more severe psoriasis. In clinical trials, calcipotrienemonotherapy is at least as effective as a class II topical corticosteroid whenused faithfully twice a day. Unlike topical corticosteroid, long-term calci-potriene therapy is not associated with skin atrophy or prominent concernregarding tachyphylaxis. In addition, calcipotriene is not associated withthe rebound effect observed with several topical steroids whereby psoriasisworsens upon discontinuation of therapy.

Most dermatologists in the United States use calcipotriene not asmonotherapy but rather in combination with other treatments. Used incombination with a superpotent topical steroid, the two drugs have asynergistic effect and are superior to either agent alone. This has beendemonstrated with halobetasol ointment (Ultravate1) and clobetasol foam(OLUX1) (see Chapter 13 for detail). Furthermore, the combination of thetwo drugs appears to offset the adverse effects of each. The topical steroidhelps to decrease the risk of skin irritation from calcipotriene, and calcipo-triene helps to prevent skin atrophy by the topical steroid. Calcipotriene isalso beneficial in combination with UVB or PUVA phototherapy.

REFERENCES

1. Bourke JF, Iqbal SJ, Hutchinson PE. A randomized double-blind comparison ofthe effects on systemic calcium homeostasis of topical calcitriol (3 micrograms/g)and calcipotriol (50 micrograms/g) in the treatment of chronic plaque psoriasisvulgaris. Acta Derm Venereol 1997; 77(3):228–230.

2. Veien NK, Bjerke JR, Rossmann-Ringdahl I, et al. Once daily treatment of psor-iasis with tacalcitol compared with twice daily treatment with calcipotriol. Adouble-blind trial. Br J Dermatol 1997; 137(4):581–586.

3. Barker JN, Ashton RE, Marks R, et al. Topical maxacalcitol for the treatment ofpsoriasis vulgaris: a placebo-controlled, double-blind, dose-finding study withactive comparator. Br J Dermatol 1999; 141(2):274–278.

4. Anonymous. The report of post-marketing vigilance system to collectinformation of side effects regarding 22-oxacalcitol in 2002. Japan: MaruhoPharmaceutical 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 ofchronic renal failure in a psoriatic patient with diabetic nephropathy; a case reportand 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-hydroxyvitaminD3. Med J Osaka Univ 1985; 35:51–54.

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7. Hansen CM, Mathiasen IS, Binderup L. The anti-proliferative and differentia-tion-inducing effects of vitamin D analogs are not determined by the bindingaffinity 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 andbiological effects of cholecalciferol analogues in rat thyroid cells. J SteroidBiochem Mol Biol 1994; 50(3/4):145–150.

9. Binderup L. Comparison of calcipotriol with selected metabolites and analoguesof vitamin D3: effects on cell growth regulation in vitro and calcium metabolismin vivo. Pharmacol Toxicol 1993; 72:240–244.

10. Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cellproliferation and differentiation in vitro and on calcium metabolism in vivo. Bio-chem Pharmacol 1988; 37(5):889–895.

11. Murdoch D, Clissold SP. Calcipotriol: a review of its pharmacological propertiesand therapeutic use in psoriasis vulgaris. Drugs 1992; 43:415–429.

12. Lea AP, Goa KL. Calcipotriol: a review of its pharmacological properties and ther-apeutic 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-severepsoriasis. In: Weinstein GD, Gottlieb AB, eds. Therapy of Moderate-to-SeverePsoriasis. 2d ed. New York: Marcel Dekker Inc., 2003:29–51.

14. Glade CP, Van Erp PE, Van Hooijdonk CA, et al. Topical treatment of psoriaticplaques with 1-a 24 dihydroxyvitamin D3: a multiparameter flow cytometricalanalysis of epidermal growth, differentiation and inflammation. Acta DermVenereol 1995; 75:381–385.

15. Van Der Vleuten CJM, De Jong E, Van de Kerkhof PCM. Epidermal differen-tiation 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 calcipotrioltreatment: a transmission electron microscopic and freeze-fracture study onpsoriatic patients. Acta Derm Venereol 1996; 76:186–189.

17. Scott LJ, Dunn CJ, Goa KL. Calcipotriol ointment: a review of its use in themanagement of psoriasis. Am J Clin Dermatol 2001; 2(2):95–120.

18. Cullen SI, Calcipotriene Study Group. Long-term effectiveness and safety oftopical calcipotriene for psoriasis. Calcipotriene Study Group. South Med J1996; 89:1053–1056.

19. Ellis JP, Griffiths WAD, Klaber MR. Long-term treatment of chronic plaquepsoriasis with calcipotriol ointment in patients unresponsive to short-contactdithranol. 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 plaquepsoriasis with calcipotriol. J Dermatol Treat 1993; 4:173–177.

22. Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipo-triol 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 childhoodpsoriasis. J Am Acad Dermatol 1997; 36(2 Pt 1):203–208.

25. Darley CR, Cunliffe WJ, Green CM, et al. Safety and efficacy of calcipotriolointment (Dovonex) in treating children with psoriasis vulgaris. Br J Dermatol1996; 135:390–393.

26. Park SB, Suh DH, Youn JI. A pilot study to assess the safety and efficacy oftopical 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 withpsoriasis 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/leftcomparison of calcipotriol and betamethasone valerate in treatment of psoriasisvulgaris [published erratum appears in Lancet 1991; 337(8747):988]. Lancet1991; 337(8735):193–196.

29. Ohgawara A, Kobayashi H, Iizuka H, et al. Clinical evaluation of MC903 (cali-potriol) ointment in patients with psoriasis vulgaris: a right to left comparativestudy 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 controlledtrial 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) and5% coal tar/2% allantoin/0.5% hydrocortisone cream in treating plaque psoria-sis. Br J Clin Pract 1997; 51:16–19.

33. Berth-Jones J, Chu AC, Dodd WA, et al. A multicentre, parallel-group compar-ison of calcipotriol ointment and short-contact dithranol therapy in chronic pla-que psoriasis. Br J Dermatol 1992; 127:266–271.

34. Christensen OB, Mørk N-J, Ashton R, et al. Comparison of a treatment phaseand a follow-up phase of short-contact dithranol and calcipotriol in outpatientswith chronic plaque psoriasis. J Dermatol Treat 1999; 10(4):261–265.

35. Wall AR, Poyner TF, Menday AP. A comparison of treatment with dithranoland calcipotriol on the clinical severity and quality of life in patients with psori-asis. Br J Dermatol 1998; 139:1005–1011.

36. Guenther LC, Poulin YP, Pariser DM. A comparison of tazarotene 0.1% gelonce daily plus mometasone furoate 0.1% cream once daily versus calcipotriene0.005% 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 calcipotrieneointment and halobetasol ointment compared with either agent alone for thetreatment of psoriasis. J Am Acad Dermatol 1996; 35:268–269.

38. Koo J, Lebwohl MG, Menter A, et al. Topical psoriasis update: today’s topicaltreatment strategies to optimize patient response and quality of life. Dermatol-ogy Times 2004:1–15.

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39. Singh S, Reddy DC, Pandey SS. Topical therapy for psoriasis with the use ofaugmented betamethasone and calcipotriene on alternate weeks. J Am AcadDermatol 2000; 43(1 Pt 1):61–65.

40. Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halobeta-sol ointment in the long-term treatment of psoriasis: effects on the duration ofimprovement. 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 treat-ment 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 creme combined withtwice weekly broad-band UVB phototherapy: a safe, effective and UVB-sparingantipsoriatic combination treatment. Dermatology 2000; 200:17–24.

43. Woo WK, McKenna KE. Combination TL01 ultraviolet B phototherapy andtopical calcipotriol for psoriasis: a prospective randomized placebo-controlledclinical trial. Br J Dermatol 2003; 149:146–150.

44. Brands S, Brakman M, Bos JD, et al. No additional effect of calcipotriol oint-ment on low-dose narrow band UVB phototherapy in psoriasis. J Am Acad Der-matol 1999; 41:991–995.

45. Frappaz A, Thivolet J. Calcipotriol in combination with PUVA: a randomizeddouble 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-PUVAwith 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 additionof calcipotriol ointment (50 micrograms/g) to acitretin therapy in psoriasis. Br JDermatol 1998; 138(1):84–89.

48. Rim JH, Park JY, Choe YB, et al. The efficacy of calcipotriolþacitretincombination 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 topsoriasis with combination calcipotriol ointment and very low-dose cyclospor-ine: results of a multicenter placebo-controlled study. J Am Acad Dermatol1994; 31(1):68–74.

50. De Jong EM, Mork NJ, Seijger MM. The combination of calcipotriol and meth-otrexate compared with methotrexate and vehicle in psoriasis: results of a multi-centre 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 andefficacy study. Calcipotriene Study Group. J Am Acad Dermatol 1992; 32:67–72.

52. Katz HI. Combined topical calcipotriene ointment 0.005% and various systemictherapies in the treatment of plaque-type psoriasis vulgaris: review of the litera-ture and results of a survey sent to 100 dermatologists. J Am Acad Dermatol1997; 37(3 Pt 2):S62–S68.

53. Koo J, Kochavi G, Kwan JC. Topical medications for psoriasis. In: Contempor-ary 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 vulgariswith topical calcipotriol has no short-term effect on calcium or bonemetabolism: a randomized, double-blind, placebo-controlled study. Acta DermVenereol 1993; 73:300–304.

55. Berth-Jones J, Bourke JF, Iqbal SJ, et al. Urine calcium excretion during treat-ment 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 cal-cium metabolism in psoriatic patients: comparison with oral calcitriol. Dermato-logica 1991; 183:275–279.

57. Berth-Jones J, Bourke JF, Elouzi H, et al. Immediate and long term effects oftopical calcipotriol on calcium homeostasis during treatment of psoriasis. Br JDermatol 1992; 127(suppl 40):17–18.

58. Saurat J-H, Gumowski-Sunek D, Rizzoli R. Topical calcipotriol and hypercal-caemia [letter]. Lancet 1991; 337:1287.

59. Gumowski-Sunek D, Rizzoli R, Saurat J-H. Calcium tolerance test in patientswith extended body surface psoriasis and treated with calcipotriol. Dermatology1992; 185(3):229–230.

60. Gawkrodger DJ. Current management of psoriasis. Audit Subcommittee of theBritish Association of Dermatologists. J Dermatol Treat 1997; 8:27–55.

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7

Fixed-Dose Corticosteroid/CalcipotrieneCombination 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 aroundthe development of biologics for the treatment of moderate-to-severe psori-asis and the use of targeted phototherapy. However, the majority of patientswith mild to moderate disease are still managed with topical therapy (1). Thetwo most widely prescribed topical therapies for psoriasis are corticosteroidsand vitamin D3 analogs. In a survey of 650 patients from an academic der-matology practice in the United States, 79% of patients were prescribedtopical steroids (2). In Europe, the most widely prescribed topical therapyis reported to be the vitamin D3 analog calcipotriene (calcipotriol) (3).Unfortunately, there have not been many new topical therapies for psoriasisdeveloped in the past few years.

Despite their widespread use and demonstrated efficacy, the chronic useof topical corticosteroids or vitamin D3 analogs is associated with safetyand efficacy concerns. Potential side effects from topical corticosteroids

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include cutaneous atrophy, striae, and, suppression of the hypothalamic-pituitary-adrenal axis. The efficacy of long-term topical corticosteroid therapymay be compromised by tachyphylaxis (4). Although this issue is unresolvedat this time, potential explanations include inability of topical corticosteroidmonotherapy to completely clear lesions, exacerbation unrelated to the topi-cal steroid, and impaired compliance. The most common side effect of topicalvitamin 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 asso-ciated with hypercalcemia (6).

COMBINATION CORTICOSTEROID/CALCIPOTRIENE THERAPY

To maximize the benefits of topical therapy, topical corticosteroids are oftenadministered in combination with a second topical agent such as calcipo-triene. Potential benefits of combination therapy include improved diseasecontrol and decreased adverse events. Benefits of combination therapy arederived from differing mechanisms of action and less overall exposure tothe individual components. For example, the combination of a topical cor-ticosteroid plus topical calcipotriene is reported to be particularly effectiveat clearing psoriatic lesions without significant cutaneous irritation fromthe latter or skin atrophy from the former. In fact, combination topical ther-apy with calcipotriene in the morning and corticosteroid in the evening hasbeen demonstrated to be more effective than either agent applied b.i.d. asmonotherapy (7–9). Unfortunately, combination therapy has its own pit-falls. For example, stacking or combining different agents may inactivateone or both products or require complicated dosing schedules. These issuesmay negatively impact compliance because of lack of anticipated efficacy ordifficulties with compliance.

A fixed-dose corticosteroid/calcipotriene ointment has been availablein Europe and Canada (Dovobet1, Daivobet1) for a few years and recentlywas approved by the U.S. Food and Drug Administration (Taclonex1). It isone of the few new topical agents to become available.

The product is a fixed-dose formulation of 0.064% betamethasonedipropionate (equivalent to 0.5 mcg of betamethasone dipropionate), a class IIhigh-potency (U.S.A. classification) synthetic fluorinated corticosteroid, and0.005% calcipotriene ointment (equivalent to 50 mcg of calcipotriene), a syn-thetic 1,24-dihydroxyvitamin D3 analog. A stable formulation of the two activeagents was achieved by mixing them in a novel anhydrous vehicle. The atro-phogenic potential and bioavailability of betamethasone dipropionate in thetwo-drug combination appears equal to that in betamethasone dipropionate(Diprosone1) ointment (10,11). Moreover, the biologic activity of calcipo-triene 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-COMBINATIONFORMULATION OF BETAMETHASONEDIPROPIONATE/CALCIPOTRIENE

Topical fixed-dose betamethasone dipropionate/calcipotriene has been evalu-ated in seven large international trials involving more than 7000 patients withpsoriasis involving 10% to 30% of total body surface area. In all trials, psoriasisseverity was assessed at baseline, during, and at the end of treatment using thePsoriasis Area and Severity Index (PASI). All seven trials demonstrated consis-tent reduction in PASI of approximately 40% after one week and 70% after fourweeks of betamethasone dipropionate/calcipotriene therapy (13).

THE FIXED-DOSE COMBINATION IS MORE EFFECTIVE THANSTEROID OR CALCIPOTRIENE MONOTHERAPY

In a four-week, double-blind study, 1106 patients were randomized into one ofthree groups: (i) b.i.d. betamethasone dipropionate/calcipotriene ointment,(ii) b.i.d. betamethasone dipropionate ointment, and (iii) b.i.d. calcipotrieneointment (13). The four-week, double-blind phase of the trial was followedby an open-label phase in which patients were treated with calcipotriene oint-ment b.i.d. for four weeks. The baseline PASI scores were 10.8, 10.5, and 10.9for 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 cal-cipotriene groups, respectively; mean percentage changes in PASI at the endof the four-week, double-blind phase were 74.4%, 61.3%, and 55.3% for thecombination, betamethasone dipropionate, and calcipotriene groups, respec-tively. Overall, the mean reduction in PASI observed with the combinationwas significantly greater (p< 0.001) than that elicited by the individualcomponents. The percentages of patients with at least 75% improvement intheir 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 adversereactions during the four-week, double-blind phase (i.e., after only four weeksof therapy) were 8.1%, 4.7%, and 12.0% for the combination, betamethasonedipropionate, and calcipotriene groups, respectively.

THE FIXED-DOSE COMBINATION B.I.D. ACHIEVESGREATER PASI REDUCTION WITHIN ONE WEEK VS.STEROID MONOTHERAPY

In a double-blind, four-week study, 1040 patients with psoriasis (mean PASIon inclusion: 10.8) were randomized into one of four groups: (i) b.i.d. betametha-sone 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 weekfor the combination group was 48.1%, which already was statistically signifi-cantly greater ( p< 0.001) than the decreases observed in the betamethasonedipropionate, calcipotriene, and vehicle groups (41.4%, 28.4%, and 21.5%, res-pectively). The mean decreases in PASI after four weeks were 73.2%, 63.1%,48.8%, and 28.8%, respectively for the combination, betamethasone dipropio-nate, calcipotriene, and vehicle groups with the decrease in patients receivingthe combination significantly greater ( p< 0.001) than in the comparator groups.Lesional/perilesional adverse events were reported in 9.9%, 8.6%, 17.2%, and15.7% of patients, respectively for the combination, betamethasone dipropio-nate, calcipotriene, and vehicle groups. There were significantly more adverseevents in the calcipotriene-only group than in the other groups ( p¼ 0.023). Bothof 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 SAFEAND EFFECTIVE

In another double-blind, four-week study, 1603 patients were randomizedinto one of four groups: (i) once-daily betamethasone dipropionate/calcipo-triene ointment, (ii) once-daily betamethasone dipropionate ointment in thesame anhydrous vehicle, (iii) once-daily calcipotriene ointment in the sameanhydrous vehicle, and (iv) the vehicle alone (15). Baseline PASI scores were9.9, 9.8, 10.4, and 9.5 for the combination, betamethasone dipropionate,calcipotriene, and vehicle-only groups, respectively. After one week of treat-ment, the mean percentage changes in PASI were 39.2%, 33.3%, 23.4%, and18.1% for the combination, betamethasone dipropionate, calcipotriene,and vehicle-only groups, respectively (Fig. 1). The mean difference in PASIreduction was significantly greater (p< 0.001) for the combination group thanfor the comparator groups. The mean percentage changes in PASI after fourweeks were 71.3%, 57.2%, 46.1%, and 22.7% for the combination, betametha-sone 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 Inves-tigators’ Global Assessment (IGA) were 56.3%, 37.0%, 22.3%, and 10.2% forthe combination, betamethasone dipropionate, calcipotriene, and vehicle-only groups, respectively (Fig. 2). The odds ratio of having controlled diseasewas significantly greater (p< 0.001) in patients treated with the combination.The percentages of patients with lesional/perilesional adverse reactions were6.0%, 4.9%, 11.4%, and 13.6% for the combination, betamethasone dipropio-nate, calcipotriene, and vehicle-only groups, respectively. The rates of adversereactions were similar between the betamethasone dipropionate/calcipotrienecombination and betamethasone dipropionate ointment, while calcipotriene

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

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

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

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ONCE-DAILY FIXED-DOSE COMBINATION IS AS SAFEAND 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) once-daily betamethasone dipropionate/calcipotriene ointment and once-dailyvehicle, (ii) b.i.d. betamethasone dipropionate/calcipotriene ointment,(iii) b.i.d. calcipotriene ointment, and (iv) b.i.d. vehicle. Mean PASI at entrywas 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 theq.d. combination, b.i.d. combination, b.i.d. calcipotriene, and b.i.d. vehiclegroups, respectively. The differences in PASI from baseline in the patientstreated with either b.i.d. or q.d. combination were significantly greater(p< 0.001) than the calcipotriene and vehicle groups. There was no statisti-cal 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. calcipotri-ene, and b.i.d. vehicle groups, respectively. Similar to results observed afterone week, the reduction in PASI elicited by either combination regimen wassignificantly greater (p< 0.001) than that of the other treatments. Similarefficacy is seen with once-daily versus b.i.d. treatment with betamethasonedipropionate/calcipotriene ointment. The percentages of patients with atleast 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 wasno statistical difference in psoriasis area and severity index between once-daily andtwice-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. combina-tion,b.i.d.calcipotriene,andb.i.d.vehiclegroups, respectively.Theproportionof patients who experienced adverse reactions was lower in the combined for-mulation groups than in the calcipotriene group (p< 0.01). Therefore, theefficacy of once-daily application was not shown to be different from thatof b.i.d. use, and once-daily combination was shown to be more effectiveand better tolerated than b.i.d. calcipotriene ointment.

ONCE-DAILY FIXED-DOSE THERAPY ACHIEVES HIGHERCLEARANCE AND FEWER ADVERSE EVENTSVS. MONOTHERAPY

In an investigator-blinded study involving 972 patients, two different regi-mens involving betamethasone dipropionate/calcipotriene ointment werecompared with eight weeks of b.i.d. calcipotriene ointment therapy (17).In one group, betamethasone dipropionate/calcipotriene ointment wasapplied daily for eight weeks; in the second group, it was applied daily forfour weeks followed by four weeks of intermittent therapy (betamethasonedipropionate/calcipotriene ointment once daily on Saturday and Sunday, andcalcipotriene ointment once daily on weekdays). Mean PASI at baseline was10.3, 10.4, and 10.9 for the combination-only, combination weekend/calcipo-triene weekday, and calcipotriene-only groups, respectively. At eight weeks,the mean percentage reductions in PASI were 73.3% in the once-daily beta-methasone dipropionate/calcipotriene group, 68.2% in the weekday–weekendbetamethasone dipropionate/calcipotriene group, and 64.1% in the calcipo-triene group. Significantly greater improvement (p< 0.001) was noted aftereight weeks of once-daily betamethasone dipropionate/calcipotriene therapycompared with four weeks of weekday–weekend therapy, but there was a pla-teau in the effect at five weeks. Lesional/perilesional adverse events werereported in 10.9%, 11.5%, and 22.3% of patients for once-daily betamethasonedipropionate/calcipotriene group, weekday–weekend betamethasone dipro-pionate/calcipotriene group, and the calcipotriene group, respectively, with sig-nificantly fewer (p< 0.001) adverse events occurring in the groups receivingcombination therapy compared with calcipotriene alone.

ONCE-DAILY FIXED-DOSE THERAPY IS EFFECTIVE FORPATIENTS 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-dosebetamethasone dipropionate/calcipotriene combination in patients with mild(PASI �6), moderate (PASI 6.1–�12), and severe (PASI >12) psoriasis.

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Although the analysis was somewhat limited by use of a correlation betweenthe IGA and imputed PASI scores and by the failure of all investigators toreport both IGA and PASI scores, it demonstrated that the fixed-dose com-bination used once-daily produced consistent efficacy across all degrees ofdisease severity (Fig. 4). At the end of one, two, and four weeks, the meanpercent PASI reduction from baseline with the fixed-drug combination was38.7%, 56.7%, and 67.6%, respectively, in mild disease; 37.8%, 55.3%, and68.1%, respectively, in moderate disease; and 41.2%, 59.5%, and 71.5%,respectively, in severe disease. Thus, the combination had a more rapidonset of action than the comparators and demonstrated efficacy in patientswith a spectrum of disease severities.

INVESTIGATORS AND PATIENTS’ ASSESSMENTS OFONCE-DAILY FIXED-DOSED THERAPY AGREE

In this study, the investigators randomized 501 patients with stable psoriasisto receive either the combination for four weeks followed by calcipotrienefor four weeks or tacalcitol only for eight weeks (19). The mean PASI atbaseline for all patients was 9.7 for the combination/calcipotriene groupand 9.9 for the tacalcitol group. Treatment with the combination followedby calcipotriene was significantly more effective than tacalcitol monother-apy in terms of mean percentage PASI reduction (65.0% vs. 33.3% at week4 and 59.0% vs. 38.4% at week 8; p< 0.001 for both). During the first fourweeks, the number of patients experiencing lesional or perilesional irritationwas greater in the tacalcitol group (11.8%) than in the combination/calcipo-triene group (2.9%; p< 0.001).

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

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LONG-TERM, ONCE-DAILY FIXED-DOSE THERAPYIS SAFE AND EFFECTIVE

Kragballe et al. completed a study designed to investigate the efficacy andsafety of three treatment regimens involving use of the fixed-dose combina-tion for up to 52 weeks (20). In this study, 634 patients were randomized toonce-daily treatment with 52 weeks of the fixed-dose combination, or 52weeks of alternating four-week periods of the combination agent and calci-potriene, or four weeks of the fixed-dose combination agent followed by 48weeks of calcipotriene ointment. All treatments were used once-daily, inter-mittently, on an as-needed basis. Patients were instructed to use as much oftheir assigned experimental drug as necessary to relieve symptoms and pro-mote clearance. The clinical response observed in the initial four-weekperiod when all patients received the combination reflected what was seenin the short-term studies reviewed above—rapid onset of action and reliablelesion clearance. These clinical benefits were best maintained in the groupusing the combination agent only (Fig. 5). Importantly, there was no appar-ent loss of efficacy or perceived tachyphylaxis in the fixed-dose combinationarm. About 76.9% of the patients using the fixed-dose combination asneeded for 52 weeks were clear or almost clear. The group that alternatedbetween the combination agent and calcipotriene ointment ‘‘flip-flopped’’back and forth between better- and lesser control with better control periodsaffected by the use of the combination agent. Finally, the group that mostlyused calcipotriene showed more loss of efficacy than the other two groupswhen they were switched from the combination agent to calcipotriene atfour 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 combina-tion agent only.

With regard to long-term safety, drug-related adverse events occurringin more than 2% of patients were significantly lower in the group receivingthe fixed-dose combination for 52 weeks than with either comparator groups(Table 1). This study establishes that the efficacy of once-daily fixed-dosecombination therapy can be maintained for as long as one year. In addition,long-term fixed-dose combination therapy was not associated with anincreased risk of cutaneous atrophy compared to the other interventions.

In summary, the above-mentioned clinical studies have shown thatfixed-dose betamethasone dipropionate/calcipotriene ointment once dailyhas greater efficacy and a faster onset of improvement than the individualcomponents. It is associated with similar cutaneous adverse events tobetamethasone dipropionate and approximately 50% less compared withcalcipotriene.

POTENTIAL BENEFITS OF FIXED-DOSECOMBINATION THERAPY

The new betamethasone dipropionate/calcipotriene combination appears tobe more than an agent with just two-in-one convenience. The innovativeanhydrous vehicle has achieved two highly advantageous characteristics:

1. Well-documented synergy between the two components allowingthe combination agent to have significantly higher efficacy than thehigh strength topical steroid betamethasone dipropionate. Also, inall likelihood, the combination agent with two ingredients eachcontributing to efficacy allowed more efficacy with less risk. Notonly is the irritation risk of calcipotriene decreased by the topicalsteroid ingredient but the combination agent also can be character-ized as ‘‘high-strength topical steroid that performs like a superhigh-strength topical steroid.’’ It clearly performs better than ahigh-strength topical steroid (i.e., betamethasone dipropionate)but is only expected to have a risk profile of high strength ratherthan a super high-strength topical steroid.

2. Allowed once-daily application of a calcipotriene-containing agentto work as effectively as b.i.d. application. Generally, calcipotrieneis appreciated as having much better efficacy when it is appliedb.i.d. than once a day. However, this combination agent in anhy-drous innovative vehicle breaks this rule by allowing outstandingefficacy even though this calcipotriene containing combinationagent is only used once a day (Figs. 6A and B). The synergisticand once-daily administration schedule lead to clinical utility inthat the combination agent seemed capable of treating widespread

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Fixed-Dose Corticosteroid/Calcipotriene Combination Therapy 85

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

IN COMBINATION WITH BIOLOGICS

The fact that this combination agent is capable of treating widespread psori-asis topically makes it possible to use this agent to ‘‘jump start’’ biologicagents such as etanercept or efalizumab. The biologic agents that are cur-rently approved by the Food and Drug Administration for psoriasis usein the United States are notable for their relative safety compared to prebio-logic systemic agents. However, the onset of action is often slow in manypatients. Consequently, clinicians often have to ‘‘hold the hands’’ of the patientuntil the efficacy of these biologic agents eventually become effective. Ifsomething as simple as a topical combination agent can be used to jumpstart improvement of biologic agents, it would be a highly advantageoususe of this novel topical combination. In a retrospective analysis of pooleddata from six of the pivotal trials of fixed-dose combination calcipotriene/betamethasone dipropionate, Anstey and Kragballe demonstrated that, in

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

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patients with severe psoriasis, the two-compound product may have efficacycomparable to a full course of biologics as reported in the literature (22).Although not a direct head-to-head comparative trial, treatment with thefixed-dose combination formulation for four weeks and biologics for 12weeks 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 canenhance the outcome of treatment modalities such as acitretin, methotrexate,cyclosporine (only low-dose cyclosporine was tested), ultraviolet B photother-apy, and psoralen plus ultraviolet A phototherapy (8,23–25). Because thefixed-dose combination agent is significantly more efficacious than the use ofcalcipotriene monotherapy, one can speculate that whatever the enhancementof efficacy that has been demonstrated experimentally with calcipotriene, theuse of this combination agent is likely to result in more enhancement.

POTENTIAL EFFECTS ON COMPLIANCE

Lastly, psoriasis is a chronic disease and, therefore, requires compliancewith a long-term treatment regimen. However, only 60% of patients arecompliant with their therapy (26). There are several reasons why psoriasispatients are not compliant with their treatments (27). The treatments maynot work well or they have worrisome potential for rare but serious sideeffects especially with systemic agents. Other reasons are that the treatmentsare inconvenient or relapse occurs too quickly. The new fixed-dose beta-methasone dipropionate/calcipotriene combination agent should improvepatient compliance, which is critical to any long-term strategy. Supportingdata from the clinical trials of the fixed-combination product indicate thatthe compliance rates were 68% and 81% when the ointment was appliedb.i.d. and once daily, respectively (13,15).

CONCLUSIONS

Although corticosteroids and calcipotriene share similar antipsoriatic prop-erties, they work by different mechanisms. Advances in drug formulationhave led to the development of a fixed-dose combination of the two drugs,which overcomes their inherent physiochemical incompatibilities. In theseven clinical trials described in this chapter, the combination has beenshown to be effective, safe, and work rapidly. Treatment is associated withboth statistically and clinically significant improvements in PASI scores.In addition, clinical responses to the topical preparation are sustained forup 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 chap-ter support the use of this drug for patients with a spectrum of disease sever-ity, both as monotherapy and in combination with other interventionsincluding 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 patientstudy: treatment history and satisfaction reported by 17,990 members ofEuropean 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 therapeutictachyphylaxis to topically applied steroids in patients with psoriasis. J Am AcadDermatol 1999; 41:546–549.

5. Ashcroft DM, Po AL, Williams HC, Griffiths CE. Systematic review ofcomparative efficacy and tolerability of calcipotriol in treating chronic plaquepsoriasis. BMJ 2000; 320:963–967.

6. Kawahara C, Okada Y, Tanikawa T, Fukusima A, Misawa H, Tanaka Y. Severehypercalcemia and hypernatremia associated with calcipotriol for treatment ofpsoriasis. J Bone Miner Metab 2004; 22:159–162.

7. Kragballe K, Barnes L, Hamberg KJ, et al. Calcipotriol cream with or withoutconcurrent topical corticosteroid in psoriasis: tolerability and efficacy. Br JDermatol 1998; 139:649–654.

8. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotrieneointment and halobetasol ointment compared with either agent alone for thetreatment of psoriasis. J Am Acad Dermatol 1996; 35:268–269.

9. Ruzicka T, Lorenz B. Comparison of calcipotriol monotherapy and a combina-tion of calcipotriol and betamethasone valerate after 2 weeks’ treatment withcalcipotriol in the topical therapy of psoriasis vulgaris: a multicentre, double-blind, randomized study. Br J Dermatol 1998; 138:254–258.

10. Traulsen J, Hughes-Formella BJ. The atrophogenic potential and dermaltolerance of calcipotriol/betamethasone dipropionate ointment compared tobetamethasone dipropionate ointment. 10th Congress of the European Academyof Dermatology and Venereology, Munich, Oct 10–14, 2001.

11. Traulsen J. The bioavailability of betamethasone dipropionate in an ointment com-bination with calcipotriol (Dovobet ointment) is equal to that of betamethasonedipropionate alone in Diprosone1 ointment. 10th Congress of the European Acad-emy of Dermatology and Venereology, Munich, Oct 10–14, 2001.

12. Hansen J. Mixing the unmixable. Verbal communication at the Leo SatelliteSymposium. 10th Congress of the European Academy of Dermatology andVenereology, Munich, Oct 10–14, 2001.

13. Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formu-lation with rapid onset of action was superior to monotherapy with betamethasone

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dipropionate or calcipotriol in psoriasis vulgaris. Acta Derm Venereol 2002;82(2):131–135.

14. Papp KA, Guenther L, Boyden B, et al. Early onset of action and efficacy of acombination of calcipotriene and betamethasone dipropionate in the treatmentof psoriasis. J Am Acad Dermatol 2003; 48(1):48–54.

15. Kauffmann R, Bibby AJ, Bissonnette R, et al. A new calcipotriol/betametha-sone dipropionate formulation (DaivobetTM) is an effective once daily treatmentfor psoriasis vulgaris. Dermatology 2002; 205(4):389–393.

16. Guenther L, Cambazard F, van de Kerhof PCM, et al. Efficacy and safety of anew combination of calcipotriol and betamethasone dipropionate (once or twicedaily) compared to calcipotriol (twice daily) in the treatment of psoriasis vul-garis; a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol2002; 147:316–323.

17. Kragballe K, Noerrelund KL. A highly effective once-daily treatment with a newcalcipotriol/betamethasone ointment in psoriasis vulgaris [poster]. J Eur AcadDermatol Venereol 2002; 16(Suppl 1):276.

18. Menter A, et al. Comparative efficacy of calcipotriene/betamethasone combina-tion product after 1, 2, 4 weeks of treatment of mild, moderate, and severepsoriasis. 63rd Annual Meeting of the American Academy of Dermatology, 2006.

19. Ortonne JP, Kaufmann R, Lecha M, et al. Efficacy of treatment with calcipo-triol/betamethasone dipropionate followed by calcipotriol alone compared withtacalcitol for the treatment of psoriasis vulgaris: a randomized, double-blindtrial. Dermatology 2004; 209:308–313.

20. Kragballe K, et al. 13th Annual Congress of the European Academy of Derma-tology and Venereologym, Florence, Italy, Nov 17–21, 2004.

21. Kragballe K, et al. A 52-week safety study of a calcipotriol/betamethasonedi-propionate two-compound product (Daivobet1/Dovobet1) in the treatmentof psoriasis vulgaris. Br J Dermatol. In Press.

22. Anstey AV, Kragballe K. A retrospective assessment of PASI 50 and PASI 75attainment with a calcipotriol/bethmethasone dipropionate ointment. Int JDermatol. In press.

23. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobe-tasol ointment in the long-term treatment of psoriasis: effects on the duration ofimprovement. J Am Acad Dermatol 1998; 39:447–450.

24. Frapazz A, Thivolet J. Calcipotriol in combination with PUVA: a randomizeddouble blind placebo study in severe psoriasis. Eur J Dermatol 1993; 3:351–354.

25. Gossman RM, Thivolet J, Claudy A, et al. A novel therapeutic approach topsoriasis with combination calcipotriol ointment and very low-dose cyclospor-ine: results of a multicenter placebo-controlled study. J Am Acad Dermatol1994; 31(1):68–74.

26. Zaghloul SS, Goodfield JJ. Objective assessment of compliance with psoriasistreatment. Arch Dermatol 2004; 140(4):408–414.

27. 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.

28. Guenther LC. Fixed-dose combination therapy for psoriasis. Am J Clin Derma-tol 2004; 5(2):71–77.

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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 treat-ment of plaque psoriasis in the United States in 1997. It is available as agel or cream in a concentration of either 0.1% or 0.05%. Despite its provenefficacy in the treatment of psoriasis, many patients experience significantlocal irritation that limits its use as monotherapy. In general, tazarotene isused most effectively in the treatment of psoriasis in combination with otherforms 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 Aderivative that is rapidly converted in vivo to its biologically active free-acidmetabolite, tazarotenic acid (1).

There are two types of retinoid receptors: retinoic acid receptors(RARs) and retinoid X receptors (RXRs). The RARs and RXRs are eachcomposed of three distinct subtypes, labeled a, b, and c (2). These subtypes

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are found in a tissue-specific manner. RARa is primarily expressed in manyembryonic and adult tissues, and RARb is found exclusively in dermal fibro-blasts. RARc is the most ubiquitous retinoic acid receptor in human adultepidermis and is thought to be the key mediator of retinoid effects onkeratinocytes (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 hetero-dimers with a wide range of other intracellular receptors, such as thyroidhormone, vitamin D3, estradiol, and glucocorticoids (4). These retinoidreceptors belong to a large superfamily of receptors also consisting of gluco-corticosteroid, thyroid hormone, and vitamin D3 receptors, all of which areDNA-binding proteins and functioning as trans-acting transcription modu-lating factors.

Tazarotenic acid, the active metabolite of tazarotene, binds to all threeRAR-subtypes, especially RARc and RARb, without having any effect onRXRs (5). Retinoids elicit their biological effects by activating nuclearreceptors and regulating gene transcription (6). The exact molecularmechanism by which tazarotene is able to exert its effects on psoriasis isunknown, but it is thought to affect the three major pathogenic causes ofpsoriasis: in keratinocytes, tazarotene has antiproliferative effects, nor-malizes their abnormal differentiation, and decreases the expression ofinflammatory markers on their cell surface (6). Studies have shown that0.05% tazarotene gel applied twice daily for 14 days improves keratinocytedifferentiation through a reduction of hyperkeratosis and acanthosis andby reappearance of the granular layer (7). Histochemically, pathogenicoverexpression of epidermal differentiation markers such as involucrin,keratinocyte transglutaminase, skin-derived antileukoproteinase (also knownas elafin), and migration-inhibitory related factor 8 (also known as calgra-nulin A) is significantly reduced (6). In addition, tazarotene elevates markerslike filaggrin in psoriatic lesions, implicating a return to a more normal andquiescent skin status (7,8).

CH3

COC3H6

O

H3C

N

S

Figure 1 Chemical structure of tazarotene.

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TAZAROTENE MONOTHERAPY

Multiple clinical trials have confirmed the efficacy and safety of tazarotenegel and cream in the treatment of psoriasis (9–11). Tazarotene 0.1% wasgenerally more effective than the 0.05% concentration, although it was lesstolerated secondary to skin irritation. In addition, the cream formulations oftazarotene (0.05% and 0.1%) might have a potentially more acceptable toler-ability 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% fluocinonidecream twice daily (12). A total of 348 psoriasis patients were enrolled for12 weeks of treatment followed by 12 weeks of post-treatment observation.Treatment success rates, defined as improvement of 50% or more, during thetreatment and post-treatment periods are shown in Figure 2. Treatment suc-cess rates were statistically significantly higher in the fluocinonide group atweek 4 than in the tazarotene 0.1% group and at week 2 to 8 than in thetazarotene 0.05% group, whereas by the end of treatment week 12 the fluo-cinonide and tazarotene groups were statistically similar. Post-treatmentreturn of psoriasis was most rapid with fluocinonide, especially during thefirst four weeks after the cessation of therapy. Signs and symptoms of localirritation were more common with tazarotene than with fluocinonide.During the treatment period, 18%, 14%, and 11% of patients experienced

0

20

40

60

80

0 4 8 12 16 20 24

0.1%0.06%FL0.06%

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up

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Figure 2 Global treatment success rates for once-daily tazarotene 0.1% gel, once-daily tazarotene 0.05% gel, and twice-daily fluocinonide cream in the treatment ofplaque 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-potencytopical 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 corticoste-roid achieves a more rapid and greater efficacy and decreases irritation ascompared to tazarotene monotherapy, followed by a more prolonged dura-tion of remission compared to corticosteroid monotherapy (12–15). In alarge-scale study to evaluate the efficacy of a combination treatment of tazaro-tene with a topical steroid, 300 psoriasis patients were randomly assigned toone of four treatment groups: 0.1% tazarotene gel once daily in combinationwith either once-daily application of placebo cream, low-potency corticoste-roid (0.01% fluocinolone acetonide cream), mid-potency corticosteroid (0.1%mometasone furoate cream), or high-potency corticosteroid (0.05% fluocino-nide cream) (16). Patients underwent 12 weeks of treatment, followed by fourweeks of post-treatment observation. It took two weeks for the tazaroteneplus mid-potency corticosteroid and three weeks for the tazarotene plushigh-potency corticosteroid versus four weeks for the tazarotene plus low-potency corticosteroid and tazarotene plus placebo groups to obtain atleast 50% improvement. At the end of 12 weeks, 91% in the tazarotene/mid-potency corticosteroid group, and 95% in the tazarotene/high-potencycorticosteroid group, versus 80% in the tazarotene 0.1% gel/placebo group,obtained at least 50% improvement. The results with tazarotene/low-potency corticosteroid group were not statistically superior to the tazarotene0.1% gel/placebo group. Local skin irritation was less frequent in the groupstreated with tazarotene plus a mid- or high-potency corticosteroid. Tazaro-tene plus high-potency corticosteroid had rates of burning that were almosthalf of those of tazarotene plus placebo (12% vs. 23%, respectively). Duringthe post-treatment observation, rebound effect, often seen after disconti-nuation of corticosteroid monotherapy, was not observed in any of thecombination tazarotene and topical steroid groups. Similarly, other studieshave also confirmed that the use of a mid- or high-potency corticosteroidenhances the efficacy and tolerability of tazarotene (17,18).

In addition, the efficacy and tolerability of tazarotene with a mid-potency 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 oncedaily was compared to monotherapy 0.1% mometasone furoate creamapplied twice daily (14). A total of 73 psoriasis patients were treated for12 weeks, followed by 12 weeks of post-treatment observation. At the endof 12 weeks, 74% of the patients treated with combination therapy oftazarotene with mometasone cream versus 58% of the patients treated withtwice-daily mometasone furoate monotherapy achieved at least 50% globalimprovement in their psoriasis. During post-treatment observation, 68%(15 of 22) of the mometasone furoate monotherapy group dropped out fromthe study during the first four weeks post-therapy due to recurrence andrebound, as compared to only 12% (three of 26) from the combinationtherapy group.

Thus, the studies above show that the combination of mid- or high-potency steroid with tazarotene achieves faster and greater therapeuticeffects, with fewer side effects and longer remission time than tazarotenemonotherapy or topical corticosteroid monotherapy.

