Treatments for Skin of Color E-Book
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Description

Written to address conditions specifically associated with ethnic disparities in skin types, Treatments for Skin of Color, by Susan C. Taylor, Sonia Badreshia, Valerie D. Callender, Raechele Cochran Gathers and David A. Rodriguez helps you effectively diagnose and treat a wide-range of skin conditions found in non-white patients. Presented in an easy-to-use, templated format, this new reference encompasses medical dermatology and cosmetic procedures and provides you with evidence-based first and second line treatment options. Practical tips and other highlighted considerations minimize the risk of potential pitfalls. A dedicated section examines alternative therapies, some of which have cultural significance and may impact medical outcomes. An abundance of vivid color images and photos provide unmatched visual guidance for accurate diagnosis and treatment.

  • Get information not found in mainstream dermatology references. Essential medical dermatology and cosmetic procedures as well as evidence-based first and second line treatment options provide you with specific information to treat a full range of conditions found in skin of color.
  • Offer your patients the best care and avoid pitfalls. Evidence-based findings and practical tips equip you with the knowledge you need to recommend and discuss the most effective treatment options with your patients.
  • Broaden your understanding of complementary and alternative medicine (CAM) used by your patients. A special section examines the cultural significance and impact on medical outcomes caused by these alternative therapies.
  • Spend less time searching with easy-to-use, templated chapters focused on visual identification and diagnosis of diseases across all skin tones, and recommended treatment options.
  • Make rapid, confident decisions on diagnosis and treatment by comparing your clinical findings to the book’s extensive collection of 270 detailed illustrations.

Sujets

Ebooks
Savoirs
Medecine
Médecine
Acné rosacea
United States of America
Generalized granuloma annulare
Localized granuloma annulare
SAFETY
Oncology
Alopecia mucinosa
Systemic lupus erythematosus
Pseudopelade of Brocq
Myocardial infarction
Skin physiology
Photocopier
Acne
List of cutaneous conditions
Systemic autoimmune disease
Lupus erythematosus
Papulosquamous disorder
Lichen nitidus
Benignity
Resource
Medical procedure
Mycophenolate mofetil
Granuloma annulare
Laser surgery
Erythema nodosum
Bullous pemphigoid
Data analysis
Adverse event
Atopic dermatitis
Dermatitis
Alopecia totalis
Dyshidrosis
Mycosis fungoides
Melasma
Neoplasm
Lichen sclerosus
Hyperpigmentation
Chapter (books)
Dermatomyositis
Erythema multiforme
Nevus
Urticaria
Lichen planus
Benzoyl peroxide
Cutaneous conditions
Melanoma
Light therapy
Basal cell carcinoma
Azithromycin
Random sample
Psoriatic arthritis
Amyloidosis
Erythema
Glucocorticoid
Sulfonamide (medicine)
Physician assistant
Seborrhoeic dermatitis
Itch
Folliculitis
Granuloma inguinale
Chancroid
Biopsy
Hypersensitivity
Lesion
Sarcoidosis
Immunosuppressive drug
Clinical trial
Isotretinoin
Internal medicine
Alopecia
General practitioner
Alopecia areata
Keloid
Impetigo
Acne vulgaris
Dermatology
Acrochordon
Philadelphia
Melanocytic nevus
Diabetes mellitus
Infection
Vehicle
Data storage device
Radiation therapy
Privatization
Pediatrics
Mechanics
Infectious disease
Erythromycin
Chemotherapy
Alternative medicine
Cyclophosphamide
Pemphigus
Coral
Doxycycline
Acupuncture
Hydroquinone
Acanthosis nigricans
Shampoo
Méthotrexate
Blister
Vitiligo
Cortisone
Azathioprine
Electronic
Minocycline
Prednisone
Papule
Hair
Psoriasis
London
Copyright

Informations

Publié par
Date de parution 08 février 2011
Nombre de lectures 2
EAN13 9781437736168
Langue English
Poids de l'ouvrage 3 Mo

Informations légales : prix de location à la page 0,0439€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Treatments for Skin of Color

Susan C Taylor, MD
Assistant Clinical Professor of Dermatology, College of Physicians and Surgeons, Columbia University, Society Hill Dermatology, Phildelphia, PA, USA

Raechele Cochran Gathers, MD
Senior Staff Physician, Henry Ford Hospital, Multicultural Dermatology Center, Detroit, MI, USA

Valerie D Callender, MD
Associate Professor of Dermatology, Howard University College of Medicine, Washington DC, USA, Callender Skin and Laser Center, Glenn Dale, MD, USA

David A Rodriguez, MD
Voluntary Associate Professor, Dermatology and Cutaneous Surgery, University of Miami, Medical Director, Dermatology Associates and Research, Coral Gables, FL, USA

Sonia Badreshia-Bansal, MD
Clinical Instructor, Department of Dermatology, University of California San Francisco, Elite MD, Inc, Advanced Dermatology, Laser, and Plastic Surgery Institute, Danville, CA, USA
Saunders
Front Matter

Treatments for Skinof Color
Susan C Taylor MD
Assistant Clinical Professor of Dermatology
College of Physicians and Surgeons
Columbia University
Society Hill Dermatology
Phildelphia, PA, USA
Sonia Badreshia-Bansal MD
Clinical Instructor
Department of Dermatology
University of California San Francisco
Elite MD, Inc
Advanced Dermatology, Laser, and Plastic Surgery Institute
Danville, CA, USA
Valerie D Callender MD
Associate Professor of Dermatology
Howard University College of Medicine
Washington DC, USA
Callender Skin and Laser Center
Glenn Dale, MD, USA
Raechele Cochran Gathers MD
Senior Staff Physician
Henry Ford Hospital
Multicultural Dermatology Center
Detroit, MI, USA
David A Rodriguez MD
Voluntary Associate Professor
Dermatology and Cutaneous Surgery
University of Miami
Medical Director
Dermatology Associates and Research
Coral Gables, FL, USA
   Edinburgh, London, New York, Oxford, Philadelphia, St Louis, Sydney, Toronto
Acquisitions Editor: Claire Bonnett/Russell Gabbedy
Development Editor: Nani Clansey
Editorial Assistant: Poppy Garraway
Project Manager: Beula Christopher
Design: Charles Gray
Illustration Manager: Bruce Hogarth
Illustrator: Gillian Richards
Marketing Manager: Richard Jones
Copyright

SAUNDERS is an imprint of Elsevier Inc.
© 2011, Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions .
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).


Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
British Library Cataloguing in Publication Data
Treatments for skin of color.
1. Skin – Diseases – Treatment. 2. Pigmentation disorders – Treatment. 3. Human skin color.
I. Taylor, Susan C.
616.5′0089 – dc22
ISBN-13: 9781437708592
Library of Congress Cataloging in Publication Data
A catalog record for this book is available from the Library of Congress


Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Preface
There are many complexities associated with selection of appropriate treatment for cutaneous diseases. These complexities increase when selecting treatment for patients with skin of color due to structural and functional differences in their skin and hair as well as differing adverse event profiles. Treatment for Skin of Color is an important resource that will allow the practicing clinician to quickly identify evidence-based treatment options for their skin of color patients. The scope of the book is extensive beginning with medical dermatology followed by follicular disorders, tumors, cosmetics and concluding with alternative medicine. Each therapy covered has been assigned an evidence level from A (the strongest scientific evidence) to E (anecdotal case reports) reflecting the amount of published evidence available to support its use.
The truly outstanding authors of Treatment for Skin of Color, to whom I am indebted, were chosen for this project based upon the strength of their clinical skills, and their ability to educate and present information in an organized, succinct and easily absorbable manner. The work of Drs. Rodriguez, Gathers, Badreshia-Bansal, and Callender with diverse patient populations coupled with their clinical research experience have allowed us to produce a unique resource.
When a question or therapeutic dilemma arises in a teaching clinic or private office setting, Treatment for Skin of Color is a quick reference for either the dermatology resident or the more experienced clinician. Additionally, by providing extensive references, it provides the first step for a seamless in-depth look into topics of interest.

Susan C. Taylor, MD
List of Contributors

Sonia Badreshia-Bansal, MD, Clinical Instructor Department of Dermatology University of California San Francisco Elite MD, Inc Advanced Dermatology, Laser, and Plastic Surgery Institute Danville, CA, USA

Vivek Bansal, MD, Medical Director of Plastic Surgery Elite MD, Inc Advanced Dermatology, Laser, and Plastic Surgery Institute Danville, CA, USA

Valerie D. Callender, MD, Associate Professor of Dermatology Howard University College of Medicine Washington DC, USA Callender Skin and Laser Center Glenn Dale, MD, USA

David Robert Crowe, MD, Dermatology Resident Department of Dermatology University of Cincinnati Cincinnati, OH, USA

Erica Chon Davis, MD, Dermatology Research Fellow Callender Skin and Laser Center Glenn Dale, MD, USA

Vijay K. Garg, MD MNAMS, Professor and Head of Department Department of Dermatology Maulana Azad Medical College New Delhi, India

Raechele Cochran Gathers, MD, Senior Staff Physician Henry Ford Hospital Multicultural Dermatology Center Detroit, MI, USA

Hugh Morris Gloster, Jr., MD, Professor of Dermatology Director of Dermatologic Surgery and Mohs Surgery University of Cincinnati Cincinnati, OH, USA

Candrice R. Heath, MD, Physician Children’s Healthcare of AtlantaAtlanta, GA, USA

Erica Mailler-Savage, MD, Clinical Instructor Dermatology Department University of Cincinnati Cincinnati, OH, USA

Vivek Nair, MD, Senior Resident Department of Dermatology Maulana Azad Medical College New Delhi, India

Vic A. Narurkar, MD FAAD, Chairman Department of Dermatology California Pacific Medical Center San Fransisco, CA, USA

Janet L. Nelson, MS Lac, Practitioner of Asian Medicine Elite MD, Inc Advanced Dermatology, Laser, and Plastic Surgery Institute Danville, CA, USA

Ninad Pendharkar, MD, Dermatology Resident Penn State, College of Medicine Department of Dermatology Milton S. Hershey Medical Center Hershey, PA, USA

Crystal Y. Pourciau, MD MPH, Resident Physician Department of Dermatology Henry Ford Hospital Detroit, MI, USA

David A. Rodriguez, MD, Clinical Assistant Professor University of Miami School of Medicine Dermatology and Cutaneous Surgery Miami, FL, USA

Rashmi Sarkar, MD MNAMS, Associate Professor Department of Dermatology Maulana Azad Medical College New Delhi, India

Surabhi Sinha, MD MNAMS DNB, Senior Resident Department of Dermatology Maulana Azad Medical College New Delhi, India

Sumayah J. Taliaferro, MD, Dermatologist Private Practice Metro Atlanta Dermatology Atlanta, GA, USA

Matthew Joseph Turner, MD PhD, Dermatology Resident Department of Dermatology University of Cincinnati Cincinnati, OH, USA

Janelle Vega, MD, Dermatology Resident University of Miami Miller School of Medicine Miami, FL, USA
Evidence Levels
Each therapy covered has been assigned a letter from A (most evidence) to E (least evidence) signifying the amount of published evidence available to support its use. The following table shows the criteria used in making this classification.
A DOUBLE-BLIND STUDY
At least one prospective randomized, double-blind, controlled trial without major design flaws (in the author’s view)
B CLINICAL TRIAL ≥ 20 SUBJECTS
Prospective clinical trials with 20 or more subjects; trials lacking adequate controls or another key facet of design, which would normally be considered desirable (in the author’s opinion)
C CLINICAL TRIAL < 20 SUBJECTS
Small trials with fewer than 20 subjects with significant design limitations, very large numbers of case reports (at least 20 cases in the literature), retrospective analyses of data
D SERIES ≥ 5 SUBJECTS
Series of patients reported to respond (at least 5 cases in the literature)
E ANECDOTAL CASE REPORTS
Individual case reports amounting to published experience of less than 5 cases
Acknowledgements
Each of us had the invaluable opportunity to collaborate with extraordinary colleagues on various chapters of this book. We thank them for their expertise and commitment to making this book a success.
We also thank Claire Bonnett of Elsevier Publishing who guided this project from the very beginning and Nani Clansey and Beula Christopher for their assistance in completing this extensive project.
Drs. Taylor, Badreshia-Bansal, Callender, Gathers, and Rodriguez
Introduction
Each day in dermatology practices and clinics throughout the United States, we find ourselves increasingly challenged as we attempt to select the most appropriate treatments for our skin of color patients. Our challenges are two-fold. First, in the United States, the number of individuals with skin of color has increased significantly and continues to do so. Those who were previously considered in the minority, by the year 2056 will become the majority of US citizens. Thus, we are increasingly encountering skin of color patients including those with more complicated and difficult to treat dermatologic disorders. Secondly, differences in the skin and hair of individuals with skin of color have important implications regarding treatment selection, success and sequelae. Treatment for Skin of Color is designed to assist and guide clinicians in the selection of the best therapeutic options for their skin of color patients, assess the likelihood of success, and educate regarding common and unexpected adverse events.
Who is the patient that we are primarily addressing in Treatment for Skin of Color ? For the purposes of this book, we are defining skin of color patients as those who have Fitzpatrick Skin Phototypes IV through VI ( Table 1 ). Thus, we are concentrating on individuals with darker skin hues including patients with light brown, brown and black skin tones as compared to patients with white skin tones.
Table 1 Fitzpatrick Skin Phototypes and Corresponding Color Hues Type Description Type I Always burns, never tans (white skin tones) Type II Always burns, minimal tan (white skin tones) Type III Burns minimally, tans moderately and gradually (white skin tones) Type IV Burns minimally, tans well (light brown skin tones) Type V Rarely burns, tans deeply (brown skin tones) Type VI Never burns, tans deeply (dark brown/black skin tones)
Additionally, individuals of several racial and ethnic groups are highly represented in the group of patients with darker skin hues including those of Southeast and South Asian, Latino or Hispanic, African, and Native American descent. Although there is clearly variability in skin hue amongst individuals of these racial and ethnic groups, many have darker skin hues.
Why is it important to distinguish skin of color patients from others when considering treatment options? Fundamental structural and functional differences exist between individuals with skin of color and those with white skin tones. These differences may have a direct effect upon a clinician’s selection of appropriate treatment as well as for the rate of success of the treatment and occurrence of adverse effects. Key differences involve melanin content and pigmentation, fibrosis and scarring, and tightly coiled hair and follicular disorders, to name just a few. For example, facial seborrheic dermatitis is a common cutaneous disorder in individuals of all skin types. However, because of the lability of melanocytes in individuals with darker skin tones, post-inflammatory hypopigmentation is often the presenting complaint in skin of color seborrheic dermatitis patients. In this patient population, treatment considerations will include agents that simultaneously treat the seborrheic dermatitis as well as the post-inflammatory hypopigmentation such as lower potency corticosteroids or topical immune modulators. Additionally, patients should be counseled that the pigmentary alteration is temporary and does not represent the more serious disorder, vitiligo. Furthermore, for patients with concomitant scalp seborrheic dermatitis, daily shampooing is often not the most appropriate treatment given the tightly coiled hair with low water content and increased fragility of this population. Rather, the addition of daily topical treatment agents coupled with once weekly shampooing often yields appropriate treatment results and avoids potential adverse events.
Often, adverse event profiles are different in skin of color patients. Consequently, the selection of treatment may vary. As an example, a disorder in which liquid nitrogen is an accepted treatment for white skin hues may not be the appropriate treatment for skin of color patients due to the sequelae of hypopigmentation or depigmentation. Additionally, cosmetic procedures, such as laser hair removal may need to be performed with a lower fluence or a particular laser may be required given the propensity of skin of color toward laser induced hyperpigmentation.
Some disorders may occur at increased frequency or even exclusively in skin of color patient populations. An important example is central centrifugal cicatricial alopecia (CCCA). Whereas alopecia areata is covered in general treatment books, central centrifugal cicatricial alopecia is usually not included. CCCA appears to be responsible for more cases of scarring alopecia in African American women as compared to all other forms of scarring alopecia combined. For this disorder, understanding treatment selection, success and sequelae is critically important. Treatment for Skin of Color will provide insight into these types of disorders.
Likewise, there are differences in the occurrence of systemic disorders in certain skin of color populations. Hypertension and diabetes affect individuals of African and Latino descent disproportionately as compared to those of Caucasian descent. One would expect increased dermatologic disorders related to these disorders. Examples would include disorders such as drug-induced eruptions which may present differently in skin of color patients, such as photodistributed hyperpigmentation.
Finally, the definition of treatment success may vary with skin of color patients as compared to those of Caucasian descent. Skin of color patients may view acne as unsuccessfully treated if post-inflammatory hyperpigmentation (PIH) remains after papules, pustules and comedones have resolved. Therefore, treatment of PIH is as important as treatment of the acne in skin of color populations. Either the selection of topical agents that can simultaneously address acne and PIH, or the simultaneous use of acne and PIH agents are required in this population.