Three different mid-potency topical steroids [i.e., betamethasone dipro-pionate 0.05% cream (Diprosone1), fluticasone propionate 0.005% ointment(Cutivate1), or diflorasone diacetate 0.05% cream (Maxiflor1)] and three dif-ferent high-potency steroid ointments [i.e., fluocinonide 0.05% ointment(Lidex1), mometasone furoate 0.1% ointment (Elocon1), or diflorasone dia-cetate 0.05% ointment (Maxiflor1)] were compared in terms of efficacy andtolerability in combination with tazarotene in a 12-week, multicenter, investi-gator-masked, randomized, parallel-group study involving 200 patients (19).Topical corticosteroid was applied in the morning and 0.1% tazarotene gelin the evening. The best-performing steroid was betamethasone dipropionate0.05% cream (a mid–high-potency steroid), followed by mometasone furoate0.1% 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 bal-ance between efficacy and tolerability was achieved with this regimen.

The combination of betamethasone valerate foam 0.12% (Luxiq1) and0.1% tazarotene cream was shown to be effective in a case series of 10 pso-riasis patients (20). Two patients were clear of their psoriasis by week 4 andfour were clear at week 8. More importantly, no adverse events, includingirritation, were reported. The authors report that the use of the corticoste-roid foam may protect against tazarotene-induced skin irritation, and thecosmetic appeal of a nongreasy corticosteroid foam improved patientcompliance with the resultant high efficacy that was seen.

A double-blind, randomized, vehicle-controlled study examined the effi-cacy of a combination of tazarotene and clobetasol both for initial efficacyand for maintenance use (15). A total of 50 psoriasis patients were treatedwith a combination of 0.1% tazarotene gel and clobetasol ointment for aninitial 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 eve-ning. During week 3 and 4, 0.1% tazarotene gel was applied every morningand clobetasol ointment was applied on Tuesday, Thursday, and Saturdayevenings. During the last two weeks, 0.1% tazarotene gel was applied on Mon-day, Wednesday, and Friday mornings and clobetasol ointment was appliedon Tuesday and Thursday evenings. After the six-week ‘‘induction’’ phase,patients with at least 50% improvement were randomized into one of the fol-lowing three maintenance treatment groups for five months: combinationtherapy with 0.1% tazarotene gel applied on Monday, Wednesday, and Fridayand clobetasol ointment applied on Tuesday and Thursday; 0.1% tazarotenegel applied on Monday, Wednesday, and Friday and white petrolatumapplied on Tuesday and Thursday; and tazarotene gel vehicle applied onMonday, Wednesday, and Friday and white petrolatum applied on Tuesdayand Thursday. At the end of the five-month maintenance therapy, 73% ontazarotene and clobetasol combination therapy, 47% on tazarotene thriceweekly, and 19% on vehicle retained at least 50% improvement relative tobaseline. Similarly, other studies have also confirmed lengthy remissions whentazarotene is used in combination with topical steroid (21).

TAZAROTENE AND TOPICAL STEROID-INDUCEDSKIN ATROPHY

Not only do tazarotene and topical steroid act synergistically but tazarotenealso reduces the degree of topical steroid-induced skin atrophy (22). In astudy involving 24 healthy volunteers, subjects were randomized to apply0.1% tazarotene gel, 0.05% diflorasone diacetate (Psorcon1), and 0.1% tazaro-tene gel combined with 0.05% diflorasone diacetate six days per week forfour weeks (22). The subjects who applied 0.1% tazarotene gel had a meanepidermal thickness increase of 62%. The subjects who applied 0.05%diflorasone diacetate experienced a 43% reduction in the mean epidermalthickness. However, in the subjects who used tazarotene in combinationwith 0.05% diflorasone diacetate, there was only a reduction of 28% in theepidermal thickness. Thus, tazarotene significantly reduced epidermalatrophy induced by topical steroid.

TAZAROTENE CHEMICAL COMPATIBILITY WITHA TOPICAL STEROID

Tazarotene and a range of topical corticosteroids (i.e., mometasone furoate0.1% cream; fluocinonide 0.05% ointment and cream; betamethasonedipropionate 0.05% gel, ointment, cream, and lotion; clobetasol propionate0.05% gel, ointment, cream, and scalp solution; diflorasone diacetate 0.05%ointment and cream; halobetasol propionate ointment and cream) may beapplied at the same time without adversely affecting the chemical stability

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of either tazarotene or the corticosteroids (23). However, chemical stabilitypast two weeks have not been studied, and therefore, tazarotene and topicalcorticosteroids should not be premixed in a jar.

TAZAROTENE AND CALCIPOTRIENE

Although tazarotene and calcipotriene might not be as potent as class Itopical steroids when each is used as monotherapy, they appear to have syner-gistic effects when combined, with the same efficacy and rapidity as a class Isuperpotent topical steroid (24). In a prospective, open-label, left–rightcomparison study, combination therapy of 0.1% tazarotene gel once daily withcalcipotriene ointment twice daily was comparable to clobetasol ointmenttwice daily (24). 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 tazarotene and calcipotrienehad the same improvement in overall lesion severity, reduction in plaque ele-vation and scaling as the clobetasol-treated lesions. Not surprisingly,erythema improved more in the clobetasol-treated lesions than the combinedtazarotene and calcipotriene-treated lesions. There does not seem to be anychemical incompatibility between calcipotriene ointment and tazarotene gelthat is clinically significant (24).

In a multicenter, randomized, investigator-masked study involving120 psoriasis patients, the combination of tazarotene gel once daily withmometasone furoate cream once daily was compared to calcipotrieneointment twice daily (25). A total of 45% of patients in the combined taza-rotene and mometasone group achieved �75% global improvement aftertwo weeks of treatment compared with only 26% of patients in the calci-potriene group (25). Furthermore, the combination tazarotene and mometasonegroup had a significantly greater reduction in scaling, erythema, plaque eleva-tion, and body surface area involvement than calcipotriene monotherapy atthe end of the four-week post-treatment observation.

TAZAROTENE AND UVB PHOTOTHERAPY

Tazarotene has been successfully combined with both broadband UVBphototherapy (BB-UVB) and narrowband UVB phototherapy (NB-UVB)for more effective and rapid clearing of psoriasis compared with either treat-ment alone (26–28).

Once daily treatment with tazarotene 0.1% gel for two weeks followedby three times a week BB-UVB and tazarotene 0.1% gel was superior toBB-UVB monotherapy (27). It took a median of 25 days for the tazaroteneand BB-UVB group to reach at least 50% improvement versus 53 days withBB-UVB monotherapy. Combined tazarotene and BB-UVB therapy alsoresulted in greater improvement in plaque elevation and scaling than did

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BB-UVB monotherapy. In addition, tazarotene significantly reduced theamount of UV radiation required to improve psoriasis. The median cumu-lative BB-UVB dose was 390 mJ/cm2 in the combined tazarotene andBB-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 withNB-UVB, a total of 10 patients were treated with 0.05% tazarotene oncedaily 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 werenoted in the tazarotene-treated side.

Tazarotene and vitamin D analogs as adjuncts to NB-UVB therapyhave also been evaluated. Schiener et al. (29) studied 10 patients withwidespread psoriasis and compared the combination of tazarotene gel0.05% plus NB-UVB to calcipotriol ointment plus NB-UVB. Patients receivedNB-UVB treatment four times weekly and applied either of the assignedtopical treatments once every evening on different halves of the body.Results showed that both regimens had identical number of exposure daysand identical cumulative NB-UVB dose. Calcipotriol was generally very welltolerated. One patient developed hyperpigmentation strictly limited to thearea where calcipotriol ointment was applied. On the side that tazarotene0.05% gel was applied, four patients complained of itching and dryness.Despite such complaints, a follow-up questionnaire showed that six out of10 patients still preferred tazarotene gel over calcipotriol ointment becauseit was easier to spread and less greasy.

To date, no trials have assessed efficacy or safety of tazarotene useprior to UVB exposure. Therefore, if used in combination with UVB, tazaro-tene should be applied after light treatment. Since tazarotene has beenshown to reduce epidermal thickness, concerns have been expressed regard-ing the increased risk of burning. It has been suggested that the UVB dosagebe reduced by one-third if tazarotene is added during phototherapy (30).

No significant photosensitivity occurred when tazarotene was usedwith phototherapy in any of these phototherapy trials. In addition, the inci-dence of irritation was less than expected when tazarotene was used withphototherapy than without. Behrens et al. (28) postulated that this mightbe the result of an enhanced barrier since UVA- and UVB-treated skin ismore resistant to irritants.

TAZAROTENE AND PUVA PHOTOTHERAPY

To determine whether administration of topical tazarotene can increase theefficacy of systemic PUVA, Tzaneva et al. (31) compared the therapeuticresponse of tazarotene plus PUVA to PUVA monotherapy in 31 chronicplaque-type psoriasis patients. Patients received PUVA treatment four timesa 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 ofUVA exposures were statistically lower in those receiving combined PUVAand tazarotene therapy than those with PUVA monotherapy. The mediancumulative 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, double-blind, vehicle-controlled study, 31 patients with fingernail psoriasis wererandomized to either 0.1% tazarotene gel or vehicle gel once daily for 24weeks (32). The treatment was applied to two fingernails, one under occlu-sion and the other one unoccluded. Tazarotene treatment under occlusionresulted in significant reduction of onycholysis at weeks 4 and 12 and signif-icant reduction of pitting by week 24. Unoccluded tazarotene treatmentresulted in significant reduction in onycholysis by week 24 but no improve-ment in pitting was noted. Tazarotene was well tolerated except for fewcases of mild-to-moderate adverse effects of irritation and erythema. Thus,although both occluded and unoccluded tazarotene gel therapies were effec-tive in decreasing onycholysis, the occluded tazarotene gel achieved its goalmuch earlier than the unoccluded tazarotene gel.

TAZAROTENE APPLICATION IN PSORIASIS

Proper patient instruction is essential when using tazarotene. Patientsshould be instructed to apply tazarotene directly on the thick and scalypsoriatic lesions, taking care to avoid surrounding unaffected skin. Oncethe skin has become flat and nonscaly, tazarotene should be discontinued.The gel and cream should be allowed to dry before wearing clothes sincewearing clothing immediately after application might inadvertently spreadthe product onto uninvolved skin and cause irritation. Only a small amountof tazarotene is required. Use of excessive amounts may result in irrita-tion. Patients should be warned of the likelihood of irritation, particularlyif the agent is used on the face and neck. Intertriginous regions and geni-tals should be avoided. The gel preparation is preferable for scalp andnail psoriasis.

If significant irritation occurs, the patient may benefit from what istermed ‘‘short contact’’ therapy (Table 1) (33,34). Duration of applicationappears to be related to rate of improvement. For example, following a veryshort contact (e.g., five minutes), first signs of improvement are seen aboutthree weeks later; following a 20-minute application, improvement is seen7–10 days later.

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Withholding treatment until irritation subsides, then reintroducingtherapy every other day or changing to the 0.05% cream formulation (ifan alternate formulation is used) may also help to reduce irritation. Forpatients with sensitive skin who might be prone to irritation, treatment withtazarotene may begin with the 0.05% cream formulation and stepped up astolerated. In addition, initiation of therapy with alternate-day applicationhas been recommended by some authors as a method to maximize tolerabil-ity (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 incombination with a mid- or high-potency topical corticosteroid, calcipotriene,UVB phototherapy, or PUVA. One of the authors’ favorite topical regimensfor treating recalcitrant thick psoriatic lesions is with triple combinationtherapy (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 creamformulation and 10% to 30% of patients using the gel formulation, with1–5 percentage points higher incidence correlated with the 0.1% concentra-tion than the 0.05% concentration (37). No other treatment-related seriousadverse effects were reported.

Although the medication is not phototoxic or photoallergenic, theFood and Drug Administration (FDA)-approved package insert cautionsagainst sunlight and sunlamp exposure. When combined with UVB, thinning

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 waterGradually increase application time by 1–5 min as tolerated

Table 2 Triple Combination Therapy

Step 1: Apply a combination of superpotent topical steroid and calcipotriene in themorning

Step 2: Apply a combination of superpotent topical steroid, calcipotriene, andtazarotene to plaques in the evening

OrApply 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 toburn more easily (30). If tazarotene is added to an ongoing phototherapyregimen, once there is evidence of decreased scaling and induration fromthe application of tazarotene, it may be prudent to lower the UVB dose by30% 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 notpracticing adequate contraception.

CONCLUSIONS

Topical tazarotene is the only topical retinoid indicated for the treatment ofpsoriasis in the United States. Rather than using tazarotene as a monotherapy,tazarotene should be used in combination with mid- or high-potency topicalcorticosteroids, calcipotriene, UVB phototherapy, or PUVA as part of along-term maintenance regimen.

REFERENCES

1. Tang-Liu DD, Matsumoto RM, Usansky JL. Clinical pharmacokinetics anddrug 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-selectiveretinoids. Curr Pharm Des 2000; 6:919–931.

3. Fisher GJ, Talwar HS, Yiao JH, et al. Immunological identification and func-tional quantification of retinoic acid and retinoid X receptor proteins in humanskin. J Biol Chem 1994; 269:20,269–635.

4. Lefebvre P. Molecular basis for designing selective modulators of retinoic acidreceptor transcriptional activities. Curr Drug Targets Immune Endocr MetabolDisord 2001; 1:153–164.

5. Nagpal S, Athanikar J, Chandraratna RA. Separation of transactivation andAP1 antagonism functions of retinoic acid receptor alpha. J Biol Chem 1995;270:923–927.

6. Roeder A, Schaller M, Schafer-Korting M, et al. Tazarotene: therapeuticstrategies in the treatment of psoriasis, acne and photoaging. Skin PharmacolPhysiol 2004; 17:111–118.

7. Esgleyes-Ribot T, Chandraratna RA, LewKaya DA, et al. Response of psoriasisto 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/SKALPgene 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 tazarotenegel, a topical acetylenic retinoid, in the treatment of psoriasis. Arch Dermatol1998; 134:57–60.

10. Weinstein GD, Krueger GG, Lowe NJ, et al. Tazarotene gel, a new retinoid, fortopical therapy of psoriasis: vehicle-controlled study of safety, efficacy and dura-tion 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 StudyGroup: tazarotene cream in the treatment of psoriasis: two multi-center,double-blind, randomized, vehicle-controlled studies of the safety and efficacyof tazarotene creams 0.05% and 0.1% applied once daily for 12 weeks. J AmAcad Dermatol 2003; 48:760–767.

12. Lebwohl M, Aste E, Callen J, et al. Once-daily tazarotene gel versus twice-dailyfloucinonide cream in the treatment of plaque psoriasis. J Am Acad Dermatol1998; 38:705–711.

13. Lebwohl M. Strategies to optimize efficacy, duration of remission and safety inthe treatment of plaque psoriasis by using tazarotene in combination withcorticosteroid. J Am Acad Dermatol 2000; 43(2 Pt 3):S43–S46.

14. Koo JY, Martin D. Investigator-masked comparison of tazarotene gel q.d. plusmometasone furoate cream q.d. vs. mometasone furoate cream b.i.d. in the treat-ment of plaque psoriasis. Int J Dermatol 2001; 40(3):210–212.

15. Lebwohl M, Lombardi K, Tan MH. Duration of improvement in psoriasis aftertreatment 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 corticosteroidcream 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 corticosteroidin treating plaque psoriasis in patients switched from treatment with calci-potriene þ/� corticosteroid. Curtis 2000; 66(suppl 6):12–18.

18. Gollnick H, Menter A. Combination therapy with tazarotene plus a topicalcorticosteroid 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 SteroidStudy Group. A clinical evaluation of tazarotene 0.1% gel, with and without ahigh-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%) incombination with betamethasone valerate foam (0.12%) for plaque-type psoria-sis. J Drug Dermatol 2005; 4(2):228–230.

21. Poulin YP. Tazarotene 0.01% gel in combination with mometasone furoate inplaque 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 oftazarotene 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 othertopical treatments of psoriasis. J Am Acad Dermatol 2000; 42:1008–1011.

24. Bowman P, Maloney J, Koo J. Combination of calcipotriene (Dovonex) oint-ment and tazarotene (Tazorac) gel versus clobetasol ointment in the treatmentof 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% gelonce 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.

26. Lowe NJ. Optimizing therapy: tazarotene in combination with phototherapy.Br J Dermatol 1999; 140(suppl 54):8–11.

27. Koo JY, Lowe NJ, Lew-Kaya DA. Tazarotene plus UVB phototherapy in thetreatment of psoriasis. J Am Acad Dermatol 2000; 43:821–828.

28. Behrens S, Grundmann-Kollamn M, Schiener R, et al. Combination photother-apy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel.J Am Acad Dermatol 2000; 42(3):493–495.

29. Schiener R, Behrens-Williams SC, Pillekamp H, et al. Calcipotriol versus tazar-otene as combination therapy with narrowband ultraviolet B (311 nm): efficacyin patients with severe psoriasis. Br J Dermatol 2000; 143:1275–1278.

30. Hecker D, Worsley J, Yueh G, et al. Interactions between tazarotene and ultra-violet light. J Am Acad Dermatol 1999; 41(6):927–930.

31. Tzaneva S, Seebar A, Honigsmann A. A comparison of psoralen plus ultravioletA (PUVA) monotherapy, tacalcitol plus PUVA and tazarotene plus PUVA inpatients with chronic plaque-type psoriasis. Br J Dermatol 2002; 147:748–753.

32. Scher RK, Stiller M, Zhu YI. Tazarotene 0.1% gel in the treatment of fingernailpsoriasis: a double-blind, randomized, vehicle-controlled study. Cutis 2000;68(5):355–358.

33. Veraldi S, Schianchi R. Short-contact therapy with tazarotene in psoriasisvulgaris. Dermatol 2003; 206:347–348.

34. Persaud A, Bershad S, Lamba S, et al. Poster Presentation, Short-ContactTazarotene Therapy for Psoriasis. Nashville, TN.: American Academy ofDermatology, 2000.

35. Koo JYM, Lebwohl MG, Lowe NJ, et al. Blueprints for optimizing topicalretinoid treatment of psoriasis using creative therapeutic regimens. Skin AllergyNews, February 16, 2002.

36. Guenther L. Optimizing treatment with topical tazarotene. Am J Clin Dermatol2003; 4(3):197–202.

37. Allergan, Inc. Tazorac1 (tazarotene) package insert. Irvine, CA., USA:Allergen, Inc.

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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 andsystemic glucocorticoids for immunosuppressive therapy. They were primar-ily used for the prevention of organ transplant rejection. These drugs includecyclosporin and the macrolides tacrolimus (FK 506) and, most recently,pimecrolimus (SDZ ASM 981), which are known to modify immunefunction by inhibition of calcineurin-dependent reactions critical in theproduction of inflammatory cytokines (1).

Cyclosporin is effective in and approved for the treatment of inflam-matory dermatoses including psoriasis, but is limited by systemic side effectssuch as renal toxicity and hypertension, and topical cyclosporin has almostnegligible skin penetration (2,3).

Tacrolimus and pimecrolimus have smaller molecular weights givingthem the advantage of better skin penetration, which led to the developmentof topical formulations. Both topical tacrolimus and pimecrolimus do notcause skin atrophy mainly because calcineurin is not needed for collagensynthesis (1,4). This is in contrast to topical corticosteroids, which are asso-ciated with telangiectasia (Fig. 1), atrophogenicity, striae (Fig. 2), and otherlocal cutaneous adverse effects when used over a long period of time (5,6).

Both tacrolimus and pimecrolimus belong to the group of macrolideimmunosuppressants, which are xenobiotics possessing a complex structure.They are derived from several strains of Streptomyces. The first macrolideto be developed was tacrolimus, which is produced by Streptomyces

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tsukubaensis (1). Several controlled trials have shown systemic tacrolimus tobe effective in the treatment of psoriasis (7,8). Pimecrolimus is an ascomycinderivative, which is produced by another strain of Streptomyces, Streptomyceshygropicus var. ascomyceticus (1). One study has shown that systemic pimecro-limus is clinically highly effective in psoriasis and is well tolerated (9).

Figure 1 (See color insert) Telangectasia, ear.

Figure 2 (See color insert) Striae distensae.

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MECHANISM OF ACTION

Tacrolimus and pimecrolimus achieve their immunosuppressive function pri-marily through preventing T-cell activation; these drugs form complexes witha specific binding protein named the tacrolimus binding protein (FK-BP),which is their intracellular receptor (1,2). Once bound together, the complexwill inhibit calcineurin leading to the prevention of cytokine expression.

More specifically, when T lymphocytes are activated through antigenicstimulation, calcium levels in the cells rise and bind to calmodulin, whichmay in turn activate calcineurin. Calcineurin is a calcium-dependent phos-phorylase enzyme that functions by dephosphorylating the cytoplasmiccomponent of the nuclear factor of activated T cell (NF-ATc) allowing itto enter the nucleus and combine with its nuclear component NF-ATn.This crucial step then leads to the transcription of cytokines includinginterleukin (IL)-1, -2, -3, -4, transforming growth factor beta, and tumornecrosis factor alpha. When tacrolimus and pimecrolimus combine withtheir intracellular receptors, they are able to bind calcineurin and preventthe dephosphorylation of NF-ATc, thus blocking the production ofproinflammatory cytokines (1–3,10).

One study found increased IL-8 and IL-8 receptor (IL-8R) levelsin psoriatic epidermis and tacrolimus in particular was shown totarget the keratinocyte IL-8R by inhibiting its function and expression invitro (11).

CLINICAL PROPERTIES

Accumulating evidence has revealed psoriasis to be a genetically directedimmunogenic inflammatory disease based on a self-reactive T-helper-1 (Th-1)response (12). Because of their chemical characteristics, tacrolimus andpimecrolimus can be effective for the topical treatment of inflammatoryskin disorders wherein T cells may play a crucial role in development (13).

Mrowietz et al. (13) demonstrated that pimecrolimus (1%) is similar inefficacy to clobetasol-17-propionate (0.05%) in plaque-type psoriasis whenapplied topically under occlusion for two weeks using the microplaqueassay, and no adverse drug effects were seen in any of the patients whoparticipated in the study (13).

Recently, a study that combined pimecrolimus ointment 0.1% in a for-mulation with 10% urea demonstrated that even without any occlusion, thepimecrolimus ointment 0.1%, in its experimental formulation, was effectivein treating psoriasis plaques (14).

A pilot study by Zonneveld et al. (15) in 1998 did not show similar effi-cacy for 0.3% tacrolimus ointment in chronic plaque-type psoriasis. Theirstudy compared calcipotriol ointment applied twice daily, and tacrolimusointment and placebo ointment applied once daily on psoriatic plaques.

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An important and main difference from the earlier topical pimecrolimusstudy is that Zonneveld et al. did not use occlusion.

Topical tacrolimus 0.3% was also applied under occlusion on descaledpsoriatic skin in microplaques, and in this model topical tacrolimus showedefficacy (16). The psoriatic plaques were first descaled by overnight treat-ment with 2% salicylic acid in petrolatum before the medications wereapplied. No adverse events at the site of application or systemic side effectswere observed.

An eight-week, randomized, double-blind, vehicle-controlled, multi-center trial demonstrated that 0.1% tacrolimus ointment was effective in thetreatment of facial and intertriginous psoriasis (Fig. 3A and B). A significantdifference was observed between the 0.1% tacrolimus ointment group and thevehicle group, with 62.5% of the 0.1% tacrolimus ointment group showingclearing or almost total clearing compared to 31.5% in the vehicle group atthe end of eight weeks. Itching, hyperesthesia, and burning were adverseevents reported for both treatment groups, but no systemic side effectswere noted (17).

Pimecrolimus cream 1% was also shown to be safe and effective for thetreatment of inverse psoriasis in a multicenter, double-blind, randomizedstudy involving 57 patients. At the conclusion of the study, 82% of thepatients in the pimecrolimus group considered their disease well or comple-tely controlled compared to 41% in the vehicle group. Adverse events wereminimal and similar for both groups of patients (18).

Topical corticosteroids and calcipotriol are not ideally used in areas ofskin that are particularly thin and sensitive, such as the intertriginous areasand the face. These areas are more prone to skin atrophy from corticoste-roid use, and calcipotriol causes significant local irritation. It seems logicalto conclude that because topical tacrolimus is effective on descaled psoriaticskin, it would probably work well on the thinner areas such as the faceand flexural regions. Several articles reported that 0.1% tacrolimus ointmentwas highly effective in the treatment of facial psoriasis and psoriasis of inter-triginous 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 topicaltacrolimus ointment (21). Approximately 10 g/day of tacrolimus was appliedon the entire body and the patient’s liver and renal functions were notaffected. The authors attribute part of the efficacy of tacrolimus to thechange in barrier function and less hyperkeratotic skin seen in generalizedpustular psoriasis compared to chronic plaque-type psoriasis.

It is evident that the type of formulation and method of application areimportant factors to consider in the use of topical tacrolimus andpimecrolimus in psoriasis (16). Also, because the skin of most patients withpsoriasis is hyperkeratotic, ways to improve drug penetration and the specificarea of the body affected with psoriasis should be taken into account.

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The most common reported adverse effects of topical tacrolimus ther-apy include a sensation of skin burning, pruritus, and erythema (5,22).Recently, there was one report of deep dermatophytosis developing duringtopical tacrolimus therapy for facial psoriasis (23).

Therapy of eyelid psoriasis can be problematic because topical corti-costeroids are associated with the development of cataracts and glaucoma(24–27). Tacrolimus 0.1% ointment has been used safely to treat eyeliddermatitis twice daily for eight weeks without any effect on intraocularpressure (28). Irritation was noted to occur in 60% of patients.

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

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Although they are relatively new, topical calcineurin inhibitors haveprovided clinicians with an effective and promising alternative to topicalcorticosteroids for the treatment of psoriasis, with the added benefit of anexcellent 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 onthe finding of a theoretical risk of lymphoma or nonmelanoma skin cancerfrom these medications based on animal models. The animal subjects were

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

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given large doses of the drugs orally or the drugs were applied topically in avehicle that enhances penetration (29). Human studies have not substantiatedan association between topical tacrolimus or pimecrolimus and malignancies.

Although definitive causation has not been established between topicaluse of tacrolimus and pimecrolimus and the development of cancer, severalcases of lymphoma and cutaneous tumors (sarcoma, squamous cell carci-noma, and malignant melanoma) were noted to occur after the use of thesedrugs (30). Of note, there have been several reports of cutaneous T-cell lym-phoma, a malignancy not associated with immunosuppressive therapy. Thelatter lymphoma is often mistaken for eczema, and it is possible that patientstreated with tacrolimus or pimecrolimus had cutaneous T-cell lymphomarather than eczema at the time the topical medications were prescribed.

The American Academy of Dermatology strongly believes that thesedrugs are safe with proper use, and acknowledges that it is the physician’sresponsibility to inform and educate patients regarding the benefits and risksinvolved, and to monitor the patients accordingly.

REFERENCES

1. Marsland AM, Griffiths CE. The macrolide immunosuppressants indermatology: mechanisms of action. Eur J Dermatol 2002; 12(6):618–622.

2. Al-Daraji WI, Grant KR, Ryan K, Saxton A, Reynolds NJ. Localization ofcalcineurin/NFAT in human skin and psoriasis and inhibition of calcineurin/NFAT activation in human keratinocytes by cyclosporin A. J Invest Dermatol2002; 118(5):779–788.

3. Nghiem P, Pearson G, Langley R. Tacrolimus and pimecrolimus: from cleverprokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am AcadDermatol 2002; 46(2):228–230.

4. Nghiem P. ‘‘Topical Immunomodulators?’’: introducing old friends and a newally, tacrolimus. J Am Acad Dermatol 2001; 44(1):111–113.

5. Freeman AK, Linowski GJ, Brady C, et al. Tacrolimus ointment for the treat-ment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol2003; 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 andoral 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, placebo-controlled 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 commongenomic anti-inflammatory profile, is clinically highly effective in psoriasis and iswell 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 inhibitscytokine gene and adhesion molecule expression in psoriatic skin lesions. Ann NY Acad Sci 1993; 696:250–256.

11. Schulz BS, Michel G, Wagner S, et al. Increased expression of epidermal IL-8receptor 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 treatingpsoriasis. Hautarzt 2003; 54(3):230–236.

13. Mrowietz U, Graeber M, Brautigam M, et al. The novel ascomycin derivativeSDZ 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. Anexperimental ointment formulation of pimecrolimus is effective in psoriasis with-out occlusion. Acta Derm Venereol 2003; 83:351–353.

15. Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effectivein chronic plaque psoriasis. A pilot study. Arch Dermatol 1998; 134(9):1101–1102.

16. Remitz A, Reitamo S, Erkko P, Granlund H, Lauerma AI. Tacrolimusointment 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 facialand intertriginious psoriasis. J Am Acad Dermatol 2004; 51:723–730.

18. Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatmentof intertriginous psoriasis: a double-blind, randomized study. J Am Acad Der-matol 2004; 51(5):731–738.

19. Yamamoto T, Nishioka K. Topical tacrolimus is effective for facial lesions ofpsoriasis. Acta Derm Venereol 2000; 80(6):451.

20. Clayton TH, Harrison PV, Nicholls R, Delap M. Topical tacrolimus for facialpsoriasis. Br J Dermatol 2003; 149(2):419–420.

21. Ishiko A, Yokoyama T, Tanikawa A, Amagai M, Nagao K. A case of general-ized 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 Tacroli-mus Ointment Study Group. Tacrolimus ointment for the treatment of atopicdermatitis in adult patients: Part II, safety. J Am Acad Dermatol 2001; 44:S39–S46.

23. Yamamoto T, Nishioka K. Deep dermatophytosis during topical tacrolimustherapy for psoriasis. Acta Derm Venereol 2003; 83(4):291–320.

24. Tan MH, Lebwohl M, Esser AC, Wei H. The penetration of 0.005% fluticasonepropionate 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. DermatolClin 1992; 10(3):505–512.

26. Eisenlohr J. Glaucoma following the prolonged use of topical steroid medicationto the eyelids. J Am Acad Dermatol 1983; 8(6):878–881.

27. Costagliola C, Cati-Giovannelli B, Piccirillo A, Delfino M. Cataracts associatedwith 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 treat-ment of eyelid dermatitis. Cutis 2004; 73(4):267–271.

29. Niwa Y, Terashima T, Sumi H. Topical application of the immunosuppressanttacrolimus 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.

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10

Treatment of Mild-to-Moderate Psoriasiswith 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 anyamount of affected body surface area, but are the mainstay of therapy forpatients whose affected area is less than 10% of their body surface area.Among the traditional options of topical therapies for mild to moderate psori-asis are coal tar, anthralin, salicylic acid, and lactic acid. All four topicaltherapies have been used for many years and are proven safe and effective.However, recently newer topical agents such as calcipotriol and tazoratenehave reduced the use of these older agents. This chapter will give an overviewof 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 usedin the treatment of skin conditions. Coal tar is the liquid byproduct of thedistillation of bituminous coal and has a pungent smell (1). Use of coal

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tar for skin conditions has been ongoing for over millenniums. Present daypreparations closely resemble the coal tar that Dioscorides described andcalled ‘‘asphalt’’ almost 2000 years ago (2). Mechanism of action is stillunknown in part due to the over 10,000 ingredients contained in coal tar.However, its antipruritic, anti-inflammatory, and antipsoriatic effects havebeen 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 moderatepsoriasis therapy during the decades preceding and following WorldWar II. Coal tar is available in several preparations including ointment,cream, lotion, shampoo, gel, solutions, and soaps. These products areavailable in multiple concentrations. Crude coal tar is often available in threeconcentrations, 2%, 5%, and 10%, and is mainly used in Goeckermantherapy. Goeckerman therapy is named after the man who first used thistreatment regimen for psoriasis in 1925 (4). Goeckerman therapy involvesthe application of crude coal tar to the entire body including unaffected areasfor several hours a day along with ultraviolet B (UVB) phototherapy.Because Goeckerman therapy involves the use of ‘‘black’’ tar as opposed tothe more elegant but less effective ‘‘brown’’ tar such as liquor carbonisdetergens (LCD), this previously was an inpatient treatment, but the modernmodified version involves a more convenient Monday through Friday outpa-tient regimen conducted in psoriasis ‘‘day treatment centers.’’ LCD, an alcoholextract of crude coal tar, is one of the most widely used refined preparations ofcoal tar, which is more cosmetically acceptable and available in a solutionform. 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 byspecialty pharmacies in an aquaphor base that is suitable for use on bodylesions. Most preparations of topical tar are designed for once daily applicationat night, but may be used more often if the patient is willing.

Coal tar efficacy has been investigated in several trials. Goeckermantherapy efficacy was investigated in an open-label study by Lee and Koo.This study examined 25 consecutive Goeckerman patients admitted toUniversity of California, San Francisco (UCSF) Psoriasis TreatmentCenter and showed that 100% reached psoriasis area severity index (PASI)75 by 12 weeks of treatment and 95% reached it by eight weeks (Figs. 1and 2) (5). This is a remarkable efficacy considering the fact that, in theyears 2003–2004 when this study was conducted, only the most recalcitrantpsoriasis patients, most of whom have failed many other, more convenienttreatment options such as entanercept, alefacept, efaluzimab, methotrexate,actretin, outpatient phototherapy, and of course topicals, were usually theones referred to Goeckerman therapy.

Another study by Menter and Cram evaluated the efficacy andremission time following Goeckerman treatment. In this study, 300 patientstreated 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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Ninety percent of the patients remained clear for a minimum of eightmonths and 73% were clear for one year or longer (6). It should be notedthat this two-center (Dallas, Texas and San Francisco, California) studywas carried out in the early 1980s before the advent of Health MaintenanceOrganizations (HMOs) and managed care when patients with generalized

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

56%

96% 100%

0%10%20%30%40%50%60%70%80%90%

100%

4 weeks 8 weeks 12 weeks

Weeks After Starting Goeckerman Therapy

% o

f Pat

ient

s R

each

ing

PA

SI 7

5

Figure 2 Percent of patients achieving psoriasis area severity index (PASI) 75 with4, 8, and 12 weeks Goeckerman therapy. Source: From Ref. 5.

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psoriasis had ready access to Goeckerman therapy. In today’s practicealmost two decades later, Goeckerman therapy is primarily being utilizedby psoriasis patients who have failed multiple other treatment methods thatrequire less commitment in time and energy. The remission time seen todaycan be as good as was documented by Menter and Cram, but primarily inthose with na€��ve generalized psoriasis who have good insurance and gainaccess to Goeckerman therapy. The remission time of the more typical recal-citrant psoriasis patients referred for Goeckerman therapy today are generallyshorter but still observed by the authors to be better than outpatient photo-therapy 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 lotionpreparation (Exorex) to conventional 5% coal tar lotion (Alphosyl) in mildto moderate psoriasis. One hundred and fifty-eight patients received 1% pro-prietary coal tar lotion and 166 patients received conventional 5% coal tarlotion applied to skin three times a day for 12 weeks. The mean PASIdecreased 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 ofcoal tar in the mid-1980s. A study by Stern et al. in 1986 concluded that coaltar did not provide any added benefit to outpatient UVB phototherapy. Thisstudy compared 22 outpatients who treated one side of their body with taroil and the other side of their body with oil vehicle twice daily and alsoreceived outpatient suberythemogenic doses of UVB phototherapy threetimes per week. This study evidenced no significant difference between thetar oil half and the oil vehicle half of the body, with only a 9% reductionin the average UVB dose required for clearing on the tar oil half (8). How-ever, it should be noted that both the tar oil and oil vehicle were applied justprior to phototherapy. Tar has been shown to block UVB and this mostlikely was the reason for lack of benefit of tar with suberythemogenic dosesof UVB witnessed in this study. A study by Lebwohl et al. (9) confirms tar’sability to block UVB light. For this very reason, in Goeckerman therapy,especially with ‘‘black’’ tar (as opposed to brown tar or LCD), UVB photo-therapy is always given prior to the application of ‘‘black’’ tar. Since thiscontroversial publication, there have been studies to validate the usefulnessof coal tar with UVB. A study by Lowe et al. indicates that tar is a beneficialaddition to suberythemogenic doses of UVB. In this study, tar was notapplied prior to phototherapy. More rapid improvement was evidenced inthe group treated with topical tar and suberythemogenic UVB than in thegroup with oil base and suberythemogenic UVB—effectively reducingthe exposure to UVB in the patients treated with topical tar. This same arti-cle also examined the combination of tar extract in oil and erythemogenicdoses of UVB in hairless mice. Erythemogenic dosages of UVB producedalmost 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 enhancedeffectiveness with the addition of refined tar products like LCD. However,from the authors’ experience, for the rare patient with extraordinarily resis-tant psoriasis, Goeckerman therapy (‘‘black’’ tar plus UVB) is much moreeffective than outpatient erythemogenic UVB alone. In our experience, thepatient who has not cleared with maximal and optimal outpatient UVBwith erythemogenic doses clears while on Goeckerman therapy.

Coal tar is a safe agent to use in mild to moderate psoriasis but doeshave some obvious disadvantages and side effects. Among the side effectsand disadvantages are staining of clothes and furniture, messy application,unpleasant odor, contact sensitivity (surprisingly rare despite its appear-ance), burning sensation, photosensitivity (although therapeutic in acontrolled treatment setting), and tar folliculitis (2). Generally, the higherthe concentration the more likely to cause skin irritation. Despite many dec-ades of use, so far there seems to be no systemic side effects of the topicalapplication of coal tar ever documented. In addition, the risk of skin cancerseems to be either very small or not demonstrably different from the generalpopulation. A 25-year follow-up study by Muller and Perry (11) found nodifference in cancer rates between those treated with coal tar at the MayoClinic and the general population. A lawsuit in 2000 claiming that tar pro-ducts are carcinogenic has made tar products hard to find in California. Inresponse to this lawsuit, the Food and Drug Administration (FDA) reviewedall available data and concluded that the therapeutic use of coal tar in con-centrations and formulations used in over-the-counter drug products doesnot pose a risk of carcinogenicity; despite this FDA ruling, in January2002, the state of California, which has strict antitoxic laws, ruled thatover-the-counter coal tar products that contain more than 0.5% coal tarare required to be labeled with cancer warnings. Due to this requirement,many companies have chosen to either change the active ingredient in theirproducts sold in California or simply discontinued sale of their tar productsin California (12,13). Although coal tar can be inconvenient and messy, itsdemonstrated efficacy, low cost, and its relatively minimal side effect profilecompared to other topicals and oral medications make it a reasonable optionfor 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 anthra-lin), was initially used mistakenly as a folk remedy for fungus infections suchas mycoses of the skin when it was discovered to have therapeutic effects forpsoriasis in 1877. It is an antipsoriatic medication derived from a tree extractknown as Goa powder. The exact mechanism of action is still unknowntoday, but it has been shown to promote kerotinocyte differentiation,

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decrease cell respiration, and inhibit inflammation (14). Anthralin is commer-cially available in the United States in cream, ointment, and paste form inmultiple concentrations from 0.05% to 1%. Anthralin can also be com-pounded by specialty pharmacies up to a concentration of 10%. There areseveral anthralin treatment regimens used for the management of plaquepsoriasis. The Ingram method is designed for inpatient therapy and involvesapplication of anthralin to the affected area followed by covering of the areawith talcum powder and then gauze or stockinette. The anthralin isthen 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 moreconvenient outpatient setting. Although no optimal treatment regimenhas been established, the ‘‘need of quick results and no time’’ mentality ofAmericans has prompted development of a more convenient methodof anthralin use. A study by Runne and Kunze indicates that applicationof higher concentrations of anthralin (1%, 2%, and 3%) using short contactanthralin therapy for 10–20 minutes at a time is more effective than a longerexposure 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 dayscompared to longer exposure (three hours) (16). Another treatment regimenis application of anthralin overnight starting at low concentrations withweekly increases in concentration. A new formulation of anthralin, Psoria-tec1, has been developed in an attempt to decrease the staining andinflammation associated with anthralin. Psoriatec is a 1% formulation ofanthralin in a temperature-sensitive vehicle. The vehicle is deliberatelydesigned to release anthralin only at skin temperatures. This temperature-sensitive activation decreases the risk of staining furniture and fabrics (17).

The efficacy of anthralin has been investigated in several trials. A ret-rospective study by Yamamoto et al. examined 70 patients who were treatedwith 0.1% to 2% anthralin. This study showed a mean improvement in PASIof 15.9 after three months of treatment (18). Another study compared shortcontact dithranol therapy with the Ingram regimen. The Ingram regimenshowed a faster rate of improvement than the short contact method, butmore irritation than with the short contact regimen (19). In general, theauthors concluded that anthralin is most useful for thinning the plaquesand is associated with a remission time of 3.9–6 months (20).

One of the most important disadvantages associated with anthralin ispurple staining of skin and other objects (clothing, furniture, etc.) and skinirritation. Careful application to only the affected areas is important, assurrounding normal skin may become more easily irritated with anthralincontact. Irritation typically improves after several days even with the sameanthralin concentration (14). A possible way to decrease this irritation wasstudied by Schulze et al. This study showed that patients receiving combina-tion therapy with 5% tar and anthralin had reduced rates of irritation thanpatients 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 perilesionallycan reduce risk of irritating surrounding uninvolved skin. Staining andinflammation can be reduced with application of triethanolamine, a neutral-izing agent, before the removal of anthralin. CuraStain, a brand name fortriethanolamine, is a prescription drug available at most pharmacies. Otherside effects of anthralin include burning, stinging, and dryness of skin (22).There are no systemic or long-term side effects reported in humans. Anthra-lin has been used safely for many years, but the staining remains a majorlimitation of this treatment. Newer formulations such as Psoriatec havetried to address this with some success.

SALICYLIC ACID

Salicylic acid is a keratolytic agent that is useful in the treatment of mild tomoderate psoriasis. It is a good adjunct to other topical medications, butgenerally not used as monotherapy because it only removes scales. It is avail-able in concentrations from 2% to 10% and in different vehicles including gels,creams, and shampoos. A commonly used preparation is Keralyt gel1, a6% salicylic acid preparation that is readily available. Salicylic acid reducesscales and therefore enhances penetration of other topical agents such as topi-cal steroids. A study by Koo et al. shows that a combination of mometasonefuroate and salicylic acid ointment is more effective in treating moderate tosevere psoriasis than mometasone furoate alone. In this study, 408 patientswere randomized to either the treatment group with mometasone furoatealone or a treatment group with combination therapy with mometasone furo-ate and salicylic acid applied to target lesions twice daily for 21 days. Thecombination therapy of mometasone furoate and salicylic acid was signifi-cantly more effective than mometasone furoate alone beginning at day 8.Combination therapy improvement continued through the end of the studywith a more significant difference between the two study groups at day 22than at day 8 (23). Salicylic acid has also been used in combination withanthralin with success. However, salicylic acid should not be used in combina-tion with calcipotriol (Dovonex1), as calcipotriol is inactivated upon contactwith salicylic acid. Salicylic acid also blocks UVB and should not be appliedprior to phototherapy. Salicylic acid may cause salicylate toxicity with appli-cation to a large body surface area (generally greater than 20% body surfacearea). Early signs of salicylate toxicity such as tinnitus and fatigue should bemonitored during therapy with salicylic acid with some vigilance, as symp-toms are reversible with discontinuation of salicylic acid. Over the pastdecades, there have been several case reports of acute hypoglycemia in dia-betic patients treated with salicylic acid over a large body surface area. Atthe University of California San Francisco, there was one case of a diabeticpatient 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 highserum salicylate levels and low blood glucose levels and the patient’s comatosestate was reversed with IV glucose. Due to this rare reported side effect fordiabetic patients, salicylic acid should be avoided in the diabetic patient(24). Alternate keratolytic agents such as lactic acid or urea should be consi-dered instead.

LACTIC ACID

Lactic acid is another less common topical keratolytic agent used in thetreatment of psoriasis. Lactic acid is a type of alpha-hydroxy acid mainlyused as a second-line keratolytic agent when salicylate toxicity is a concernsuch as in diabetic patients. Lactic acid is effective and has proven kerato-lytic properties as evidenced by a study on hairless mice that shows that micetreated with lactic acid show enhanced desquamation of normal skin (25).Lactic acid also can be used on a larger surface area, as risk of salicylismis not a concern. In short, lactic acid is a beneficial second-line keratolyticagent when salicylic acid is not an option.

CONCLUSION

The initial approach with most cases of mild to moderate psoriasis is topicaltherapy. Topical agents for psoriasis are usually well tolerated withoutserious systemic side effects. It is important not to forget the ‘‘tried andtrue’’ inexpensive agents such as coal tar, anthralin, or keratolytics suchas salicylic acid and lactic acid.

REFERENCES

1. Thami GP, Sarkar R. Coal tar: past, present and future. Clin Exp Dermatol2002; 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 assess-ment of a very effective therapy for psoriasis resistant to both prebiologic andbiologic therapies. J Dermatol Treat 2005; 16(2):102–107.

6. Menter A, Cram DL. The Goeckerman regimen in two psoriasis day carecenters. 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. JDermatol Treat 2004; 15(1):14–22.

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8. Stern RS, Gange RW, Parrish JA, Tang SV, Arndt KA. Contribution of topicaltar 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 onthe erythemogenicity of UVB: implications for psoriasis phototherapy. J AmAcad Dermatol 1995; 32(3):469–471.

10. Lowe NJ, Wortzman MS, Breeding J, Koudsi H, Taylor L. Coal tar photother-apy for psoriasis reevaluated: erythemogenic versus suberythemogenic ultravio-let 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 ofexperience 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 psori-

asis: 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 for-

mulation in individually adjusted dosages in the management of psoriasis. ActaDerm Venereol Suppl (Stockh) 1992; 172:28–29.

18. Yamamoto T, Matsuuchi M, Irimajiri J, Otoyama K, Nishioka K. Topicalanthralin for psoriasis vulgaris: evaluation of 70 Japanese patients. J Dermatol2000; 27(7):482–485.

19. Statham BN, Ryatt KS, Rowell NR. Short-contact dithranol therapy—a com-parison 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 AcadDermatol 2005; 53(1 suppl 1):S59–S69.

21. Schulze HJ, Schauder S, Mahrle G, Steigleder GK. Combined tar–anthralin ver-sus anthralin treatment lowers irritancy with unchanged antipsoriatic efficacy.Modifications of short-contact therapy and Ingram therapy. J Am Acad Derma-tol 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 ofmoderate-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 compli-cation 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 alpha-hydroxyacids on the normal skin barrier of hairless mice. Br J Dermatol 2001;144(2):267–273.

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11

Phototherapy and Laserfor 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 5to 10 years, there have been exciting new light sources developed for the treat-ment of psoriasis. These newer technologies have allowed us to increase ourefficacy 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 inthe 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 biologicproperty that is closer to that of UVB. UVA1 has only recently been evaluatedfor 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. Inaddition, an excimer laser light source, delivering 308 nm radiation to tar-geted psoriatic lesions, has been shown to be another effective therapeuticmodality for psoriasis.

Although phototherapy is generally not used as first-line therapyfor the treatment of localized psoriasis, it is a safe and effective second-line therapy, either as a monotherapy, or as a combination therapy formany patients.

MECHANISM OF ACTION

T cells play a central role in the pathophysiology of psoriasis. The inductionof T-cell apoptosis is felt to be the main mechanism by which phototherapy iseffective in the treatment of psoriasis. T-cell apoptosis has been shown withthe treatment of broadband UVB (BB-UVB), narrowband UVB (NB-UVB),PUVA, the 308 nm excimer laser, and UVA1 (1–5). In one study, excimerlaser was shown to be more effective than NB-UVB in inducing apoptosisof T cells (6). Other effects of UV include suppression of DNA synthesis,and generation of prostaglandins and cytokines. The cutaneous immuno-modulation induced by phototherapy is an effective mode of treatment, withoutsystemic immunosuppression and its associated side effects. With PUVA, anadditional mechanism of action is the formation of cross-links between pso-ralen and the pyrimidine bases in the DNA, inhibiting DNA replication.

ULTRAVIOLET B

UVB phototherapy as monotherapy, or in combination with other thera-pies, is an effective therapy for the treatment of psoriasis. Clearance rateswith UVB can be as high as 80% or greater in combination with topical ther-apy. The potential to induce remission is also an attractive feature.

BB-UVB has been one of the mainstay therapies in the past for psori-asis. In 1981, Parrish and Jaenicke (7) identified that the 313 nm wavelengthis the most effective one for the treatment of psoriasis; this lead to the devel-opment of NB-UVB (which emits 311–312 nm), which is becoming the newstandard of care. Both booth and hand and foot phototherapy machinesare available.

Efficacy

Numerous studies have compared BB-UVB to NB-UVB for the treatment ofpsoriasis, all of which demonstrate superiority of NB-UVB (8). Several stud-ies have compared the efficacy of NB-UVB with PUVA. In a randomizedcomparison of 100 patients with chronic plaque psoriasis, 84% of patientsreceiving 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 requiredsignificantly fewer treatments to achieve clearance, and they remained inremission longer than the NB-UVB–treated group. A comparison ofNB-UVB to systemic PUVA for the treatment of chronic plaque psoriasisrevealed a reduction in the psoriasis area sensitivity index of 84% and 89%,respectively (10). There was a trend towards increased efficacy and mainte-nance of clearance with PUVA. A report of 45 patients who completed a com-parison study between three times per week of NB-UVB and oral PUVAshowed that there was no statistically significant difference in the number ofdays to clear, or the number of days in remission; however, the PUVA grouprequired fewer treatments to clear (11). A randomized controlled trial com-pared the efficacy of NB-UVB and trimethoxypsoralen (TMP) bath PUVAfor chronic plaque psoriasis in 28 patients (skin phototypes I–III). Each bodyhalf was treated with either NB-UVB or bath PUVA. The NB-UVB–treatedhalf 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-basedtherapy, especially in Caucasians. However, in patients with skin type V orVI, or in those with very thick or large psoriatic lesions, PUVA may offer anadvantage over NB-UVB due to the deeper penetration of UVA radiation.

Combination Therapy

NB-UVB in combination with anthralin or topical tazarotene has beenshown to be more effective than monotherapy (13,14). There are conflictingreports of the efficacy of the combination of NB-UVB and calcipotriol;however, it appears to have some added benefit (15–18). Addition of topicalcorticosteroids to BB-UVB has not shown any added benefit as compared toBB-UVB monotherapy, and may even induce a higher relapse rate (19).Systemic retinoids in combination with NB-UVB is more effective thanNB-UVB alone (20); with the added anticarcinogenic effects of retinoids,this combination is a very useful treatment option. Acitretin in combinationwith NB-UVB results in faster improvement even in difficult-to-treatpatients. The combination of the two treatments appears to have synergisticeffects (21). The combination of methotrexate and UVB resulted in clearingin 26 subjects with extensive psoriasis (22). Methotrexate was initiated threeweeks before UVB phototherapy, and methotrexate was stopped when sig-nificant clearing occurred. This combination resulted in low total cumulativedoses of methotrexate, thus minimizing the risk of hepatotoxicity. However,in view of the potentiating effect of methotrexate in PUVA-induced photo-carcinogenesis (23), the combination of methotrexate and NB-UVB shouldbe used with caution.

In cultured keratinocytes, calcineurin inhibitors (cyclosporine, tacroli-mus, 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 combineUVB phototherapy with topical calcineurin inhibitors.

Indications

The indications for UVB therapy include stable plaque psoriasis, history ofrapid clearance with exposure to sunlight, resistant plaques to topical ther-apy, the ability of the patient to comply with treatment regimen, and patientpreference. UVB is safe in patients who are pregnant, breast-feeding, orplanning to become pregnant when topical agents, such as retinoids, arenot a treatment option. In patients with skin type I or II, or a past historyof X-ray therapy, arsenic exposure, or the use of immunosuppressive agents,UVB would be a better phototherapy option than PUVA. Should it benecessary, it is generally considered safer to treat patients with knownhistory of non-melanoma skin cancer, or melanoma, with UVB comparedto treatment with PUVA. Patient preference for avoiding oral medicationsis also an important factor in the decision-making process. As comparedto PUVA, NB-UVB does not use photosensitizing agents; therefore, it isbetter tolerated and is more cost effective.

Contraindications

There are very few absolute contraindications to UVB phototherapy; theseinclude patients with xeroderma pigmentosum, and those with basal cellnevus syndrome. Relative contraindications include photosensitive dis-orders, use of photosensitizing medications with an action spectrum in theUVB range, and history of skin cancer. Photodermatoses whose action spec-trum may include the UVB range include polymorphous light eruption,chronic actinic dermatitis, and solar urticaria. It should be noted that theaction spectrum of the vast majority of drug-induced photosensitivity isUVA; because NB-UVB emits at 311–312 nm, it is a safe light source touse. Due to the thin skin in the genital region and the increased risk of cuta-neous malignancies, it is preferable not to treat this area with phototherapy.

In a study involving a small number of subjects, UVB irradiation wasshown to result in activation of HIV in the skin (25). However, multipleother studies showed effectiveness of UVB for many HIV-related derma-toses without any adverse side effects (26).

Advantages and Disadvantages

The advantages of NB-UVB are ease of administration and potential toinduce remission. It is well tolerated, and hand and foot units are availablefor localized disease. The major disadvantage of NB-UVB phototherapy,which can be generalized to all forms of office-based phototherapy, is thetime 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 treat-ments as compared to PUVA; this obviously needs to be balanced with theapparently higher photocarcinogenicity of PUVA, especially in fair-skinnedindividuals. If the patient is responsive to UVB, home phototherapy unitscan 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 mini-mally perceptible erythema covering the entire irradiated area. The guidelinethat we use for MED testing at Henry Ford Hospital is shown in Table 1. Theinitial fluence is usually 70% of the patient’s MED. An alternate method ofstarting NB-UVB is based on skin type. The guideline for this method isshown in Table 2. In both methods, the dose is increased by 10–15% at eachvisit, guided by the patient’s side effects of the previous dose.

NB-UVB three times per week has been shown to clear psoriasis signif-icantly faster than twice-weekly treatment, and therefore is preferable formost patients (27). Once satisfactory clearing of the psoriatic lesions hasoccurred, at our institution, the frequency of therapy is usually decreasedto twice a week for four weeks, and finally maintained once a week for afew weeks and then stopped if the patient remains clear. Some patientsmay require long-term treatment with UVB therapy, since their psoriasis willrelapse if phototherapy treatments are discontinued.

Goggles for eye protection are routinely used during the treatment ses-sion. In addition, as discussed previously, male genitalia should be shieldedduring treatment (28).

Thick application of creams and ointments can actually block the trans-mission of UVB. Several topical treatments for psoriasis have been shown toblock UVB. Anthralin can be found in a base containing salicylic acid;the latter absorbs UVB, hence limiting UVB transmission. Tar should alsobe removed before phototherapy because it physically blocks UV trans-mission. Clear liquid emollients such as mineral oil can be applied prior tophototherapy. Topical and systemic retinoids can decrease the MED dueto their property of thinning the epidermis; therefore, if a retinoid is addedto 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 hrMED 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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If the patient’s psoriasis is limited to a few areas of the body, oneshould consider shielding the unaffected skin from UV radiation. The arti-cles that are used to shield healthy tissue should be kept consistent toprevent UV-induced erythema in previously shielded sites.

Adverse Effects

The acute side effect of UVB is erythema, which appears four to six hoursafter radiation and peaks at 12–24 hours. If the fluence is too high, blisteringcan occur. Patients will become tanned. UVB can induce a keratitis if propereyewear is not used.

The long-term side effects of UVB include photoaging. Animal studiesshow that the carcinogenicity of NB-UVB is approximately twice that of BB-UVB at equivalent doses. Extrapolation of these data suggests that NB-UVBis two to three times more carcinogenic than BB-UVB per MED. However,the MED equivalent of NB-UVB required to clear psoriasis is around one-third of that for BB-UVB; therefore, there should be no greater risk forNB-UVB compared to BB-UVB (29). The role of BB-UVB or NB-UVBtherapy in skin carcinogenesis of humans with psoriasis is not clear. The inci-dence of skin tumors in 195 psoriasis patients, receiving BB- or NB-UVBphototherapy with up to nine years of follow-up, did not provide evidencefor an increased skin cancer risk (30). In a recent review of the literature,treatment with UVB phototherapy did not show an increased skin cancerrisk in all studies reviewed but one, which showed an increased risk of genitaltumors with UVB (28). A study of 1908 patients treated with NB-UVB in

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

Skintype

Initial dose(mJ/cm2)

Suggested maximumdose (mJ/cm2)

I 150 3000II 150 3000III 250 3000IV 250 3000V 400 3000VI 400 3000

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 pre-

vious 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.

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Dundee, Scotland, with a mean follow-up period of four years, did not detectany increased incidence of basal cell carcinoma (BCC) or melanoma; therewas an increased incidence of BCC, which the authors felt could be explainedby a number of other factors (31). Therefore, based on currently availabledata, both BB- and NB-UVB are safe treatment modalities.

PSORALEN AND UVA

PUVA photochemotherapy can be considered the gold standard of UV-based therapy for the treatment of psoriasis. The absorption spectrum of8-methoxypsoralen (8-MOP) is 315–350 nm, with the maximum absorptionoccurring at 330–335 nm. The spectral output of the UVA light bulb used inPUVA ranges from 320 to 400 nm, with a peak emission at 352 nm.

The efficacy of PUVA is likely due to a few mechanisms. Psoralensintercalate into double-stranded DNA; with the absorption of a photon inthe UVA range, 3,4- or 40,50-cyclobutane monoadducts with pyrimidinebases are formed. When a second photon of light is absorbed by either ofthese two monoadducts, a bifunctional adduct is formed, which cross-linksthe DNA double helix. This inhibits DNA replication and ultimately causesarrest of the cell cycle. This is likely the main mechanism of action in thetreatment of psoriasis. Psoralens in an excited state can also react with mole-cular oxygen, resulting in reactive oxygen species and cell damage. PUVAcan also cause apoptosis of cutaneous lymphocytes.

Psoralen can be administered orally, or topically. 8-MOP is the onlyform of psoralen available in the United States; it is used for systemic andtopical 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 canbe administered by booth phototherapy or hand and foot units.

Efficacy

Patients treated with PUVA are able to achieve long remissions withoutrequiring maintenance therapies (32). After 20–30 treatments twice or threetimes per week, almost 90% of patients achieve marked improvement orclearing (33,34).

Combination Therapy

PUVA can be combined with other therapies to improve its efficacy, todecrease the cumulative dose of UVA, and, ultimately, to minimize itsadverse effects. Topical therapies such as anthralin, tar, calcipotriol, andtazarotene can be effectively used in combination with PUVA (35,36). Tar,with an action spectrum in the UVA range, is not widely used incombination with PUVA due to its photosensitizing potential. Studies on

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efficacy of topical corticosteroids in combination with PUVA have yieldedconflicting results. Five studies comparing PUVA alone with PUVA andtopical corticosteroids showed more rapid rates of clearing with the combi-nation regimen; however, one of the five studies showed a more rapid relapserate in the combination group (19). In a recent study of 40 patients, there wasno significant difference in clinical improvement of psoriasis treated either byPUVA plus topical steroids or PUVA plus bland emollients (37).

PUVA combined with systemic retinoids is one of the most effectivecombination therapies. In a randomized, double-blind study, patients withsevere, widespread psoriasis were treated either with PUVA as monother-apy or in combination with acitretin. Eighty percent of patients achievedmarked or complete clearance with PUVA monotherapy, as compared to96% of the patients with adjunctive acitretin administration. The cumulativeUVA dose in the acitretin-PUVA group was 42% less than the PUVA-onlygroup (38). Similar results have been seen in other studies. In a study per-formed by Lauharanta and Geiger (39), 34 patients with plaque psoriasiswere treated with either acitretin or etretinate and bath PUVA; all patientsachieved remission. There were no differences in the clinical response of thetwo groups, suggesting that acitretin is as effective as etretinate in combina-tion with bath PUVA for the treatment of psoriasis. The combination ofmethotrexate and PUVA can be an effective treatment; however, due tothe immunosuppressive properties of both treatment modalities, this combi-nation should only be considered after the use of retinoids. Retinoids ormethotrexate should be started one to three weeks prior to the initiationof PUVA, and continued until the psoriasis is almost clear. The retinoidsor methotrexate can be tapered and then stopped, and PUVA should becontinued as maintenance therapy; the latter is then tapered as appropriate.

The combination of NB-UVB whole-body irradiation, followed bytopical PUVA therapy utilizing cream preparation of psoralen for selectedpsoriatic plaques, has been shown to have significantly higher efficacycompared with either monotherapy (40). The cumulative UV doses were sig-nificantly lower in the combination therapy group. It should be noted that thisstudy, which was performed in Germany, used 0.001% 8-MOP in a creambase; whether the 0.1% 8-MOP lotion commonly used in the United Stateswould 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 darkerskin types, likely due to the longer wavelength, which results in deeperUV penetration. As well, thick plaques or involvement of hands and solesare generally more effectively treated with PUVA. Additional indicationsinclude failure to respond to UVB phototherapy and aggressive disease suchas pustular psoriasis.

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Contraindications

Absolute contraindications to PUVA include xeroderma pigmentosum,basal cell nevus syndrome, personal history of melanoma, and photosensi-tive or photoaggravated disorders such as lupus erythematosus anddermatomyositis. Other absolute contraindications include young age(<10 years, because of the known chronic side effects of PUVA), and nur-sing mothers (because of the presence of 8-MOP in breast milk). Althoughpsoralens are not considered to be teratogenic, it is not advisable to usePUVA in pregnant patients. Relative contraindications include family his-tory of melanoma, history of non-melanoma skin cancer or dysplastic nevi,ingestion of photosensitizing medications, significant solar damage, and pre-vious treatment with ionizing radiation, arsenic, methotrexate, cyclosporine,or tacrolimus. PUVA should be used with caution in patients between 10and 18 years of age, due to its long-term side effects. Caution should be usedin patients with hepatic insufficiency as the metabolism of systemic psoralenmay be delayed, resulting in prolonged photosensitivity. Renal insufficiencycan slow down psoralen excretion.

Advantages and Disadvantages

In light-skinned individuals with thinner psoriatic plaques, PUVA has a roleas a second-line light-based therapy, after NB-UVB. PUVA is preferableover NB-UVB in dark-skinned patients, and for thick lesions. The disadvan-tages of oral PUVA are its acute and chronic side effects (see side effectslater). Bath PUVA provides uniform psoralen distribution to the skin withlow plasma levels, and it results in a shortened duration of photosensitivityto approximately hours. Moreover, available data so far have shown noevidence for increased risk of skin cancer of any type with bath PUVA.However, to administer this treatment, one needs to have a bathtub, andbecause of the rapid decline of phototoxicity, the patient has to be exposedto UVA within 10–15 minutes after soaking in psoralen-containing bathwater; the latter needs to be freshly prepared for each patient. It is, therefore,a resource-intensive therapy to administer. Topical psoralens in the form ofcreams or lotions avoid most of the systemic side effects of psoralens, andare convenient to administer; however, their nonuniform distribution canresult in unpredictable phototoxicity. Furthermore, topical PUVA has a nar-row therapeutic window, namely, with a slight increase in UVA, there couldbe a significant increase in phototoxicity. The areas that receive localizedtopical PUVA may become quite tanned and the uneven pigmentationmay be of cosmetic concern.

Dose and Administration

With the newer Oxsoralen Ultra formulation, 8-MOP is taken 1–1.5 hoursprior 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- andintraindividual variations in the absorption of 8-MOP. Therefore, it is veryimportant that the psoralen dose, type and amount of food intake, and tim-ing of phototherapy after ingestion of psoralen are kept constant. Psoralenis preferable to be taken on an empty stomach, as food intake slows absorp-tion and reduces the peak blood levels. However, due to gastrointestinal sideeffects, especially with 8-MOP, non-fat small meals may be taken to allevi-ate some of these symptoms. In some patients, the capsules may have tobe 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 beadministered in a bath or cream/lotion, avoiding the gastrointestinal tract.In our institution, topical PUVA is administered using 0.1% 8-MOP solutionin Lubriderm1 lotion, applied 20 minutes prior to exposure to UVA. TheUVA dose protocol is shown in Table 3. Bath PUVA is only performed invery 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, needsto 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 mgof Oxsoralen Ultra in a hot cup of water first and then adding it to 100 L ofbath water. Exposure to the UVA needs to be performed within 30 minutesafter the patient steps out of the bathtub.

In Europe, oral 5-MOP is commonly used. It is less phototoxic than8-MOP, therefore requiring a higher cumulative UVA dose. The dose rangeused is 1.2–1.8 mg/kg. It has less of a gastrointestinal side effect, hence isbetter tolerated. It is not available in the United States.

Avoidance of prolonged sun exposure and wearing UVA-absorbingsunscreens on the days of PUVA therapy are necessary to prevent significantphototoxicity. Unlike UVB-induced erythema, PUVA-induced phototoxic-ity begins approximately 24 hours after exposure and peaks at 48–72 hoursafter exposure. This is the reason that PUVA should not be administeredtwo 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 areas20–30 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 weekThe maximum dose is 8 J/cm2

Once the condition has improved, treatment frequency can be decreased to twice perweek 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 twodays of the week, followed by a nontreatment third day; an increased butidentical 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 photo-toxicity dose (MPD) or more commonly by Fitzpatrick skin type. The MPDis the minimal dose of PUVA that produces well-defined erythema. Thesereadings are performed at 48–72 hours. The skin-type–based protocol usedat our institution is shown in Table 4. The dose of UVA should be adjusted,usually decreased by 25%, if patients are taking photosensitizing medica-tions. UVA doses should also be decreased if topical or systemic retinoidsare 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. Malegenitalia are particularly sensitive to the development of squamous cell car-cinomas (SCCs) (41); male genitals should be shielded during all of the UVAexposure. If PUVA is required for limited disease, careful shielding of unaf-fected skin is recommended.

Therapy is usually administered twice to three times per week until thepsoriasis is well controlled; it then can be decreased to twice and eventuallyonce a week. Maintenance therapy has been shown to decrease the probabil-ity of remission; however, it will increase the patient’s cumulative dose ofUVA. The British Phototherapy Group recommends that long-term PUVAtherapy should only be considered in patients with a history of rapidrelapses (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 patientswith chronic plaque psoriasis who received paired PUVA regimens (43). Itwas shown that reducing the number of treatments while maintaining thesame UVA dose per week did not reduce efficacy. Reducing the numberof treatments from four times per week to twice a week and reducing theUVA dose from 1 to 0.75 or 0.5 MPD per treatment only slightly affected

Table 4 Guideline for Psoralen and Ultraviolet A Photo-chemotherapy for the Treatment of Psoriasis Based on Skin Type

Skin typeInitial dose

(J/cm2)

Dose increaseper treatment

(J/cm2)Maximum dose

(J/cm2)

I 0.5 0.5 8 (4-face)II 1.0 0.5 8 (4-face)III 1.5 1.0 12 (4-face)IV 2.0 1.0 12 (4-face)V 2.5 1.5 20 (4-face)VI 3.0 1.5 20 (4-face)

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intermediate therapeutic efficacy, and had no effect on final clearance ratesor time to complete clearance. The mean cumulative UVA dose was signifi-cantly lower for the least intensive dose regimen (0.5 MPD twice/wk) thanfor the more intensive regimens.

Due to the increased development of cutaneous malignancies withPUVA therapy, one should strongly consider the combination with otherdrugs such as retinoids or in rotation with other treatments to minimizetotal cumulative dose of PUVA.

Adverse Effects

The acute side effects can be due to either the psoralen or the UVA radia-tion. Systemic psoralen causes nausea and occasionally vomiting in up to30% of patients taking 8-MOP. 5-MOP has fewer gastrointestinal symptomsand is better tolerated. Most drug-induced photosensitivities are due toUVA; therefore, a careful medication history will help prevent this adverseevent. PUVA-induced phototoxic reactions, such as erythema and vesicula-tion, appear at 24–36 hours and peak at 48–72 hours; they can persist for aweek or longer. Other known side effects include photo-onycholysis, mela-nonychia, and friction blisters. Subacute side effects can be an intractablepruritus known as ‘‘PUVA itch.’’ In some patients, therapy may have tobe stopped until the pruritus resolves, and one can then consider restartingthe treatment with a lower UVA dose. Tanning is a constant feature, espe-cially in patients with darker skin.

Long-term side effects include photoaging, the development of smallbrown to black macules in PUVA-exposed sites, known as PUVA lentigines,and photocarcinogenesis. Many of these long-term side effects have beenreported by the PUVA follow-up study, a 16-center prospective cohort studyof 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 handsof 61% of patients, and in the buttocks of 21%. Pigmentary changes were seenin the hands of 59% of patients, and in the buttocks of 25% (45).

Increased risk of SCCs is a well-documented dose-dependent adverseeffect in Caucasians. In the U.S. 16-center study, there was no increase innon-melanoma skin cancer in the first 15 years of the study. However, after25 years, 50% of patients who had received greater than 400 treatments hadSCC, and 33% of patients who had received greater than 200 treatmentshad BCC (44). A Swedish study followed 4799 patients who had receivedPUVA between 1974 and 1985 with an average follow-up period of 15.9 yearsfor 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 withrespect to non-melanoma skin cancer so far revealed no increase in risk innon-melanoma skin cancer in non-Caucasians (47).

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There is a significant dose-dependent increase in SCC in the genitals ofPUVA-treated male patients. The incidence of invasive penile and scrotalSCCs was increased by 52.6-fold. This dose-dependent increase in the riskof genital tumors is persistent long after PUVA therapy has been stopped,especially among those with high-dose exposures to both PUVA and taror UVB (41).

There are conflicting results on long-term studies on the incidence ofmelanoma after PUVA therapy. The PUVA follow-up study reported anincreased risk of melanoma, greatest in patients exposed to high doses ofPUVA (�250 treatments), beginning 15 years after first exposure to PUVA.The incidence rate ratio was 8.4 (48). In contrast, the Swedish follow-upstudy of 4799 patients who had received PUVA between 1974 and 1985 withan average follow-up period of 15.9 years for men and 16.2 for women didnot find an increased risk for melanoma, nor in a subcohort comprising 1867patients followed for 15–21 years (46).

In another study by the U.S. PUVA follow-up group of over 1000patients treated with PUVA, UVB exposure (�300 treatments vs. <300 treat-ments) was associated with a modest but significant increase in SCC and BCCrisk (49). These occurred on body sites typically exposed to UVB therapy, butnot on chronically sun-exposed sites typically covered during therapy.

Using the U.S. PUVA follow-up database, 135 patients who had usedoral retinoids for greater than 26 weeks in one year were studied. The devel-opment of SCC and BCC for each patient during the retinoid use year wascompared to the non-retinoid use years. It was found that oral retinoidsreduced 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 sparehealthy skin from the side effects of UV radiation. In addition, the affectedareas can usually tolerate a higher dose than unaffected skin, as the rate-determining factor for generalized phototherapy is usually erythema ofuninvolved skin. It is known that normal skin can be exposed to up to threeMEDs without blistering, while psoriatic skin may be exposed to up tothree times this dose (nine MEDs) without blistering (51,52). The recentcommercial introduction of fiber-coupled UVB phototherapy systems facil-itates the use of this treatment modality for localized psoriasis plaques.

The mechanism of action of targeted phototherapy is similar to that ofthe other UV-based therapy, namely by inducing T-cell apoptosis, suppressionof DNA synthesis, and generation of prostaglandins and cytokines. It hasbeen reported that the 308 nm excimer laser is more effective in the inductionof T-cell apoptosis compared to NB-UVB (6).

At the time of this writing, there are several targeted phototherapysystems available (Table 5): XTrac excimer laser system (PhotoMedex,

Phototherapy and Laser Treatment 137

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138 Kerr et al.

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Montgomeryville, Pennsylvania, U.S.A.), BClear targeted photoclearingsystem (Lumenis, Santa Clara, California, U.S.A.), DuaLight UVA/UVBphototherapy system (TheraLight Inc., Carlsbad, California, U.S.A.), LovelyII (MSq Ltd., Caesarea, Israel), MultiClear (Curelight Ltd., Margate, Florida,U.S.A.), T-500x (Daavlin, Bryan, Ohio, U.S.A.), Excilite-m (NationalBiological Corporation, Twinsburg, Ohio, U.S.A.). XTrac is the only laser-targeted phototherapy system; the rest are non-laser light sources.

Efficacy

Most of the published studies on targeted phototherapy have been performedwith the 308 nm excimer laser system, which will be the focus of the discus-sion in this section. There are not a lot of published studies on the otherUV phototherapy machines; however, because their wavelengths are similarto that of BB-UVB, NB-UVB, or UVA, theoretically they should be asefficacious as booth phototherapy.

Initial case reports and subsequent larger studies (53) have shownsignificant improvement and even remission of psoriatic lesions followingexposure to the 308 nm excimer laser. In a multicenter study of 80 patients,stable mild to moderate plaque-type psoriasis was treated twice per weekfor a total of 10 treatments or clear disease (54). The initial dose was basedon MED testing and the following treatments were based on plaqueresponse. Seventy-two percent achieved at least 75% clearing in an averageof 6.2 treatments. Eighty-four percent of patients reached improvement ofat least 75% after 10 or fewer treatments. Fifty percent reached improvementof at least 90% after 10 or fewer treatments. In a follow-up study, 55% ofpatients reported an overall satisfaction with their treatments and 25%reported that their treatment was better than other therapies they had triedfor localized disease (55).

Higher doses can be used on psoriatic plaques with faster clearing anddecreased 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 werenot observed despite the side effects of transient painful blistering. Treatmentwith higher fluences was more effective than with low and medium fluences.In addition, the lesions treated with high fluences remained in remissionlonger. The four-month relapse-free outcome is comparable or better thanthe standard topical or systemic therapy for psoriasis (52). In a study withfour children with psoriasis, mean age 11, the excimer laser was found tobe a safe and effective treatment for localized psoriasis in these children (57).

Two studies have compared the excimer laser to incoherent UVBphototherapy with similar outcomes. Tanghetti and Gillis (58) comparedthe clinical outcome of treatment with the excimer laser to a continuous-wave, incoherent UVB light source. Both systems cleared the treatedpsoriasis plaques equivalently, requiring no more than two to five weeks

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of treatment. When used at equally erythemogenic high doses, both systemsproduced rapid plaque clearance with minimal side effects. Kollner et al.(59) treated 15 patients with plaque psoriasis. Three different psoriaticlesions 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. UVBdoses were increased slowly and stepwise. There was no statistically significantdifference among the three groups after 10 weeks. The mean number of treat-ments needed to achieve clearance was 24. Both 308 nm light sources treatedpsoriasis with a similar efficacy to standard NB-UVB phototherapy.

Combination Therapy

To date, there are no published studies on the combination of targetedphototherapy 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 tothe corresponding wavelength.

Advantages and Disadvantages

The advantages of targeted phototherapy include sparing healthy tissue fromUV radiation and ability to deliver high fluences to affected areas. This couldresult in faster rate of response, and probably less cumulative dose. However,the time to administer therapy is greatly increased as compared to boothphototherapy. One can spend up to 20 minutes per session twice to threetimes per week. Under appropriate supervision, the therapy can be deliveredby 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 activeinvestigation. Treatments are usually delivered twice or three times per week.The initial dosing is usually based on a predetermined MED as well as plaquethickness and location. Fluences should be adjusted according to symptomsand response to treatment. The initial dose is usually maintained until theplaques flatten, at which point the dose is decreased. Likewise, if there isno 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 treat-ments promote clearance of psoriatic plaques and tapering the treatmentsmay be beneficial in maintaining the level of plaque clearance obtained frombiweekly laser treatments.

Kollner et al. (59) treated 16 patients with the 308 nm excimer laser orwith the 308 nm lamp with an accelerated scheme three times per week. Theycompared this with UVB therapy in which the dose was increased every sec-ond treatment. With the accelerated scheme, clearance was achieved withfewer treatments and with half the cumulative dose of a slow and stepwiseregime. The side effects such as blistering and crusting were also increased.

Adverse Effects

The adverse effects of targeted phototherapy are related to the wavelengthadministered. The lesional and perilesional skin can develop erythema, tan-ning, vesiculation, erosion, or crusting. This may result in an uneven skin toneand may be a cosmetic concern for some patients. This dyspigmentation fadesgradually with time once phototherapy is stopped. Interestingly, koebneriza-tion has not been reported with vesiculation. In fact, just the opposite, fasterclearance in the vesiculated areas or a ‘‘reverse’’ Koebner phenomenon hasbeen reported. There are no long-term studies on carcinogenesis.

ULTRAVIOLET A1

UVA1 is a relatively new type of phototherapy in the United States; how-ever, it has been used since the early 1990s in Europe. Its main indicationsare for the treatment of atopic dermatitis and sclerosing disorders.

Efficacy

There are two small studies published on the use of UVA1 for the treatmentof psoriasis. Kowalzick et al. (61) performed a paired controlled trial in threepatients using medium dose UVA1 and BB-UVB for three weeks. Both theUVA1- and BB-UVB–treated lesions improved. A review cited three HIV-positive 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 forHIV-positive patients with psoriasis (63). Three HIV patients with psoriasiswere treated with high dose (130 J/cm2) UVA1 with benefit. A quantitativepolymerase chain reaction (PCR)-based assay was performed in bothlesional and nonlesional skin after one UVB or UVA1 exposure. TheUVB-treated skin showed a 6–15-fold increase in the HIV copy number,whereas the UVA1-treated skin did not show any increase (62). Furtherstudies are clearly needed.

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Combination Therapy

To our knowledge, there have been no published studies looking at the com-bination of UVA1 with other therapies.

Indications

The indications for UVA1 for psoriasis are not clear, as further investiga-tions are necessary to determine its efficacy.

Contraindications

Contraindications include photodermatoses with action spectrum in theUVA1 range. In patients taking photosensitizing medications, UVA1 needsto 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 establisheddose for this treatment. For atopic dermatitis and localized scleroderma, stud-ies 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 com-monly used regimen at the present time.

Adverse Effects

UVA1 is generally well tolerated. Exposed skin will become tanned. There isa significant amount of heat generated by the equipment throughout thetreatment. Other possible side effects include xerosis, pruritus, and rarelyskin 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 oflocalized and generalized psoriasis. Patient compliance and the ability forthe patient to come to the office regularly for the treatment are factors thatneed to be considered. Targeted phototherapy sparing uninvolved skin is anew development that is beneficial for selected patients. The side effects ofPUVA are well established. UVB, when judiciously administered, has mini-mal side effects.

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36. Behrens S, Grundmann-Kollmann M, Peter RU, et al. Combination treatmentof psoriasis with photochemotherapy and tazarotene gel, a receptor-selectivetopical retinoid. Br J Dermatol 1999; 141(1):177.

37. Tahir R, Mujtaba G. Comparison of psoralen ultraviolet A (PUVA) photoche-motherapy plus topical corticosteroids with PUVA plus bland emollients in thetreatment of psoriasis. J Ayub Med Coll Abbottabad 2005; 17(1):34–36.

38. Tanew A, Guggenbichler A, Honigsmann H, et al. Photochemotherapyfor 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 etretinatein combination with bath PUVA in the treatment of extensive psoriasis. Br JDermatol 1989; 121(1):107–112.

40. Grundmann-Kollmann M, Ludwig R, Zollner TM, et al. Narrowband UVB andcream psoralen-UVA combination therapy for plaque-type psoriasis. J Am AcadDermatol 2004; 50(5):734–739.

41. Stern RS, Bagheri S, Nichols K. PUVA follow up study. The persistent risk ofgenital 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 JDermatol 1994; 130(2):246–255.

43. Legat FJ, Hofer A, Quehenberger F, et al. Reduction of treatment frequency andUVA dose does not substantially compromise the antipsoriatic effect of oralpsoralen-UVA. J Am Acad Dermatol 2004; 51(5):746–754.

44. Nijsten TE, Stern RS. The increased risk of skin cancer is persistent after discon-tinuation 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 psor-alen 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 Swedishfollow-up study. Br J Dermatol 1999; 141(1):108–112.

47. Murase JE, Lee EE, Koo J. Effect of ethnicity on the risk of developingnonmelanoma skin cancer following long-term PUVA therapy. Online Int JDermatol 2005; 44(12):1016–1021.

48. Stern RS. PUVA follow up study. The risk of melanoma in association withlong-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 non-melanoma skin cancer in psoralen and ultraviolet A-treated patients. J InvestDermatol 2005; 124(3):505–513.

50. Nijsten TE, Stern RS. Oral retinoid use reduces cutaneous squamous cell carci-noma risk in patients with psoriasis treated with psoralen-UVA: a nested cohortstudy. 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 treat-ment 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 ofpsoriasis: 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 excimerlaser for the treatment of psoriasis: results of a multicenter study. J Am AcadDermatol 2002; 46:900–906.

55. Rodewald EJ, Housman TS, Mellen BG, et al. Follow-up survey of 308-nm lasertreatment of psoriasis. Lasers Surg Med 2002; 31(3):202–206.

56. Trehan M, Taylor CR. High-dose 308-nm excimer laser for the treatment ofpsoriasis. J Am Acad Dermatol 2002; 46(5):732–737.

57. Pahlajani N, Katz BJ, Lozano AM, et al. Comparison of the efficacy and safetyof the 308 nm excimer laser for the treatment of localized psoriasis in adults andin children: a pilot study. Pediatr Dermatol 2005; 22(2):161–165.

58. Tanghetti E, Gillis PR. Photometric and clinical assessment of localized UVBphototherapy 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 excimerlaser and a 308-nm excimer lamp with 311-nm narrowband ultraviolet B in thetreatment of psoriasis. Br J Dermatol 2005; 152(4):750–754.

60. Housman TS, Pearce DJ, Feldman SR. A maintenance protocol for psoriasisplaques 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-B-Therapie bei Psoriasis. Z Dermatol 1999; 185:92–94.

62. Krutmann J, Stege H, Morita A. Ultraviolet-A1 phototherapy: indications andmode of action. In: Krutmann J, Honigsmann 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 PhotoimmunolPhotomed 2005; 21(2):103–108.

64. Sterenborg HJ, van der Leun JC. Tumorigenesis by a long wavelength UV-Asource. Photochem Photobiol 1990; 51(3):325–330.

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12

Combination Therapy

Wendy Myers and Jennifer Tan

Department of Medicine, Division of Clinical Pharmacology, Robert Wood JohnsonMedical 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 failsto provide patients with adequate disease control. Fortunately, valid alter-natives are available, as topical agents can be used in conjunction with othertopical medications, systemic therapies, and phototherapy through a com-binational, sequential, or rotational approach to treatment. This translatesinto management plans that extend from the simultaneous use of twotreatment entities to well-choreographed time courses featuring multipletherapeutic agents. Situations in the treatment of mild to moderate psoriasisthat may warrant this approach include refractory disease, acute flares, poorquality of life, or an upcoming major life event for which total clearance isdesired. Diversifying treatment tends to reduce the required dosages andadverse effects associated with aggressive treatment modalities, as well asbenefit the patient through potential cost reduction, ease of administration,and improved quality of life.

The concept of maximizing efficacy and minimizing adverse effectsthrough the combined use of multiple treatment modalities for psoriasishas been used extensively (1). Combination therapy is most useful to treat

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patients who have failed monotherapy, are taking or may take a medicationwhose toxicity will decrease when used in combination, or require taperingfrom a single therapeutic agent (1). This approach frequently involves usingsmaller doses of each agent for a limited period of time, with the more potentagent discontinued as clinical improvement is attained. Just as there is no sin-gle topical agent that can be used to treat all patients with psoriasis, flexibilitywith 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 mono-therapy. In a 2000 review investigating disease clearance rates associatedwith various treatments for psoriasis, phototherapy was associated with63% 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 ratefor topical therapies. When a second topical agent was added to topicalmonotherapy, there was a higher likelihood of clearing. Combination thera-pies involving systemic agents or phototherapy, however, yielded evenhigher clearing rates with the pair of acitretin plus psoralen and ultravioletA (PUVA) and the Goeckerman regimen reaching 100% clearance. Includedamong the most successful combinations were ultraviolet B (UVB) plusanthralin, PUVA plus anthralin, and PUVA plus topical calcipotriol, withreported clearance rates of greater than 90% (2). Combination therapieshave been superior to monotherapy in many double-blind studies, particu-larly 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

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.