How should you use this book?
Treatment for Skin of Color is a great resource that should not be read once and then filed away in a bookcase. Rather, it should be kept near you in your practice or clinic to be referred to on a daily basis. It will provide you with the most up to date treatment recommendations and you will find that it will be particularly helpful as you navigate treatment dilemmas. In addition, under each disease, you will find two invaluable sections: Commonly Encountered Pitfalls in Skin of Color and Special Management and Counseling Considerations. These sections provide diagnostic pearls, examples of potential hindrances to achieving treatment goals and how to avoid them, and effective ways to counsel your skin of color patient.

Organization of the book
Treatment for Skin of Color is organized into six easy to use sections. Pediatric perspectives on treatment have been added at the end of certain sections.
• Medical dermatology
• Pigmentary disorders
• Follicular disorders including alopecia
• Tumors benign and malignant
• Cosmetics
• Alternative medicine.
In each section, treatment will be outlined specifically with your skin of color patients in mind. Additionally, each treatment will be evaluated and assessed based upon the current evidence available in the literature. The evidence level scale utilized in this book is one that you may be familiar with as it encompasses five grades, A through E.
A Double blind, control trial
B Clinical trial involving more than 20 subjects
C Clinical trial involving fewer than 20 subjects
D Case series involving more than 5 subjects
E Anecdotal case reports involving fewer than 5 subjects.
As you will see, there is a relative paucity of data for the treatment of certain diseases that occur in your skin of color patients. In recent years, the FDA has required populations of diverse subjects in pivotal trials for new drugs and devices. Existing clinical trials or case series that include skin of color patients, when available, have been cited for each treatment. Nevertheless, there are many disorders in which there are no clinical trials or case reports that include skin of color subjects. In these instances, we rely on anecdotal case reports, the experience of skin of color experts or experience with non-skin of color patients.
Unlike other books that provide a guide to treatment, we thought it important to include a section on complementary and alternative medicine (CAM) because of its importance to many skin of color populations. Even if you do not suggest or prescribe to these particular treatments, the CAM section in this book will provide a firm foundation for you to understand the fundamentals of these treatments. As you will learn in this chapter, Americans spend $34 billion dollars annually on complementary and alternative medicine. CAM’s use by adults with dermatologic disorders in the US has been estimated at between 50% and 62%. It has been estimated that in skin of color patients, 50% of Native Americans, 40% of Asians, 25% of Blacks and 25% of Hispanics utilize some form of CAM. This section will provide insight and guide you as to treatments that your patients may already be participating in.
We trust that you will find Treatment for Skin of Color a valuable and trusted resource. The treatment sections offer first-line, second-line and third-line recommendations which will provide the entire scope of available therapeutic options. We trust that Treatment for Skin of Color will allow you to select the most effective and safest treatments for your skin of color patients.
Susan C Taylor, MD
Table of Contents
Front Matter
Copyright
Preface
List of Contributors
Evidence Levels
Acknowledgements
Introduction
Part 1: Medical Dermatology
Chapter 1: Acneiform Disorders
Chapter 2: Bullous and Pustular Disorders
Chapter 3: Collagen Vascular Diseases
Chapter 4: Eczematous Disorders
Chapter 5: Granulomatous Disorders
Chapter 6: Hypersensitivity and Allergic Disorders
Chapter 7: Infectious Diseases
Chapter 8: Lichenoid Disorders
Chapter 9: Papulosquamous Disorders
Part 2: Pigmentary Disorders
Chapter 10: Hyperpigmented Disorders
Chapter 11: Hypopigmented Disorders
Part 3: Follicular Disorders and Alopecias
Chapter 12: Alopecias
Chapter 13: Follicular Disorders
Part 4: Tumors Benign and Malignant
Chapter 14: Benign Tumors
Chapter 15: Malignant Neoplasms
Part 5: Cosmetics
Chapter 16: Cosmetic Applications
Chapter 17: Cosmetic Treatments
Part 6: Complementary and Alternative Medicine
Chapter 18: An Overview of Complementary and Alternative Medicine
Index
Part 1
Medical Dermatology
1 Acneiform Disorders

Sonia Badreshia-Bansal, Vivek Bansal

Acne 3
Acne vulgaris 3
Pomade acne 12
Steroid acne 13
Pediatric perspectives: Infantile acne 13
Pediatric perspectives: Neonatal acne (acne neonatorum) 14
Acne rosacea 14
Hidradenitis suppurativa 19
Perioral dermatitis 21

Acne

Acne vulgaris
Acne vulgaris is a multifactorial disorder of the pilosebaceous unit. 1 - 4 The pathogenesis involves a complex interaction of multiple internal and external factors. The four main factors that cause acne include excess sebum from increased androgenic hormonal stimulation (especially at adrenarche), follicular epidermal hyperkeratosis with subsequent plugging of the follicle, elevated P. acnes population, and subsequent inflammation. 1 - 4 Medications that can precipitate acneiform lesions include corticosteroids, lithium, some antiepileptics, and iodides. 5 Genetic factors may also play a role. 6
Acne vulgaris is a common skin disease that affects over 85% of people at some time point. It is also an extremely common dermatological problem among ethnic patients and is found predominantly during adolescence. 7 Acne may be present in the first few weeks and months of life while a newborn is still under the influence of maternal hormones and when the androgen-producing portion of the adrenal gland is disproportionately large. 8 Neonatal acne resolves spontaneously. Adolescent acne commonly begins prior to the onset of puberty, when the adrenal gland begins to produce and release higher levels of the androgen hormone. However, acne is not limited to adolescence – 12% of women and 5% of men at 25 years of age have acne. By 45 years of age 5% of both men and women are still affected. 7
The diagnosis of acne is primarily clinical and may be characterized by comedones, papules, pustules, nodules and cysts. Acne vulgaris affects areas of the skin more densely populated with sebaceous follicles, including the face, upper chest, and back. A severe inflammatory variant of acne, acne fulminans, can be associated with fever, arthritis, and additional systemic symptoms. Darker skin types represent a particular clinical challenge for dermatologists treating acne due to the higher risk of post-inflammatory hyperpigmentation (PIH), hypertrophic scarring, and keloids ( Fig. 1.1 ). Additionally, acne lesions may lead to permanent scarring. Although the overall prognosis is good, acne can result in long-lasting psychosocial impairment and physical scarring.