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as numerous combinations of ultraviolet phototherapy and topical andsystemic medications.

UVB and PUVA

A study by Momtaz and Parrish (3) found that the simultaneous administra-tion of UVB and PUVA in patients with psoriasis led to more rapid clearingthan either therapy used alone. In the study, the investigators administeredUVB and PUVA to patients who were previously unsuccessful with eitherPUVA or UVB. All 42 of the study subjects tolerated the treatments welland cleared in an average of 11.3 treatments, half the number of treatmentsusually required with either therapy alone. In addition, the cumulative UVBdose was 18% of that normally used with UVB. The mean cumulativePUVA 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 bathPUVA followed by narrowband UVB (NB-UVB) was examined. Twelvepatients were treated with bath PUVA in addition to NB-UVB on the otherside of the body. It was found that NB-UVB enhanced the effects of bathPUVA. In addition, it was found that bath PUVA–NB-UVB cleared thepsoriatic lesions with fewer total exposures as well as lower cumulativeultraviolet A (UVA) doses. A major disadvantage of the study was the lim-ited follow-up of study participants with regard to long-term side effects,especially carcinogenesis. Currently, there is limited information of the car-cinogenic potential of simultaneous PUVA and NB-UVB.

NB-UVB and Cream PUVA

It is well known that the systemic absorption of oral psoralens is associatedwith many risks, including the risk of developing cutaneous malignanciesafter 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 andfewer side effects, although ease of use and economic burden are obviouslimitations. Bath PUVA requires several visits a week to the physician’soffice, may have costly copayments, and may result in the loss of many hoursfrom the workplace. In a study of 30 patients with moderate to plaque psor-iasis, Grundmann-Kollman et al. (6) examined the use of cream PUVA, anewer and less burdensome and costly modality compared to bath PUVA,in combination with narrowband UVB. In the study, 8-methoxypsoralen inDorithin cream at a concentration of 0.001% was applied four times a weekin an even layer for 30 minutes on psoriatic lesions. After this time period, theremaining cream was removed and followed by UVA administration after30 minutes. Although both therapies induced clearance in all patients withinfive 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 cumulativeUV doses were greatly reduced in the combination regimens versus eithertherapy alone. The study strongly suggests that cream PUVA in conjunctionwith NB-UVB would be useful in psoriasis, especially in individuals withmore resistant lesions that tend to clear less quickly.

Although the studies by Momtaz and Calzavara-Pinton demonstratedbenefits of dual UVB and PUVA therapy, a study by Park and colleagues (7)examining PUVA and UVB against PUVA alone in 19 patients with psori-asis was unable to show a difference in the mean number of treatments, themean 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 andtopical vitamin D analogues such as calcipotriol and calcipotriene arevaried. In 1990, Kragbelle (8) performed a study of 20 patients using calcipo-triol in combination with UVB phototherapy. After eight weeks, a difference,although not statistical, in lesion clearance was noted between lesions treatedwith UVB and calcipotriol and calcipotriol alone (39% vs. 17%, respectively).

Molin (9) conducted a large multicenter trial that examined a total of101 patients treated with both UVB and calcipotriol and UVB or calcipotriolalone over the course of eight weeks. By the end of the study, the combinedtherapy group had an 82% mean reduction in the psoriasis area severity index(PASI) score versus 70% in the calcipotriol-alone group of patients. In addi-tion, it was noted during study follow-up that patients who had receivedcombination calcipotriol and UVB had slower onset of new lesions.

Another study performed by Hecker and Lebwohl (10) examined a totalof 20 patients with symmetric plaque-type psoriasis. Patients were treatedwith a combination of calcipotriene ointment and UVB on one side of thebody, 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 com-bined therapy versus UVB with mineral oil. These differences were found tobe statistically significant as early as week 1. Another study by Ramsay andcolleagues (11) examining twice weekly UVB plus calcipotriene cream versusthree times a week UVB plus placebo cream found that efficacy was generallycomparable, but patients with combination therapy required statisticallysignificantly fewer exposures and cumulative UVB therapy to achieve totalclearance than those patients receiving UVB alone.

A more recent study by Woo and McKenna (12) aimed to determineif the combination of NB-UVB and topical calcipotriol produced the sameUVB-sparing effects that were seen in previous studies with broadbandUVB. Fifty patients with psoriasis were randomized into two groups: onethat 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 theNB-UVB–calcipotriol group was significantly lower than the NB-UVBgroup, confirming that NB-UVB with topical calcipotriol cream has a UVB-sparing effect.

UVA and Topical Vitamin D

The first study exploring calcipotriol with PUVA phototherapy involved103 patients (13). The patients were randomized to receive pretreatmentwith calcipotriol or placebo, then PUVA with continued calcipotriol or pla-cebo for a total of 10 weeks. At the study’s end, there was a mean reductionin PASI scores of 91.4% in those treated with calcipotriol and PUVA, and75.7% for those with PUVA and placebo. In addition, it was found that thecumulative UVA dose for the combination group was statistically significantcompared to the PUVA and placebo group.

A second study using the left–right body comparison method exam-ined 11 patients with plaque psoriasis receiving calcipotriene with PUVAversus PUVA alone (14). It was found that the plaques treated with calci-potriene needed fewer treatments as well as lower cumulative doses ofUVA to clear their lesions.

Recommendations Regarding UVB and Topical Vitamin D

In 1997, Lebwohl and colleagues (15) studied the interactions betweencalcipotriene and ultraviolet light. Minimal erythema doses (MEDs) weredetermined for UVB and immediate pigment darkening was measured forUVA. Calcipotriene was applied to a small patch of skin prior to UVB,PUVA, UVA, or no phototherapy. It was found that MEDs for UVBand immediate pigment darkening for UVA were not affected by calcipo-triene. On the other hand, the thick application of calcipotriene resultedin an increased MED with UVA phototherapy. UVA phototherapy alsoresulted in a significant decrease in the concentration of calcipotrienepresent in the ointment after therapy, as tested by high-performance liquidchromatography. Therefore, when using calcipotriene/calcipotriol withphototherapy, it should be applied after UVA light administration. In addi-tion, calcipotriene should be applied more than two hours before UVBexposure to prevent a burning sensation in sensitive patients (16).

UVB and Tazarotene

Tazarotene is a topical retinoid that mediates cell differentiation and prolif-eration (17). Studies examining the use of tazarotene and light therapysuggest improved efficacy and safety when combining these therapies.Behrens et al. (17) performed a whole-body right–left comparison ofNB-UVB plus tazarotene compared to NB-UVB in 10 patients with plaquepsoriasis. After two weeks, both treatments markedly reduced PASI scores,

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and after four weeks, the median PASI reduction with combination therapywas 64% versus 48% with NB-UVB alone.

A study by Koo and colleagues (18) examined whether the additionof topical tazarotene to broadband UVB phototherapy improved efficacywithout causing adverse events including photosensitivity. A randomized,investigator-blinded study of 40 patients evaluated the outcomes of subjectstreated with UVB alone or UVB in addition to 0.1% tazarotene gel appliedthree times per week. At the study’s end (81 days), it was found that tazar-otene plus UVB phototherapy achieved faster and significantly greaterreductions in plaque severity. By day 81, 82% of the plaques treated withtazarotene and UVB showed a marked response (75% improvement orbetter), whereas only 68% of the plaques treated with UVB-placebo, and50% in UVB alone responded. Plaques treated with tazarotene and UVBachieved 75% improvement or better a median of 28 days earlier than didlesions treated only with UVB. It was also found that the cumulative UVB dosewas significantly lower in those with tazarotene and UVB than those with UVBalone or UVB with vehicle.

Tazarotene and PUVA

Behrens and colleagues (19) evaluated the efficacy of tazarotene in combina-tion 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 bodytreated either with tazarotene or placebo once daily, as well as both sides ofthe body treated with PUVA bath therapy four times a week. After threeweeks, the mean PASI reduction with combination therapy was 76%, whereasa 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 photo-therapy is beneficial, allowing for improved efficacy and fewer cumulativephototherapy doses. Applying tazarotene three times a week for two weeksdoes cause thinning of the stratum corneum, permitting patients to burn morereadily. Due to the fact that thinning of this layer of skin can drop theerythema induction threshold nearly 25%, doses of UVB should be reducedapproximately one-third when tazorotene is added in the middle of a courseof phototherapy (20). It has also been recommended to initiate PUVA ther-apy at slightly lower doses than usual (21).

UVB and Tar/Anthralin

The Goeckerman regimen, in which coal tar is applied to the skin, followedby UVB phototherapy, is among one of the oldest treatments for patientswith psoriasis. Although effective, as is the comparable Ingram method(anthralin and UVB), both are very time-consuming, messy, and expensivetherapies that usually require a supervised medical setting.

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There have been a few studies examining modified variants of thesemethods in order to determine if similar effectiveness is possible with moreamiability. A left–right comparison study by Lebwohl and colleagues (22)looked at short contact anthralin with UVB phototherapy versus no anthra-lin and UVB. Of the 11 study participants, two patients treated withanthralin had a more rapid response. Boer and Smeenk (23), who examinedvarious concentrations of short-acting anthralin with UVB or UVB alone,performed a similar study. Of the 15 patients participating in the study, fourshowed moderately improved clearance of psoriasis with short-actinganthralin and UVB versus UVB alone.

Another variation of the Goeckerman and Ingram methods was per-formed by Swinehart and Lowe (24) where high-pressure, high-output metalhalide UVA–UVB lamps, along with short-contact tar and more potent short-contact anthralin, were examined to see if time of therapy could be reducedwhile maintaining effectiveness. At the end of the study, there was a meanclearance of 89%, with about 75% of these patients maintaining clearancefor six months without the need for further therapy. Compared to the moretraditional methods, this technique required fewer hours in contact withthe 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 combi-nation therapy of PUVA with anthralin. Although it was found that thecombination 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 steroidcream used together with UVB phototherapy on clearing of psoriatic lesionsas well as duration of remission. A randomized, double-blind, placebo-controlled study was performed with patients being treated with UVB threetimes a week, with approximately half the patients applying topical cortico-steroids twice daily and the other half applying placebo. The study foundthat there was no statistical significance between clearance rates. In addi-tion, there were no statistically significant differences in the number oftreatments or dosages of UVB required in order to achieve clearance. Thisstudy is in agreement with other earlier studies that also found there to be noadvantageous effects of combination UVB and topical steroids.

PUVA and Topical Steroids

Data regarding the use of topical steroids in combination with PUVA, incontrast to studies with UVB, have shown some benefit. In a comparisonof 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 fewerquantitative UVA doses with the latter. One of the studies in the review didshow a higher relapse rate with corticosteroid use (25).

COMBINING SYSTEMIC AGENTS WITH TOPICAL THERAPIESIN THE TREATMENT OF MILD-TO-MODERATE PSORIASIS

While systemic therapies are often reserved for patients with moderate tosevere psoriasis, there are several capacities in which these potent medica-tions may play a role in the management of mild to moderate disease.According to the American Academy of Dermatology Consensus Statementon psoriasis therapies, systemic therapy may be employed in the treatment ofmild to moderate psoriasis when the disease is unresponsive to topical agentsor if there is lifestyle and/or employment disturbance (28). Patients meetingthese qualifications may still demonstrate a limited affected body surfacearea, since treatment decisions ultimately involve the combined consider-ation 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’sdesires (29). Cases initially perceived as mild may have a substantial impacton a patient’s quality of life and may therefore merit the consideration of amore vigorous treatment plan than originally envisioned by the physician (30).

Patients with mild to moderate disease who have not responded totopical monotherapy are typically introduced to a combination of topicalagents or phototherapy. Systemic therapy is considered if a patient’s lesionscontinue to resist these therapeutic measures or an adverse reaction tophototherapy occurs. In some cases, systemic therapy may be indicatedearlier due to widespread disease, involvement of areas severely impactingquality of life, frequent relapse, or joint involvement (28,31). Furthermore,patients with moderate disease may request systemic therapy in an effort toavoid the excessive usage of topical agents or to ease the administration oftherapy. For these reasons, as well as to increase compliance, there iscurrently a demand to develop systemic medications for the treatment ofmoderate disease (31).

The systemic medications traditionally used in the treatment of psori-asis are methotrexate, cyclosporin, and acitretin. Novel developments in theimmunopathogenesis of psoriasis have led to the introduction of biologictherapies such as alefacept, etanercept, and efalizumab. Less conven-tional systemic treatments that are not Food and Drug Administration(FDA)-approved for the treatment of psoriasis include pimecrolimus, myco-phenolate mofetil, hydroxyurea, and 6-thioguanine. Usage of these agentsmay either follow or accompany topical therapy. An approach to treatmentis generally governed by the physical characteristics of lesions, the locationsaffected, 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 withsystemic agents often allows for a reduction in the amount of systemic ther-apy administered as well as a decrease in associated toxicities.

Combining topical and systemic therapies is commonplace in thetreatment of psoriasis. For instance, in a retrospective analysis of 650patients treated for psoriasis in an academic setting, over one-third ofthe patients receiving systemic therapy were simultaneously treated with aclass I steroid (33). While not used as first-line agents in the treatment ofmild to moderate disease, systemic therapy plays an integral role in generalpsoriatic therapy and therefore is important to all physicians treatingpatients with this disease. As this manuscript is not focused on the treatmentof moderate to severe psoriasis, discussion of systemic therapy will belimited 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 withincreased toxicity. It is important to recall that although several combina-tion therapies may be presented here, therapy for psoriasis is designed onan individual basis. In addition, while combination therapy may sufficefor some patients, others will require rotational or sequential therapy.Introduced by Weinstein and White (34), rotational therapy was originallydesigned for the treatment of moderate to severe disease using rotations ofUVB plus tar, PUVA, methotrexate, and etretinate. Now, with the introduc-tion of safer systemics, such as acitretin and biologic therapies, and moreeffective topicals, such as calcipotriene and tazarotene, rotational therapymay play a larger role in patients with clinically unresponsive mild to mod-erate disease. Furthermore, as described in the subsequent chapter, sequentialtherapy involving various treatment modalities is also instrumental in treat-ing the entire clinical spectrum of psoriatic disease.

Methotrexate

Methotrexate is an immunosuppressant well known for its hepatic andhematologic toxicities, which was approved by the FDA for psoriasis treat-ment in 1971. An antagonist of folic acid, methotrexate prevents the divisionof rapidly proliferating cells through its inhibition of amino acid and DNAsynthesis. Although proliferating lymphocytes and keratinocytes associatedwith disease pathogenesis are targeted, multiple organ systems are alsoaffected, which leads to toxicities. It is among the oldest and most effectivesystemic 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 unrespon-sive to topical therapy (35). A decision to administer methotrexate to patientswith mild to moderate disease should be carefully deliberated because of theassociated immunosuppression, potential for multiorgan toxicity, and possi-ble need for liver biopsies. Although methotrexate is useful in acute flares ofpsoriasis, short-term usage is accompanied by the risk of bone marrowtoxicity. Phototherapy and other systemic therapies such as retinoids shouldbe considered prior to starting methotrexate (36).

Combination therapy with topicals such as tars and vitamin D analogsis encouraged and methotrexate has also been used successfully in combina-tion with anthralin (36,37). A study conducted in India demonstrated thatdisease could be adequately controlled with short-term methotrexate inter-spersed by topical therapy with coal tar, anthralin, or calcipotriene. In manypatients, remission was facilitated by the application of aggressive topicaltherapy to residual lesions during the tapering of methotrexate (38). Metho-trexate has also been used in combination with systemic agents for severepsoriasis; clinical improvement was noted in 13 out of 14 patients treatedwith methotrexate and hydroxyurea at doses that were half of those pre-viously required for individual treatment with either agent. There was alsono difference in laboratory measures such as serum transaminases, bloodurea nitrogen, and creatinine (39).

Cyclosporine

As an inhibitor of the enzyme calcineurin, cyclosporine thwarts the produc-tion of nuclear factor of activated T cells (NF-AT), a nuclear transcriptionfactor for interleukin-2 and other inflammatory genes, and thus inhibits theactivation and proliferation of T cells. These findings have been confirmedby in vivo observations in psoriatic skin (40). Cyclosporine was originallyintroduced in the 1970s as an immunosuppressant used to prevent organrejection in kidney transplant patients. In the treatment of psoriasis, itsuse is generally limited to patients with moderate to severe disease due toassociated side effects such as nephrotoxicity, immunosuppression, and mul-tiple drug interactions. Indicated for patients with severe, recalcitrant plaquepsoriasis, use of cyclosporine in patients with more mild disease should beconsidered only after the patient has been formally educated in regard tothe drug’s toxicities and risks. The medication should only be contemplatedfor short-term use in those who have generally tried another agent first orwho require short-term treatment for a severe flare (41).

Short courses of cyclosporine as monotherapy have been shown torapidly clear chronic plaque psoriasis over a range of severities with gener-ally good tolerability (42). Combinational therapy with topical agents suchas anthralin, corticosteroids, and vitamin D analogs result in a superior clin-ical 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 dosageof up to 5 mg/kg/day. Towards the end of therapy, topical preparationsincluding tar, anthralin, retinoids, or calcipotriene can be used on the resis-tant areas. The immunosuppressive nature of the drug tends to diminishcutaneous irritation caused by these agents. When the same topical agentsare applied at the onset of treatment, a dose of only 2 mg/kg/day is gener-ally needed to obtain clinical efficacy (28).

A study of 12 patients with chronic, plaque-type psoriasis receivingcyclosporine in combination with topical anthralin showed a beneficial effectin patients who were slow to initially respond to cyclosporine alone (44). Whilethe local antiproliferative effects of anthralin on keratinocytes may work inconjunction with the systemic effects of cyclosporine, the addition of topicaltherapy made little clinical difference in patients who were considered to berapid responders. However, the addition of cyclosporine to topical anthralintherapy yielded a response rate higher than that achieved by anthralin alone.The only adverse effect was a cutaneous hypersensitivity to anthralin noted insome patients after the discontinuation of cyclosporine (44). Observed relapsesof psoriatic lesions upon withdrawal of cyclosporine led to trials investigat-ing the use of the drug in combination with topical clobetasol propionate.The addition of clobetasol to a daily cyclosporine dose of 3 mg/kg clearedpsoriasis in 3.5 weeks rather than in six weeks in patients treated with cyclo-sporine alone. There was no difference in the noted side effects between thegroups; however, there was also no significant difference in relapse rates. Thesedata suggest that when used in combination with clobetasol, a lower cumula-tive dose of cyclosporine can be used to achieve clearance (45).

Unlike methotrexate, cyclosporine is not associated with acute bonemarrow toxicity and may be a safer alternative for short-term use. Interest-ingly, however, the combination of methotrexate and cyclosporine has beeneffective 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-knownnephrotoxicity associated with cyclosporine. Methotrexate in combinationwith cyclosporine has successfully cleared recalcitrant psoriasis with bothagents 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, inaddition to the risk of multiorgan system toxicity, limits the role of cyclospor-ine in the treatment to mild to moderate disease to the short-term treatmentof flares or to disease unresponsive to first-line agents.

Acitretin

Acitretin, an oral retinoid, is an FDA-approved treatment for psoriasis thatis most effective in treating pustular psoriasis. When combined with UVB or

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PUVA phototherapy, topical calcipotriene, cyclosporine, or methotrexate, aci-tretin has successfully improved other types of psoriasis as well (48). Acitretin isthe metabolite of etretinate, a molecule that is approximately 50 times more lipo-philic 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 itsreplacement by acitretin in June 1997 (49). The ingestion of alcohol with acitretinleads to its enzymatic conversion to etretinate and subsequently to the clinicallysignificant accumulation of the teratogenic compound. It is therefore imperativethat all women treated with acitretin are educated of the risks associated withconcurrent alcohol ingestion and acitretin therapy (49,50). Also noteworthyfor patient discussion is the ethanol content of various over-the-counter pre-parations, cold medications, and cooking supplies.

As with all systemic medications, the use of acitretin is most oftenreserved for moderate to severe disease but may still have a role in combina-tion with other agents in mild to moderate disease. As a class, oral retinoidsare not as efficacious as phototherapy or methotrexate (51). In plaque-typepsoriasis, acitretin is used in combination with topical steroids, dithranol,or phototherapy (52). These regimens tend to decrease the dose of acitre-tin required for clinical improvement while also maximizing efficacy anddecreasing adverse effects.

Combinations of oral retinoids with PUVA, anthralin, and topical ste-roids have been extensively studied, though clinical experience was largelygained using etretinate (53). A retinoid in combination with betamethasonevalerate cream 0.1% applied twice daily was found to be more effective thaneither agent alone (54). The effectiveness of acitretin for plaque-type psoriasisis markedly improved with UVA or UVB treatment (55,56). Benefits of usingthe two therapies in combination include lower ultraviolet and retinoid doses,reduction of retinoid-associated side effects, and the possible suppression ofcutaneous malignancies associated with UVB and PUVA (57). Likewise,patients treated with a retinoid and topical anthralin have maintained remis-sion for longer than those treated with monotherapy of either agent (53).From these studies, there is evidence that patients with mild to moderatedisease may benefit from maintenance therapy with topical agents or photo-therapy with an oral retinoid available intermittently to treat relapses.

FUTURE THERAPIES FOR THE COMBINATION TREATMENTOF MILD-TO-MODERATE PSORIASIS

There are a variety of medications currently in clinical trials for the treat-ment of psoriasis, including inhibitors of angiogenesis, oral pimecrolimus,lasers, newer retinoids and vitamin derivatives, antidiabetic agents, andcytokine inhibitors. The development of targeted therapies in conjunctionwith a novel understanding of disease pathogenesis has created a promisingfuture 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; AbbottLabs, Ligand Pharmaceuticals Inc.; Beiersdorf, Inc.; Fujisawa Healthcare,Inc.; Celgene Corp.; Synta, Bristol Myers Squibb, Inc.

Speakers’ Bureau Memberships: Amgen Inc.; BiogenIdec, Inc.; WyethPharmaceuticals.

Current Consulting Agreements: Amgen Inc.; BiogenIdec, Inc.; CellGate,Inc.; Centocor, Inc; Genetech, Inc; Novartis AG; Wyeth Pharmaceuticals;Schering-Plough Corporation; Eisai; Celgene Corporation; Bristol MyersSquibb Co.; Beiersdorf, Inc.; Warner Chilcott; Abbott Labs; Allergan; Kemia;Roche; Sankyo; Advanced ImmuniT; Medarex; Celera.

Dr. Wendy Myers is participating in a research fellowship partiallyfunded by Amgen Inc.

REFERENCES

1. Menter MA, See JA, Amend WJ, et al. Proceedings of the psoriasis combinationand rotation therapy conference. Deer Valley, Utah, Oct. 7–9, 1994. J Am AcadDermatol 1996; 34(2 Pt 1):315–321.

2. Al-Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of psori-asis treatment. J Am Acad Dermatol 2000; 42(5 Pt 1):796–802.

3. Momtaz KT, Parrish JA. Combination of psoralens and ultraviolet A and ultra-violet B in the treatment of psoriasis vulgaris: a bilateral comparison study. J AmAcad Dermatol 1984; 10:481–486.

4. Calzavara-Pinton P. Narrow band UVB (311 nm) phototherapy and PUVAphotochemotherapy: a combination. J Am Acad Dermatol 1998; 38:687–690.

5. Morison WL. Systemic and topical PUVA. In: Treatment of moderate to severepsoriasis. 2d ed. New York, NY: Marcel Dekker, 2003:91–114.

6. Grundmann-Kollman M, Ludwig R, Zollner TM, et al. Narrowband UVB andcream psoralen-UVA combination therapy for plaque-type psoriasis. J Am AcadDermatol 2004; 50:734–739.

7. Park YK, Kim HJ, Koh YJ. Combination of photochemotherapy (PUVA) andultraviolet 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 radiationfor psoriasis vulgaris. Dermatologica. 1990; 181(3):211–214.

9. Molin L. Topical calcipotriol combined with phototherapy for psoriasis. Theresults of two randomized trials and a review of the literature. Calipotriol-UVB Study Group. Dermatology 1999; 198:375–381.

10. Hecker D, Lebwohl M. Topical calcipotriene in combination with UVB photo-therapy for psoriasis. Int J Dermatol 1997; 36:302–303.

11. Ramsay CA, Schwartz BE, Lowson D, et al. Calcipotriol cream combined withtwice weekly broad-band UVB phototherapy: a safe, effective, and UVB-sparing

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antipsoriatic combination treatment. The Canadian Calcipotriol and UVB StudyGroup. Dermatology 2000; 200(1):17–24.

12. Woo WK, McKenna KE. Combination TL-01 ultraviolet B phototherapy andtopical calcipotriol for psoriasis: a prospective randomized placebo-controlledclinical trial. Br J Dermatol 2003; 149:146–150.

13. Frappaz A, Thivolet J. Calcipotriol in combination with PUVA: a randomizeddouble blind placebo study in severe psoriasis. Eur J Dermatol 1993; 3:351–354.

14. Speight EL, Farr PM. Calcipotriol improves the response of psoriasis to PUVA. BrJ Dermatol 1994; 130:79–82.

15. Lebwohl M, Hecker D, Martinez J, et al. Interactions between calcipotriene andultraviolet light. J Am Acad Dermatol 1997; 37:93–95.

16. Lebwohl M, Menter A, Koo J, et al. Combination therapy to treat moderate tosevere psoriasis. J Am Acad Dermatol 2004; 50:416–430.

17. Behrens S, Grundmann-Kollmann M, Schiener R, et al. Combination photother-apy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel.J Am Acad Dermatol 2000; 42:493–495.

18. Koo JY, Lowe NJ, Lew-Kaya DA, et al. Tazarotene plus UVB phototherapy inthe treatment of psoriasis. J Am Acad Dermatol 2000; 43:821–828.

19. Behrens S, Grundmann-Kollmann M, Peter RU, et al. Combination treatmentof psoriasis with phototherapy and tazarotene gel, a receptor-selective topicalretinoid. Br J Dermatol 1999; 141:177.

20. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy and photo-therapy. J Am Acad Dermatol 2001; 45:487–498.

21. Hecker D, Worsley J, Yeuh G, et al. Interactions between tazarotene and ultra-violet light. J Am Acad Dermatol 1999; 41:927–930.

22. Lebwohl M, Berman B, France DS. Addition of short-contact anthralin therapyto an ultraviolet B phototherapy regimen: assessment of efficacy. J Am AcadDermatol 1985; 13:780–784.

23. Boer J, Smeenk G. Effect of short-contact anthralin therapy on ultraviolet Birradiation of psoriasis. J Am Acad Dermatol 1986; 15:198–204.

24. Swinehart JM, Lowe NJ. UVABA therapy for psoriasis. Efficacy with shortenedtreatment times with combined use of coal, tar, anthralin, and metal halide ultra-violet machines. J Am Acad Dermatol 1991; 24:594–597.

25. Morison WL, Parrish JA, Fitzpatrick TB. Controlled study of PUVA andadjunctive topical therapy in the management of psoriasis. Br J Dermatol 1978;98:125–132.

26. Dover JS, McEvoy MT, Rosen CF, et al. Are topical steroids useful in photo-therapy for psoriasis? J Am Acad Dermatol 1989; 20:748–754.

27. Meola T Jr., Soter NA, Lim HW. Are topical steroids useful adjunctive therapyfor the treatment of psoriasis with ultraviolet radiation? A review of the litera-ture. Arch Dermatol 1991; 127:1708–1713.

28. Callen JP, Krueger GG, Lebwohl M, et al. AAD consensus statement on psori-asis therapies. J Am Acad Dermatol 2003; 49(5):897–899.

29. Krueger GG, Feldman SR, Camisa C, et al. Two considerations for patients withpsoriasis 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 Dermatol2001; 26(4):362–367.

32. Marchetti A, Feldman SR, Kimball AB, et al. Treatments for mild-to-moderaterecalcitrant plaque psoriasis: expected clinical and economic outcomes for first-line 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 psoriasispatients 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 severepsoriasis 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: con-sensus conference. J Am Acad Dermatol 1998; 38(3):478–485.

37. van de Kerkhof PC, Mali JW. Methotrexate maintenance following Ingram ther-apy in ‘‘difficult psoriasis.’’ Br J Dermatol 1982; 106:623–627.

38. Kumar B, Saraswat A, Kaur I, et al. Short-term methotrexate therapy in psori-asis: a study of 197 patients. Int J Dermatol 2002; 41(7):444–448.

39. Sauer GC. Combined methotrexate and hydroxyurea therapy for psoriasis. ArchDermatol 1973; 107(3):369–370.

40. Gottlieb AB, Grossman RM, Khandke L, et al. Studies of the effect of cyclo-sporine in psoriasis in vivo: combined effects on activated T lymphocytes andepidermal regenerative maturation. J Invest Dermatol 1992; 98(3):302–309.

41. Lebwohl M, Ellis C, Gottlieb AB, et al. Cyclosporine consensus conference: withemphasis 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 inter-mittent 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 treatmentaugments therapeutic efficacy of cyclosporine in psoriasis: a clinical and patho-logic study. J Am Acad Dermatol 1995; 33(4):637–645.

45. Griffiths CE, Powles AV, Baker BS, et al. Combination of cyclosporine A andtopical 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 com-bined therapy in severe psoriatic arthritis. A pilot study. Acta Dermatol VenereolSuppl (Stockh) 1994; 186:116–117.

47. Clark CM, Kirby B, Morris AD, et al. Combination treatment with methotrex-ate 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 andemerging directed therapies. Ann Rheum Dis 2005; 64(suppl 2):ii87–ii90, discus-sion ii91–ii92.

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49. Wiegand UW, Chou RC. Pharmacokinetics of acitretin and etretinate. J AmAcad Dermatol 1998; 39(2 Pt 3):S25–S33.

50. Larsen FG, Jakobsen P, Knudsen J, et al. Conversion of acetretin to etretinate inpsoriatic patients is influenced by ethanol. J Invest Dermatol 1993; 100:623–627.

51. Linden KG, Weinstein GD. Psoriasis: current perspectives with an emphasis ontreatment. Am J Med 1999; 107(6):595–605.

52. van de Kerkhof PC, Cambazard F, Hutchinson PE, et al. The effect of additionof calcipotriol ointment (50 micrograms/g) to acitretin therapy in psoriasis. Br JDermatol 1998; 138(1):84–89.

53. Lowe NJ, Lazarus V, Matt L, et al. Systemic retinoid therapy for psoriasis. J AmAcad Dermatol 1988; 19(1 Pt 2):186–191.

54. Christiansen JV, Holm P, Moller R, et al. Etretinate (Tigason) and betametha-sone valerate (Celeston valerate) in the treatment of psoriasis. A double blind,randomized, multicenter trial. Dermatologica 1982; 165(3):204–207.

55. Tanew A, Guggenbichler A, Honigsmann H, et al. Photochemotherapy forsevere psoriasis without or in combination with acitretin: a randomized, double-blind comparison study. J Am Acad Dermatol 1991; 25(4):682–684.

56. Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of acitretin in com-bination with UV-B in the treatment of severe psoriasis. Arch Dermatol 1990;126(4):482–486.

57. Lebwohl M, Drake L, Menter A, et al. Consensus conference: acitretin incombination with UVB or PUVA in the treatment of psoriasis. J Am AcadDermatol 2001; 45(4):544–553.

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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 includea strategy for initial rapid symptomatic relief as well as long-term main-tenance therapy. Sequential therapy is a therapeutic approach that employsa deliberate sequence of specific therapies to maximize the rate of initialimprovement and smooth transition to long-term maintenance therapy.The traditional therapeutic approach to psoriasis has been the initiationof a single treatment modality. If the chosen medication does not workeffectively, it is discontinued and replaced by a new therapy and so on.A natural consequence of this simplistic monotherapy approach is thetendency to evaluate treatments predominantly based on the rate at whichthey result in initial symptomatic relief. In reality, there are other factorsthat should also guide treatment choice including long-term safety, durationof response, and propensity toward tachyphylaxis. The idea of sequentialtherapy is to optimize these factors by recognizing the advantages anddisadvantages of each therapeutic option and then creating the most idealpairs. Most psoriasis therapies can be categorized into ‘‘rabbits,’’ whichare fast acting and very effective but have questionable long-term safety pro-files, or ‘‘turtles,’’ which have a slower onset of action and are less effective

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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 symptomaticrelief to suffering patients while also emphasizing the importance of provid-ing a strategy for safe, long-term control of their disease. This is typicallyaccomplished in three phases: the clearing phase (Phase 1), which employsa rapid-acting or ‘‘quick fix’’ agent for fast relief; the transition phase (Phase 2),the most challenging phase in which one attempts carefully, patiently, andcreatively to have the ‘‘turtle’’ successfully take over from the ‘‘rabbit’’ withoutinciting worsening of psoriasis; and the maintenance phase (Phase 3), the goalof which is long-term control with minimal side effects (Table 1). As the clearingphase agent is usually a superpotent topical steroid, there is a risk of rebound ofpsoriatic lesions while transitioning to the safer, less potent maintenance phaseagent. The skillful combinational use of therapeutic agents and optimal timingof regimen changes during the transition phase can significantly reduce this riskand 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 includesystemic sequential therapy involving the newer biological agents as wellas various phototherapy options. This chapter will only focus on the conceptof sequential therapy using topical agents. The most common topicalsequential therapy scheme in practice today will be described and used toillustrate the principles that guide clinicians in choosing among existingschemes as well as creating new schemes. The concept of sequential therapyusing systemic or phototherapy modalities are addressed in other publications.

TOPICAL SEQUENTIAL THERAPY: CALCIPOTRIENEAND HALOBETASOL PROPIONATE

The most commonly practiced topical sequential therapy scheme forpsoriasis 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 ofhalobetasol propionate once daily in the morning and calcipotriene once dailyat bedtime for approximately one month (Phase 1, clearing phase), thencalcipotriene twice daily on weekdays and halobetasol propionate twice dailyon weekends for one month or longer (Phase 2, transition phase), and finally,calcipotriene twice daily until psoriasis completely resolves, at which timetherapy can be tapered off (Phase 3, maintenance phase). This particular

Table 1 Sequential Therapy

Phase 1: Clearing phase !Phase 2: Transition phase !Phase 3: Maintenance phase

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scheme has been chosen to illustrate the idea of topical sequential therapybecause it is the only scheme in which the merit of each step has beenvalidated by double-blind, randomized clinical trials directly comparing thevarious options.

Calcipotriene has been shown through well-controlled studies to be asafe and effective treatment for psoriasis (1–5). For example, calcipotrieneointment was found in a double-blind, multicenter study to be superior tofluocinonide (Lidex1) ointment, both in rate of improvement and degreeof efficacy (6). It is not surprising that the frequency of calcipotriene andother vitamin D analogs used in the treatment of psoriasis falls second onlyto higher-strength topical corticosteroids. However, there are a significantnumber of dermatologists in the United States who question the effective-ness of calcipotriene after experiencing somewhat disappointing results withthe medication when it was first introduced. This less than expected ‘‘real-life’’ efficacy of calcipotriene may stem from a few issues. First, it was notrealized until years after introduction that the efficacy of calcipotriene isessentially halved and it has an even slower onset of action when it is usedonly once daily instead of twice daily (7). Unfortunately, most patients wereusing calcipotriene once daily at bedtime, as it was initially only available inan ointment formulation, which is less conducive to morning application.Interestingly, the efficacy of once-daily calcipotriene use approaches thatof twice-daily use if it is continued for eight weeks. However, most patients(and their physicians) were disappointed by the slow onset of action, whichis especially true of once daily use, and concluded that calcipotriene was nota useful medication long before eight weeks had passed. Second, a randomstring of calcipotriene nonresponders may have biased some dermatologists’clinical impression of this medication. Third, calcipotriene could have causeddisappointment when used to abruptly replace a superpotent topical steroid

Table 2 Example of Topical Sequential Therapy

Phase 1: halobetasolpropionate qam,calcipotriene qhs

Phase 2: pulse therapy,calcipotriene bid onweekdays, halobetasolpropionate bid onweekends

Phase 3: calcipotriene bid,then taper off

Phase 1: clobetasolfoam andcalcipotriene bid

Phase 2: pulse therapy,calcipotriene bid onweekdays, clobetasolfoam and calcipotrienebid on weekends

Phase 3: calcipotriene bid,then taper off

Approximately1 month

Approximately 1 month Until psoriasis resolvescompletely

! !

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only to result in rebound of psoriatic lesions. Finally, the use of calcipo-triene as monotherapy is associated with a 2% to 3% incidence of significantlesional and perilesional irritation, which is bothersome enough to patientsthat they discontinue use (8,9).

The sequential use of calcipotriene and halobetasol propionate asdescribed previously provides a solution to many of the aforementionedconcerns. While superpotent topical steroids such as halobetasol propionatework very well, the combined use of topical steroids and calcipotrieneappears to work even better. In fact, the two medications seem to be idealpartners. A double-blind, randomized, multicenter study found that, afteronly 14 days of therapy, the use of calcipotriene ointment in the morningand halobetasol propionate ointment in the evening was significantly moreeffective when compared to twice-daily monotherapy with either agent andalso resulted in a lower incidence of irritation from calcipotriene (10). Addi-tional double-blind, randomized studies have also supported the finding thatcalcipotriene and corticosteroids work synergistically to enhance efficacyand result in fewer side effects than treatment with either agent alone(11). Moreover, the use of halobetasol propionate at the start of therapycan compensate for calcipotriene’s slow onset of action and cover patientswho might be calcipotriene-slow or nonresponders. Finally, using calcipo-triene in conjunction with halobetasol propionate may decrease theincidence of skin thinning from topical steroid use (12). Similar results werefound using a combination of calcitriol, another vitamin D analog, andbetamethasone valerate, another topical steroid (13).

The side effect profile of superpotent topical steroids makes them apoor choice for long-term control of psoriasis. This well-known fact is therationale for the ‘‘weekday–weekend’’ regimen of the transition phase(Phase 2). The first regimen of this kind was introduced in the late 1980sby which the patient applies a potent topical steroid daily until flatteningof the plaque occurs and then uses the steroid on weekends only (14). Ithas since been modified to include calcipotriene after Lebwohl et al. (15)found that the addition of calcipotriene ointment twice daily on weekdaysto the use of halobetasol ointment twice daily on weekends resulted in nearlytwice as many patients achieving a six-month remission and a decreasedincidence of side effects associated with long-term topical steroid use. Theuse of this type of intermittent pulse dosing during Phase 2 allows cliniciansto safely extend treatment of psoriasis with superpotent topical steroids.Pulse therapy also minimizes the risk of rebound by allowing superpotenttopical steroids to be gradually tapered off rather than abruptly discontin-ued once psoriatic plaques have become macular.

During the maintenance phase (Phase 3), the twice-daily application ofcalcipotriene alone (Phase 3) can be initiated once lesions have not onlyflattened 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 pre-scription medications can be discontinued.

Of note, the calcipotriene molecule is relatively unstable and can beinactivated when combined with some topical medications, especially if anacidic environment is created (16). In the aforementioned study that demon-strated the superiority of using once-daily calcipotriene and halobetasolpropionate to twice-daily monotherapy with either agent, the once-dailycalcipotriene and halobetasol propionate ointments were applied separately,morning and night, in order to prevent inactivation of either agent (10). Thisis also true of the Phase 1 regimen presented in Table 2. Halobetasol propio-nate ointment and cream have since been found to be among the medicationsthat are compatible with calcipotriene (17). Therefore, as calcipotriene andhalobetasol propionate are individually known to have better efficacy whenapplied twice a day compared to once a day, the best theoretical regimenwould be to use both calcipotriene and halobetasol propionate twice daily.The author recommends mixing the agents in one palm just prior to each appli-cation instead of premixing agents, as inactivation can begin as soon as 50hours after mixing (17). Similarly, calcipotriene can be continued on weekendsduring Phase 2 pulse therapy, with halobetasol propionate applied in additionto calcipotriene. From common clinical experience, the simultaneous use ofthe two medications appears to work well, although clinical studies have yetto be performed. Recommending that patients mix calcipotriene and halobe-tasol propionate creams for morning application and the two ointment formu-lations for nighttime application may increase compliance.

OPTIMAL TIMING TO PROCEED DOWN SEQUENTIALTHERAPY SCHEME

The issue of timing of each treatment phase can be approached in two differentways. The first is to establish approximate timeframes for the individualtreatment phases based on clinical experience and prior studies. Generallyspeaking, 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 ensurethat the majority of lesions are responding appropriately to treatment. If thepatients’ 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 ther-apy (Phase 2). Fortunately, this ‘‘weekday–weekend’’ regimen appears to beremarkably safe. In my experience, patients do not have any significant skinatrophy on this regimen as long as superpotent topical steroids are not appliedmore than two days per week or to the patient’s face, axilla, groin, and othersensitive areas. Adrenal suppression should not be a concern when topicalsteroids are used only two days per week.

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The second approach to the issue of timing is more sophisticated butalso seems to be more effective. Patients are instructed to transition therapyfrom Phase 1 to Phase 2 for plaques that have flattened and from Phase 2 toPhase 3 for flattened lesions in which the degree of erythema has decreasedfrom red to pink. With this approach, treatment is individualized so thatfaster-responding lesions move quickly along the sequence and thick,recalcitrant plaques stay in Phase 1 for more time (where indurationobviates the concern for skin atrophy).

SEQUENTIAL THERAPY AS A FLEXIBLETHERAPEUTIC STRATEGY

The activity of psoriatic lesions is often unpredictable and therapeutic goalsrange from maintenance of long-term remission, control of acute flares, oreven a period of treatment cessation if the severity of psoriasis decreases.Patients with this chronic disease can certainly benefit from individualizedtreatment plans. The advantage of sequential therapy is that the intensityof treatment can be easily adjusted to the level of activity of psoriasis. Astheir psoriasis improves, patients transition to the next phase, or if theirpsoriasis worsens (for example, during winter months), they can regress toan earlier treatment phase. Not only do patients appear to have better clin-ical outcomes with this flexible therapeutic strategy but they also appreciatethe greater sense of control they feel over a disease that is known to unpre-dictably fluctuate in severity during its chronic course.