Figure 1.1 This African-American patient presents with active acne and PIH.
The differential diagnosis of acne is extensive. During the neonatal period, it includes transient sebaceous hyperplasia, miliaria, and Candida. In adolescence and adulthood, appendageal tumors such as trichoepithelioma, trichodiscomas, cysts, steatocystoma multiplex, and eruptive vellus hair cysts should be considered in the differential diagnosis. Bacterial folliculitis, pseudomonas folliculitis (if on the lower trunk), rosacea, pseudofolliculitis barbae, acne keloidalis nuchae, perioral dermatitis (if previously treated with topical corticosteroids), and steroid acne (if treated with oral corticosteroids) may also be considered. Cultures of skin lesions to rule out Gram-negative folliculitis are necessary when acne is unresponsive to treatment or when improvement is not maintained with treatment.
As with all patients, therapy should be directed toward the known pathogenic factors. The grade and the severity of the acne determines which of the following treatments is most appropriate ( Fig. 1.2 ). When using a topical or systemic antibiotic, a benzoyl peroxide should be utilized in conjunction to reduce the emergence of bacterial resistance. The patient’s skin color, skin type, and propensity for PIH can influence choice of formulation of a topical regimen. The ideal acne treatment for ethnic skin would specifically target the inflammatory process as well as the resulting hyperpigmentation.

Figure 1.2 Acne algorithm. 20, 27 - 31
There are several components to the treatment of mild acne including topical retinoids, antibiotics and benzoyl peroxide. Topical retinoids, including tretinoin, adaalene and tazarotene, are comedolytic, normalize follicular hyperkeratinization, and are anti-inflammatory. 9 - 11 Retinoids may enhance the penetration of other topical products and medications. 12 They are known to thin the stratum corneum, cause irritation, and increase the risk of sunburn. 13 Therefore, the use of sunscreen is essential. Short contact method and gradual titration may be attempted to increase tolerance and minimize contact irritant dermatitis. 14 Although topical retinoids may result in improvement of PIH, the potential for irritation may provoke further PIH. Each retinoid has unique characteristics. For example, the synthetic retinoid, adapalene is light stable and resistant to oxidation by benzoyl peroxide. 15 Finally, retinoids are known teratogens and contraceptive counseling must be provided to women of childbearing age.
Benzoyl peroxide is an important bacteriostatic agent that exerts its affect through the interaction of oxidized intermediates with elements of bacterial cells. It decreases inflammatory damage by inhibiting the release of reactive oxygen species from polymorphonuclear leukocytes. 16 However, the risk of irritation with subsequent PIH may occur. Benzoyl peroxide is most effective when used in a combination as resistance to this agent has not been reported. 17 - 18
Topical antibiotics are helpful in controlling P. acnes colonization and its pro-inflammatory mediators. The development of resistance is significant when antibiotics are used as monotherapy, and greatly lowered when used in combination treatment with benzoyl peroxide. Clindamycin inhibits bacterial protein synthesis by binding to the 50S ribosomal subunits, causing inhibition of peptide-bond formation. 19 Clindamycin suppresses the complement-derived chemotaxis of polymorphonuclear leukocytes in vitro, thereby reducing the potential for inflammation. 20 Azelaic acid is a naturally occurring dicarboxylic acid which inhibits growth of P. acnes , alters hyperkeratinization and may help to lighten PIH. 21 Sodium sulfacetamide is a generally well tolerated topical antibiotic that restricts P. acnes growth. 22 It is available in a 10% lotion in combination with 5% sulfur with tinted formulations available. Salicylic acids are widely used over-the-counter products for their comedolytic and mild anti-inflammatory ability.
Moderate to severe inflammatory acne unresponsive to a topical combination regimen will require systemic treatment. First-line antibiotic therapy with tetracycline or its derivatives doxycycline and minocycline, suppress growth of P. acnes and are anti-inflammatory. At this time, minocycline is felt to have less antibiotic resistance but increased side effects including nausea, vomiting, esophagitis, yeast infection, and sun sensitivity compared to tetracycline. 23, 24 In addition, minocycline crosses the blood–brain barrier and increases susceptibility to pseudotumor cerebri and also can cause a serum sickness-like reaction, drug-induced lupus, or blue-black pigmentation. 23, 24 Erythromycin has the greatest amount of resistance. 25 Other antibiotics reportedly useful include trimethoprim-sulfamethoxazole, and azithromycin. Hormonal therapies may be effective in the treatment of acne. When hyperandrogenism is suspected, especially in a female patient with dysmennorhea or hirsutism, a hormonal evaluation including total and free testosterone and DHEA sulfate should be performed. Oral contraceptive agents have been shown to be effective in decreasing circulating free testosterone while spironolactone binds the androgen receptor and reduces androgen production. 26 Side effects with spironolactone include breast tenderness, dysmennorhea, and abnormalities in blood pressure.
Severe, scarring acne is best treated with the oral retinoid, 13- cis -retinoic acid. Isotretinoin normalizes follicular hyperkeratinization and causes sebaceous gland atrophy, thus reducing sebum production and producing an unfavorable environment for P. acnes. 9 In patients with marked inflammatory acne, lower starting doses may be indicated to prevent the induction of severe flares during the first month of treatment. 28 In cases of acne fulminans or initial retinoid induced flares, prednisone may decrease the severity of the flare and subsequent exuberant granulation tissue formation. Potential adverse events are numerous and may include generalized xerosis, eczematous dermatitis, and elevated triglycerides, decreased night vision, arthralgias, myalgias, headache, depression, skeletal hyperkeratosis, elevations in liver function tests or an abnormal blood count. Teratogenicity is among the most serious adverse events and pregnancy should not occur during or one month post-treatment with oral isotretinoin. Thorough contraception counseling in females of child bearing age must be performed and two forms of contraception must be used concomitantly.
Several other options may be used adjunctively which include comedone extraction, intralesional injections, chemical peels, and photodynamic therapy. Comedone extraction may improve responsiveness to prescribed comedolytic agents, but inflamed lesions should be avoided. For deep or inflamed cysts, intralesional corticosteroids can be effective. Chemical peels with lipophilic comedolytics such as salicylic acid, glycolic acid, and trichloracetic acid can decrease corneocyte cohesion. 28
The sequela of acne includes acne scarring and PIH which may be improved after the active acne has been treated ( Fig. 1.3 ). Options for acne scarring may include dermabrasion, laser resurfacing, and soft tissue augmentation. PIH will improve with time regardless of therapy. However, resolution can be hastened with vigilant use of sunscreen along with topical skin lightening agents such as hydroquinone, retinoic acid, kojic acid, soy, niacinamide, licorice extract, azelaic acid, glycolic acid, salicylic acid, antioxidants such as vitamin C, as well as chemical peels and lasers. 20

Figure 1.3 Asian patient with acne scarring and biopsy consistent with osteoma cutis.