SEQUENTIAL THERAPY WITH NEW TOPICALSTEROID FORMULATIONS

One of the new, innovative formulations of topical steroids uses a foamvehicle to deliver medication. Foam is thermolabile and breaks down oncontact 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 moreefficient vehicle for topical drug delivery in comparison to traditionalcreams, ointments, and solutions (18–22).

Clobetasol propionate (Olux1 foam) is one of the topical steroids nowavailable in a foam formulation. Clobetasol propionate foam, like other foamformulations, is quickly absorbed and leaves minimal residue, which makes itideal for use in combination with other topical agents, such as calcipotriene.The foam vehicle is absorbed so quickly that there is no theoretical concernfor dilution or incompatibility when combined with other therapeutic agents.

The efficacy of clobetasol propionate foam and calcipotriene ointmentwhen used in a topical sequential therapy scheme was recently evaluatedin 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 asthe clearing phase regimen (23). Eighty-six subjects were randomized tothree groups: twice-daily monotherapy with clobetasol propionate foam,monotherapy with calcipotriene ointment, or combination therapy. Subjectsin the combination group were directed to apply calcipotriene ointmentimmediately after the clobetasol propionate foam was absorbed. Aftertwo weeks of treatment, reductions in psoriasis severity scores for the targetlesions were significantly greater in the combination therapy group com-pared to either monotherapy group [clobetasol alone: p¼ 0.0017 (trunklesions) and p< 0.0001 (extremity lesions); calcipotriene alone: p< 0.0001(both trunk and extremity lesions)]. With respect to the trunk psoriaticlesions, the combination therapy group achieved a 69.3% mean reductionin psoriasis severity scores, compared to 48.1% with clobetasol propionatefoam alone and 36.6% with calcipotriene ointment alone. A similar patternwas seen with extremity lesions. The results also support in vitro data, asdescribed earlier, suggesting that calcipotriene inactivation does not occurwhen it is applied immediately after a topical steroid foam (25).

The results of the second phase of this sequential therapy study werereported 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 wererandomized to one of two groups: twice-daily calcipotriene ointmenton weekdays plus twice-daily clobetasol propionate foam or placebo onweekends. Treatment groups were compared using intent-to-treat analysis.After six months of treatment, the combination therapy group showed aconsistent trend toward longer maintenance of remission compared to themonotherapy group. Although the data were not found to be statisticallysignificant, this same trend continued throughout all study assessments.The data led the authors to suggest that there might be a positive effectassociated with using clobetasol propionate foam and calcipotriene oint-ment in pulse therapy. Given the consistency of these trends, it is probablethat the results would have been statistically significant if a greater numberof subjects were enrolled in the study. The above results strongly suggestthat there is an advantage to using foam vehicles for drug delivery incombination sequential therapy. Once again, the foam vehicle is absorbedso quickly that calcipotriene can be applied soon thereafter without concernfor dilution and incompatibility with other medications.

TOPICAL SEQUENTIAL THERAPY POSSIBILITIESBEYOND CALCIPOTRIENE

The idea of sequential therapy can be applied to the combined use of anytopical agents with ‘‘rabbit’’ (quick fix) characteristics and ‘‘turtle’’ (safe long-term) 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-dailytreatment with either agent alone (26,27). These two medications appearto work synergistically and could possibly be used in a sequential mode.The more traditional topical agents such as tar or anthralin might also bemore effective in combination with topical steroids in a sequential therapyscheme. The possibilities with respect to topical sequential therapy in thetreatment of psoriasis are limited only by the skill and creativity of the der-matologist. Development of sequential therapy schemes using new agentssuch as combined calcipotriol and betamethasone dipropionate (Dovobet1)promises increased rate of initial improvement relative to calcipotriene aloneand minimized long-term side effects if used in a sequential scheme, and maymake the treatment of this chronic disease more convenient.

REFERENCES

1. Kragballe K, Gjertsen BT, de Hoop D, et al. Double-blind, right/leftcomparison of calcipotriol and betamethasone valerate in treatment of psoriasisvulgaris. 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 withpsoriasis vulgaris. J Am Acad Dermatol 1992; 26:736–743.

3. Berth-Jones J, Chu AC, Dodd WAH, et al. A multi-centre, parallel-group com-parison of calcipotriol ointment and short-contact dithranol therapy in chronicplaque psoriasis. Br J Dermatol 1992; 127:266–271.

4. Ellis JP, Griffiths WAD, Klaber MR. Long-term treatment of chronic plaquepsoriasis with calcipotriol ointment in patients unresponsive to short-contactdithranol. Eur J Clin Res 1995; 7:247–257.

5. Ramsay CA, Berth-Jones J, Brundin G, et al. Long-term use of topical calcipo-triol in chronic plaque psoriasis. Dermatology 1994; 189:260–264.

6. Bruce S, Epinette W, Funicella T, Ison A, Johns EL, Loss R. Comparative studyof calcipotriene (MC903) ointment and fluocinonide ointment in the treatmentof 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 psori-

asis: 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. DermatolOnline J 2003; 9:2.

10. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotrieneointment with halobetasol ointment compared with either agent alone for thetreatment of psoriasis. J Am Acad Dermatol 1996; 35:268–269.

11. Lamba S, Lebwohl M. Combination therapy with vitamin D analogues. Br JDermatol 2001; 144:27–32.

12. Lebwohl M. Topical application of calcipotriene and corticosteroids: combina-tion 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 dihydroxyvitaminD3) in psoriasis. Br J Dermatol 2001; 144:21–25.

14. Katz HI, Hien NT, Prawer SE, et al. Betamethasone dipropionate in optimizedvehicle: intermittent pulse dosing for extended maintenance treatment of psori-asis. Arch Dermatol 1987; 123:1308–1311.

15. Lebwohl M, Siskin SB, Epinette W, et al. Calcipotriene ointment and halobeta-sol ointment in the long-term treatment of psoriasis: effects on the duration ofimprovement. 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 annualmeeting of the Academy of Dermatology, Washington, D.C., 2004.

19. Huang X, Tanojo H, Lenn J, Deng CH, Krochmal L. A novel foam vehiclefor 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 clobetasolpropionate skin permeation and drug distribution in vitro from various topicaldrug delivery vehicles (foam, lotion, and wash-off shampoo). Presented atsummer 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 intopical therapy. Presented at 62nd annual meeting of the American Academyof Dermatology, Washington, D.C., 2004.

22. Huang X, Tanojo H, Lenn J, Cuesico C, Deng H. Impact of vehicle on clobeta-sol propionate skin permeation and drug distribution in vitro. Presented at 62ndannual 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 studyof calcipotriene 0.005% ointment and clobetasol propionate 0.05% foam in thesequential treatment of localized plaque-type psoriasis. Presented at summer meet-ing 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 propionatefoam 0.05% in the sequential treatment of localized plaque-type psoriasis:long-term outcomes. Presented at 63rd annual meeting of the AmericanAcademy of Dermatology, New Orleans, LA., 2005.

25. Franz T, Lehman P, Spellman M. Calcipotriene stability in the presence ofsteroid foam. Presented at 60th annual meeting of the American Academyof Dermatology, New Orleans, LA., 2002.

26. Green L, Sadoff W. A clinical evaluation of tazarotene 0.1% gel, with andwithout a high- or mid-high-potency corticosteroid, in patients with stableplaque psoriasis. J Cutan Med Surg 2002; 6(2):95–102.

27. Koo JY, Martin D. Investigator-masked comparison of tazarotene gel q.d. plusmometasone furoate cream q.d. vs. mometasone furoate cream b.i.d. in the treat-ment of plaque psoriasis. Int J Dermatol 2001; 40(3):210–212.

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14

New Developments in TopicalPsoriasis 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 psori-asis in the past few years. One of the few new topical agents that was recentlyapproved by the United States Food and Drug Administration is a fixed-dose formulation of 0.064% betamethasone dipropionate and 0.005%calcipotriene ointment (Taclonex). This fixed-dose combination therapy isdiscussed separately in Chapter 7. In this chapter, we will discuss othernew topical psoriatic therapies including a new spray formulation of clo-betasol propionate 0.05% (Clobex Spray) and two other formulations ofclobetasol 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 treatmoderate to severe psoriasis in the United States and Europe (1). Various for-mulations 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 toincrease patient compliance and patient satisfaction with treatment is to pickthe formulation that is most pleasing for the particular patient. Althoughthe ointment for mulation has traditionally been thought to be more effec-tive than other formulations due to its occlusive property, many patientsdislike using ointment because it is greasy and difficult to apply on largeareas. A new spray formulation of clobetasol propionate is now availablethat is effective, safe, well tolerated, and may be more acceptable for regularuse by patients.

Clobetasol propionate spray is indicated for the treatment of moderateto severe plaque psoriasis affecting up to 20% body surface area in 18-yearold patients or older. The total dosage should not exceed 50 g/wk.

Two multicenter, randomized, double-blind, vehicle-controlled phaseIII studies have shown consistent rapid reduction in overall disease severitywith twice daily clobetasol propionate spray in patients aged 18 years andolder with moderate to severe plaque psoriasis (2). In study 1, 55% ofpatients were completely clear or almost clear by week 2, and 78% werecompletely clear or almost clear at week 4. In study 2, 47% of patientswere clear or almost clear by week 2, and 82% were clear or almost clearat week 4. Approximately 25% of patients were judged completely clear instudy 1, and 30% were completely clear in study 2 by week 4.

The same studies also suggested that patients who had it cleared dur-ing treatment with clobetasol propionate spray tended to remain clear for atleast four weeks after treatment had ended. All patients who had diseasethat was judged clear, almost clear, or mild in the two phase III studieshad a follow-up visit scheduled at four weeks after the end of treatment.During the four-week posttreatment period, patients were allowed to useonly a moisturizer. Seventy-two percent of patients in study 1 and 76% ofpatients in study 2 were still clear, almost clear, or mild.

Clobetasol propionate spray was very well tolerated during the phaseIII studies. The most common adverse event was application site burning.However, there were no significant differences between adverse events inthe treatment and control groups.

In summary, clobetasol propionate spray is a new formulation thatmay be more cosmetically elegant and user-friendly than the traditionalointment or cream formulations. Patient compliance may therefore improveand 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 con-venient, safe, well-tolerated, efficacious treatment for moderate to severe scalppsoriasis. It is applied once daily on the dry scalp for 15 minutes before lather-ing and rinsing and can be used continuously for a period of four weeks.

Many patients may find the more traditional formulations of clobetasolpropionate such as ointments and creams cosmetically unacceptable fortreating the scalp location. The solution formulation can cause burning andstinging. The foam formulation of clobetasol propionate (Olux) offered sev-eral advantages compared to previous treatments. However, several factorsmay affect treatment compliance with the foam. The foam treatment requirestwice a day application and contains 60% alcohol that may sting and dry thehair (3). In comparison, clobetasol propionate shampoo is to be applied oncea day, contains only 10% alcohol, and can be used for a period of four weekscompared to just two weeks. In addition, this short contact formulationshould minimize the systemic absorption of clobetasol propionate, and thushelp to avoid the potentially harmful adverse effects of potent corticosteroidssuch as hypothalamic pituitary adrenal axis axis suppression (4).

In a phase III study, the adverse event rate was similar between clobe-tasol propionate shampoo and vehicle groups (2). The most commonadverse event was skin discomfort, which included stinging and burning(10.6% of shampoo subjects vs. 17% of vehicle subjects). All adverse eventswere transient and mild or moderate in intensity. None of these adverseevents caused the subjects to discontinue treatment.

In a multicenter, randomized, investigator-blinded study, the applica-tion of clobetasol propionate shampoo once daily was compared to theapplication of calcipotriene solution (Dovonex) twice daily for four weeksin the treatment of moderate to severe scalp psoriasis (5). Clobetasol propio-nate shampoo was significantly more effective than calcipotriene solution.Furthermore, clobetasol propionate shampoo was better tolerated than cal-cipotriene solution. A burning sensation was significantly more common inthe calcipotriene solution group.

In another multicenter, randomized, investigator-blinded study, clobetasolpropionate shampoo once daily was compared to clobetasol propionate gel(Temovate Scalp Application) once daily for four weeks in the treatment of mod-erate to severe scalp psoriasis (2). Clobetasol propionate shampoo and TemovateScalp Application were shown to have similar efficacy and safety profile.

In summary, clobetasol propionate shampoo offers a convenient, effec-tive, safe, well-tolerated treatment option for the treatment of moderate tosevere scalp psoriasis. Since many patients wash their hair every day already,treatment with clobetasol propionate shampoo can be incorporated into thepatient’s daily schedule without taking too much time. This can greatly increasepatient 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 beenrecently introduced. This lotion is unique from the standpoint of not con-taining alcohols and providing a more patient friendly application for morewidespread body application. In clinical trials, the lotion was as effective asTemovate Cream in treating moderate to severe psoriasis. Interestingly, inthese trials, four weeks posttherapy, statistically (p¼ 0.044) 50% more patientswho responded to therapy remained in remission from the Lotion cohort incomparison to those treated with Temovate cream (2). The clobetasol lotionhas been shown in vitro to deliver twice as much clobetasol to the epidermalcompartment (2). Hence the prevailing theory is that psoriatic lesions respon-sive to therapy are more thoroughly treated with the Lotion versus TemovateCream resulting in a longer duration of response with the Lotion.

HYDROGEL PATCH

One of the promising developments in topical therapy of psoriasis is the useof Hydrogel for occlusion of topical agents. It is a well-established fact thatocclusion of a topical agent with an impermeable substance significantlyincreases percutaneous absorption of the medication leading to enhancedefficacy (6–8). However the cost and/or inconvenience of current availabledevices for occlusion has precluded the use of occlusion in the day-to-dayclinical practice of dermatology. Accordingly, occlusion is generally con-sidered only after other topical therapeutic options have proven to beinadequate. Once a dermatologist chooses to pursue occlusion as a thera-peutic strategy; saran wrap or plastic food wrap is the most commonly usedmaterial. However, plastic wrap is notoriously difficult to use for severalreasons. Plastic wrap has no adhesive and needs to be secured in place withadhesive tape, which can irritate the skin. Significant skin irritation or ‘‘tapeburn’’ can sometimes result in koebnerization of the traumatized site.Furthermore, patients report that plastic wrap is unsightly, has no inherentelasticity, and does not allow skin to breathe, which results in excessivesweating and discomfort to the patient. Hydrocolloid dressings (e.g.,Duoderm1) are a more convenient and aesthetically pleasing alternativeto plastic wrap for occlusion of topical agents. Randomized, controlledtrials have clearly demonstrated the benefit of occlusive therapy usinghydrocolloid dressings with and without the concomitant use of high-potency topical steroids in psoriasis (8). However, hydrocolloid dressingsare much too expensive for use in enhancing topical therapy of psoriasisand are currently used mainly for the purpose of wound healing. Althoughdermatologists are well aware of the benefit of occluding topical agentsin psoriasis, the lack of a convenient and affordable material for occlusionprecludes use of this valuable therapeutic option in real life.

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The technological developments taking place in Japan could changethis current situation. In Japan and other parts of Asia, there is a long tradi-tion of using medicated patches for muscular skeletal pain instead of oralnonsteroidal anti-inflammatory agents, as is more common in the UnitedStates. These medicated patches have evolved to become inexpensive, dis-crete, and flexible with an extremely low incidence of skin irritation. Oneof the newest materials used to create these patches is Hydrogel, which iscomposed of more than 50% water. Hydrogel patches are quite versatile.They range from those that resembled human skin to those that aretransparent or look like a thin slice of tofu. Hydrogel patches have manyadvantages when compared to other agents used for occlusion. They are sig-nificantly more cost effective than hydrocolloid patches, have an extremelylow incidence of skin irritation, and are highly flexible and elastic so as tomake them almost unnoticeable to patients once placed on their skin.Because Hydrogel is hydrophilic rather than hydrophobic, for optimallyenhanced penetration of topical agents, it can be constructed in such away that one side adheres to the skin and the other side is coated witha material that makes the Hydrogel virtually impermeable.

Hydrogel occlusion as monotherapy for mild psoriasis has been shownto improve lesions in six to eight weeks. This is not surprising as severalresearch studies have already demonstrated that occlusion alone can resultin improvement, if not complete resolution of psoriasis (6,8–14). Moreover,this specially designed impermeable Hydrogel can also enhance the efficacyof various available topical therapies ranging from steroids to nonsteroids(Figs. 1–6). Currently, there is an ongoing study evaluating the efficacy ofHydrogel occlusion in combination with several topical medications and

Figure 1 (See color insert) Pretreatment Hydrogel alone.

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as a monotherapy for psoriasis. The preliminary results are promising interms of patient acceptance, a low estimated production cost, and the capa-bility of Hydrogel to enhance the treatment of psoriasis, both alone and inconjunction with topical agents.

There are at least three potential uses of Hydrogel in the topical ther-apy of psoriasis. First, Hydrogel can be used as a ‘‘second line therapy.’’ It iswell known by clinicians that all psoriatic plaques, even in the same individ-ual, are not created equal—some plaques are responsive to therapy while

Figure 2 (See color insert) Posttreatment Hydrogel alone.

Figure 3 (See color insert) Pretreatment Hydrogel/TAC 0.1% cream versus TAC0.1% cream alone.

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others are recalcitrant. A certain treatment regimen will often clear 80% to90% of a patient’s psoriatic lesions, leaving them with 5% to 20% of lesionsthat are resistant to treatment. Resistant plaques are commonly found onthe 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.

Figure 4 (See color insert) Posttreatment Hydrogel/TAC 0.1% cream versus TAC0.1% cream alone.

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regimen, such as the combination of calcipotriol with a super-potent topicalsteroid, patients are often forced to live with their stubborn lesions. This iswhere Hydrogel occlusion can be used to enhance the efficacy of the mosteffective topical treatments. Second, Hydrogel may be used to ‘‘jump start’’topical therapy of select plaques with particularly severe morphology in termsof scaling, induration, and erythema. Once again, these lesions are typicallylocated on elbows, knees, and shins. In addition to enhancing efficacy of topi-cal agents, application of Hydrogel in these locations can also conceal lesionsand stop scales from shedding onto clothes, furniture, etc. The third potentialuse of Hydrogel in the treatment of psoriasis is as a ‘‘first line therapy’’ bypatients with mild psoriatic lesions. In these patients, Hydrogel occlusionmay be effective in conjunction with a mild topical agent such as hydrocorti-sone 1% cream or even as monotherapy. Use of Hydrogel in this mannerrequires minimal physician supervision due to the relatively benign nature of thetherapy. Finally, Hydrogel patches may be useful in the treatment of pruritic,lichenified chronic psoriatic plaques. Lichen Simplex Chronicus is most com-monly considered in the differential diagnosis of patients who present with thiscondition. However, patients with a pruritic variant of psoriasis can alsodevelop lichenified psoriatic plaques, which are notoriously difficult to treatas long as patients continue to scratch. In addition to acting as a physical bar-rier to scratching, Hydrogel appears to have a cooling effect on the skinsurface, which provides relief from pruritus. In summary, Hydrogel patchespresent an affordable, convenient alternative to current methods of occlusionin psoriasis and may significantly enhance topical therapy of psoriasis.

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

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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). Thereare several reasons why psoriasis patients are not compliant with their treat-ments (16). The treatments may not work well or they are too toxic. Otherreasons are the treatments are inconvenient or relapse occurs too quickly.The new topical treatment options discussed in this chapter should improvepatient compliance and patient satisfaction. The development of Hydrogelpatches for use in occlusive enhancement of topical therapies of psoriasismay increase the efficacy of all topical agents.

REFERENCES

1. Al Suwaidan SN, Feldman SR. Clearance is not a realistic expectation of psori-asis 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 shampoo0.05% and calcipotriol solution 0.005%: A randomized comparison of efficacyand safety in subjects with scalp psoriasis. J Dermatol Treat 2005; 16:31–36.

6. David M, Lowe NJ. Psoriasis therapy: comparative studies with a hydrocolloiddressing, plastic film occlusion, and triamcinolone acetonide cream. J Am AcadDermatol 1989; 21:511–514.

7. Gottlieb AB, Staiano Coico L, Cohen SR, Varghese M, Carter DM. Occlusivehydrocolloid dressings decrease keratinocyte population growth fraction andclinical scale and skin thickness in active psoriatic plaques. J Dermatol Sci1990; 1:93–96.

8. Griffiths CEM, Tranfaglia MG, Kang S. Prolonged occlusion in the treatment ofpsoriasis: 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 psor-iatic epidermis. Br J Dermatol 1970; 82:458–462.

10. Halprin KM, Fukui K, Ohkawara A. Flurandrenolon (Cordran) tape and carbo-hydrate metabolizing enzyme. Arch Dermatol 1969; 100:336–341.

11. Baxter DL, Stoughton RB. Mitotic index of psoriatic lesions treated with anthra-lin, 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 occlusivedressing. Arch Dermatol 1987; 123:1046–1052.

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15. Zaghloul SS, Goodfield JJ. Objective assessment of compliance with psoriasistreatment. 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.

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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 Healthcareand Northwestern University, Skokie, Illinois, U.S.A.

While patients with limited psoriasis may, in general, suffer from a significantdisease burden, those with involvement of the palms of the hands and soles ofthe feet, palmoplantar psoriasis, can be disabled to an even greater extent.Both cosmetically and physically, these patients have been shown to bear agreater burden of disease (1). The presence of plaques with fissures and/orpustules on the hands and feet can be painful, debilitating, and sociallystigmatizing. These plaques can greatly interfere with a patient’s daily activ-ities, and their location makes it difficult to avoid trauma and irritation. In arecent publication, a task force of the American Academy of Dermatologyspecifically pointed out that disease limited to the palms and soles can besevere even though the total body surface area involved may be small.

Surprisingly, with potential for such extensive disability associated withpalmoplantar psoriasis, there has been remarkably little study into the inci-dence of this condition and even less investigation into its potential treatment.Psoriasis affects 1% to 2% of the population, but the pattern and incidenceof the palmoplantar disease is still unclear. In one study of 3065 Indian psori-atic patients, 92% had plantar involvement and 56% of manual laborers hadhand 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 wasthe result of trauma to the hand resulting in the Koebner phenomena (2).Limited studies suggest that these lesions are not the result of dermatophyteinfection or contact sensitivities (3).

One of the challenges in treating palmoplantar psoriasis is distinguish-ing it from other diseases that may affect the hands and feet. Palmoplantarpsoriasis may appear as typical erythematous scaling plaques on the handsand feet similar to plaques elsewhere on the body, or the skin may develop ageneralized thickening and scaling (keratoderma). This thickened skin candevelop deep fissures that are quite painful and can interfere with patient’sability to walk or use their hands. The plaques are usually sharply demar-cated, with clinically apparent disease on the hands ending at the wristflexures with involvement of the finger pads but not their lateral aspectsof the fingers. In most patients the disease is symmetrical. Nail pitting withnormal-appearing paronychial skin is a classic finding. In addition, patientsfrequently have sterile pustules on the palms and soles and, unlike gener-alized pustular psoriasis, these deep-seated vesicles are chronic, with thecondition often lasting for years.

The differential diagnosis of palmoplantar psoriasis is extensive andis listed in Table 1. Most commonly, erythematous, hyperkeratotitic con-ditions like chronic hand or foot dermatitis may be confused with palmo-plantar disease. If this is the case, allergic contact dermatitis may be theunderlying cause of the inflammatory condition. Importantly, inflammatoryfungal infection is an important aspect of the differential of plantar disease.The diagnosis of palmoplantar psoriasis is facilitated by the presence ofpsoriatic disease elsewhere on the body or by the presence of nail changes.However, in isolation, it can be more difficult to differentiate from otherdiseases in the differential diagnosis. Though diagnosis of palmoplantarpsoriasis is generally made on clinical appearance, a skin biopsy maybe helpful. The histological appearance of palmoplantar psoriasis may besimilar to typical psoriatic lesions but may have an increased number of

Table 1 Differential Diagnosis of Palmoplantar Psoriasis

Common disordersChronic hand eczemaContact dermatitisDermatophyte infection

Uncommon disordersAcquired palmoplantar keratodermaCutaneous T-cell lymphomaKeratoderma blennorrhagicumPityriasis rubra pilarisSyphilis

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neutrophilic pustules in the epidermis. A potassium hydroxide preparationor fungal culture may be helpful in distinguishing palmoplantar psoriasisfrom a dermatophyte infection. All potential clues may be necessary inmaking the appropriate diagnosis and allow for effective therapy of thepatient’s condition.

One condition in the differential diagnosis deserves particular men-tion: palmoplantar pustulosis, including acrodermatitis of Hallapeau. Thisdisease can appear clinically identical to palmoplantar psoriasis and is fre-quently categorized as a subset of palmoplantar psoriasis. Palmoplantarpustulosis is associated with previous smoking and patients frequently haveautoimmune thyroid disease (4). While there is significant clinical and histo-logic similarity between the two conditions, current studies have separatedgenetic susceptibility for these two diseases. Palmoplantar pustulosis, forexample, is not associated with high-risk loci of the psoriasis susceptibility 1(PSORS1) locus in the major histocompatibility (MHC) locus of thegenome. Moreover, it may respond differently to treatment (5). Thus, dataconcerning the treatment of palmoplantar psoriasis may not be translatableto palmoplantar pustulosis.

TREATMENT

As mentioned above, patients with palmoplantar psoriasis may have diseaselimited in extent but severe in its impact on their daily lives. Most studies oftherapy for psoriasis have been concentrated on the most common formof the disease, chronic plaque disease. Studies of topical therapy, photother-apy, and systemic therapy for palmoplantar psoriasis are often performedafter the primary investigations of plaque psoriasis. These studies may notbe well-designed, placebo-controlled trials and are fraught with other poten-tial confounding factors. For example, given the difficulty in distinguishingpalmoplantar psoriasis from other conditions, the lack of solid diagnosticcriteria makes finding a consistent study population difficult. Even morefrustrating is that in studies of plaque psoriasis, data specific to palmoplantardisease are rarely captured. Thus, we are left with scattered studies and casereports to identify potential treatments, which could have a great impact onpatient welfare. We will classify treatment of palmoplantar psoriasis intothree 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 patientswho suffer from palmoplantar psoriasis is protection from exposures thatcan worsen the disease. Palmoplantar psoriasis patients have diminished

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cutaneous barrier function and may suffer from the Koebner phenomenonand, therefore, are at particular risk of aggravating their disease from traumaand exposure to noxious agents. Patients can benefit greatly from instruc-tion in avoiding irritation to their hands and feet. It is important that theyavoid harsh cleansers and contact with chemicals and solvents. These pati-ents should protect their hands from repeated wetting and drying bywearing protective gloves during activities such as washing dishes. Avoidingtrauma during manual labor can also be of benefit. When doing ordinarydaily housework, the avoidance of skin irritation can be partially accom-plished by using protective cotton gloves. These simple instructions that canbe discussed in just a few minutes during an office visit may have a signifi-cant impact on the efficacy of therapy for this disease.

Emollients

Another benign therapy that should always be included in a general plan forthe treatment of palmoplantar psoriasis is proper lubrication of the skin. Theuse 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 impacton patient comfort. Applying oil or ointment-based preparations, such aspetrolatum, frequently to the hands may help maintain barrier function.This therapeutic intervention, however, is frequently found to be difficult forpatients who may find using greasy substances to the hands and feet animpediment to work or cosmetically unacceptable. In these cases, the useof other emollients can be used, but patients must be careful to avoid agentswith additives that may aggravate their condition. In these cases, compli-ance with the use of a suboptimal agent is likely superior to noncompliancewith a more effective treatment.

Topical Corticosteroids

Similar to most other forms of psoriasis, topical corticosteroids are themainstay of treatment. However, treatment of the palms and soles withthese topical agents is complicated by a number of factors. As mentionedabove, the application of topical substances to these areas can be an incon-venience to those who work with their hands or must use their feetconsistently; that is everyone. Moreover, the thickness of the stratum cor-neum and the epidermis on the palms and soles inhibits the penetration oftopical agents. In particular, agents that may impact the dermal immuneprocess may not be delivered to the appropriate layers of the skin in a suffi-cient amount to have a significant impact on the disease. For this reason,treatment with more potent corticosteroids, occlusion, and combinationwith agents that induce exfoliation of the stratum corneum can be used.Conversely, the thickness of the skin in the palms and soles allows forclass 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 becontinued for a greater length of time than in other regions of the skin wherethere is lesser thickness of the epidermis. Importantly, care must be taken toensure that skin other than the palms and soles, especially the dorsal handsand finger tips, is not treated, as this skin will be at risk of thinning.

To increase efficacy of topical corticosteroids, nighttime occlusion orkeratolytic agents are often employed (6). Occlusion can be accomplishedthrough the use of plastics including gloves or wraps. Care should betaken to avoid contact allergy to these barriers, which can complicatethe potential benefit of their use. Occlusion will increase the potency of thetopical corticosteroid by about 10-fold, and the occlusion itself will aid inthe resolution of the psoriatic plaques. Because of the increased potencyof topical medication when adding occlusive techniques, the use of class Icorticosteroids is usually not recommended and patients should be care-fully monitored for evidence of local side effects including skin atrophy.The addition of keratolytic agents like salicylic acid, urea, or lactic acidcan reduce the hyperkeratosis associated with palmoplantar psoriasis andincrease 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 palmo-plantar disease, but good data on their efficacy are not readily available.Calcipotriene has been reported to have some efficacy in a number of casereports and uncontrolled small series in the literature (7). There have, how-ever, been no reported placebo-controlled trials. In one randomized trial,calcipotriol used twice weekly under occlusion was compared to twice a dayapplication in a six-week period (8). In this small study, occlusive therapywas equivalent to twice-daily treatment (26% and 25% improvement inclinical score, respectively), potentially allowing for a tolerable protocolfor the use of occlusive therapy for this disease. In a report from a large psoria-sis treatment center in the United States, patients with palmoplantar psoriasistreated with topical vitamin D derivatives are almost always treated in com-bination with topical corticosteroids (9).

Topical Retinoids

Systemic retinoids have been used for the treatment of palmoplantar psori-asis for many years (see later). Thus, it has been assumed that topicalapplication of antipsoriatic topical retinoids would also be beneficial. How-ever, very little information is available in the literature about the use oftopical retinoids in this condition. One patient with keratoderma blennor-rhagicum, a condition with clinical similarities to psoriasis, has beenreported with a good response (10). Additionally, one large center has reporteduse of topical tazarotene with qualitatively good responses when used in

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combination with topical corticosteroids, though no objective response ratesare reported (9). Clearly, further investigation is warranted.

Topical Methotrexate

Topical 0.25% methotrexate gel was shown not to be statistically signifi-cantly effective for palmoplantar psoriasis (11). In a 14-patient trial, therewas an average of 40% improvement in the palms and 29% improvementin the soles of treated subjects. Unfortunately, it is not clear whether thistrial was sufficiently powered to demonstrate therapeutic effects. One per-cent methotrexate gel in propylene glycol used twice a day was shown togive at least a 50% improvement in 80% of palmar and 64% of plantar psor-iasis in a small series of 15 patients. This preparation is not readily availablebut could be of potential therapeutic benefit.

PHOTOTHERAPY

Ultraviolet B Therapy

Ultraviolet B (UVB) phototherapy has been a standard therapy for psoriasisfor decades. More recently, narrowband UVB (NB-UVB) treatment hascome into common usage. Like other treatments for palmoplantar psoriasis,however, data on its effectiveness are limited. In one open-label prospectivestudy of of NB-UVB therapy, 9 of 11 patients with refractory palmoplantarpsoriasis responded to hand–foot UVB treatment. Additionally, one ofthree patients with palmoplantar pustulosis had a good response to thistherapy (12). Though additional studies are unavailable, clinical experiencesuggests that NB-UVB is potentially a reasonable early intervention in thetreatment of palmoplantar psoriasis.

Topical Psoralen and Ultraviolet A

One of the unique aspects of treating palmoplantar psoriasis with photother-apy is the potential to apply the photosensitizing agent methoxypsoralendirectly to the affected area without requiring systemic exposure to the drug.This can be applied through application of a cream or solution of psoralenor by soaking in a solution of the medication. This therapy avoids many ofthe complications and side effects associated with oral 8-methoxypsoralen.

Topical psoralen and ultraviolet A (PUVA) therapy has probablybeen the most widely studied treatment for palmoplantar psoriasis andhas been demonstrated to be of great efficacy in treating patients for whomtopical treatment has been unsuccessful. Both prospective and retrospectiveanalyses 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 aswell. In a study comparing bath and cream preparations of psoralen in asmall number of patients, response rates were similar. Thus, topical PUVAseems to be an effective modality for patients with palmoplantar psoriasis.

Directed Phototherapy

Treatment of palmoplantar psoriasis with directed phototherapy, both of thelaser and non-laser varieties, has been reported. The 308 nm excimer laser hasbeen suggested as an alternative to traditional phototherapy in one large cen-ter. This therapy can be administered with or without the addition of systemicretinoids. A recent pilot study has demonstrated efficacy of a non-laser 308 nmlight source inpalmoplantarpustulosis ina very limitednumberofpatients (21).Like all aspects of palmoplantar psoriasis, more study is required for any defi-nitive understanding of directed phototherapy efficacy in this disease.

SYSTEMIC THERAPY

Systemic therapy for palmoplantar psoriasis can be used in patients whohave severe disability at presentation or added to the regimen of thosewho have failed topical therapy.

Retinoids

Systemic retinoids have long been a staple of treatment for refractory palmo-plantar disease. Much of the literature regarding retinoid use for thisindication is with etretinate, a chemical precursor of the more readily avail-able acitretin. A number of trials have demonstrated that etretinate asmonotherapy has some efficacy when treating palmoplantar disease (22–24).This effect is significantly improved with the addition of photochemother-apy, a protocol that has been studied in controlled trials (25–27). Oralretinoids, with or without phototherapy, are frequently the first oral medi-cation chosen for palmoplantar psoriasis (9). Importantly, due to risksassociated with teratogenicity, the U.S. Food and Drug Administrationrecommends that women of childbearing potential should not become preg-nant for three years after taking acitretin. It is the opinion of the authors thatthis concern precludes the use of acitretin in this population.

Methotrexate

Systemic methotrexate is generally considered to be effective in palmoplan-tar psoriasis. Unfortunately, there is no significant literature on this subject.In a retrospective analysis, methotrexate has been reported to be used andeffective in one large treatment center (9). The limitation of methotrexateuse 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 con-trol of psoriatic disease and can be an effective bridge to other longer-termsystemic therapies. CsA has been studied in a randomized placebo-controlled trial with a dose of 2.5 mg/kg/day demonstrating response in17 out of 19 patients, while only 4 out of 15 patients on placebo showedbenefit. Further study showed that doses as low as 0.25 mg/kg/day can beeffective (28). Additional prospective analyses have verified the efficacy ofCsA (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 isimmunosuppressive and patients need to be evaluated for hepatitis B andC, human immunodeficiency virus, and tuberculosis prior to starting. Addi-tionally, patients need regular monitoring of renal function and bloodpressure while taking CsA (29,30).

BIOLOGIC THERAPIES

There have been limited case reports in the literature suggesting efficacy ofbiologic immunotherapies in the treatment of palmoplantar psoriasis orpalmoplantar pustulosis. Alefacept and etanercept have had published casereports suggesting efficacy (31,32). Importantly, for patients who also sufferfrom psoriatic arthritis, anti-tumor necrosis factor (TNF-a) biologic thera-pies such as infliximab, adalimumab, and etanercept have been shown tohalt the progression of their disease. For these patients, anti-TNF-a thera-pies should be considered a first-line therapy (33).

SUMMARY: A TREATMENT APPROACH FOR THERAPYOF PALMOPLANTAR PSORIASIS

Given the limited data available on treating this condition, it is difficult tomake evidence-based decisions for the appropriate therapy of palmoplantarpsoriasis. Thus, treatment recommendations must be made on the basis ofexperience as well as the limited information in the literature. In the nextsection, suggestions are given based on the authors’ treatment protocolfor 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 isunique in that the disease is, by definition, local and limited. Thus, the use oftopical therapies is sometimes more reasonable in patients with extensivedisease. In general, the authors begin with combination topical therapies,usually a potent topical corticosteroid used in combination with calicipotriol

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or tazarotene. If necessary, occlusion is added to increase efficacy. A treat-ment 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 ensurecompliance with treatment.

If topical therapy is insufficient, and the patient’s disease is still havinga significant impact on daily life, the authors usually turn to phototherapy.They find topical PUVA therapy to be more effective than NB-UVB, butmany patients prefer the ease of avoiding the photosensitizing agent. They

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

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do not use systemic PUVA for localized palmoplantar disease, as applica-tion to these areas of 8-methoxypsoralen is readily available, and many ofthe systemic side effects of the oral medication are avoided with topicalapplication. In male patients or postmenopausal females, they will oftenstart acitretin prior to starting NB-UVB in order to maximize benefit.

If phototherapy is not available or is inconvenient for the patient, theyconsider systemic treatment. In patients who are male or are female andpostmenopausal, their first agent is acitretin. This agent may have significantbenefit for palmoplantar disease, particularly of the pustular variety, and isgenerally well tolerated for extended periods. In women of childbearingpotential, they generally prefer a biologic agent or methotrexate. With allmedications in this population, special attention needs to be paid to the issueof pregnancy with at least three months off methotrexate and six weeks off abiologic therapy prior to conception. In patients with psoriatic arthritis,they generally prefer an anti-TNF agent. Cyclosporine is generally reservedfor patients who have failed alternative therapy or require rapid resolutionof their condition.

CONCLUSION

Palmoplantar psoriasis can be limited in extent but have devastating impacton patients. Though it is often amenable to topical therapy, it is of greatimportance for the practitioner to be aware of the diminished quality of lifeassociated with this condition and treat aggressively. Unfortunately, data onthe efficacy of the various treatments available for palmoplantar psoriasisare limited and therapeutic decisions often need to be made on the basisof personal experience rather than evidence-based approaches.

REFERENCES

1. Pettey AA, Balkrishnan R, Rapp SR, Fleischer AB, Feldman SR. Patients withpalmoplantar psoriasis have more physical disability and discomfort thanpatients with other forms of psoriasis: implications for clinical practice. J AmAcad Dermatol 2003; 49(2):271–275.

2. Kumar B, Saraswat A, Kaur I. Palmoplantar lesions in psoriasis: a study of 3065patients. Acta Derm Venereol 2002; 82(3):192–195.

3. Fransson J, Storgards K, Hammar H. Palmoplantar lesions in psoriatic patientsand their relation to inverse psoriasis, tinea infection and contact allergy. ActaDerm Venereol 1985; 64:218–223.

4. Eriksson MO, Hagforsen E, Lundin IP, Michaelsson G. Palmoplantar pus-tulosis: 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 distin-guishes 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 pro-pionate 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 thanplaque-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 palmoplantarpsoriasis. Int J Tissue React 2001; 23(2):59–62; 3.

9. Spuls PI, Hadi S, Rivera L, Lebwohl M. Retrospective analysis of the treatmentof 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 withtazarotene 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 basefor palmoplantar psoriasis. J Dermatol 2004; 31(10):798–801.

12. Nordal EJ, Christensen OB. Treatment of chronic hand dermatoses with UVB-TL01. Acta Derm Venereol 2004; 84(4):302–304.

13. Agren-Jonsson S, Tegner E. PUVA therapy for palmoplantar pustulosis. ActaDerm 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 derma-toses 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 therapyfor palmoplantar dermatoses: experience with 35 consecutive patients. MayoClin Proc 1998; 73(5):407–411.

16. Grundmann-Kollmann M, Behrens S, Peter RU, Kerscher M. Treatment ofsevere recalcitrant dermatoses of the palms and soles with PUVA-bath versusPUVA-cream therapy. Photodermatol Photoimmunol Photomed 1999; 15(2):87–89.

17. Hawk JL, Grice PL. The efficacy of localized PUVA therapy for chronic handand foot dermatoses. Clin Exp Dermatol 1994; 19(6):479–482.

18. Layton AM, Sheehan-Dare R, Cunliffe WJ. A double-blind, placebo-controlledtrial 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 forsevere recalcitrant palmoplantar dermatoses. A randomized, single-blinded pros-pective study. Photodermatol Photoimmunol Photomed 2005; 21(2):62–67.

20. Taylor CR, Baron ED. Hand and foot PUVA soaks: an audit of the Massachu-setts General Hospital’s experience from 1994 to 1998. Photodermatol Photoim-munol Photomed 1999; 15(5):188–192.

21. Aubin F, Vigan M, Puzenat E, et al. Evaluation of a novel 308-nm monochro-matic excimer light delivery system in dermatology: a pilot study in differentchronic localized dermatoses. Br J Dermatol 2005; 152(1):99–103.

22. Thune P. Treatment of palmoplantar pustulosis with Tigason. Dermatologica1982; 164(1):67–72.

23. White SI, Marks JM, Shuster S. Etretinate in pustular psoriasis of palms andsoles. 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 ofremission of palmoplantar pustular psoriasis. Br J Dermatol 1986; 115(5):577–582.

25. Rosen K, Mobacken H, Swanbeck G. PUVA, etretinate, and PUVA-etretinatetherapy 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 dif-ferent 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-etretinateand 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. Cyclos-porine 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 clearingpersistent 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 psor-iasis: 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 withintramuscular alefacept. J Am Acad Dermatol 2005; 53(suppl 2):S127–S129.

32. Weinberg JM. Successful treatment of recalcitrant palmoplantar psoriasis withetanercept. Cutis 72(5):396–398.

33. Mease PJ. Recent advances in the management of psoriatic arthritis. Curr OpinRheumatol 2004; 16(4):366–370.

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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 mayseriously impair the quality of life. After a presentation of the epidemi-ological aspects, clinical morphology, and differential diagnosis of scalppsoriasis, 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 wasthe most frequently affected area (1). In many patients psoriasis of the scalpis a major problem; in fact, 31% of patients, respectively, with scalp psoriasisindicated that the condition is distressing (2).