First-Line Therapies (For Mild to Moderate Acne Vulgaris)

Topical retinoids A Topical benzoyl peroxide A Topical salicylic acid A Topical antibiotics A Topical azelaic acid A Topical sulfur D Topical dapsone A Oral antibiotics A Combination therapy A
The mainstay of acne treatment includes a regimen that targets the four pathogenic factors. There is strong evidence to support the use of retinoids and benzoyl peroxide in every acne regimen. In addition, in mild to moderate acne, topical and oral antibiotics can be considered to reduce the inflammatory component found in ethnic skin which is felt to lead to PIH.
Adapalene in the treatment of African patients. Jacyk WK. J Eur Acad Dermatol Venereol 2001; 15(Suppl 3):37–42.
To assess the efficacy and safety of topical adapalene gel 0.1% as a treatment for acne vulgaris in Black South African patients, an open-label study was performed over a 12-week period. In the 44 subjects completing the trial, adapalene gel 0.1% showed clear efficacy against both inflammatory and non-inflammatory lesions. In two-thirds of cases, patients experienced reductions in both the number of hyperpigmented macules and the density of hyperpigmentation. Adapalene gel 0.1% is an effective, well-tolerated topical therapy for Black patients.
A comparison of adapalene gel 0.1% vs tretinoin gel 0.025% in the treatment of acne vulgaris in China. Tu P, Li GQ, Zhu XJ, Zheng J, Wong WZ. J Eur Acad Dermatol Venereol 2001; 15(Suppl 3):31–36.
In this Chinese patient population, 150 patients with grade II-III acne vulgaris were randomized to 8 weeks of daily treatment with either adapalene gel 0.1% or tretinoin gel 0.025%. Both adapalene and tretinoin produced dramatic reductions in total, inflammatory and non-inflammatory lesion counts, in the range of 69–74% on average. More than 70% of patients in both groups had complete clearance or marked improvement. In general, irritation was mild, but was more common and more severe in the tretinoin group vs the adapalene group.
Tretinoin gel microspheres 0.04% versus 0.1% in adolescents and adults with mild to moderate acne vulgaris: A 12-week, multicenter, randomized, double-blind, parallel-group, phase IV trial. Berger R, Rizer R, Barba A, Wilson D, Stewart D, Grossman R. Clin Ther. 2007 Jun; 29(6):1086–1097.
In this multicenter, double-blind, controlled, parallel-group, Phase IV dose-ranging study, patients with facial acne were randomized to apply either tretinoin gel 0.04% or 0.1% each night for 12 weeks in 156 patients (57.1% white, 19% Black, 2% Asian, 18.6% Hispanic, 2% Native American, 1.3% Other). Both resulted in effective and similar reductions in inflammatory and noninflammatory lesions, likely from its action on the microcomedone, the precusor lesion of acne. However, there was greater reduction in inflammatory lesions with the 0.1% concentration. The 0.4% concentration resulted in fewer side effects such as dryness during the early phase of the treatment, but this was not found to be significant.
A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris. Webster GF, Guenther L, Poulin YP, Solomon BA, Loven K, Lee J. Cutis 2002; 69(2 Suppl):4–11.
The efficacy and tolerability of tazarotene 0.1% gel and adapalene 0.1% gel over 12 weeks was compared in a multicenter, double-blind, randomized, parallel-group study in 145 patients with mild-to-moderate facial acne vulgaris. Compared with adapalene, treatment with tazarotene was associated with a significantly greater incidence of treatment success and significantly greater reductions in overall disease severity, non-inflammatory lesion count, and inflammatory lesion count. However, adapalene demonstrated a superior tolerability profile, especially in the early weeks of therapy. By the end of treatment, patients considered both treatments to be comparably well tolerated.
Although retinoids can improve PIH in ethnic patients, caution must be taken to slowly titrate upward so as to avoid irritant contact dermatitis and subsequent PIH.
Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Ozolins M, Eady EA, Avery AJ, Cunliffe WJ, Po AL, O’Neill C. Lancet 2004; 364(9452):2188–2195.
In this randomized, observer-masked trial, participants with facial and/or truncal acne were allocated to one of five antibacterial regimens. Of approximately 130 participants for each regimen, moderate or greater improvement at 18 weeks was reported in about 55% of participants assigned either oral oxytetracycline or oral minocycline plus topical placebo; in an average of 63% assigned topical benzoyl peroxide or topical erythromycin and benzoyl peroxide in a combined formulation plus oral placebo; and in an average of 63% assigned topical erythromycin and benzoyl peroxide separately. Most improvement occurred in the first 6 weeks. Differences in efficacy were small and, generally not statistically significant. In particular, modified-release minocycline, the most expensive regimen, was not found to be superior. Benzoyl peroxide alone was the most cost-effective regimen for mild to moderate facial acne and represents the best value antimicrobial for first-line use if irritant potential is limited.
Comparison of the efficacy and safety of a combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris. Leyden JJ, Berger RS, Dunlap FE, Ellis CN, Connolly MA, Levy SF. Am J Clin Dermatol 2001; 2(1):33–39.
Combined use of benzoyl peroxide with topical antibiotics has been shown to decrease the emergence of antibacterial resistant species. To determine the efficacy and safety of a combination benzoyl peroxide plus clindamycin gel, a 10-week, multicenter, double-blind trial of 480 patients with moderate to severe acne was performed. Patients were randomized to receive twice-daily treatment with 5% benzoyl peroxide plus 1% clindamycin, 5% benzoyl peroxide, 1% clindamycin, or vehicle. Significantly greater reductions in the number of inflammatory and total lesions were demonstrated in patients using combination therapy compared with those using any of its three individual components.
A novel gel formulation of 0.25% tretinoin and 1.2% clindamycin phosphate: efficacy in acne vulgaris patients aged 12 to 18 years. Eichenfield LF, Wortzman M. Pediatr Dermatol. 2009 May-Jun; 26(3):257–261.
This was a subgroup analysis of a phase 3, 12-week, multicenter, double-blind, randomized, placebo-controlled study that compared clindamycin/retinoic acid(CLIN/RA) gel, clindamycin phosphate, tretinoin, and vehicle in 1710 patients aged 12–18 years old (23% non-Caucasian). CLIN/RA is significantly more effective in reducing mean lesion counts for all types of lesions regardless of baseline severity than vehicle, clindamycin, or tretinoin (p < 0.001). The difference in efficacy was significant at or before week 2 when compared with vehicle, week 4 when compared with tretinoin monotherapy, and week 8 when compared with clindamycin monotherapy.