A questionnaire, mailed to 6000 members of the Dutch PsoriasisAssociation, revealed that in 57% of them scalp involvement is an importantpsychological handicap (3). In fact, scalp psoriasis had existed for more thanfive years in 81% of the patients and in 48% of them, psoriasis covered morethan half of the scalp. Visibility of the lesions and itch were the most annoy-ing 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 erythematousplaques with white-silvery scales. The scales extend as sleeves around the hair,which appearance is also described as ‘‘pseudoteigne amiantacee.’’ The lesionsoften expand onto the face, in particular in the hairline area. But also involve-ment of the retroauricular fold is often seen. Figure 1 illustrates the classicalmanifestations of scalp psoriasis. Scalp psoriasis may itch in most patients inat least some episodes.

It is the traditional view that scalp psoriasis is not characterized by hair lossor atrophy of the skin. However, it has been shown that the number of telogenhair in trichograms of plucks of hair is increased (4). Scanning electron micro-scopy has revealed that hairs of psoriatic patients show cuticular breakageand an abraded cuticular surface (5). Furthermore, it is borne out of clinicalpraxis that long-lasting psoriatic plaques may cause alopecia cicatricialis (6–8).

As scalp psoriasis may result in irreversible hair loss, it is important toconvince the patient that active treatment is important not only for theimmediate improvement of the condition but also for the long-term appear-ance of the patient.

Figure 1 (See color insert) Classical manifestations of scalp psoriasis: (A) psoriasisof 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 adequatediagnosis and treatment. Classic psoriatic plaques elsewhere or classicmanifestations of seborrheic dermatitis, lupus erythematosus, or lichenplanopilaris may help the diagnosis. Therefore, inspection of the entire skinis important.

The scalp lesions of psoriasis may strongly resemble seborrheic derma-titis, which also is a papulosquamous condition, however with more yellowscale crusts and preferential localization on upper trunk, face, and flexures.Fungal lesions may strongly resemble scalp psoriasis. Broken hair, pustula-tion, and prominent atrophy may increase suspicion that a fungus isinvolved. Lichen planus is characterized by violaceous papules in folliculararrangement resulting in atrophy. Lupus erythematodes is also character-ized by atrophy and follicular hyperkeratoses.

A group of 85 patients with scaling of the scalp (‘‘pityriasis amianta-cea’’) 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 atopicdermatitis. In 12.9%, the diagnosis of tinea capitis was confirmed by potas-sium hydroxide preparation, fungal culture, and periodic-acid Schiffstaining. Overgrowth of staphylococcus isolates was evident in 96.5% ofthe patients.

In another study, patients who had been diagnosed as having scalppsoriasis proved to show colonization with Malassezia species (10).M. globosa, M. slooffiae, and M. restricta were predominant species in55%, 18%, and 10% of the patients, respectively. Therefore, in the case ofpityriasis amiantacea, the differential diagnosis is broad, and in case the clin-ical picture is not conclusive, histological examination and cultures may beindicated (11). In psoriasis of the scalp, overgrowth of Malassezia speciesremains an important feature, which may be of therapeutical relevance.

GENERAL THERAPEUTIC ASPECTS

A questionnaire mailed to patients of the Dutch Society for Psoriasis(n¼ 922 responders) (3) revealed that 99.6% of patients used a topical corti-costeroid for scalp psoriasis (Table 1). Shampoos were used by 51% and cal-cipotriol treatment by 28% of the patients responding to the questionnaire.The majority of these patients used the treatment for prolonged periods oftime. Seventy-two percent of them indicated that they had used treatmentsfor more than eight weeks. Of particular importance is the fact that thepatients indicated that the formulation, allowing a cosmetically acceptabletreatment, was of utmost importance.

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SHAMPOOS

Shampoos are used as a vehicle for active treatment principles. Althoughno double-blind studies are available on the efficacy of tar shampoos, theusage of tar shampoo is a popular approach under patients suffering fromscalp psoriasis.

Open studies indicated that shampoos containing 2% to 10% coal tarmight be effective in psoriasis (12,13).

Some reservation on the usage of coal tar shampoos is justified, as thesecretion of 10-hydroxy pyrene in urine is increased in patients using tarshampoo, indicating resorption of hydrocarbons through the skin (14).

Zinc pyrithion shampoos are well appreciated. But again, no double-blind studies are available to substantiate their efficacy. In open studies,scalp psoriasis proved to respond to zinc pyrithion shampoos in concentra-tions between 1% and 2% (14–16).

Table 1 Actual Frequency of Use of Various Treatments inScalp Psoriasis (n¼ 922 Patients)

Treatment No. of patients

CorticosteroidsHydrocortisone cream 13Clobetasone cream 14Hydrocortisone butyrate cream 32Hydrocortisone butyrate lotion 16Hydrocortisone butyrate emulsion 18Triamcinolone cream 28Betamethasone valerate cream 65Betamethasone valerate emulsion 19Betamethasone valerate lotion 125Clobetasol cream 106Clobetasol lotion 101Betamethasone diproprionate hydrogel 26Betamethasone diproprionate cream 37Betamethasone diproprionate lotion 72Desoximethasone emulsion 292

Other treatmentsCalcipotriol ointment 258Coal tar shampoo 474UVB phototherapy 119Salicylic acid 65Other/unknowna 161

aOther/unknown implies a series of alternative treatment approaches.

Abbreviation: UVB, ultraviolet B.

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More recently, clobetasol propionate shampoo 0.05% was reported to bea new option for the treatment of patients with moderate to severe scalp psori-asis (17). In a multicenter, randomized, vehicle-controlled, double-masked,and parallel group study, clobetasol propionate shampoo was compared withthe corresponding vehicle shampoo in patients with moderate–severe scalppsoriasis during a four-week treatment. A total of 143 patients were treated.Clobetasol shampoo was significantly more effective as compared to thevehicle shampoo with the same safety profile.

DESCALING OF THE SCALP

Debridement of the scalp by an automatized shampooing and debridementmachine has been shown to markedly empower the response to antipsoriatictreatments (18).

Salicylic acid 5% to 10% has been shown to have a marked keratolyticeffect. Salicylic acid is formulated in an ointment that can be washed offeasily. Application of salicylic acid ointments is done for a few days, beforeactive 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 smellof coal tar is a limitation. Coal tar solution (5–20%) can be formulated in alotion or added to a topical corticosteroid preparation.

Dithranol is another time-honored principle. Dithranol 0.1% to 3% ismanufactured in various formulations. The treatment is started at a low con-centration and increased stepwise, aimed at preserving a minimal degree ofirritation. Dithranol treatment of the scalp may cause temporary discol-oration of the hair. In an open study, dithranol in a cream formulation caused58% reduction of the modified psoriasis area severity index (PASI) for thescalp during an eight-week treatment (20). The application of dithranol inscalp 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, sorbitanperoleate, PEG-40 hydrogenated castor oil, trideceth-9, propylparaben, buty-lated hydroxytoluene (BHT), ascorbyl palmitate, glyceryl stearate, glyceryloleate, and citric acid) and crystalline monoglycerides (Micanol Bioglan,Giessen, Germany) have been shown to be suitable vehicles for dithranoltreatment of scalp psoriasis (21).

IMIDAZOLE ANTIFUNGALS

As scalp psoriasis is accompanied by an overgrowth of pityrosporon, anantifungal treatment seems to be a rational approach. The outcome of

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various studies on topical and systemic antifungal treatments is contradic-tory (22–25). However, in treatment-resistant manifestations a reductionof pityrosporon overgrowth may be effective in improving the condition.

TOPICAL CORTICOSTEROIDS

Topical corticosteroids are frequently used in scalp psoriasis. From an epi-demiological survey we know that topical corticosteroids are used by themajority of patients for more than eight weeks (3).

In scalp psoriasis, the formulation is relevant, in particular with respectto the cosmetic appearance. A cream or lotion is preferred to an ointment,although an ointment provides better bioavailability. More recently, a foamvehicle became available. The advantage of the foam is that it spreadsbetween the hairs until it reaches the scalp, where it melts. The total coveragearea for 100 g of foam was comparable to the coverage area of 100 g oftraditional vehicles (26). In a comparative study against standard treatment(corticosteroid lotion or vitamin D3 treatments) betamethasone 17-valeratein 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 applica-tions of betamethasone 17-valerate was as effective as twice-daily application(28). The average sign scores (erythemaþ indurationþ scaling) reduced from8.1 to 3.9 and 7.7 to 3.0 during a four-week head to head study (28). In acomparative study of clobetasol propionate foam 0.05% against clobetasolcream and vehicle the decrease of PASI during a two-week study was 41%against 31%. Patients using foam had a significantly greater increase in qual-ity of life parameters and had spent less time applying their medication (29).Side effects of topical corticosteroids on the scalp are limited. In case thefacial areas are exposed to the steroids, perioral dermatitis may develop. Itmay be relevant, however, that topical corticosteroids may suppress hairgrowth and that the skin of the scalp is by far more permeable to topicalcorticosteroids than most other regions of the skin (30,31).

The efficacy and safety ratio of topical corticosteroids may beenhanced by applying corticosteroid preparations intermittently two to threedays per week. Furthermore, the addition of salicylic acid may increase thebioavailability of topical corticosteroids considerably, enhancing efficacy.Plastic occlusion (e.g., a shower cap) may be helpful in enhancing theefficacy of corticosteroids. However, penetration may be enhanced consider-ably. Zinc pyrithione spray has been used in combination with a topicalcorticosteroid. In a double-blind study the added value of zinc pyrithionecould not be shown (32). Combination treatments with vitamin D3 analog,the topical retinoid tazarotene (33), and ultraviolet B (UVB) phototherapyare 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 treat-ments of psoriasis. Calcipotriol lotion has become a mainstay in the topicaltreatment of scalp psoriasis. More recently, tacalcitol has become availablein several countries.

In a double-blind comparative study during four weeks, calcipotriollotion proved to be effective, though less effective as compared to beta-methasone lotion (34). In 73% to 75% of the patients treated withbetamethasone, a marked improvement or clearing was observed and in57% to 58% of the calcipotriol-treated patients such an improvement wasseen. The majority of the patients were treated for another six weeks withcalcipotriol lotion in an open-label phase, which resulted in a markedimprovement in 82.6% of the patients. In this respect, it should be noted thatoptimal efficacy with calcipotriol lotion requires eight weeks, whereas apotent topical corticosteroid results in maximum efficacy already aftertwo to three weeks. In another comparative study (open-label) during sixweeks both treatments were equally effective (35).

The combined use of calcipotriol ointment (80–100 g/wk) and calcipo-triol lotion (30–50 mL/wk) proved to be safe, without affecting the indicesof calcium metabolism or bone turnover (36). In 202 patients, the long-termefficacy 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 wasobserved in 91 out of 276 events and no significant changes of systemiccalcium metabolism have been observed (37). In a multicenter prospectiveobservational cohort consisting of 3396 patients treated with calcipotriollotion twice daily over an eight-week period, the following observationswere made (38). In the total cohort, the scalp severity index reduced from18.4 to 5.6. In 80%, the improvement was rated as good to very good. Inthose patients who were treated only with calcipotriol lotion without addi-tional treatments, the scalp severity index decreased from 16.0 to 4.9 in eightweeks’ treatment.

More recently, tacalcitol in an emulsion has become available in var-ious countries. Once-daily tacalcitol emulsion proved to be effective and safein a double-blind, placebo-controlled study. After eight weeks’ treatment,the median sum score had decreased by 53% in the tacalcitol group with80% of the patients showing marked improvement to clearing (39). Localadverse reactions were transient and uncommon and systemic calcium meta-bolism was not affected.

Topical vitamin D3 treatment can be combined with topical cortico-steroids. An elegant, effective and safe strategy is once-daily applicationsof a topical corticosteroid during weekend days and once or twice daily ofa vitamin D3 analog during weekdays (40).

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PHOTOTHERAPY

Phototherapy, although effective in plaque psoriasis, has limited applica-tions in scalp psoriasis, as the hair prevents adequate UV exposition ofthe skin surface.

The UVB/fiber optic comb has been shown in a pilot study of 14patients to improve the treated sides well above the untreated sides (41).The 308 nm excimer laser also has been investigated with respect to efficacyin the treatment of scalp psoriasis. In a study of 13 patients, excimer laser-treated sides improved well above untreated sides (42).

A challenging development is photodynamic therapy (43). Applicationof aminolevulinic acid results in intracellular accumulation of protopor-phyrin IX, which can be activated by visible light to produce reactive oxygenspecies and free radicals. This process has an antipsoriatic potential. Visiblelight penetrates better through keratin structures as compared to ultra-violet light and may well improve phototherapy of scalp psoriasis.

SYSTEMIC TREATMENTS

In general, scalp psoriasis can be managed by a topical treatment. In casetopical treatments are not effective and phototherapy does not provide anadequate solution, a systemic treatment may be indicated. Cyclosporin isa very effective antipsoriatic treatment, which can be used up to one ortwo years for reason of cumulative toxicity. Methotrexate, fumarates, andacitretin 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-blindcontrolled studies against active comparators are available. Guidelines onthe treatment of scalp psoriasis are largely based on the open studies asdescribed above and on expert opinions. In this section, we will integratethe available knowledge into treatment recommendations for scalp psoriasis.

The first phase is active descaling. In the case of mild scaling, regularshampooing is an option. Application of salicylic acid 5% to 10% or urea upto 40% in a wash-off ointment may enhance descaling. An automatic sham-pooing machine may help at outpatient centers for efficient descaling.

The second phase is active clearing treatment. The first-line approachis a vitamin D3 lotion or emulsion once a day and an ultrapotent topicalcorticosteroid in a vehicle that is well accepted by the patient for scalp treat-ment. If this approach is not effective after eight weeks or not appreciatedfor reason of intolerance, an ultrapotent topical corticosteroid may becombined 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 alternativefor the second phase is dithranol and tar-based treatments at an outpatientcenter. If all these approaches are not effective, cultures for Malassezia shouldbe taken and a systemic antifungal treatment can be started. In case all thesetreatments are not effective, a systemic antipsoriatic treatment should be con-sidered with methotrexate, fumarates, cyclosporine, or acitretin.

The third phase of treatment is stabilization with a vitamin D3 analogon weekdays (once or twice daily) and an ultrapotent topical corticosteroidonce 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 vitaminD3 analog is the preferred treatment, either once or twice daily. A tar sham-poo may further support this phase.

CONCLUSION

Scalp psoriasis is a frequently occurring condition, which may impair qual-ity of life considerably. A spectrum of treatments for this condition isavailable, although few double-blind comparative studies support the efficacyof 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 oftopical drug treatment in psoriasis. Dermatology 1998; 197:31–36.

2. Poyner TF, Fell PJ. Frequency of patients with plaque psoriasis who had not con-sulted 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 pre-sentations and therapeutic management Dermatology 1998; 197:326–334.

4. Schoorl WJ, Baar HJ, Kerkhof PCM van de. The hair root pattern in psoriasis ofthe scalp. Acta Derm Venereol 1992; 72:141–142.

5. Plozzer C, Coletti C, Kokelj F, Trevisan G. Scanning electron microscopy studyof 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 Dermatol1992; 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 inthe management of desquamative disease of the scalp. Mycopathologica 2002;153:71–75.

12. Olansky S. Whole coal tar shampoo: a therapeutic hair repair system. Cutis1980; 25:99–104.

13. Lowe NJ, Breeding JH, Wortzmann MS. New coal tar extract and coal tar sham-poos. Arch Dermatol 1982; 118:487–489.

14. Jongeneelen FJ, Bos RP, Azion RBM. Biological monitoring of polycyclicaromatic hydrocarbons: metabolites in urine. Scand J Work Environ Health1986; 12:137–143.

15. Snijder FH, Beuhler EV, Winek CL. Safety evaluation of zinc-2-pyridine-thiol 1-ozide in a shampoo formulation. Toxicol Appl Pharmacol 1965; 7:425–437.

16. Orentreich N. A clinical evaluation of two shampoos in the treatment of psori-asis. J Soc Cosmet Chem 1972; 23:189–194.

17. Jarrat M. Breneman D, Gottlieb AB, et al. Clobetasol propionate shampoo0.05%: 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 psoriasiswith auton shampooing and debridement. J Am Acad Dermatol 1999; 41:638–651.

19. Shemer A, Nathansohn N, Kaplan B, et al. Treatment of scalp seborrhoeicdermatitis and psoriasis with a ointment of 40% urea and 1% bifonazole. Int JDermatol 2000; 39:532–534.

20. Prins M, Swinkels OQJ, Bertholet B, Valk PGM van der. Dithranol short con-tact 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 oilbase (bio-wash-oil) for the treatment of psoriasis of the scalp. Skin PharmacolPhysiol 2004; 17:91–97.

22. Farr PM, Krause LB, Marks JM, et al. Response of scalp psoriasis to oralketoconazole. 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 antimicro-bial agents. Semin Dermatol 1985; 4:307–311.

25. Jury CS, Hugh McL, Shankland GS, et al. A randomized, placebo-controlledtrial 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 offerscomparable covered compared with traditional vehicles. J Am Acad Dermatol2000; 42:1017–1020.

27. Andreassi L, Giannetti A, Milani, et al. Efficacy of betamethasone valeratemousse in comparison with standard therapies on scalp psoriasis: an open,multicentre, randomized, controlled, cross-over study on 241 patients. Br JDermatol 2003; 148:134–138.

28. Feldman SR, Ravis SM, Fleischer AB Jr, et al. Betamethasone valerate infoam 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 qual-ity of life: a randomized single-blind study of clobetasol propionate foam 0.05%comparison with a combined program of clobetasol cream 0.05% and solution0.05% 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 normalskin, 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 spraydoes not enhance the efficacy of clobetasol propionate 0.05% foam in the treat-ment of psoriasis. J Am Acad Dermatol 2003; 49:79–82.

33. Gollnick HP, Finzi AF, Marks R, et al. Optimizing the use of tazarotene inclinical practice: consensus statement from the European advisory panel fortazarotene (ZoracTM). Dermatology 1999; 199:40–46.

34. Klaber MR, Hutchinson PE, Pedvisleftick, et al. Comparative effects of calcipo-triol 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 calcipotriol50 micrograms/g/ml solution vs. Betamethasone valerate 1% lotion. Int J ClinPharmacol Res 2000; 20:65–68.

36. Kerkhof PCM van de, Green C, Hamberg KJ, et al. Safety and efficacy of com-bined high-dose treatment with calcipotriol ointment and solution in patientswith psoriasis. Dermatology 2002; 204:214–221.

37. Barnes L, Altmeyer P, Forstrom L, Stenstrom MH. Long-term treatment ofpsoriasis 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 thetreatment of scalp psoriasis: evaluation of efficacy, safety and acceptance in3,396 patients. Dermatology 2001; 203:153–156.

39. Ruzicka T, Trompke C. Treatment of scalp psoriasis. An effective and safe tacal-citol emulsion. Hautarzt 2004; 55:165–170.

40. Lebwohl M, Yoles A, Lombardi K, Lou W. Calcipotriene ointment and halobe-tasol ointment in the long-term of psoriasis: effects on the duration of improve-ment. J Am Acad Dermatol 1998; 39:447–450.

41. Taneja A, Racette A, Gourgouliatos Z, Taylor CR. Broad-band UVB fiber-opticcomb 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 pso-riasis. 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.

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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 characterizedby erythematous well-circumscribed plaques with thick, silvery scale and apredilection for the extensor surfaces of the extremities, lower back, andumbilical area (1–3). Yet the morphology and presentation of cutaneouslesions can vary considerably and can be divided into subtypes, includingchronic plaque psoriasis, guttate psoriasis, erythrodermic psoriasis, general-ized pustular psoriasis, pustular palmar and plantar psoriasis, and inversepsoriasis (2). Moreover, these subtypes are not mutually exclusive withone type evolving into another over time. Inverse psoriasis is also knownas flexural or intertriginous psoriasis because of its selective involvementof skin folds such as the axillae, groin, inframammary folds, navel, andgluteal crease as well as the palms, soles, and nails. Because of its particularlocalization, inverse psoriasis has clinical impact out of proportion to thetotal body surface area affected and poses unique therapeutic challenges.

EPIDEMIOLOGY

In the United States, psoriasis affects approximately 2.2% to 2.5% of thegeneral population. Inverse psoriasis accounts for roughly 2% to 6% of thesecases (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 andsecond 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 withthe disease. Incidence of monozygotic twins exhibit a 65% rate of concor-dance opposed to 30% for dizygotic twins. Certain major histocompabilitycomplex types [human leukocyte antigen (HLA)-Cw6, HLA-B57, HLA-DR7] are associated with a higher incidence of psoriasis with some corre-sponding to specific clinical patterns: pustular type (HLA-B27), guttate type(HLA-B13 and HLA-B17), and palmoplantar pustulosis (HLA-B8, HLA-Bw35, HLA-Cw7, HLA-DR3) (7–9). No HLA type has been specifically asso-ciated with inverse psoriasis.

CLINICAL PRESENTATION

Inverse psoriasis often appears as glossy, sharply demarcated erythematousplaques with little to no scale (Fig. 1). Often lesions are moist and can be fis-sured. Nail pits and onycholysis at the proximal nail (oil spots) are commonin inverse psoriasis. Characteristic histopathology is identical for psoriasisvulgaris and inverse psoriasis, and includes regular acanthosis, club-shapeddermal papillae, focally absent granular layer, focal parakeratosis, elongatedand tortuous capillaries, and collections of neutrophils in the epidermis (10).

The effect of psoriasis on a patient is multidimensional, includingthe physical, social, and psychological health of the person. Overall clinicalseverity of psoriasis, as assessed by the psoriasis area and severity index(PASI), and duration of psoriasis may not always be related directly tohealth-related quality-of-life measures (11). Patients with psoriasis often as-cribe 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 stig-matization, social isolation, and discrimination. Eighty-four percent of patientswith psoriasis expressed difficulties in establishing social contacts and relation-ships and stated that this was the worst aspect of their psoriasis. Psoriasispatients also had reduction in physical functioning and mental functioningcomparable to that seen in cancer, arthritis, hypertension, heart disease, dia-betes, and depression (13). While approximately 40% of patients report thatpsoriasis negatively affected their sexual activity and enjoyment, no studyhas been performed to specifically address the impact of inverse psoriasis(14). For inverse psoriasis, the extent of skin involvement may not be a reliableguide to disability. By the same token, the presence of psoriasis on the face maycontribute to depression. As a consequence, patients should be assessed using aholistic approach that considers physical and psychological measures (15).

ETIOLOGY

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

DIFFERENTIAL DIAGNOSIS

Inverse psoriasis can be a difficult diagnosis in the intertriginous areas becauselesions often lack the characteristic silvery scale seen in plaque-type psoriasis

Table 1 Drugs That Exacerbate Psoriasis

AntimalarialsLithiumb-BlockersNSAIDsTrazadoneInterferon-alphaTerbenifineACE inhibitorsGemfibrizolTetracyclinePenicillin

Abbreviations: NSAIDs, nonsteroidal anti-inflammatory

drugs; ACE, angiotension converting enzyme.

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(Table 2). The lesions are generally deep red, smooth, even glistening with awell-demarcated edge. Friction, heat, and moisture in these areas are thoughtto induce psoriasis as a Koebner phenomenon. Pustules or papules extendingbeyond the border suggest secondary Candida infection. Intertrigo, erythr-asma, and seborrheic dermatitis may be indistinguishable in some cases.

MANAGEMENT

Topical Corticosteroids

Corticosteroids persist as the mainstay for topical treatment. Topical corti-costeroids 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 classVII steroids. They are believed to reduce inflammation by reducing inflam-matory cells and cytokines, including interleukin (IL)-1, IL-2, interferon(IFN)-gamma, tumor necrosis factor (TNF)-alpha, and granulocyte macro-phage-colony stimulating factor (GM-CSF) (19–21).

Topical corticosteroids have side effects that limit their long-termuse in the treatment of psoriasis. Common side effects can occur locallyat the site of prolonged topical corticosteroid application resulting in skinatrophy, irreversible striae, and telangiectasias. These findings are mostoften seen when high-potency corticosteroids are used on the face and inter-triginous areas for prolonged periods of time. Because of the thinness ofintertriginous psoriasis lesions and possible occlusion in these areas, theyare even more sensitive to topical corticosteroids. An open-label study of

Table 2 Differential Diagnosis of Inverse Psoriasis

IntertrigoSeborrheic dermatitisErythrasmaCutaneous candidiasisContact dermatitisDarier’s diseaseBowen’s diseaseExtramammary Paget’s diseaseMycosis fungoidesAcrodermatitis enteropathicaRadiation dermatitisGlucagonoma syndromeEpidermolysis bullosaHistiocytosis XAcanthosis nigricansAxillary granular parakeratosisConfluent and reticulated papillomatosis

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20 patients applying fluticasone proprionate 0.005% (class III) twice a dayfor two weeks followed by twice-weekly application for 10 weeks demon-strated greater than 75% clearance in 95% of facial and intertriginous lesionscompared to 35% of nonfacial, nonintertriginous lesions (22). There was noevidence of skin atrophy after 10 weeks. Long-term studies have not beendone for inverse psoriasis. Tachyphylaxis is also a common phenomenonwith prolonged use (23). Pulse therapy has been shown to prevent tachyphyl-axis in psoriasis vulgaris but has not been studied for inverse psoriasis.Rarely, the hypothalamic–pituitary–adrenal axis can be suppressed in casesof 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 prolif-eration and causing terminal differentiation. It also inhibits production ofIL-2, IL-6, IFN-gamma, and GM-CSF by T cells. Because it is not asso-ciated with skin atrophy, calcipotriene has potential advantages when usedin intertriginous areas (24).

For psoriasis vulgaris, calcipotriene has been shown to be as effective asa class II corticosteroid. In a randomized, double-blind study with 114 sub-jects, mean scores of scaling and plaque elevation in calcipotriene-treatedsubjects were significantly lower by week 2 than in the fluocinonide-treated subjects and continued to be significantly lower through week 6 (25).Calcipotriene can also be used in conjunction with topical corticosteroids toextend the duration of remissions while minimizing the effects of chronicsteroid use. In a randomized, double-blind study of 44 patients, 76% ofpatients using a combination of calcipotriene twice a day on weekdaysand a class I corticosteroid twice a day on weekends were able to maintainremission at six months of treatment compared to 40% using a class Icorticosteroid steroid twice a day on weekends and vehicle twice a day onweekdays (26). There have been no randomized control studies studyingthe efficacy of calcipotriene for inverse psoriasis. In an open, uncontrolledtrial, 10 or 12 patients with inverse psoriasis showed clinically significantimprovement by six weeks of treatment (27).

However, calcipotriene can cause irritant contact dermatitis, particu-larly on the face and in intertriginous sites. Dilution of calcipotriene withpetrolatum or the addition of a topical steroid may prevent the irritant con-tact dermatitis. Rarely, hypercalcemia can occur but is always associatedwith excess use over large surface area (28).

Topical Retinoids

Tazarotene has multiple effects on keratinocyte differentiation and prolif-eration, and inflammation processes that contribute to psoriasis. There are

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two classes of nuclear retinoid receptors that have been identified: the reti-noic acid receptor (RAR) and retinoid X receptor (RXR) (29). Tazaroteneselectively binds to RAR and RXR. The function of these RARs and RXRsis not well understood in skin. In animal models, topical tazarotene blocksinduction of ornithine decarboxylase activity, which is associated with cellproliferation and expression. In vitro skin models and cell cultures alsodemonstrate that tazarotene suppresses epidermal hyperproliferation.

A randomized, double-blind, placebo-controlled study involving 324plaque psoriasis patients using tazarotene gel 0.05% or 0.1% applied once aday for three months demonstrated clearance in 63% and 50% of cases,respectively, compared to 30% of the vehicle (30). There have been no random-ized 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 localirritation of tazarotene can be seen, it is not commonly used for intertri-ginous areas but may be effective on the face. Common side effects fromlocal application include irritation, pruritus, erythema, stinging, and des-quamation (31). Short contact with tazarotene minimizes the local irritationon the skin, which is especially applicable to intertriginous areas.

Topical Immunomodulators

Immunosuppression in the treatment of psoriasis can be achieved by inhi-bition of cytokine production, which is essential in the development ofpsoriasis (32). Tacrolimus, a lipophilic agent produced by Streptomycestsukubaensis, exhibits similar in vivo and in vitro biological characteristicsto cyclosporin A. Furthermore, it is more potent than cyclosporin A. Inhibi-tion of calcineurin blocks the activity of nuclear factor (NF) of activatedT cells, which in turn suppresses IL-2 production as well as T-cell response.Both systemically and topically, tacrolimus inhibits T-cell infiltration andskin reddening, and levels of IL-2 receptors decrease during treatment.There is also inhibition of keratinocyte proliferation induced by epidermalgrowth factor (EGF), transforming growth factor (TGF)-alpha, or IL-6through influence on the keratinocyte cell cycle at G0/1 phases and dose-dependent inhibition of IL-8, which is elevated in psoriatic plaques.

Tacrolimus has a lower molecular weight and is therefore a much betterskin penetrant than cyclosporine, and can thus be used topically. Adverseevents include burning, heat sensation, itching, and erythema. In contrastto topically applied corticosteroids, there is no influence on collagen bio-synthesis and therefore no skin atrophy. As psoriatic plaques on the trunkand the extremities can be thick, topical tacrolimus formulations are onlyminimally effective in treating these lesions (33). A randomized, double-blind, vehicle-controlled study of inverse psoriasis with 167 patients using0.1% 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 skinatrophy, telangiectasias, or striae during the eight-week study.

Pimecrolimus also belongs to the macrolide group of immunomodula-tors. Compared to tacrolimus, it is 20 times more lipophilic and has a lowerpermeation potential through the skin. A randomized, double-blind, vehicle-controlled trial involving 57 patients studying inverse psoriasis showed 82%of the pimecrolimus group and 41% of the vehicle were 90% clear by eightweeks (35).

However, topical tacrolimus and pimecrolimus should be used withcaution due to the rare but potentially severe adverse events (36–38). Useof systemic tacrolimus has been shown to be associated with both lymphoidand nonlymphoid malignancies in the post-transplant setting (39,40). Topicaltacrolimus has been implicated in squamous cell carcinoma of the penis (41).Oral pimecrolimus has been associated with development of lymphoma inmonkey models (42). In mouse models, topical tacrolimus has been shownto accelerate the development of squamous cell carcinomas (43). In March2005, the Food and Drug Administration (FDA) issued a public healthadvisory for topical pimecrolimus reporting 10 cases of cancer-relatedadverse events including lymphoma, basal cell carcinoma, and squamous cellcarcinoma (42). At the same time, an advisory was also issued for topicaltacrolimus 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 riskof topical formulations in humans. Therefore, prolonged use over large areasof the body should be used with caution.

Topical Anthralin and Tar

Anthralin and tar can be moderately irritating, and can stain skin and cloth-ing. They are generally not well tolerated in intertriginous areas and are notwidely used in the treatment of inverse psoriasis having been replaced withbetter-tolerated topical agents (20).

Light Therapy

Ultraviolet (UV) light causes DNA damage to cutaneous tissue and therebycan inhibit cell proliferation (2). Specifically, it appears to target cutaneousimmune cells and reduce the production of inflammatory cytokines impor-tant in psoriasis pathogenesis. It is widely used in the treatment of psoriasisvulgaris (20).

Broadband ultraviolet B (BB-UVB) and narrowband UVB (NB-UVB)can be used to treat plaque psoriasis. NB-UVB maximizes psoriasis clear-ance compared with its erythrogenic potential but has the disadvantageof 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 remainsunknown. Its overall safety is generally believed to be better than psoralenplus ultraviolet A (UVA) (PUVA) (44). Genitalia are often shielded due tothe possible increased risk of carcinogenesis. Typical UVB light units aredesigned to treat large surface areas and generally do not reach intertriginousareas because of body habitus and positioning of the patient. Smaller hand-held units are promising alternatives to allow better targeting of occludedareas such as the axilla and inframammary folds. Specific studies addressingthe efficacy and safety of BB-UVB and NB-UVB in inverse psoriasis have notbeen done.

PUVA is commonly employed for widespread and resistant psoriasis.Psoralen (8-methoxypsoralen) causes the formation of pyrimidine dimers thatlead to cross-linkage of DNA strands and genomic instability and apoptosis.In a randomized trial involving 100 patients comparing NB-UVB with PUVAgiven twice weekly, 88% of patients were cleared with PUVA compared with63% with NB-UVB (45). Also PUVA-treated patients required significantlyfewer treatments and had almost three times the remission rate at six monthsafter treatment. The potential side effects of PUVA include an increasedincidence of squamous cell carcinoma, basal cell carcinoma, and possiblymalignant melanoma (46,47). The genitalia are usually shielded during UVAexposure because of the risk of developing carcinoma in that region. PUVA isnot commonly used for inverse psoriasis because of the tendency for intertri-ginous skin to burn, the risk of carcinogenesis, and the technical difficulty ofdelivering UV light to the intertriginous areas. No studies using PUVAspecifically for inverse psoriasis have been performed.

Targeted UV light therapy, which allows for sparing of uninvolvedskin, has recently been considered. In a preliminary case report, a singleinverse psoriasis patient using the excimer laser (308 nm) obtained 90%improvement of lesions after three weeks of treatment (48). Furtherstudies are necessary to better demonstrate the efficacy and safety of thismodality. The disadvantages of this approach include cost, limited availabil-ity, risk of burning, and unknown risk of carcinogenesis.

Methotrexate

Methotrexate is a synthetic analog of folic acid and a competitive inhibitor ofthe enzyme dihydrofolate reductase (49). The inhibition of thymidylatesynthesis appears to be the most important effect exerted by methotrexate,which results in inhibition of DNA synthesis and arrest of cell divisionin the S-phase. T and B cells are preferentially targeted and thereby inhibitthe elaboration of inflammatory cytokines. Methotrexate also suppressesepidermal cell division in psoriasis.

Methotrexate is indicated in patients with moderate to severe psoriasisand 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 than10% body surface involvement, pustular psoriasis, erythrodermic psoriasis,psoriatic arthritis, and more localized, recalcitrant psoriasis. Because of itsdistribution, inverse psoriasis can be much more debilitating than the totalbody surface area might suggest, in which case intervention with metho-trexate can be considered.

A randomized, single-blind, controlled trial comparing cyclosporineand methotrexate involving 88 patients with psoriasis vulgaris showed no sig-nificant difference in effectiveness or side effects between the two drugs. Sixtypercent in the methotrexate group compared to 71% in the cyclosporine groupachieved at least 75% clinical improvement over the 16 weeks of the study(52). Also, the time needed to reach an almost complete remission and apartial remission did not differ significantly between the groups. No specificstudies 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 asso-ciated with methotrexate include nausea and vomiting. Ulcerative stomatitis,pulmonary fibrosis, bone marrow suppression, and induction of lymphomahave also been described. The most serious long-term adverse effect associatedwith methotrexate is the induction of hepatotoxicity. The liver biopsy is themost definitive test for ascertaining whether fibrotic changes in the liver arepresent or not during methotrexate therapy.

Cyclosporine

Cyclosporine is an immunosuppressive agent derived from the fungus Tolypo-cladium inflatum gams. Cyclosporine is used to prevent allograft rejection andis FDA approved for the treatment of psoriasis. Cyclosporine induces immu-nosuppression by inhibiting the first phase of T-cell activation. Cyclosporinebinds to cyclophilins, which then complexes to inhibit the enzyme, calcineurin,a calcium-activated phosphatase. Calcineurin inhibition, in turn, results in theinhibition 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 psoriasisin patients who are not immunocompromised (55). In addition, cyclosporineis effective in treating various forms of psoriasis, which have been recalci-trant to other modalities. When used as monotherapy, cyclosporine caninduce rapid clearance of plaques in a large majority of patients with attain-ment of 60% and 80% reduction at 8 and 12 weeks, respectively. Its use forinverse 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 thedosage 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 sideeffects include hypertrichosis and gingival hypertrophy. Cyclosporine hasbeen associated with the induction of various lymphoproliferative disordersin transplant patients. In contrast, an increase in incidence of non-mela-noma skin cancer has not been observed in psoriatic patients treated withcyclosporine, presumably because of much shorter courses of therapy withlower doses that have been utilized.

Biologic Agents

Psoriasis is thought to be induced and maintained by a complex pattern ofoverexpressed Th1 cytokines such as IL-2, -6, -8 or IFN-gamma and TNF-alpha (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 mole-cule (ICAM)-1 and vascular cell adhesion molecule type 1 on endothelialcells and keratinocytes, which are both involved in trafficking lymphocytesto inflammatory lesions. TNF-alpha also stimulates migration of Langer-hans’ cells to lymph nodes and enhances capability to present antigens toprimed T cells. Several agents targeting specific steps in the immunopatho-genesis of psoriasis are now available in clinical practice (57).

Etanercept is a recombinant soluble fusion protein consisting of twoidentical chains of the TNF-alpha receptor fused with the Fc portionof human immunoglobulin G1 (IgG1). It is functioning as a competitive inhi-bitor for binding of TNF-alpha at its receptor. Inflammatory cytokines suchas TNF have been implicated in the pathogenesis of psoriasis. In a random-ized, double-blind study, 672 plaque psoriasis patients either receivedplacebo or received etanercept subcutaneously at 25 mg once weekly,25 mg twice weekly, or 50 mg twice weekly. At 12 weeks, 14%, 34%, and49% of patients, respectively, demonstrated a 75% reduction in severitycompared to 4% of patients receiving placebo (58). In another randomized,double-blind, placebo-controlled study, of 148 plaque psoriasis patientsreceiving placebo or etanercept 25 mg, subcutaneously twice weekly, 30%of the etanercept-treated patients demonstrated 75% severity reduction ascompared to 1% of the patients in the placebo group at 12 weeks (59).

Infliximab is a human–mouse monoclonal chimeric antibody against theTNF-alpha molecules. Adalimumab is a humanized monoclonal antibodyagainst the TNF-alpha molecules. Both bind to soluble and membrane-boundTNF leading to cell lysis. In a randomized, double-blind study, 33 patientswith plaque psoriasis received intravenous placebo, infliximab 5 mg/kg, orinfliximab 10 mg/kg at weeks 0, 2, and 6. At 10 weeks, 82% of patientsin 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 function-associated antigen (LFA)-3 with the Fc portion of human IgG and bindsto cluster of differentiation 2 (CD2) on T cells to block costimulation by anti-gen 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, withfollow-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 placebogroup. Twelve weeks after treatment, 33%, 31%, and 19% of the patients in thethree alefacept groups, respectively, had a 75% improvement in the PASIscores compared to 11% of the patients in the placebo group at 12 weeks.

Efalizumab is a humanized monoclonal anti-CD11a antibody that bindsto the CD11a portion of human LFA-1 and blocks the LFA-1/intercellularadhesion molecule interaction, thus blocking costimulation and T-cell migra-tion. In a randomized, placebo-controlled, double-blind study, 597 subjectswith plaque psoriasis received subcutaneous efalizumab 1 mg/kg, efalizumab2 mg/kg, or placebo weekly. At week 12, 22% of patients who received efalizu-mab 1 mg/kg and 28% of patients who received efalizumab 2 mg demonstrated75% response as compared with 5% of patients who received placebo (62).

At present, there are no published data specifically addressing theeffectiveness of the various biologics for the treatment of inverse psoriasis.

CONCLUSION

Inverse psoriasis is a common, chronically relapsing, potentially debilitatingdisease that belies proportion to the total body surface area affected. Carefulattention needs to be paid to the patient in assessing the true impact of thedisease as well as designing an individualized treatment regimen thatthoughtfully addresses the challenges of treating these areas of the body.

REFERENCES

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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: BlackwellScience, 2003.

4. Koo J. Population-based epidemiologic study of psoriasis with emphasis onquality 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 sub-stantial burden even when not extensive, and is associated with widespread treat-ment dissatisfaction. J Investig Dermatol Symp Proc 2004; 9(2):136–139.

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9. Zachariae H, Overgaard Petersen H, Kissmeyer Nielsen F, et al. HLA antigensin 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 arenecessary 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 anddisability in patients with psoriasis: consensus and variation in the contributionof illness perceptions, coping and alexithymia. Br J Clin Psychol 2002; 41(Pt2):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 severelyaffected 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 treatmentoptions. Drugs Aging 2002; 19(11):847–863.

16. Pauluzzi P, Boccucci N. Inverse psoriasis induced by terbinafine. Acta DermVenereol 1999; 79(5):389.

17. Gilleaudeau P, Vallat VP, Carter DM, et al. Angiotensin-converting enzyme inhi-bitors 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 intertriginouspsoriasis: 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 photo-therapy. J Am Acad Dermatol 2001; 45(4):487–498; Quiz 499–502.

21. Lebwohl M, Ting PT, Koo JY. Psoriasis treatment: traditional therapy. AnnRheum Dis 2005; 64(suppl 2):ii83–ii86.

22. Lebwohl MG, Tan MH, Meador SL, et al. Limited application of fluticasonepropionate ointment, 0.005% in patients with psoriasis of the face and intertrigi-nous areas. J Am Acad Dermatol 2001; 44(1):77–82.

23. du Vivier A, Stoughton RB. Tachyphylaxis to the action of topically applied cor-ticosteroids. Arch Dermatol 1975; 111(5):581–583.

24. Duweb GA, Eldebani S, Alhaddar J. Calcipotriol cream in the treatment of flex-ural 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 halobeta-sol ointment in the long-term treatment of psoriasis: effects on the durationof improvement. J Am Acad Dermatol 1998; 39(3):447–450.

27. Kienbaum S, Lehmann P, Ruzicka T. Topical calcipotriol in the treatment ofintertriginous psoriasis. Br J Dermatol 1996; 135(4):647–650.

28. Russell S, Young MJ. Hypercalcaemia during treatment of psoriasis with calci-potriol. Br J Dermatol 1994; 130(6):795–796.