Combination therapy is ideal to offer synergy in their mechanism of action. The medications should penetrate the follicle without causing excessive tolerability problems. The manufacturer of this dual product shows at least 90% of tretinoin particles by count have sizes ≤20 µm and at least 50% have sizes ≤10 µm. In addition, the gel contains a mixture of solubilized and crystalline tretinoin which may impact tolerability by slowing the delivery of tretinoin.
Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. Thiboutot DM, Weiss J, Bucko A, Eichenfield L, Jones T, Clark S; Adapalene-BPO Study Group. J Am Acad Dermatol. 2007 Nov; 57(5):791–799.
This was a randomized, multicenter, double-blind, parallel group study conducted at 36 centers in the United States in 517 patients 12 years and older. Patients were 72% Caucasion, 11% Black, 13% Hispanic, 1% Asian, 3% other. They were randomized in a 2 : 2 : 2 : 1 ratio to receive either adapalene-BPO gel, adapalene gel, BPO gel, or gel vehicle for 12 weeks. The combination therapy regimen consistently provided an additional decrease of inflammatory and noninflammatory lesions, with statistically significant differences in total lesion counts observed as early as the first postbaseline assessment with good tolerability. Total acne lesions were reduced by 51%, inflammatory lesions by 63%, and noninflammatory lesions by 51%.
Combination therapies are highly effective. Retinoids are anticomedogenic, antiinflammatory, and enhance penetration. Adapalene is stable when combined with BPO in the presence or absence of light. Adapalene and tretinoin have been shown to induce a dose-dependent inhibition of toll-like receptor 2 in cultured human monocytes. P acnes acts through the toll-like receptor 2 to induce the production of proinflammatory cytokines. There is likely a synergistic anti-inflammatory action where BPO kills P acnes and adapalene down-regulates the cell surface receptor that P acnes uses to induce cytokine production.
Comparison of a salicylic acid cleanser and a benzoyl peroxide wash in the treatment of acne vulgaris. Shalita AR. Clin Ther 1989; 11(2):264–267.
A 4-week crossover study to compare the efficacy of an acne cleanser containing 2% salicylic acid with that of a 10% benzoyl peroxide wash was conducted in 30 patients with mild-moderate acne vulgaris. A review of four clinical studies and a comedolytic assay attests to the efficacy and safety of 0.5% and 2% solutions of salicylic acid for the treatment of acne vulgaris. Interestingly, patients treated with the salicylic acid cleanser for the first 2 weeks showed a significant improvement in acne, but worsened during benzoyl peroxide therapy over the following 2 weeks. In contrast, patients initially treated with the benzoyl peroxide wash for the first 2 weeks continued to improve with salicylic acid cleanser over the next 2 weeks.
Utilizing combination therapy for ethnic skin. Taylor SC. Cutis 2007; 80(1 Suppl):15–20.
Combination therapy has become the gold standard for the management of acne, particularly for moderate-to-severe cases. In an attempt to treat and prevent PIH, subjects received combination clindamycin 1%-benzoyl peroxide (BPO) 5% topical gel containing glycerin and dimethicone. Subjects were randomized to receive this combination therapy in addition to either a tretinoin microsphere (RAM) gel at concentrations of either 0.04% or 0.1% or adapalene gel 0.1%. There was a trend toward better resolution of hyperpigmentation in the subjects receiving the clindamycin-BPO topical gel in combination with RAM gel 0.04%. Retinoids have anti-inflammatory activity while decreasing microcomedo formation resulting in dual function for acne and PIH.
Early and aggressive treatment of acne and PIH while minimizing side effects is essential for successful treatment in ethnic skin.
Versatility of azelaic acid 15% gel in treatment of inflammatory acne vulgaris. Thiboutot D. J Drugs Dermatol 2008; 7(1):13–16.
Two randomized, multicenter, controlled clinical trials compared the effects of azelaic acid (AzA) 15% gel with either topical benzoyl peroxide 5% or topical clindamycin 1%, using a twice-daily dosing regimen. AzA 15% gel resulted in a 70% median reduction of facial papules and pustules compared with a 77% reduction with benzoyl peroxide 5% gel and a 63% reduction with clindamycin. 93.9% of physicians reported patient improvement after an average of 73.1 days. The majority of patients were more satisfied with AzA than with previous therapies.
Azelaic acid represents a mild but effective treatment option for active acne, the maintenance phase of acne, and in reducing PIH due to its skin lightening properties.
Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. Draelos ZD, Carter E, Maloney JM, Elewski B, Poulin Y, Lynde C; United States/Canada Dapsone Gel Study Group. J Am Acad Dermatol. 2007 Mar; 56(3):439.
Two 12-week, randomized, double-blind phase III studies were conducted under identical protocols to evaluate the efficacy and safety of twice daily dapsone 5% gel monotherapy compared with a vehicle gel control in the treatment of acne vulgaris in 3010 patients (72.9% Caucasian, 14% African American, 9.4% Hispanic, Asian 2.2%, 1.6% other). Although clinical improvement was observed with both inflammatory and noninflammatory lesions, dapsone gel was particularly effective for inflammatory acne lesions. Reductions in inflammatory lesions occurred earlier, within 2 weeks, and were of greater magnitude by the end of treatment. No significant change in hemoglobin or other laboratory values, even among the 44 patients with G6PD deficiencies (glucose-6-phosphate dehydrogenase) was noted.
Potential mechanisms of action of this sulfone medication in acne include antiinflammatory and antimicrobial properties such as direct inhibition of leukocyte trafficking, inhibition of chemical mediators of inflammation, and altered levels and/or activity of propionibacteria located in the upper third of the follicles. Although oral dapsone has been associated with adverse hematologic reactions especially in G6PD, topical formulation has minimal systemic absorption. Although African Americans are more likely to have G6PD deficiency, topical dapsone is considered a safe and well tolerated option.
Topical therapy of acne vulgaris using 2% tea lotion in comparison with 5% zinc sulphate solution. Sharquie KE, Noaimi AA, Al-Salih MM. Saudi Med J 2008; 29(12):1757–1761.
This is a randomized, single-blinded comparative clinical trial in Iraq of 40 patients, ages 13–27 years. 2% tea lotion was statistically significant in decreasing the number of inflammatory lesions in acne vulgaris, while 5% zinc sulphate solution was beneficial, but did not reach a statistical significance. 2% tea lotion was felt to be a good alternative remedy in the treatment of acne vulgaris, and was superior to topical 5% zinc sulphate solution.

Second-Line Therapies (or First-Line Therapies For Moderate to Severe Acne Vulgaris)

Intralesional corticosteroid B Oral antibiotics A Oral contraceptive pills (if clinically hyperandrogenic) A Antiandrogens (if clinically hyperandrogenic) B
Use of more aggressive treatment options including oral antibiotics in conjunction with retinoids and benzoyl peroxide containing products has been observed to be effective in first line therapies for moderate to severe acne or second line therapy for mild to moderate acne. In addition, hormonal flares have been treated effectively with oral contraceptive pills and anti-androgenic agents. Treatment of individual nodulocystic lesions with intralesional corticosteroids is effective.
Intralesional corticosteroids in the treatment of nodulocystic acne. Levine RM, Rasmussen JE. Arch Dermatol 1983; 119(6):480–481.
Triamcinolone acetonide at a concentration of 0.63 mg/mL was as efficacious as the higher concentration of 2.5 mg/mL in the treatment of nodulocystic acne. Lower concentrations of intralesional corticosteroids are effective, while minimizing side effects including skin atrophy. Intralesional steroid injections are most effective as adjunctive treatment for nodulocystic acne when a more rapid response is desired.
Lymecycline in the treatment of acne: an efficacious, safe and cost-effective alternative to minocycline. Bossuyt L, Bosschaert J, Richert B, Cromphaut P, Mitchell T, Al Abadie M. Eur J Dermatol. 2003 Mar-Apr; 13(2):130–135.
A randomized, investigator masked UK study comparing lymecycline and minocycline in two parallel groups of 134 patients with acne vulgaris was conducted. Lymecycline 300 mg day is comparable to minocycline in terms of percent decrease in lesion counts and slightly superior in terms of efficacy compared to lowered dose of lymecycline. Treatment with lymecycline was found to be 4 times more cost-effective than with minocycline.
Doxycycline plus levamisole: combination treatment for severe nodulocystic acne. Ansarin H, Savabynasab S, Behzadi AH, Sadigh N, Hasanloo J. J Drugs Dermatol 2008; 7(8):737–740.
A double-blind, randomized, placebo-controlled trial in 60 Iranian patients with severe and reclacitrant acne vulgaris were randomly administered oral levamisole 2.5 mg/kg/wk (up to 150 mg/wk) plus doxycycline 100 mg daily or 100 mg of oral doxycycline daily and a placebo. This study is the first clinical trial that suggests levamisole as an effective and well tolerated new treatment for severe acne vulgaris.
Optimizing use of oral antibiotics in acne vulgaris. Del Rosso JQ, Kim G. Dermatol Clin 2009; 27(1):33–42.
For moderate to severe facial or truncal disease, the most common oral antibiotics for treating acne vulgaris are the tetracycline derivatives, although macrolide agents such as erythromycin have also been used extensively. Due to increased resistance, efficacy of oral tetracycline and erythromycin has markedly diminished, leading to increased use of doxycycline, minocycline, and other agents, such as trimethoprim/sulfamethoxazole and azithromycin. Oral azithromycin has been reported to be effective in treating acne vulgaris in four open and two investigator-blinded clinical trials, inclusive of 187 subjects and 341 subjects, respectively, using various treatment regimens. Most commonly used regimens included intermittent dosing schedules, such as three 250 mg doses per week, because of a long terminal half-life of 68 hours.
Despite documentation of widespread global prevalence of antibiotic-resistant P acnes, topical and oral antibiotics that have been used extensively over several years, such as topical clindamycin, oral minocycline, and oral doxycycline, continue to show efficacy in acne vulgaris.
These oral treatments are most appropriately used in combination with a topical regimen containing benzoyl peroxide and a topical retinoid. Trimethoprim/sulfamethoxazole may be associated with adverse reactions that are uncommon but potentially severe, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), primarily within the first 1 to 2 months after initiation of therapy, and hematologic reactions, including agranulocytosis, hrombocytopenia, and pancytopenia, when used in high doses or preexisting folic acid deficiency or megaloblastic hematopoiesis.
Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. Shaw JC. J Am Acad Dermatol 2000; 43(3):498–502.
Spironolactone, an established androgen receptor blocker, is successful in treating adult women with acne, but side effects are common at the doses reported in published studies to date. 85 women with acne were treated with low dose spironolactone at 50–100 mg/day, administered either as single-drug therapy or as an adjunct to standard therapies for a maximum of 24 months. Clearing or marked improvement of acne occurred in 66% of patients treated with low doses of spironolactone while 27% showed partial improvement, and 7% showed no improvement.
Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians. Sato K, Matsumoto D, Iizuka F, Aiba-Kojima E, Watanabe-Ono A, Suga H. Aesthetic Plast Surg 2006; 30(6):689–694.
Spironolactone (initial dose, 200 mg/day) was administered orally to 139 Japanese patients (116 females and 23 males) with severe, recurring, or widespread acne. Most female patients exhibited excellent improvement over 20 weeks, although some discontinued treatment because of menstrual disturbances or other reasons. The treatment was less efficacious for the males than for the females, and because gynecomastia developed in three male patients, spironolactone treatment for males was stopped. Drug eruptions and edema in the lower extremities were seen in three patients. Hormonal anti-androgenic treatments can inhibit sebum production and acne. Obtaining this race-specific information is important because Caucasians and Asians respond differently to hormone therapy.
Despite its proven efficacy, other hormonal anti-androgenic treatments have limitations. For instance, cyproterone acetate is potentially carcinogenic, but is still widely used for severe acne in many countries. Flutamide is also restricted due to its hepatotoxicity.
Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Redmond GP, Olson WH, Lippman JS, Kafrissen ME, Jones TM, Jorizzo JL. Obstet Gynecol 1997; 89(4):615–622.
A prospective study of 250 women (84% white, 11% black, 1.7% oriental, 3.4% hispanic) were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial with moderate acne vulgaris. Subjects received either 3 consecutive weeks of active triphasic oral contraceptive treatment followed by 1 week of inactive drug for 6 months or 4 weeks of placebo tablets. Oral contraceptive group was better than placebo for inflammatory lesions, total lesions, and investigator’s global assessment. Free testosterone decreased significantly and sex hormone-binding globulin increased significantly in the oral contraceptive group thereby reducing the androgen stimulus in acne pathogenesis.
A combined oral contraceptive containing 3-mg drospirenone/20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment. Lucky AW, Koltun W, Thiboutot D, Niknian M, Sampson-Landers C, Korner P. Cutis 2008; 82(2):143–150.
This study compared the efficacy of a low-dose combined oral contraceptive containing 3-mg drospirenone and 20-microg ethinyl estradiol administered in a 24-day active pill/4-day inert pill (24/4) regimen and placebo in 534 women with moderate acne vulgaris. Greater reduction was noted from baseline to end point in individual lesion counts (papules, pustules, open and closed comedones) compared with placebo, but did not affect nodule count.
Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. Lucky AW, Henderson TA, Olson WH, Robisch DM, Lebwohl M, Swinyer LJ. J Am Acad Dermatol 1997; 37(5 Pt 1):746–754.
To evaluate the efficacy of a triphasic combination oral contraceptive compared with placebo in the treatment of moderate acne vulgaris, 257 healthy female subjects (82% Caucasian, 9.1% Black, 2.7% Oriental, 5.5% Hispanic, 0.9% Other) with moderate comedonal or inflammatory acne vulgaris were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 weeks of the oral contraceptive containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate followed by 7 days of inactive drug. The mean decrease in inflammatory lesion count was 62.0% and the mean decrease in total lesion count was 53.1% in the oral contraceptive group.


Third-Line Therapies (or First Line Therapies For Severe Acne Vulgaris)

Oral isotretinoin A
The most effective medication in the treatment of severe or resistant acne is oral isotretinoin. However, the close monitoring required can be a limiting factor for patients and the increased regulation of the medication can be a barrier to physicians wishing to prescribe it.
Roaccutane treatment guidelines: results of an international survey. Cunliffe WJ, van de Kerkhof PC, Caputo R, et al. Dermatology 1997; 194(4):351–357.
Twelve dermatologists from several countries reviewed the surveys of 1000 patients. 55% of patients had severe nodular cystic acne or severe inflammatory acne resistant to conventional treatment and 45% of patients had either moderate or mild acne which was either recalcitrant, scarring or psychologically distressing. Treatment was initiated at daily doses of 0.5 mg/kg and increased to 1.0 mg/kg, with the aim of achieving a cumulative dose of > 100–120 mg/kg. Mucocutaneous side effects occur frequently but were manageable while severe systemic side effects were rarely problematic (2%). Significant cost savings when treating acne patients with oral isotretinoin as compared to other treatment modalities were further proven in this study.
This study highlights the important role that oral isotretinoin plays not only in patients with severe disease but also in patients with less severe acne, especially if there is scarring and significant psychological stress associated with their disease. Acne patients should, when appropriate, be prescribed isotretinoin early in their condition to prevent further scarring.