29. Duvic M, Nagpal S, Asano AT, et al. Molecular mechanisms of tazaroteneaction 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, fortopical therapy of psoriasis: vehicle-controlled study of safety, efficacy, andduration of therapeutic effect. J Am Acad Dermatol 1997; 37(1):85–92.

31. Yamauchi PS, Rizk D, Lowe NJ. Retinoid therapy for psoriasis. Dermatol Clin2004; 22(4):467–476.

32. Reynolds NJ, Al-Daraji WI. Calcineurin inhibitors and sirolimus: mechanismsof 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 inchronic plaque psoriasis. A pilot study. Arch Dermatol 1998; 134(9):1101–1102.

34. Lebwohl M, Freeman AK, Chapman MS, et al. Tacrolimus ointment is effectivefor 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 treatmentof intertriginous psoriasis: a double-blind, randomized study. J Am AcadDermatol 2004; 51(5):731–738.

36. Gupta AK, Adamiak A, Chow M. Tacrolimus: a review of its use for the man-agement of dermatoses. J Eur Acad Dermatol Venereol 2002; 16(2):100–114.

37. Gupta AK, Chow M. Pimecrolimus: a review. J Eur Acad Dermatol Venereol2003; 17(5):493–503.

38. Ashcroft DM, Dimmock P, Garside R, et al. Efficacy and tolerability of topicalpimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis 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 novononlymphoid malignancies after liver transplantation under tacrolimus using sur-veillance epidemiologic end result data. Transplantation 1998; 66(9):1193–1200.

41. Langeland T, Engh V. Topical use of tacrolimus and squamous cell carcinomaon the penis. Br J Dermatol 2005; 152(1):183–185.

42. US Food and Drug Administration. FDA Public Health Advisory: Elidel (pime-crolimus) 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 immunosuppressanttacrolimus 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 cancerrisk in psoriasis patients treated with broadband or narrowband UVB photo-therapy: a first retrospective study. Acta Derm Venereol 2004; 84(5):370–374.

45. Gordon PM, Diffey BL, Matthews JN, et al. A randomized comparison ofnarrow-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 (psor-alen) 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 forpsoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). ThePUVA follow-up study. N Engl J Med 1997; 336(15):1041–1045.

48. Mafong EA, Friedman PM, Kauvar AN, et al. Treatment of inverse psoriasiswith the 308 nm excimer laser. Dermatol Surg 2002; 28(6):530–532.

49. Cronstein BN. The mechanism of action of methotrexate. Rheum Dis ClinNorth 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 tosevere chronic plaque psoriasis: an assessment of the benefits and risks. Br J Der-matol 2005; 152(4):597–615.

52. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporinein 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 AcadDermatol 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 cyclos-porin A (CyA; Sandimmun) for long-term treatment of chronic severe plaquepsoriasis. Br J Dermatol 1994; 130(3):366–375.

56. Krueger JG. The immunologic basis for the treatment of psoriasis with newbiologic 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 inpatients with psoriasis. N Engl J Med 2003; 349(21):2014–2022.

59. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanerceptas 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 infliximabmonotherapy 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 target-ing 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.

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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 disorderaffecting millions of people worldwide. An epidemiologic study of psoriasisconducted 10 years ago reported that approximately seven million people inthe United States, or roughly 2.6% of the population, were affected (1).While the number of people with psoriasis in the United States has un-doubtedly increased, the percentage affected likely remains the same. Noteveryone who develops psoriasis will have nail changes. Indeed, no morethan half of those patients who have cutaneous psoriasis will have asso-ciated nail psoriasis (2). There is a much tighter association of nail diseasein patients who have psoriatic arthritis. Nearly 90% of patients who de-velop psoriatic arthritis will have nail changes as the first external indicatorof joint disease. Heeding the early visual clues can prevent the develop-ment of severe, debilitating permanent joint destruction (3). There arenumerous types of psoriatic nail changes, some of which are more closelyassociated with arthropathy than others. Nail psoriasis without joint orskin involvement can occur and presents a diagnostic challenge. Due tothe morphologic similarities, isolated nail psoriasis is most frequently mis-taken for onychomycosis (4,5).

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The psychosocial impact and functional impairment of severe multi-nail psoriasis cannot be understated (6). It is often a source of embarrassmentfor psoriasis patients who try to disguise their fingernails under coats of nailpolish or hide their toenails under the safety of socks (7). This is especiallytrue in patients who have concomitant onychomycosis due to psoriasis-induced nail injury (8). The various manifestations of nail psoriasis and itsassociations and mimics, as well as objective means of measuring nail altera-tions will be discussed in this chapter. Furthermore, therapeutic options forthis challenging disease will also be explored.

MANIFESTATIONS OF NAIL PSORIASIS

Psoriatic nail changes have various manifestations depending on the loca-tion of the disease within the nail unit (Fig. 1) (9). The largest portion ofthe nail unit is the nail plate, which is derived from the nail matrix that iscarefully protected under the proximal nail fold. There are two portionsof nail matrix also known as the nail ‘‘growth center.’’

The distal matrix forms the ventral portion of the nail plate and theproximal 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 sur-rounded by the nail folds, which include the cuticle adjacent to the proximalnail 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: nailmatrix, nail bed, proximal nail fold, and hyponychium (Table 1) (2,10).

When the nail matrix is involved, then pitting and leukonychia com-monly occur (Fig. 2). Pitting is a phenomenon attributed to an abnormalityin the maturation and keratinization of the proximal nail matrix (11). Thehistopathology is the same as classic psoriasis but on a much smaller scale.The ‘‘pits’’ are actually produced by small foci of hyperproliferative para-keratotic cells. Just like in classic psoriasis, the overexuberant cell turnoverleads to a buildup of parakeratotic proximal matrix cells pressing against thedorsal nail plate (10). Zaias’ landmark study demonstrated that as the nailplate grows out, the poorly adherent parakeratotic cells desquamate fromthe surface of the nail plate, leaving an indentation as clinical evidenceof their former activity (10,12). The nail pits’ depth and shape depend uponthe extent and duration that the parakeratotic cells remain in place beforebecoming dislodged. This is a direct indicator of disease activity (2). Whilepitting may be seen in other disorders, the large size, irregular shape, andrandom distribution of the pits are the hallmark of fingernail psoriasis (10).

Interestingly, nail pitting is infrequently seen on toenails (13). One pos-sible mechanism to account for nail pitting in fingernails rather than toenailscan be attributed to the varying growth rates of finger versus toenails. Intoenails, the growth rate is much slower and therefore, the parakeratoticfocus and the nail plate may grow out toward the hyponychium together (2).This would account for the lack of pitting and the marked increase insubungual hyperkeratosis as the key manifestation of toenail psoriasis. Sub-ungual hyperkeratosis is analogous to thick plaque psoriasis on the skin.Like psoriasis elsewhere on the body, the hyponychial skin is subject tothe Koebner phenomenon. Therefore, severe hyponychial involvement lead-ing to subungual hyperkeratosis is more common in toenails because theyare subject to more trauma than fingernails (10). However, the exact causehas yet to be elucidated.

Beau’s lines are horizontal indentations in the nail plate due totemporary arrest of matrix growth during a period of inflammation (10).Onychomadesis is due to severe disease leading to separation of the nailplate from the proximal nail fold (10). Trachyonychia is due to proximalmatrix disease that manifests as roughened or ‘‘sandpaper’’ nails (14).Crumbling is a more severe form of trachyonychia and pitting. The whitishchalky plaque overlying the bed occurs when the entire matrix is involvedfor such a long duration that parakeratotic cells outnumber normal cells.Thus, the psoriatic changes are so severe that there is no semblance of nor-mal 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,

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224 Nandedkar-Thomas and Scher

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and splinter hemorrhages are common (15,16). Oil spots, also known as‘‘salmon patches,’’ refer to a yellow-orange discoloration due to psoriasisof 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 thatcannot be dislodged. Onycholysis is a distinct phenomenon that results fromseparation of the nail bed from the plate (Fig. 4). The separation beginsdistally and progresses proximally toward the matrix. The plate appearswhitish rather than yellow because air becomes trapped underneath it. Itis usually surrounded by a reddish hue (10) and is distinguished from trueleukonychia by location. Leukonychia is usually seen on the proximal

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

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

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portion of the plate whereas onycholysis appears whitish distally. Splinterhemorrhages are due to trauma and are analogous to the Auspitz sign asso-ciated with cutaneous psoriasis (10). Proximal nail fold plaques are markedby classic cutaneous psoriasis with silvery scales over a red base (2). Thismay appear as chronic paronychia (11). Nail bed psoriasis in conjunctionwith hyponychial involvement leads to subungual hyperkeratosis andultimately crumbling of the nail plate (18). While there are numerous man-ifestations of nail psoriasis, very few are characteristic of psoriasis alone.The classic oil spot is the most diagnostic lesion, followed by random finger-nail pitting and subungual hyperkeratosis, respectively (12,17).

Extensive onychodystrophy with painful pustules and loss of the nailplate is usually due to a more severe and distinct type of nail psoriasis knownas acrodermatitis continua of Hallopeau (19). While most manifestations ofnail psoriasis do not lead to scarring, pustular psoriasis remains the excep-tion. Fortunately, this debilitating disorder is rare and often isolated to asingle digit (13). Unfortunately, despite several treatment options describedin the literature, successful eradication of the disorder prior to anonychiaand scarring remains poor (20).

ASSOCIATION WITH PSORIATIC ARTHRITIS

The most common signs of fingernail psoriasis are oil spots and pitting, withsubungual hyperkeratosis being the most common sign associated with psoriatic

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

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arthritis (21). While subungual hyperkeratosis is also the most common formof toenail psoriasis, it is less often associated with arthritis. Many studies haveestablished that patients with psoriatic distal interphalangeal (DIP) joint dis-ease 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 diseasecorrelates with the severity of DIP joint disease. Furthermore, even if arthriticchanges are not clinically evident, radiographic changes may be seen in theDIP joint of the same fingertip that has visible psoriatic nail disease (24).

DIP joint inflammation is not the only form of psoriatic arthritis. Molland Wright (25) originally classified psoriatic arthritis into five types based onclinical features. Type I refers to primarily DIP bone and joint erosion, whichradiographically presents as the classic ‘‘pencil in cup deformity.’’ It affectsapproximately 5% of all patients. The rarest is Type II, also known as arthritismutilans, which presents as a severe mutilating arthritis that can have ocularinvolvement. Type III manifests as a symmetric polyarthritis that affects thesmall joints of the hands and feet and the large joints of the legs, such asthe hips and knees. Type IV is the most common type, affecting approximately70% of those patients who present with psoriatic arthritis. Asymmetric oli-goarthritis is the hallmark of this type of psoriatic arthritis. It affects the samejoints 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 sacroiliacjoints. It usually presents with ankylosing spondylitis. Of all the psoriaticarthritis types, this one has the least association with nail disease.

The major distinguishing characteristic of psoriatic arthritis is thatunlike rheumatoid arthritis, it usually presents with asymmetric joint dis-ease. Furthermore, enthesopathy is unique to psoriatic arthritis; it is notseen in rheumatoid arthritis (26). Enthesopathy specifically refers to inflam-mation occurring at the attachment site of tendons and ligaments to bone.

Symptoms include joint pain, stiffness, and enthesitis with swelling at thetendon insertion points leading to ‘‘sausage digits’’ and joint deformation (27).It is classified as a seronegative, inflammatory arthropathy, meaning rheu-matoid factor is usually negative. Much like cutaneous psoriasis, it waxesand wanes unpredictably (28).

A recent study sought to determine if psoriatic nail alteration can beused as an independent predictor of psoriatic arthritis, regardless of thetype (29). The study looked specifically at patients with the various typesof psoriatic arthritis and found that 83% had clinically evident nail disease.As predicted, those patients with DIP involvement had more severe naildamage. Likewise, the severity of nail psoriasis directly correlated with theseverity of the enthesitis and skin psoriasis. The arthritis also tended to beprogressive and unremitting in those patients. However, dactylitis and axialdisease was not associated with nail disease. In fact, the lesser the nailinvolvement, the more likely the patient was to have the human leukocyte

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antigen (HLA)-B27 genetic haplotype, which is associated with axial ratherthan DIP joint disease (28).

ASSOCIATED GENETIC HAPLOTYPES

While the exact pathogenesis of nail psoriasis remains unclear, certain keyHLA subtypes are known to be associated with certain psoriatic types(Table 2) (28,30,31). However, genetic factors alone cannot account forthe occurrence of psoriasis. Environmental and immunologic factors mostcertainly play a role in its inception.

The simultaneous onset of skin and joint disease has been correlatedwith an increased frequency of disease eruptions (3). Although nail changescan be evident, the severity and extent of scalp involvement has been foundto be an even better marker for psoriatic arthritis (3). Apparently, worseningof scalp psoriasis is directly correlated with an increase in the number ofdeformed and swollen joints, sausage digits, and DIP alterations. Therefore,while nail disease may forecast joint disease on the concomitantly affected dig-it, 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 numerousand varied. A recent Asian study examining the epidemiology of childhoodpsoriasis in 419 patients found that boys tend to develop psoriasis at an earlierage than girls (32). Inflammatory nail changes were found in 31% of patients,with pitting being the most common finding, followed by ridging and discol-oration. Interestingly, 2.3% of patients presented with nail disease as the initial

Table 2 Key Genetic Haplotypes Associated with Psoriatic Arthritis andNail Disease

Major histocompatibility class I type

HLA B27 and HLA-Cw2 HLA-Cw6HLA-Cw6negative

HLA-B13 andHLA-B57 (B17)

Later onset; less nail disease;strong association withaxial disease. If earlyonset, then linked topediatricspondyloarthropathy, butstill has a poor associationwith nail disease.

Earlier onset;nail diseasebut lessdystrophythan if Cw6negative

Strongerassociationwithdystrophicnails than ifCw6 positive

If more severeskin disease,then joint ornail disease

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presentation of their psoriasis. Various studies from around the world havehad conflicting findings (33,34). This is likely based on varying genetic haplo-types and immunosusceptibility patterns to infectious disease that predisposeto the development of psoriasis (35). A Denmark study found a female prepon-derance with childhood onset psoriasis (36). An Australian study found thatthe mean onset of psoriasis in children was less than five years of age, whereasmost studies note onset to be between the ages of 5 and 14 (32–37).

However, despite some contradictory data, certain generalities may bemade regarding childhood versus adult onset nail psoriasis. When a familialhistory of psoriasis is found in association with juvenile-onset psoriasis, thedisease course is inevitably more severe, more strongly associated withpsoriatic arthritis, and more likely to display nail changes (6,38,39). Mostpatients, regardless of gender, develop psoriasis after the age of 20 (40).When childhood onset of nail psoriasis occurs, it is commonly precipitatedby trauma or infectious disease (32,36,41). Also, the later the onset of cuta-neous psoriasis, the less often concomitant fingernail or toenail psoriasisoccurs. This is especially true for toenail psoriasis (42). Although rare, whena child presents with nail alteration as the sole manifestation of psoriasis, anevaluation for juvenile psoriatic arthritis should be considered (43).

DIAGNOSTIC CHALLENGE: ISOLATED NAIL PSORIASISAND ITS IMPERSONATORS

Onychomycosis

The most common misdiagnosis for psoriatic nail disease is onychomy-cosis (2). It is easy to see why this occurs, especially if subungual hyperkeratosisis the primary feature in an isolated nail. For this reason, it is prudent toperform a potassium hydroxide (KOH) wet mount, culture, or nail clippingfor a periodic-acid–Schiff stain to ensure that there is no superimposedonychomycosis. Treatment of the overlying onychomycosis often causesdiminution of the hyperkeratosis, allowing the more characteristic psoriaticchanges such as oil spots to be revealed. Onychomycosis does not usuallycause 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 super-imposed infection is due to molds rather than dermatophytes (45).

Allergic Contact Dermatitis in One Nail

Typically, most patients with ungual contact dermatitis also have someother skin site involved, which helps to confirm the diagnosis, although itmay be confined to one digit. It is most commonly due to nail trauma or nailcosmetics (46,47). Like most diagnostic dilemmas, a thorough history andexamination usually help to ascertain the correct diagnosis.

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Drug Reactions

These are often seen in patients taking antibiotics such as minocycline orother phototoxic drugs (48). However, drug-induced onycholysis may occurwith no associated cutaneous photosensitivity. Beau’s lines and onychomad-esis are the most common abnormalities associated with drug reactions (49).When they are also associated with onycholysis, the clinical picture can clearlymimic psoriasis (50). A careful evaluation of the history of the lesions shouldidentify the likely culprit. Psoriatic nail changes typically have a slower onsetthan 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). Itis difficult to distinguish from linear verrucous epidermal nevus, althoughit is likely a true condition that has been well described in the literature(52,53). Biopsy alone may not confirm the diagnosis because histologicalfeatures may overlap (54,55). Therefore, when only an isolated nail is thepresenting sign, unless other presenting signs of psoriasis become manifestit may be impossible to discriminate between the two conditions (56).

Lichen Striatus

This is an interesting disorder that is also commonly confused with linearepidermal nevus and linear psoriasis. It is more commonly seen in childrenon an isolated nail. The characteristic finding is linear trachyonychia anddystrophy of the nail plate with partial pterygium formation and then spon-taneous resolution (57). It does not present with pitting or onycholysis.

Parakeratosis Pustulosa

This disorder is seen only in children. It presents with occasional isolatedfingertip scaling and erythema in either the thumb or index finger. It maybe a variant of psoriasis. Nail changes are always present and includeonycholysis and hyperkeratosis on only one side of the nail. Typically, chil-dren have spontaneous resolution of the disorder by the time they reachpuberty. However, some may later manifest widespread cutaneous psoriasisafter they reach adulthood (11).

Squamous Cell Carcinoma

Albeit rare, there have been reports of squamous cell carcinoma (SCC) aris-ing in psoriatic nails (58–60). There is only one report of SCC arising in apsoriatic nail bed (50). Interestingly, this man had an exophytic verrucousplaque 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 tothe physician. Because it had progressed substantially, the terminal phalanxrequired amputation. Histological exam of the amputated digit revealedwell-differentiated SCC with erosion through the dermis and into the bone.The important feature of this case is that there was a delay in diagnosisbecause both the patient and the physician assumed that the excess hyper-keratosis was due to worsening psoriasis.

DIAGNOSTIC PROCEDURE: THE NAIL BIOPSY

There are numerous excellent textbooks that describe the appropriatemethod 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 per-formed in the office setting. With difficult or challenging cases, the biopsycan be invaluable in ascertaining the cause of the nail abnormality. On occa-sion, both the nail bed and the matrix require biopsy simultaneously. In thiscase a longitudinal biopsy may be appropriate (65).

MEASUREMENT OF SEVERITY: THE NAIL PSORIASISSEVERITY INDEX

It is important to have an objective scale with which to measure diseaseseverity. The psoriasis area and severity index is used primarily for cutaneouspsoriasis but does not adequately measure nail disease activity. Therefore,the nail psoriasis severity index (NAPSI) was developed to objectively quan-tify the severity of nail disease in a reproducible manner (66). It was alsodesigned to assess efficacy of drug therapy for different manifestations ofnail psoriasis (e.g., pitting vs. subungual hyperkeratosis). Using NAPSI,the nail is divided into four quadrants, each of which is then graded basedon the presence or absence of nail matrix or nail bed disease. The highestscore 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 sumof the scores is calculated and used to judge the severity of nail psoriasis. Notincluded in this grading system are proximal nail fold psoriasis, pustularpsoriasis, and psoriatic arthritis. Other methods have also been proposedbut we find NAPSI the least complex (67).

TREATMENT OPTIONS AND COMPLICATIONS FROM THERAPY

There are numerous treatments for nail psoriasis. The drugs are usually clas-sified as follows: steroids, biologic agents, retinoids, and other miscellaneoustherapies such as chemotherapy or phototherapy. Each therapeutic class willbe discussed in detail.

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Steroids and Steroid-Like Drugs

The high-potency topical steroids are likely the most utilized form of ther-apy for nail psoriasis. Although they are relatively inexpensive and readilyavailable, tachyphylaxis occurs with prolonged use. The most effective ofall steroids for nail matrix psoriasis appears to be the triamcinolone aceto-nide (2.5 mg/mL) injection administered into the proximal and/or lateralnail fold every month for six months. Some dermatologists prefer using aring block for anesthesia prior to the injection (68). However, in our experi-ence dilution of the triamcinolone acetonide with 1% lidocaine and applica-tion of anesthetic refrigerant spray prior to rapid injection minimizes patientdiscomfort and increases tolerability. Both authors utilize this technique on

Table 3 NAPSI Scoring System

NAPSI scoringsystema Nail matrixb Nail bedc Total scored

0 None None 0

1 Present in 1quadrant

Present in 1quadrant

Possible points: 1 or 2Enter score:

2 Present in 2quadrants

Present in 2quadrants

Possible points: 2 or 4Enter score:

3 Present in 3quadrants

Present in 3quadrants

Possible points: 3 or 6Enter score:

4 Present in 4quadrants

Present in 4quadrants

Possible points: 4 or 8Enter score:

aFor each nail, score the points as shown in the column.bThis means evidence of any: (1) pitting, (2) leukonychia, (3) red spots in the lunula, or (4) crum-

bling.cThis means evidence of any: (1) onycholysis, (2) splinter hemorrhages, (3) subungual hyper-

keratosis, or (4) oil spots/salmon patch.dThere 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.

Table 4 NAPSI Scoring Table

Nail scoring table—compile the score for each nailNail 1________ Nail 2________ Nail 3________ Nail 4________Nail 5________ Nail 6________ Nail 7________ Nail 8________Nail 9________ Nail 10________Final score total:_______________

Note: Minimum score is zero and maximum score is 80.

Abbreviation: NAPSI, nail psoriasis severity index.

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a routine basis for psoriatic nails with good results. The major complica-tions from this therapy are hemorrhage under the nail plate and steroid-induced atrophy of the skin and subcutaneous tissues (2,69). However, inour experience, careful injection at the inflammatory psoriatic site with smallamounts of steroid does not cause major atrophy. As an added positive sideeffect, patients report that associated painful DIP joint arthritis seems todiminish with repeated injections.

Calcipotriene (DovonexTM) is a vitamin D3 analog that binds to a similarsteroid receptor in the skin. The cream and ointment forms have beenstudied in comparison to a topical steroid for use in the treatment of nailpsoriasis (70). They appear to be just as effective in decreasing hyperkerato-sis. However, the ideal use of calcipotriene appears to be in combinationwith other oral agents such as cyclosporine or even topical steroids (71,72).Combination therapies seem to be more effective at producing clinicalimprovement 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 arthritiswith varying degrees of success (73–75), very little reproducible scientificinformation 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). Theinduction of both cytokines is a normal host response required forthe inflammatory cascade to occur. TNF-a overproduction and subsequentactivation of T cells lead to pathologic disease states (76). Thus, the ratio-nale for use of some of these therapies is that they are designed to diminishTNF-a, which, in turn, appears to decrease the inflammatory, destructivecomponent of psoriasis resulting in clinical improvement in disease. Theycan be loosely grouped as TNF-a inhibitors (etanercept, adalimumab, andinfliximab) and T-cell modulators (alefacept and efalizumab).

Etanercept is a TNF-a receptor antibody fusion protein, which acts likea soluble TNF-a receptor that competitively binds TNF-a (78). Thus, thebound TNF-a cannot bind to its native receptor on the target cell. This meansthat although the TNF-a molecule is still present, it becomes biologicallyinactive because it is bound to a receptor that impersonates its normalbinding companion. Then the TNF-a bound etanercept is metabolized andeliminated via the liver and kidneys. Twice-weekly self-administered subcu-taneous (SQ) injections are required initially and then decrease to onceweekly. The human monoclonal antibody adalimumab is also SQ injectable,which is self-administered every two weeks (76). Infliximab is a chimericmouse/human monoclonal antibody that is administered intravenously (IV)

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once every two months (79). Rather than acting as a counterfeit receptor likeetanercept, the other two TNF-a inhibitors are antibodies that actually bindcirculating TNF-a, thus impairing its ability to bind to its receptor. Whileadalimumab and infliximab are structurally distinct from etanercept andhave a discrete mechanism of action, the end result is similar. All threedrugs bind TNF-a, blocking its ability to bind to its receptor and therebyreducing localized inflammation (76).

Alefacept is a fusion protein that binds to T cells and induces apopto-sis. It provides targeted destruction of pathogenic T cells (80). Efalizumab isa human monoclonal antibody that binds to leukocyte function-associatedantigen (LFA) on T cells. When LFA is bound, the T cells cannot bindto the intercellular adhesion molecule on the antigen presenting cell. Nor-mally, the interaction of LFA to the intercellular adhesion molecule allowsan 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 alphasubunit of LFA-1. This leads to a sequestration of pathogenic T cells inthe circulatory system, resulting in less evidence of psoriasis clinically (81).Because it does not actually destroy the activated pathogenic T cells likealefacept, the psoriasis can actually worsen upon cessation of the drugdue to a sudden influx of T cells into the skin.

So far, there are only three reports of nail psoriasis improvement usingthe biologic agents. Two are for alefacept and the other is for infliximab(82–84). Given the mechanism of action of the biologic agents, improvementin nail psoriasis is a highly probable consequence with increased use. In oneauthor’s experience (M.N.T.), etanercept appears to improve the amount ofpitting present but does not alter oil spots. Alefacept appears to have noeffect at all. The same author has treated multiple patients with alefaceptand has seen remarkable clearing of all cutaneous plaques. Clinically, thereis usually no remaining evidence that these patients ever had psoriasis exceptfor the isolated persistent nail psoriasis. Of all the biologics, etanercept maybe very effective for nail psoriasis, as it is the only agent specifically designedto prevent joint destruction, which is anatomically adjacent to the nailunit. Thus, it is not surprising that this agent appears to have improvedpsoriatic nails. However, this is anecdotal evidence. Clearly, more studiesare required to ascertain whether biologic agents are effective for nailpsoriasis and which ones.

Retinoids

Tazarotene 0.1% gel is a topical retinoid whose active metabolite tazarotenicacid binds with high affinity to the gamma subunit of the retinoic acid recep-tors (RARs) in the skin and nails. The RAR-gamma is the predominate typeof RAR in the epidermis (85). Topical tazarotene impairs keratinocyteproliferation and inflammation, which may be one of the mechanisms for

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onycholysis. One study from Columbia University demonstrated that tazar-otene under occlusion appears to reduce onycholysis and also improvethe appearance of pitting (86). A subsequent study has confirmed this find-ing (87). Both studies found that the drug was well tolerated; repeated usecaused minimal irritation.

Acitretin and isotretinoin are systemic retinoids that are more effectivewhen combined with phototherapy, either ultraviolet B (UVB) or psoralenand ultraviolet A (PUVA) (88,89). Acitretin is the treatment of choice for pust-ular psoriasis but is less effective against plaque psoriasis (90). There is onereport of near total clearance of severe nail psoriasis with acitretin (91). Whilethis report shows impressive results, it is not the best choice for isolated nailpsoriasis given the systemic side effects such as hyperlipidemia and hyperosto-sis, and the localized side effects such as oral xerosis and periungual pyogenicgranulomas (92). One major limitation of both the topical and systemicretinoid is that they are contraindicated in pregnancy. Both are category X.

Chemotherapy and Keratolytic Agents

Cyclosporine is well established as an effective oral immunosuppressiveagent 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. Unlikethe skin and gastrointestinal (GI) tract that have lipid permeable mem-branes, the nail plate is actually more of a concentrated hydrogel (94).Therefore, small hydrophilic molecules preferentially diffuse through thestructure to the nail bed. This is the reason gels (e.g., tazarotene 0.1% gelrather than cream) or other water-based preparations are needed whenchoosing a topical agent for nail psoriasis. Cyclosporine cannot dissolvein water, so one study used a 70% maize-oil–dissolved oral cyclosporinesolution applied to the nail plate versus a maize-oil–only vehicle (95). Thismethod was effective in improving nail psoriasis. The key feature of thisstudy is that an inappropriate vehicle can alter the efficacy of a potentiallygood drug because it is unable to penetrate the nail plate. The oral form ofthe drug is pregnancy category C.

Numerous studies have shown that daily topical 1% to 5% 5-fluorouracilis effective for the treatment of psoriatic nails (96,97). Fluorouracil is a che-motherapeutic agent that inhibits the enzyme thymidylate synthetase, whichleads to a decrease in cellular proliferation. It appears that using the low-dose formulation of the drug in a delayed nail penetration vehicle such asurea and propylene glycol enhances penetration (98). Like most agents thatinterfere with DNA synthesis, it is pregnancy category X. Most of the stud-ies with the drug have shown localized irritation with occlusive dressings asthe most serious adverse effect. However, there is one report of transientrhabdomyolysis occurring after use of topical 5-fluorouracil (99).

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There are no reports of isolated nail psoriasis treated with methotrex-ate. Like fluorouracil, it inhibits DNA synthesis but the exact mechanismfor blocking inflammation is still unknown. Because it is an immunosup-pressive agent like cyclosporine, it is difficult to justify use of this agentfor isolated nail psoriasis except if there is severe impairment of digit func-tion. 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 withacitretin for 12 months. Like most oral medications, the benefit of the drugfor isolated nail psoriasis must outweigh the potential side effects.

Topical anthralin is not usually a first-line medication due to the riskof long-term pigmentation of the nail plate. However, it has been used withmoderate success for refractory nail psoriasis (101). In this study, theauthors were careful to ensure that the anthralin was washed away after30 minutes of contact followed by application of 10% triethanolamine toprevent pigmentation.

Phototherapy

PUVA has been reported to be effective for all the different manifestationsof nail psoriasis except for pitting (102,103). Presumably, this is due to theinability of the light to penetrate the proximal nail fold skin sufficiently toaffect matrix normalization. The major drawback of this therapy is the riskof severe PUVA burns with overexposure.

Grenz ray therapy has been used with moderate success to treat pso-riatic nails. In a Swedish study, 5 Gy of Grenz rays were applied once a weekfor 10 weeks (104). This is no longer a practical therapy for office dermatol-ogy but it may be an option for patients who require therapy for refractorynail psoriasis.

Radiotherapy appears to have little curative benefit for nail psoriasis,and may result in temporary thinning of the nail plate (103). This perhapscould be used as a method for preparing the nails for one of the topicalocclusive therapies, but the concern for radiations adverse effects rendersit impractical.

Compared to classic cutaneous psoriasis, nail psoriasis is a poorlystudied entity. The reasons for this are multifactorial. It is commonlymisdiagnosed or diagnosis is delayed because it mimics numerous otherdisorders. 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 haveyet to be studied in full. No doubt the elusive definitive treatment has yet tobe developed. Meanwhile, for isolated nail psoriasis, the best treatmentremains simple intralesional corticosteroids.

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29. Williamson L, Dalbeth N, Dockerty JL, et al. Extended report: nail disease inpsoriatic arthritis-clinically important, potentially treatable and often overlooked. Rheumatology 2004; 43:790–794.

30. Guojonsson JE, Karason A, Antonsdottir AA, et al. HLA-Cw6-positive andHLA-Cw6-negative patients with psoriasis vulgaris have distinct clinical fea-tures. J Invest Dermatol 2002; 118(2):362.

31. Henseler T. The genetics of psoriasis. J Am Acad Dermatol 1997; 37(2):S1–S11.32. Kumar B, Jain R, Sandhu K, et al. Epidemiology of childhood psoriasis: a

study of 419 patients from northern India. Int J Dermatol 2004; 43:654–658.33. Al Fouzan AS, Nanda A. A survey of childhood psoriasis in Kuwait. Pediatr

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36. Nyfors A, Lomholt K. Psoriasis in children. Br J Dermatol 1975; 72:437–442.37. Morris A, Rogers M, Fischer G, et al. Childhood psoriasis: a clinical review of

1262 cases. Pediatr Dermatol 2001; 18:188–198.38. Melski JW, Stern RS. The separation of susceptibility to psoriasis from age at

onset. J Invest Dermatol 1981; 77(6):474–477.39. Henseler T, Christophers E. Psoriasis of early and later onset: characterization

of two types of psoriasis vulgaris. J Am Acad Dermatol 1985; 13:450–456.40. Farber EM, Nall ML. The natural history of psoriasis in 5600 patients.

Dermatologica 1974; 148:1–18.41. Farber EM, Carlsen RA. Psoriasis in childhood. Calif Med 1966; 105:415–420.

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42. Stuart P, Malick F, Nair RP, et al. Analysis of phenotypic variation in psoriasisas a function of age at onset and family history. Arch Dermatol Res 2002;294:207–213.

43. Duran-McKinster C, Ortiz-Solas D, Granados J, et al. Juvenile psoriatic arthri-tis with nail psoriasis in the absence of cutaneous lesions. Int J Dermatol 2000;39:30–40.

44. Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing torecurrence. Br J Dermatol 2003; 149(suppl):5–9.

45. Staberg B, Gammeltoft M, Onsberg P. Onychomycosis in patients with psoria-sis. Acta Derm Venereol 1983; 63(5):436–438.

46. Wilkinson DS. Dermatitis from repeated trauma to the skin. Am J Ind Med1985; 8(4–5):307–317.

47. Hemmer W, Focke M, Wantke F, et al. Allergic contact dermatitis to artificialfingernails prepared from UV light-cured acrylates. J Am Acad Dermatol 1996;35(3 Pt 1):377–380.

48. Gould JW, Mercurio MG, Elmets CA. Cutaneous photosensitivity diseasesinduced by exogenous agents. J Am Acad Dermatol 1995; 33:551.

49. Piraccini BM, Iorizzo M, Tosti A. Drug-induced nail abnormalities. Am J ClinDermatol 2003; 4(1):31–37.

50. Robbins TO, Kouskoukis CE, Ackerman AB. Onycholysis in psoriatic nails.Am J Dermatopathol 1983; 5(1):39–41.

51. Goujon C, Pierini AM, Thivolet J. Does linear psoriasis exist? Ann DermatolVenereol 1981; 108:643–650.

52. Saraswat A, Sandhu K, Shukla R, et al. Unilateral linear psoriasis with palmo-plantar, nail, and scalp involvement. Pediatr Dermatol 2004; 21(1):70–73.

53. Leslie G. Linear psoriasis. Br J Dermatol 1951; 63:262–263.54. Sugai T, Shimotoge M, Saito T. Psoriasis and systematized epidermal nevus.

Arch Dermatol 1970; 102:656–660.55. Bondi EE. Psoriasis overlying and epidermal nevus. Arch Dermatol 1979;

115:624–625.56. deJong EM, Rulo HF, van de Kerkhof PC. Inflammatory linear verrucous epi-

dermal nevus (ILVEN) versus linear psoriasis. Acta Derm Venereol (Stockh)1991; 71:343–346.

57. Tosti A, Peluso AM, Misciali C, Cameli N. Nail lichen striatus: clinical featuresand long-term follow up of five patients. J Am Acad Dermatol 1997; 36:908–913.

58. Tosti A, Morelli R, Fanti PA, et al. Carcinoma cuniculatum of the nail appa-ratus. Report of three cases. Dermatology 1993; 186:217–221.

59. Dobson CM, Azurdia RM, King CM. Squamous cell carcinoma arising in apsoriatic nail bed: case report and discussion of diagnostic difficulties and thera-peutic options. Br J Dermatol 2002; 147:144–149.

60. Baran R, Parrin C. Longitudinal erythronychia with distal subungual keratosis:onychopapilloma of the nail bed and Bowen’s disease. Br J Dermatol 2000;143:132–135.

61. Baran R, Dawber RPR, Deberker D, Haneke E, Tosti A, editors. Diseases ofthe nails and their management. 3d ed. New York: Blackwell Science; 2001.

62. Scher RK, Daniel CR III. Nails. 2d ed. New York: WB Saunders, 2000.

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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. Philadel-phia. Eselvier Saunders. 2005:1–324.

65. Grover C, Khandpur S, Reddy BSN, et al. Longitudinal nail biopsy: utility in20-nail dystrophy. Dermatol Surg 2003; 29:1125–1129.

66. Rich P, Scher RK. Nail psoriasis severity index: a useful tool for evaluation ofnail 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 sal-icylic acid. Br J Dermatol 1998; 139(4):655–659.

71. Feliciani C, Zampetti A, Forleo P, et al. Nail psoriasis: combined therapywith 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 treat-ment using calcipotriol cream and clobetasol proprionate cream. Acta DermVenereol 2002; 82(2):140.

73. Goedkoop AY, De Rie MA, Picavet DI, et al. Alefacept therapy reduces theeffector T-cell population in lesional psoriatic epidermis. Arch Dermatol Res2004; 295(11):465–473.

74. Weinberg JM. An overview of infliximab, etanercept, efalizumab and alefaceptas biologic therapy for psoriasis. Clin Ther 2003; 25(10):2487–2505.

75. Weinberg JM, Saini R, Tutrone WD. Biologic therapy for psoriasis—the firstwave: infliximab, etanercept, efalizumab, and alefacept. J Drugs Dermatol2002; 1(3):303–310.

76. Saripalli YV, Gaspari AA. Focus on: biologics that affect therapeutic agents indermatology. J Drugs Dermatol 2005; 4(2):233–245.

77. Mehlis Sl, Gordon KB. The immunology of psoriasis and biologic immunother-apy. 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.

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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 fingernailpsoriasis: 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 finger-nails 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 psoralensand 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 AcadDermatol 1999; 41:S22–S24.

90. Moy RL, Kinston TP, Lowe NJ. Isotretinoin vs. etretinate therapy in general-ized pustular and chronic psoriasis. Arch Dermatol 1985; 121:1297–1301.

91. Brazzelli V, Martinoli S, Prestinari F, et al. An impressive therapeutic result ofnail psoriasis to acitretin. J Eur Acad Dermatol Venereol 2004; 18(2):229–230.

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93. Mahrle G, Schulze HJ, Farber L, et al. Low-dose short-term cyclosporine ver-sus 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 Pharm2002; 236:1–26.

95. Cannavo SP, Guarneri F, Vaccaro M, et al. Treatment of psoriatic nails withtopical cyclosporine: a prospective, randomized placebo-controlled study. Der-matol 2003; 206(2):153–156.

96. Schissel DJ, Elston DM. Topical 5-fluorouracil treatment for psoriatictrachyonychia. Cutis 1998; 62(1):27–28.

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98. deJong EM, Menke HE, van Praag MC, et al. Dystrophic psoriatic fingernailstreated with 1% 5-fluorouracil in a nail penetration-enhancing vehicle. Derma-tology 1999; 199(4):313–318.

99. Schmied E, Levy PM. Transient rhabdomyolysis connected with topical use of5-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 sulfasala-zine treatment. Ann Rheum Dis 2002; 61:277.

101. Yamamoto Y, Katayama I, Nishioka K. Topical anthralin therapy for refrac-tory nail psoriasis. J Dermatol 1998; 25:231–233.

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19

Summary of Therapeutic Options forMild-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. Ingeneral, patients with psoriasis limited to less than 5% body surface area(BSA) with no associated joint disease and little or no impact on their qualityof life (QOL) are labeled as mild psoriasis and best managed with topicalmedications (Fig. 1) (1). Patients with moderate psoriasis have between 2%and 10% of involved BSA, with or without associated arthritis, with somealteration of the patient’s QOL (Fig. 2) (2). These patients frequently requirephototherapy and/or systemic therapy in addition to topical therapy.Patients with severe psoriasis generally have greater than 10% BSA involve-ment, with or without associated arthritis, with a broad impact on health andQOL, and generally will require phototherapy and/or systemic therapy inaddition to topical therapy.

Psoriasis is a dynamic disease that responds to a wide range of thera-pies, including topical, light, and systemic therapies, each with varyingdegrees of success. The primary treatment goals for patients with psoriasisare to reduce the size, thickness, and extent of plaque involvement, preventprogressive joint destruction, and improve QOL (1). Several factors

243

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influence therapeutic selections for patients with mild-to-moderate psoriasis,including the nature (thick vs. thin plaques), anatomical location, and distri-bution of the lesions.

Corticosteroids are the most frequently used topical therapy forpsoriasis in the United States. Additional topical agents used include

Figure 1 (See color insert) Localized mild psoriasis.

Figure 2 (See color insert) Moderate psoriasis.

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calcipotriene, a vitamin D analog, a newly available combination of calcipo-triene betamethasone dipropionate, tazarotene, the only retinoid approvedfor the treatment of psoriasis, derivatives of coal tar, and anthralin (Table 1).Each has varying degrees of effectiveness for mild-to-moderate psoriasiswith unique safety and tolerability profiles. The majority of patients withpsoriasis presenting to dermatologists have used a variety of topical medi-cations in an attempt to limit the physical (itching, burning, redness, andscaling) and emotional impact of their disease.

Certain patients with what may be considered mild disease by defini-tion (< 5% BSA) are so anxious about the physical and emotional aspectsof their limited disease, e.g., scalp, hands, and/or feet, that systemic treat-ment may be considered. Patient preference must also be considered, assome therapies are cosmetically unappealing, time consuming, and can stainskin, clothing, and bed linens. Hence, education of patients relating to thenuances of topical therapy, e.g., frequency, application techniques, andamount of drug required per body surface unit, is essential. Ultimately, treat-ment selection for each patient must take into account the patient’s diseaseseverity, expectations for improvement, pregnancy consideration, and therisk–benefit ratio associated with each potential topical, phototherapy, andsystemic therapy.

A summary of therapeutic options for the treatment of mild-to-moderate psoriasis will be presented based on our cumulative experiencesin running a tertiary referral clinical and research psoriasis unit.

TOPICAL THERAPIES

Corticosteroids

Topical corticosteroids account for the vast majority of prescriptions writ-ten by dermatologists and primary care physicians for mild-to-moderatepsoriasis. These agents act on nuclear hormone receptors to exert their anti-inflammatory, antiproliferative, and immunosuppressive properties. Clinicalefficacy, which correlates to the Stoughton–Cornell classification (an assay ofa corticosteroid’s ability to cause vasoconstriction) is dictated by the potencyof a particular molecule and the delivery vehicle (3). Steroid potencies rangefrom class VII corticosteroids (weakest agents), including over the counter1% 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 SaranWrap1 maximizes potency of topical steroids (Figs. 3 and 4) (4). Noveldelivery systems, such as the foam preparations of betamethasone valerate0.1% and spray and shampoo formulations of clobetasol propionate 0.05%,may be associated with increased patient compliance (5).

Therapeutic Options for Mild-to-Moderate Psoriasis 245

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246 Berthelot et al.

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

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

occlusion.

Figure 4 (See color insert) Lewis technique.

Therapeutic Options for Mild-to-Moderate Psoriasis 247

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effects uses a class I ointment applied three times over a 24-hour period eachweek with improvement of psoriasis maintained for up to six months in 60%of patients (10). Intermittent pulse dosing on the weekends or two consecu-tive days can be used to maintain response, either as monotherapy or incombination with nonsteroidal preparations used five days a week (11,12).

Anatomical Considerations

It is important to recognize that different regions of the body require vary-ing steroid potencies to avoid cutaneous side effects, especially atrophy inareas of thin skin (e.g., flexures) (Table 2).

Safety

Safety concerns are related predominately to local toxicity seen with improperuse, for example using a class I preparation on a thin skin site, or overlyprolonged duration of therapy. Side effects of topical corticosteroids, espe-cially those of the superpotent category, include cutaneous atrophy, thedevelopment 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 ofexcessive amounts of topical corticosteroids, this is seldom an issue if thetotal weekly dosage limit does not exceed 50 g in an adult (3). Other mani-festations of local toxicity may include hypopigmentation, especially inpatients with skin types 3 and above, and masking of skin infections liketinea incognito (Fig. 7) (14). In addition, a rebound phenomenon may occurafter discontinuation of prolonged use of topical corticosteroids (15,16).A finger-tip unit (FTU) is a practical and simple measure for patients tounderstand (Table 3). This unit is the amount of ointment expressed froma tube with a 5-mm diameter nozzle, applied from the distal skin creaseto the tip of the index finger (17).

Table 2 Anatomical Considerations for Corticosteroid Application

Anatomical area Treatment options

Face, intertriginous,and genital areas

Class VI or VII corticosteroid, tacrolimus or pimecrolimus,topical antifungals

Thicker skin (elbow,knees, back)

High-potency corticosteroids with or without vitamin D3

or A preparationsScalp Gel, foam, shampoo, topical or intralesional corticosteroids,

anthralin, tar, salicylic acid, or vitamin D3

Extremities Class I or II corticosteroid in an ointment, spray, or foamvehicle with or without occlusion

Palmar-plantar Class I or II corticosteroids with or without occlusion

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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 com-pared to calcitriol, and is thus far less likely to produce hypercalcemia (7).Calcipotriene can be combined with other treatment modalities to providemore rapid clearance of disease with potential dose-sparing effects. Calci-potriol ointment has comparable or slightly better efficacy than class IIcorticosteroid ointments for the treatment of psoriasis (18). While less effec-tive than superpotent corticosteroids, regimens utilizing a combination ofcalcipotriene and a class I corticosteroid have demonstrated greater effec-tiveness over each agent alone (19,20). Currently, corticosteroids are used

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

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in an induction regimen (twice a day for two weeks), due to their faster onsetof action, followed by maintenance therapy with calcipotriene on the week-days and corticosteroid on the weekends (19,20). In trials that compared cal-cipotriene and anthralin, calcipotriene was preferred by patients because ofless staining, less irritation, and also improved QOL issues (21).

The combination of calcipotriene and other therapeutic modalitieshave also been shown to be beneficial. Two studies have shown greater clear-ing with the combination of calcipotriene and ultraviolet B (UVB) than withmonotherapy with either treatment (22,23). This combination results infewer UVB exposures and a lower cumulative dose, suggesting that patientsmay be able to achieve lesion clearing with less frequent UVB treatments. Arecent study showed that the combination of the two were more effective inreducing the psoriasis area and severity index (PASI) early on in treatment,than narrow-band UVB (NB-UVB) alone (24,25). Combination therapywith calcipotriene and psoralen and ultraviolet A (PUVA) has also beenshown to be beneficial (26). A calcipotriol/betamethasone dipropionate com-bination is available in Europe and has recently been approved for use in theUnited States. In clinical trials, patients with a mean baseline PASI of 9.5 to10.9 experienced a mean 65% to 74.4% PASI improvement within fourweeks utilizing this combination preparation on a once daily basis signifi-cantly better than placebo (27).

Safety

Regular twice-daily application of topical calcipotriene for extended periodsof time as monotherapy is essential to maintain clinical responsiveness.

Figure 6 Striae due to topical corticosteroid application.

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Figure 7 (See color insert) Tinea incognito.

Table 3 The Number of FTU Required for Differ-ent Areas of the Body

Area of body Number of FTU

Face and neck 2.5 (s.d.� 0.8)Front of trunk 6.7 (s.d.� 1.7)Back of trunk 6.8 (s.d.� 1.2)Arm and forearm 3.3 (s.d.� 1.0)Hand 1.2 (s.d.� 0.4)Leg and thigh 5.8 (s.d.� 1.7)Foot 1.8 (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 oftheir psoriasis. The most common side effect is lesional or perilesionalerythema, scaling, stinging, or burning, noted in up to 20% of patients,especially when used on the face and intertriginous areas (18,19). Reducingthe frequency of applications using concomitant topical corticosteroids ordiluting calcipotriene with petrolatum has been suggested to reduce theirritation (28,29). While hypercalcemia has been reported in patients whohave applied excessive amounts over large surface areas, restricting theapplication to less than 100 g a week has shown no significant alterationsin calcium or bone metabolism (30,31). Calcipotriene should not be usedwhere there is an increased risk of systemic absorption, such as in patientswith inflammatory erythrodermic or pustular forms of psoriasis (7). Calci-potriene is pregnancy category C (safety for use during pregnancy has notbeen established), not teratogenic, and is not known whether the agent orits metabolite enters breast milk (32,33). The use of calcipotriol has beenstudied in children, showing a statistically significant reduction in the PASIfrom 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 regulategene transcription, thereby normalizing keratinocyte differentiation andproliferation (35). The efficacy of tazarotene compared to placebo has beenestablished in randomized, double-blind trials and its therapeutic effectsappear 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 regi-men of tazarotene gel 0.1% applied Mondays, Wednesdays, and Fridays,and clobetasol ointment applied Tuesdays and Thursdays (36). Addition-ally, like calcipotriene, tazarotene avoids the side effects of corticosteroidsincluding atrophy and tachyphylaxis (37).

In one clinical study, the combination of calcipotriene and tazarotenewas shown to have similar efficacy when compared to clobetasol alone (38).The combination of tazarotene and UVB has also been studied. It is importantto note that neither UVB nor UVA inactivates tazarotene, as compared tocalcipotriene (39). Patients also responded more favorably when treated witha UVB and tazarotene combination than when treated with UVB alone(40,41). However, as application of tazarotene results in thinning of thestratum corneum, caution must be exercised by reducing the dose of UVB.

Safety

Tazarotene’s main concern is the development of local irritation, frequentlyseen 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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including short contact therapy, intermittent therapy, and combination ther-apy with topical corticosteroids (3). When tazarotene is used once daily withmometasone furoate 0.1% cream or fluocinonide 0.05% cream, improvementis enhanced and irritation diminished (43). In addition to the synergisticaction of these two drugs, tazarotene has also been shown to counteractthe atrophogenic effects of corticosteroids.

While the 0.1% formulation is more effective than the 0.05%, it is alsoassociated with a potential for irritation (44). Tazarotene should be usedsparingly with a pea-sized amount generally sufficient for a lesion of psori-asis the size of a palm (1% BSA) and the patients should be advised toanticipate a transient (four weeks) mild increase in erythema.

Tazarotene is contraindicated in pregnancy (pregnancy class X). Fol-lowing topical application of tazarotene gel or cream to the skin, systemicabsorption of the active metabolite and the parent drug is negligible, pro-vided 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 andthere is no systemic accumulation of the drug following multiple topicalapplications; therefore, if any were absorbed, we advise a two-week washoutprior to pregnancy (46).

Immunomodulators

Tacrolimus and pimecrolimus are calcineurin inhibitors functioning asimmunosuppressants and both are approved by the U.S. Food and DrugAdministration for the treatment of atopic dermatitis (47). While topicalcorticosteroids are frequently utilized for psoriasis in the intertriginous

Figure 8 (See color insert) Retinoid dermatitis.

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and facial areas, their side effects may mitigate use in these areas. Topicaltacrolimus offers the potential for an anti-inflammatory effect, while avoid-ing the atrophy and acneiform eruptions commonly associated with the useof topical corticosteroids (48). Several studies have shown the benefits oftacrolimus for facial and intertriginous psoriasis (49,50). One study showedexcellent improvement at the end of an eight-week treatment period, with65.2% of the tacrolimus ointment group, versus 31.5% of the vehicle group,giving a clear or almost clear response (50). Adverse events were similar inthe 0.1% tacrolimus ointment and vehicle groups. In a study of pimecroli-mus in 57 patients with moderate to severe inverse psoriasis, 54% of thepimecrolimus group versus 21% of the placebo group had an Investigator’sGlobal Assessment score of 0 or 1 (clear or almost clear) at week 2 (51). Byweek 8, 71% of the pimecrolimus group had an Investigator’s Global Assess-ment score of 0 or 1. Pimecrolimus was safe and well-tolerated, with adverseevents similar between groups. Topical tacrolimus and pimecrolimus areineffective for standard plaque psoriasis.

Safety

Recently, concern has been raised due to the development of tumors asso-ciated with these agents. Nine cases of tumor adverse events and 21 casesof tumor adverse events with pimecrolimus and tacrolimus, respectively,have been reported to the U.S. Food and Drug Administration’s AdverseEvent Reporting System (52). Although systemic tacrolimus used duringpregnancy may result in fetal malformations and preterm deliveries, thebioavailability of topical tacrolimus is less than 5% of the orally adminis-tered form, making the potential for tumors with standard topical therapyextremely low indeed (53–55). Both topical and systemic tacrolimus prep-arations are pregnancy category C (56).

Coal Tar

This agent is messy, malodorous, and stains clothing and other fabrics, lead-ing to poor patient compliance despite being inexpensive. Liquor carbonisdetergens is better tolerated and may be compounded in various vehicles (57).We frequently use 10% to 20% liquor carbonis detergens with one-fourthstrength betamethasone valerate in a hydrophilic emollient base at night forthin plaque psoriasis or as an adjunct to phototherapy. It is important toinstruct patient not to apply tar preparations prior to their phototherapyto avoid ‘‘tar smarts.’’

Safety

From a safety standpoint, skin irritation, acneiform eruptions, and fol-liculitis 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 potentiatedby concomitant use of UV radiation (58). In addition, cases of skin cancerhave been linked with coal tar use, especially on the genitalia (59). Tarpreparations are frequently used by dermatologists as shampoos for thetreatment of scalp psoriasis. In addition, a vast array of over-the-countertar-containing products are advertised and still used by psoriasis patients.Coal tar is safe to apply during pregnancy (pregnancy class A), and aretrospective study of 23 pregnant patients during which the dermatologicaluse of tar was clear was not associated with any adverse outcomes (60).

Anthralin

Anthralin, or dithranol, has historically been used as part of the Ingramregimen (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, andbathroom tile, and therefore it has largely been abandoned outside of photo-therapy and outpatient regimens. Short contact regimens (minutes to 1–2hours) and more cosmetically acceptable formulations are used in the out-patient setting as monotherapy or in combination with other agents toreduce these side effects. Short contact anthralin therapy, using concentra-tions of 1% or greater, entail application of five minutes on the first dayand then increasing by five minutes every other day until minimal irritationdevelops, after which the period of application is maintained until clearing(61). Staining of the skin and irritation may be lessened by applicationof triethanolamine before removal of the anthralin (62). Micanol1 is a1% anthralin formulation in a temperature-sensitive vehicle that releasesactive medication at skin surface temperature (63). It is possibly moreacceptable to patients because staining of household fabrics and furnitureis minimized. Studies have demonstrated efficacy of Micanol1 in short-and long-term regimens, as well as utility in scalp psoriasis refractory toother treatments.

Safety

Anthralin should be used with care because of potential for irritation andstaining. Thus, it must be applied only to plaques and not to surroundingnormal skin, as irritation and staining of the skin may develop. Anthralinis pregnancy category C and no reproduction studies, human or animal, orreports of adverse fetal effects have been published (59). While studies haveshown that anthralins is a tumor promoter producing transient changes inthe growth or differentiation of the epidermis, no significant increase inpre-malignant or malignant skin tumors have been noted in over 50 yearsof usage (64).

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Emollients and Keratolytics

These agents are recommended as concomitant therapy for the treatment ofpsoriasis. Hydration of the dysfunctional epidermal barrier helps decreaseerythema, pruritus, and scaling within lesions (65). In general, while oint-ments are the most effective, patient preference and compliance is betterwith less greasy emollient bases (66). In addition, in certain body areas(e.g., legs) and patient populations (e.g., elderly), emollients should be usedas an adjunct to topical steroid usage, especially after bathing.

The only combination keratolytic creams commercially available inthe United States are lactic acid/urea based (67). Outside the United States,a combination of 0.05% betamethasone dipropionate ointment and 3% sali-cylic acid is available (68). Salicylate-containing preparations should not beapplied before light therapy given their photoprotective effects. We usuallylimit the use of these products for hands, feet, elbows, and knees to aid inexfoliation 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, andpsychiatric disturbances (69). Keratolytics are pregnancy class C (safety foruse 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 aretreated successfully with topical agents, some may also require photother-apy. Because of its efficacy and safety profile, UVB continues to havewidespread use in spite of the development of newer treatment modalitiesfor psoriasis. Studies have shown that UVB in conjunction with other treat-ment modalities shows additional benefits, and results in lesion clearing withless frequent UVB radiation treatments. UVB therapy with a lubricatingbase results in shorter treatment periods, which means the surrounding skinwill be exposed to smaller doses of UVB, with a diminished risk of actinicdamage (71). UVB combination with tazarotene 0.1% gel may be more ben-eficial than UVB alone (40,41). Similarly, the addition of calcipotriene toUVB results in lesion clearing with less frequent UVB radiation treatments(22,23). UVB phototherapy combined with topical corticosteroids hasshown no dose-sparing effect or therapeutic advantage, and may evenshorten remission time. The use of broadband UVB has diminished in recentyears with the introduction and widespread availability of narrow-bandUVB, 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 loca-lized plaques of psoriasis (‘‘targeted phototherapy’’), including those on thepalms and soles (72).

PUVA therapy is considered more durable than UVB, with somepatients even achieving long-term remission without maintenance therapy.Methoxsalen is pregnancy category C and should be given to pregnantfemales only in cases where it is clearly needed. Because PUVA is mutagenicand induces sister chromatid exchanges, it should be considered a potentialteratogen and women at risk of becoming pregnant who are treated withPUVA should consider using contraception (73).

SUMMARY

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

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60. Tauscher AE, Fleischer AB Jr., Phelps KC, et al. Psoriasis and pregnancy.J Cutan Med Surg 2002; 6(6):561–570. E-pub 2002 Oct 9.

61. Miller AC. Anthralin cream as short contact therapy for psoriasis. Cutis 1985;35(6):578–582.

62. Ramsay B, Lawrence CM, Bruce JM, et al. The effect of triethanolamine appli-cation on anthralin-induced inflammation and therapeutic effect in psoriasis.J Am Acad Dermatol 1990; 23(1):73–76.

63. Volden G, Bjornberg A, Tegner E, et al. Short-contact treatment at home withMicanol. Acta Derm Venereol Suppl (Stockh) 1992; 172:20–22.

64. Yuspa SH. Cutaneous chemical carcinogenesis. J Am Acad Dermatol 1986; 15(5Pt 1):1031–1044.

65. Bernstein JE, Parish LC, Rapaport M, et al. Effects of topically applied capsaicinon moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986; 15(3):504–507.

66. Housman TS, Mellen BG, Rapp SR, et al. Patients with psoriasis prefer solutionand foam vehicles: a quantitative assessment of vehicle preference. Cutis 2002;70(6):327–332.

67. Stern RS. Psoriasis. Lancet 1997; 350(9074):349–353.68. Guenther LC. Fixed-dose combination therapy for psoriasis. Am J Clin

Dermatol 2004; 5(2):71–77.69. Brien JA. Ototoxicity associated with salicylates. A brief review. Drug Saf 1993;

9(2):143–148.70. Lebwohl M. The role of salicylic acid in the treatment of psoriasis. Int J

Dermatol 1999; 38(1):16–24.71. Berne B, Blom I, Spangberg S. Enhanced response of psoriasis to UVB therapy

after pretreatment with a lubricating base. A single-blind controlled study. ActaDerm Venereol 1990; 70(6):474–477.

72. Housman TS, Pearce DJ, Feldman SR. A maintenance protocol for psoriasisplaques cleared by the 308 nm excimer laser. J Dermatol Treat 2004; 15(2):94–97.

73. Stern RS, Lange R. Outcomes of pregnancies among women and partners ofmen with a history of exposure to methoxsalen photochemotherapy (PUVA)for the treatment of psoriasis. Arch Dermatol 1991; 127:347–350.

Therapeutic Options for Mild-to-Moderate Psoriasis 261

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Index

1a,25-Dihydroxycholecalciferol, 605-Methoxypsoralen (5-MOP), 1318-Methoxypsoralen (8-MOP), 131Absorption spectrum, 131Acetonide side groups, 45Acitretin, 157, 235Adalimumab, 233Adjunctive therapy, 256Alefacept, T-cell-like, 234Alopecia cicatricialis, 196Anhydrous vehicle, 78–79

advantageous characteristics of,84–85

Anthralin, 255application of, 120combination therapy of, 120disadvantages of, 120efficacy of, 120in psoriasis treatment, 119–121side effects of, 121topical, 236

Anthralin therapy, 255short contact, 120

Anthralin treatment regimens,of plaque psoriasis, 120

Anti-inflammatory agents,nonsteroidal, 177

Antiemetics, 134

Antifungalsimidazole, 199treatment, 199

Antipsoriatic treatment, 202Arthritis

mutilans, 227psoriatic, types of, 227

Asymmetric oligoarthritis, 227Axial disease, 227

Basal cell carcinoma (BCC), 131Beau’s lines, 223, 230Betamethasone dipropionate

b.i.d., 77cream, 95ointment, 76, 256once-daily, 78, 80

Betamethasone dipropionate plussalicyclic acid, 62

Betamethasone dipropionate/calcipotriene combination,84–85

with biologics, 85–86clinical trials and analyses of, 77effectiveness of, 77formulation of, 76with other systemic agents, 86

263

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[Betamethasone dipropionate/calcipotriene combination]

potential effects on compliance, 86therapy, 77

Betamethasone valerate ointment, 62Biologic therapies, 190Biopsy, nail, 231Black tar, 116Blennorrhagicum, keratoderma, 187Body surface area (BSA), 29, 243Bonalfa1, 59Brown tar, 116Butylated hydroxytoluene (BHT), 199

Calcineurin, 107inhibitors, 127, 253

topical, 110Calcipotriene, 1, 30, 34, 59,

164, 187, 233application of, 60application in psoriasis, 68beneficial effects of, 60chemical structure of, 61in children, 61combination of, 63combined with UVB

phototheraphy, 64effectiveness of, 165efficacy of, 165features of, 66molecule, 167monotherapy, 61ointment, 76–77

b.i.d., 77, 80and corticosteroids combination, 2

plus narrowband UVB, 64for psoriasis treatment, 165side effect of, 66skin irritation from, 66–68and systemic agents, 65–66and tazarotene, 64topical, 75–76

steroids, 63versus other topical agents, 62

Calcipotriene and halobetasolpropionate, use of, 166

Calcipotriol, 187lotion, 201ointment, 59treatment, 197

Calcitriol, 59Calcium metabolism, 251Carcinogenesis, skin, 130Carcinogenic potential, 149Cellular proliferation, 235Chemotherapeutic agent, 235Chemotherapy, 235–236Class I topical steroids, 64Clear liquid emollients, 129Clinical morphology, 196Clobetasol, 157

containing topical corticosteroidproducts, 6

foam, 70Clobetasol propionate, 174

foam, 46efficacy of, 168twice-daily monotherapy with, 169

lotion, 176shampoo, 175, 199spray, 174

Clobex lotion, 176Clobex shampoo. See Clobetasol

propionate, shampooClobex spray. See Clobetasol

propionate, sprayCoal tar

efficacy of, 116preparations of, 116psoriasis treatment with, 115–119therapeutic use of, 119

Coal tar in mild-to-moderatepsoriasis, side effects anddisadvantages, 119

Coal tar lotion, efficacy of, 118Combination therapy, 127, 131, 147, 255

rationale for, 147Corticosteroid(s), 245

adherence of, 46–48aspect of, 50atrophogenic effects of, 252biological activity of, 42–44and calcipotriene combination, 2

264 Index

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[Corticosteroid(s)]cost considerations for, 52delivery of, 44effects of, 51efficacy of, 49–50essential abilities of, 42functional effects of changing, 43high-potency, 94intralesional, 2mechanism action of, 42–44mid-potency, 94ointments, 251physiologic potency, 44practical use of, 52preparation, 199propylene glycol present in, 45psoriasis treated with, 41safety profile of, 51–52side effects from topical, 75skin cap treatment for, 48–49and tazarotene combination, 2therapy, 76topical, 1, 75–76, 96, 120–121use of, 50

Corticosteroid/calcipotrienecombination therapy

benefits of, 76pitfalls of, 76

Corticosteroid/calcipotriene ointment,fixed-dose, 76

Corticosteroid clobetasol propionate, 1Cronbach’s a, 24CsA. See Cyclosporin ACutaneous immune cells, 213Cutaneous lesions, presentation of, 207Cutaneous psoriasis, 226Cutaneous tumors, 111Cutivate1, 95Cyclosporin A (CsA), 105, 156, 190,

215, 235, 236vitro biological characteristics, 212

Cyclosporine therapy, effect of, 215Cytokine expression, prevention of, 107Cytokines, 42

inflammatory, 214, 216expression, 215production of, 213

Daivobet1, 76Daivonex1, 76Demarcated erythematous

plaques, 196Dermatitis, retinoid, 252Dermatology life quality

index (DLQI), 15Dermatophyte infection, 184Dermatoses, inflammatory

treatment of, 105Diabetic patients, acute hypoglycemia

in, 121Diprosone1, 76, 95Disease-modifying systemic therapies, 32Distal interphalangeal (DIP) joint

disease, 227Dithranol therapy, short

contact, 120, 199Diversifying treatment, 147Deoxyribonucleic acid (DNA)-binding

proteins, 92Deoxyribonucleic acid (DNA)

synthesis, 155inhibition of, 214

Dovobet1, 76, 170Dovonex1, 59, 76, 164, 233Drug reactions, 230Drug, steroid-like, 232–233Drug within vehicles, 45Duoderm1, 176Dysfunctional epidermal barrier,

hydration of, 255

Ear telangectasia, 106Efalizumab, 234Elidel1, 111Elocon1, 95Emollients

clear liquid, 129, 186and keratolytics, 255

Endothelial cells, 216Enthesopathy, 227Epidermal growth factor (EGF), 212Epidermal hyperproliferation, 212Epidermal T cell, 61Erythema, 64

Index 265

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

Fissured psoriatic lesions, 35Fixed-dose combination therapy, 77

clinical improvement inpatient with, 85

corticosteroid/calcipotrieneointment, 76

effectiveness of, 77once-daily, 78

b.i.d. therapy versus, 80efficacy of, 80, 83higher clearance of, 81investigators and patients’

assessments of, 82monotherapy versus, 80psoriasis activity with, 81–82twice-daily versus, 77

potential benefits of, 84Flow cytometric analysis, 60Fluocinonide

cream, 93ointment, 62

Fluorouracil, 235–236Flurandrenolide-impregnated

tape, 50Follicular hyperkeratoses, 197Food and Drug Administration (FDA),

30, 154, 213Fungal culture, 185Fungal infection, 207

inflammatory, 184Fungal lesions, 197Future therapies, 158

Gastrointestinal distress, 256Gastrointestinal side effect, 134Gastrointestinal symptoms, 216General therapeutic

aspects, 197–198Genetic haplotypes, 228Gene transcription, 252Goa powder, 119

Goeckerman therapy, 116with black tar, 117study of, 118

Grenz ray therapy, 236

Halobetasolcream, 167ointment, 63, 70, 167propionate, 164

Haplotypes, genetic, 228Hemorrhages, splinter, 223, 225Histopathology, 207HRQOL measure, 15, 26Human immunoglobulin, 216Human leukocyte antigen (HLA)-B27

genetic haplotype, 228Human–mouse monoclonal chimeric

antibody, 216, 233Hydrocolloid

dressings, 176patches, 177

Hydrogel, 177occlusion, 177, 180patches, 176, 180use of, 180

Hydrophilic emollient base, 253Hypercalcemia and hypercalciuria, 60,

67, 252Hyperkeratosis

nail bed, 225subungual, 223, 227

Hyponychial skin, 223Hypothalamic pituitary–adrenal (HPA)

axis suppression, 211, 248

Imidazole antifungals, 199Immune cells, 207Immunogenic inflammatory disease, 107Immunomodulation, cautaneous, 126Immunomodulators, topical, 32, 253Immunopathogenesis, 216Immunosuppression, 26

agent, 236function of, 107properties of, 132, 245

266 Index

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Inflammatory cytokines, 214, 216expression, 215production of, 213

Inflammatory dermatoses,treatment of, 105

Inflammatory fungal infection, 184Inflammatory nail changes, 229Infliximab, 32, 233Ingram method, for inpatient

therapy, 120Intercellular adhesion molecule

interaction, 216–217Interleukin (IL), 43, 107Intertriginous psoriasis, 207, 211Intracellular accumulation, 202Irritation, 66–67

lesional, 66perilesional, 66

Juvenile-onset psoriasis, 229

Keralyt1 gel, 121Keratinocyte

cell cycle, 212differentiation, 252proliferation, 212retinoid effects on, 92

Keratoderma blennorrhagicum, 184, 187Keratolytics

agents of, 122, 188, 235–236uses of, 33

Koebner phenomena, 184, 186, 233Koebner reactions, 139Koo–Menter Psoriasis Instrument

(KMPI)components of, 10discussions on, 27PQOL-12 score calculation within, 26quality-of-life measure for, 13use in psoriasis, 27

Leukocyte function-associated antigen(LFA), 234

Leukonychia, 225, 226

Lichenplanopilaris, 197simplex chronicus, 180striatus, 230

Lidex1, 95Light therapy, 213Likert-type scale, 14Linear psoriasis, 230Linear verrucous epidermal nevus, 230Liquor carbonis detergens

(LCD), 116, 253Liver biopsy, 215Lupus erythematodes, 197Lymphoid malignancies, 213Lymphoma, theoretical risk of, 111Lymphoproliferative disorders, 216

Maxacalcitol, 59Maxiflor1, 95Messenger RNA (mRNA),

transcription of, 42Methotrexate, 32, 127, 155, 189, 214

therapy, 66, 215topical, 188

Mid-matrix disease, 5–6, 154, 225Minimal erythema dose (MED)

testing, 129, 151Minimally important difference (MID)

of PQOL-12 score, 24, 26Minimal phototoxicity dose (MPD), 135Mometasone furoate and salicylic

acid ointment, combinationtherapy of, 121

Mometasone furoate monotherapy, 95Muscular skeletal pain, 177

Nailallergic contact dermatitis in, 229–230bed

hyperkeratosis, 225psoriasis, 226

biopsy, 231fold plaques, 226growth center, 223inflammatory changes, 229

Index 267

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[Nail]matrix, 222, 223

psoriasis, 232penetration, 235pitting, 184, 223psoriatic changes, 222sandpaper, 223

Nail psoriasis, 99childhood versus adult onset, 228–229clinical manifestations of, 224diagnostic challenge, 229–231diagnostic procedure, 231manifestations of, 222–226treatments for, 231–236

Nail psoriasis severity index (NAPSI), 231scoring system, 232scoring table, 232uses of, 231

NAPSI. See Nail psoriasis severity indexNarrowband ultraviolet B (NB-UVB)

treatment, 188, 191Nephrotoxicity, 215Nonsteroidal anti-inflammatory

agents, 177Nonsteroidal preparations, 247Nuclear factor of activated T cell

(NF-ATc), 107, 156Nuclear hormone receptors, 245, 251Nuclear retinoid receptors, 212Nuclear transcription factor, 156

Oil spots, 225, 226Oily sebaceous glands, 66Ointment

betamethasone dipropionate, 76betamethasone dipropionate/

calcipotriene, 77betamethasone valerate, 62calcipotriene, 76–77calcipotriol, 59corticosteroid/calcipotriene, 76fluocinonide, 62halobetasol, 63, 70

Oligoarthritis, asymmetric, 227OLUX1, 70

foam, 168

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

Palmoplantar psoriasisdiagnosis of, 184phototherapy, 188–189systemic therapy, 189–190topical therapy of, 185–188treatment, 185treatment algorithm for, 191treatment approach for

therapy of, 190–192Palmoplantar pustulosis, 185Parakeratosis pustulosa, 230Parakeratotic cells, 223, 225Paronychial skin, 184Periodic-acid–Schiff stain, 229Perioral dermatitis, 248Photoaging, 136Photocarcinogenesis, 136Photochemotherapy, 189Photodermatoses, 128Photodynamic therapy, 202Photoprotective effects, 256Photosensitivity, 152

drug-induced, 128Phototheraphy, 125, 188–189,

202, 236, 256and calcipotriene, 64combinations, 148directed, 189mechanism of, 126narrowband ultraviolet B (UVB), 64psoralen and ultraviolet A (PUVA), 64targeted (localized), 137

advantages and disadvantagesof, 140

adverse effects for, 141combination therapy of, 140contraindications of, 140dose and administration for, 140

268 Index

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[Phototheraphy]efficacy of, 139indications for, 140mechanism of action of, 137

ultraviolet 1advantages and disadvantages

of, 142adverse effects of, 142combination therapy for, 142contraindications, 142dose and administration of, 142efficacy of, 141indications of, 142

ultraviolet A (UVA), 65ultraviolet B (UVB)

absolute contraindications for, 128advantages and disadvantages

of, 128adverse effects for, 130contraindications for, 128dose and administration for, 129indications of, 128irradiation of, 128as monotherapy, 126relative contraindications of, 128

Phototoxic reactions, 136Pimecrolimus

an ascomycin derivative, 106ointment, 107

Pityriasis amiantacea, 197Placebo, 62, 65Plaque psoriasis, 107, 187, 202, 247

anthralin treatment regimensof, 120

chronic, 207treatment of, 91

fluocinonide cream in, 93Plaques, 184

chalky, 225nail fold, 226

Polyarthritis, symmetric, 227Potassium hydroxide preparation, 185Potencies, range of, 33Potential dose-sparing effects., 252PQOL. See Psoriasis Quality-of-Life

QuestionnaireProtein mediators, 43

Protocolskin-type–based, 135UVA dose, 134

Pseudoteigne amiantacee, 196Psoralen and ultraviolet A (PUVA), 148,

235–236absolute contraindications, 133bath, 149combination therapy for, 131contraindications, 133cream, 149efficacy of, 131indications of, 132photochemotherapy, 131and Tar/Anthralin, 153and topical steroids, 153

Psoralens, 131Psoriasis

arthritis, 13calcipotriene application in, 68candidacy for systemic therapy for, 14categorization of, 5chronic plaque, 207combination, rotational, and

sequential therapy for, 2, 37–38cutaneous, 226definition of, 29effect of, 207erythrodermic, 207eyelid, therapy of, 110facial and intertriginous, 108factors of, 30familial history of, 229foundation, 4general approach to, 3inflammatory erythrodermic

forms of, 252intertriginous, 207, 211joint symptoms of, 13KMPI use in, 27linear, 230localized

outcomes of, 6treatment of, 5–6

measuring compliance in, 47medications for, 30, 32mild, 5

Index 269

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[Psoriasis]modalities for, 147nail, 99, 224nail bed, 226nail matrix, 232narrowband ultraviolet B

(UVB) for, 2palmar-plantar, 31pathogenic causes of, 92patients

compliance in, 5–6, 47indication of, 13psychosocial needs of, 3–5recalcitrant, remission time

of, 118self-assessment in, 10–13

phototherapy for, 2, 14, 31physician assessment in, 13physician’s approach to, 4pimecrolimus, use of, 109plaque, 91, 107, 109, 110, 202, 247plaque evaluation of, 64pustular, 108scalp, 5, 116, 195, 228severe, 5severity, 13strength of agent for, 36tazarotene application in, 99–100Temovate1, 176therapies, categories of, 163topical tacrolimus for, 54

use of, 109topical therapies for, 1, 32, 115

algorithm of, 33treatment of, 106, 116, 245

agents in, 5anthralin in, 119–121calcipotriene in, 1with corticosteroids in, 1–2, 41effective agents in, 1–2inverse, 108lactic acid in, 122mild-to-moderate, 119–121salicylic acid in, 121–122tazarotene in, 1

treatment phasetiming of, 167–168

[Psoriasis]types of, 31vehicle for, 35vitamin D

analogs in, 1and vitamin A analogues in, 5

Psoriasis Activity and Severity Index(PASI), 15, 30–31, 77, 116, 150,199, 251

of Goeckerman patients, 117reduction in, 78

Psoriasis plaques, 107on face, 109on intertriginous areas, 110

Psoriasis Quality-of-Life Questionnaire(PQOL) items, 10

41 items of, 14, 24application of original, 14–15confirmatory analysis of, 15–16rating of, 14refining and reducing to 12 item

instrument, 1512-item Psoriasis Quality-of-Life

Questionnaire (PQOL-12), 10, 24background on, 14development of, 15item descriptive statistics for, 17, 25minimally important difference (MID)

of, 24, 26multicentered office-based study of, 15

responsiveness of, 24validity and reliability of, 16

psychometric properties of, 15, 18–22responsiveness of, 24score

at baseline and end of treatment,23–25

calculation within KMPI, 26test–retest reliability of, 26

Psoriasis severity scores, 169Psoriasis susceptibility 1 (PSORS1), 185Psoriasis therapies, categories of, 163Psoriatec1, 120Psoriatic arthritis, 227–228

causes of, 32characters of, 227presence or absence of, 31

270 Index

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[Psoriatic arthritis]slowing joint destruction

caused by, 32types of, 227

Psoriatic lesions, 168, 207rebound of, 166risk of, 164

Psoriatic nail changes, 222Psoriatic nail disease,

misdiagnosis for, 229Pulse therapy, 167PUVA. See Psoralen and ultraviolet A

Renal function tests, 60Retinoic acid receptors (RARs), 91–92,

212, 234Retinoid, 189, 234–235, 252

dermatitis, 252oral, 189topical, 187–188, 211

Retinoid receptors, 252types of, 91

Retinoid X receptors(RXRs), 91–92, 212

Rhabdomyolysis, transient, 235Rheumatoid arthritis, 227

Salicylate toxicity, 256signs of, 121

Salicylic acidapplications of, 199keratolytic agent, 121

Salicylic acid gel trials, feature of, 47Salmon patches. See Oil spots.Sandpaper nails, 223Scalp psoriasis, 5, 116, 195, 228

refractory, 255treatment strategies, 202–203

Scanning electron microscopy, 196SCC. See Squamous cell carcinomaSeborrheic dermatitis, 197, 210Sequential therapy, 164, 168, 169

advantage of, 168combination, drug delivery in, 169factors of, 163

[Sequential therapy]as flexible therapeutic strategy, 168phases of, 164second phase of, 169topical, 164–167

Serum calcium level, 60Shampoos, 198–199

clobetasol propionate, 175, 198zinc pyrithion, 198

Short contact therapy, 100Silkis1, 59Skin cancer, risk of, 119Skin cap spray, 48Skin carcinogenesis, 130Skin conditions, treatment of, coal tar

used in, 115Skin irritation, 176

incidence of, 177Skin, paronychial, 184Skin surface temperature, 255Small blood vessels,

vasoconstriction of, 210Splinter hemorrhages, 223, 225Squamous cell carcinomas (SCCs), 135,

213, 214, 230–231Staphylococcus isolates, 197Steroid, 30, 33–34, 232–233

applications of, 37aspects of using, 33chronic effect of, 211class I topical, 64mid–high-potency, 95monotherapy, 77side effect profile of, 166superpotent topical, 166topical, 33

Steroid-like drugs, 232–233Stoughton–Cornell classification system,

210, 245Stratum corneum, 60

thickness of, 186Streptomyces hygropicus var.

ascomyceticus, 106Streptomyces tsukubaensis, 54, 105, 212Striae distensae, 106Subcutaneous (SQ) injections, 233Subungual hyperkeratosis, 223, 227

Index 271

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

T-cell, 42, 126, 233, 234apoptosis, 126infiltration, 212like alefacept, 234

T-cell lymphoma, cutaneous, 111T lymphocytes, 107Tacalcitol, 59Tachyphylaxis, 47, 76, 211Taclonex1, 76Tacrolimus

ointment, 107–108and pimecrolimus use, 111topical, 54, 108

therapy, adverse effects of, 109Tacrolimus binding protein

(FK-BP), 107Tar

black, 116brown, 116coal, 115–119types of, 115

Tazarotene, 34, 234active metabolite of, 92application, 99–100and calcipotriene, 97chemical compatibility

with topical steroid, 96–97chemical structure of, 92and corticosteroids combination, 2combination therapy of, 94–95efficacy and tolerability of, 94gel, 93, 95–96

and clobetasol ointment, 95combination therapy, 96efficacy and safety of, 93treatment success rates for, 93

and mometasone group, 97

[Tazarotene]monotherapy, 93and nail psoriasis, 99in pregnancy, 101and psoralen and ultraviolet A

(PUVA) phototherapy, 98–99,152

symptoms of, 93topical, 187and topical steroid, 94–96and topical steroid-induced skin

atrophy, 96treatment side effects of, 100–101and ultraviolet B (UVB)

phototherapy, 97–98use of, 93–94versus topical steroids, 93

Tazarotene chemical compatibility,with topical steroid, 96–97

Tazarotene gelTazarotenic acid, 92Telangectasia, ear, 106Temovate cream, 176Temperature-sensitive vehicle, 255Therapeutic effects, 252Therapy

combination, 34, 37complications from, 231–236Goeckerman, 116methotrexate, 66rotational, 37sequential, 38short contact, 100topical, 31

amount of, 34occlusion used to, 36techniques to enhance, 36–37

triple combination, 100Thymidylate synthesis, 214TNF-a. See Tumor necrosis

factor-alphaToenails, 223Tolypocladium inflatum gams, 215

advantages and disadvantages of, 133adverse effects, 136dose and administration fo, 133relative contraindications, 133

272 Index

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Topical agents, 187Topical anthralin, 236Topical calcipotriene,

application of, 251Topical corticosteroids, 186–187, 200Topical immunomodulators, 212Topical methotrexate, 188Topical psoralen and ultraviolet A

(PUVA) therapy, 188–189, 191Topical retinoids, 187–188, 211Topical retinoid tazarotene, 200Topical tazarotene, use of, 187Topical vitamin D derivatives, 187Trachyonychia, 223Transforming growth factor (TGF), 212Transient rhabdomyolysis, 235Trimethoxypsoralen (TMP), 127Tumor necrosis factor (TNF), 210Tumor necrosis factor-alpha

(TNF-a ), 233bound etanercept, 233inhibitors, 233, 234molecule, 233

Tumors, cutaneous, 111

Ultravate1, 70, 164Ultraviolet A (UVA)

dose protocol, 134and topical vitamin D, 151

Ultraviolet B (UVB)narrowband, 149and Anthralin, 152

[Ultraviolet B (UVB)]and tazarotene, 151and topical steroids, 153and topical vitamin D, 150radiation treatments, 256sparing effect, 64

Ultraviolet B (UVB) phototherapy, 116,188–189

suberythemogenic doses of, 117and topical medications, 150

Ultraviolet (UV) spectrum, categoriesof, 125

UVA. See Ultraviolet A.UVB. See Ultraviolet B.

Vascular cell adhesion molecule, 216Vasoconstriction, 36Vasoconstrictor assay, uses of, 45Vehicles, 44

types of, 35–36Violaceous papules, 197Vitamin D3 analog, 59

available in United States, 60chemical structure of, 60–61mechanism of action for, 60

Vitamin D derivatives, 187

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

Index 273

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Figure 6.2 Skin irritation from calcipotriene.(See p. 67)

Figure 6.3 Skin irritationfrom calcipotriene. (See p. 68)

Figure 9.1 Telangectasia, ear. (See p. 106) Figure 9.2 Striae distensae.(See p. 106)

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

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

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

Figure 9.3 Psoriasis plaques on face (A) before therapy; (B) after therapy. (See p. 109)

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Figure 14.1 Pretreatment Hydrogelalone. (See p. 177)

Figure 14.2 Posttreatment Hydrogelalone. (See p. 178)

Figure 14.3 Pretreatment Hydrogel/TAC 0.1% cream versus TAC0.1% cream alone. (See p. 178)

Figure 14.4 Posttreatment Hydrogel/TAC 0.1% cream versus TAC0.1% cream alone. (See p. 179)

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

Figure 14.5 Hydrogel/Protopic 0.1% ointment versus Protopic 0.1% ointment alone.(See p. 179)

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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)

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Figure 18.4 Onycholysis in nail psoriasis.(See p. 226)

Figure 18.3 Oil spot in nailpsoriasis. (See p. 225)

Figure 18.2 Pitting in nail psoriasis. (See p. 225)

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

Figure 19.4 Lewis technique.(See p. 247)

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

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Figure 19.7 Tinea incog-nito. (See p. 251)

Figure 19.8Retinoid dermatitis.(See p. 253)

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

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