Other therapies

Acne

• Chemical peels
• Photodynamic therapy
• Blue and red light
• Nonablative lasers
• Comedone extraction
• Microdermabrasion

Acne scarring

• Surgery:
– Subcision, punch grafts, dermabrasion

• Lasers:
– Ablative – CO 2 , erbium, radiofrequency fractional resurfacing
– Nonablative – Nd:YAG, IPL, fractional photothermolysis, diode, Er:YAG

• Chemical peels:
– Superficial depth: glycolic, salicylic acid
– Medium depth: Jessner’s, TCA 35%
– Deep peel: Focal trichloracetic acid 95–100%

Keloid scarring

• Silicone gel sheeting
• Intralesional corticosteroids
• Nonablative lasers
• Surgical excision
• Radiation

Post-inflammatory hyperpigmentation

• Topicals:
– Lightening agents (see Chapter 10 )
– Azelaic acid
– Retinoids
– Sunscreens
• Chemical peels
• Lasers
Insight into skin lightening cosmeceuticals for women of color. Badreshia-Bansal S, Draelos ZD, J Drugs Dermatol 2007; 6(1):32–39.
This article highlights the research behind several common skin lightening cosmeceuticals addressing their advantages and disadvantages. Commercially available products are discussed with mechanisms of action including phenolic and non-phenolic compounds with tyrosinase inhibition, inhibition of melanosome transfer, antioxidants, and increased skin turnover. Their synergistic role with sunscreens and corrective cosmetic camouflage that are available over the counter are addressed.

Commonly encountered pitfalls
Acne is the number one reason that the African-American population consults a dermatologist. 32 Acne vulgaris displays histological and clinical differences in people with skin of color compared with Caucasians. 33 Differences may include a trend toward greater P. acnes density and differences in sebaceous gland size and activity. 34 In skin of color acne patients, acne is primarily inflammatory. Surprisingly comedonal lesions in Blacks display marked inflammation and points towards a subcategory of inflammatory comedonal acne which may predispose to PIH. This may be important when selecting appropriate therapy. Of the available topical treatments, benzoyl peroxide is effective as an anti-inflammatory. Retinoids act on both the comedonal and inflammatory components of acne and have skin lightening properties. However, a commonly encountered pitfall with these agents is the occurrence of an irritant contact dermatitis. It is important that dermatologists minimize epidermal irritation when treating skin of color because of the risk of either PIH or postinflammatory hypopigmentation. In Dakar, Senegal, acne patients are commonly treated with benzoyl peroxide and a topical retinoid for their more advanced disease. 4 It is important to note that the use of alternative medicine occurs frequently, particularly in Asian populations, where increasing PIH can occur. 5
The family of tetracyclines are useful in the treatment of acne in skin of color but they are not without adverse events which can lead to common pitfalls. The tetracycline family of antibiotics are useful in the treatment of acne in skin of color as they are anti-inflammatory. However, they are not without adverse events which can lead to pitfalls. Although minocycline has been used safely in this population, it has been reported to cause a drug hypersensitivity syndrome that can resemble infectious mononucleosis, as well as fatalities in the ethnic population. 35 In addition, minocycline can induce generalized dark brown to gray discolorations or dark blue-black macules (localized at sites of inflammation) on the lower legs or sun exposed areas. Doxycycline is an effective treatment, but has photosensitizing properties.
Acne patients with ethnic skin are at an increased risk for developing post-inflammatory hyperpigmentation and keloidal scarring. Treatment approaches for acne in darker skin patients must balance early aggressive intervention with the selection of efficacious and non-irritating agents. For most patients, a combination of topical retinoids, and topical or oral antibiotics, with hydroquinone to control hyperpigmentation, will be successful. For patients with sensitive skin, topical agents in lower concentrations and with cream vehicles are preferred. While PIH tends to gradually disappear over time, it is the number one complaint among acne patients with darker skin tones. PIH should be treated aggressively with a combination of sunblock, hydroquinone, retinoid, chemical peels, and microdermabrasion, when appropriate. Caution must be taken when treating ethnic skin with ablative or nonablative lasers and superficial or deep chemical peels due to the high risk of further PIH, scarring, and permanent hypopigmentation. Keloid scarring secondary to acne can be treated with pressure, silicone gels, intralesional coritcosteroids, surgery, laser treatment or radiation therapy. However, keloids treated with surgical excision can have rates of recurrence as high as 50%.

Special management & counseling considerations
Successful management of acne in ethnic patients can be achieved with early initiation of an appropriate combination drug regimen coupled with good patient compliance. Topical medications, such as retinoids, may be used safely and effectively to treat acne in skin of color patients. Dryness and irritation can be minimized by counseling patients to use retinoids initially in lower concentrations with every other day application in addition to daily use of a hydrating agent. Patients should also be instructed to treat their skin gently, avoiding scrubbing and picking of acne lesions. Mild, non-abrasive cleansers, non-comedogenic moisturizers and cosmetics are preferred. Moisturizers treat the dry skin and prevent irritant contact dermatitis that may commonly occur. In addition, use of cocoa butter, a comedogenic agent, is very common among Black patients and should be avoided. For best results, clinicians should manage the entire grooming regimen of the skin and hair of their ethnic patients. Patients should be advised to avoid comedogenic hair and scalp preparations that can cause or exacerbate acne.
Sunscreen use has been found to be scarce in ethnic patients. 32 Chemical sunscreens have a higher likelihood of exacerbating acne and causing contact dermatitis. Physical sunblocks containing micronized zinc oxide or titanium dioxide are preferred for best protection, especially with coexisting post inflammatory hyperpigmentation. The administration of a skin bleaching agent combined with a photoprotective agent for application in the morning, instead of hydrating cream, is acceptable to patients, improves compliance, and is effective.
Additionally, acne may be improved by controlling hormones and inflammation, both of which may be influenced by diet. Concurrent with standard anti-acne therapy, a trial of discontinuing all dairy products and high glycemic foods should be stopped for at least 6 months to evaluate the effect, since it is thought to contribute to elevations in growth factors and hormones that cause acne. Vitamin A supplementation may help reduce plugging of pores in deficient individuals, while foods containing ω-3 essential fatty acids (EFAs) may help to control inflammation. 36 - 42 Individualized care and close monitoring is required.

References

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2 Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in sebaceous glands from subjects with and without acne. Arch Dermatol . Sep 1999;135(9):1041-1045.
3 Pochi PE, Strauss JS. Sebaceous gland activity in black skin. Dermatol Clin . Jul 1988;6(3):349-351.
4 Kim J, Ochoa MT, Krutzik SR, Takeuchi O, Uematsu S, Legaspi AJ, et al. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol . Aug 1 2002;169(3):1535-1541.
5 Weiss JS. Current options for the topical treatment of acne vulgaris. Pediatr Dermatol . 1997;14:480-488.
6 Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol . Aug 1999;141(2):297-300.
7 Krowchuk DP, Lucky AW. Managing adolescent acne. Adolesc Med . 12(2), 2001 Jun.
8 Katsambas AD, Katoulis AC, Stavropoulos P. Acne neonatorum: a study of 22 cases. Int J Dermatol . 1999 Feb;38(2):128-130.
9 Gollnick H, Cunliffe W, Berson D, Dreno B, Finlay A, Leyden JJ, et alGlobal Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol . 2003;49(suppl 1):S1-S37.
10 Thielitz A, Helmdach M, Röpke EM, Gollnick H. Lipid analysis of follicular casts from cyanoacrylate strips as a new method for studying therapeutic effects of antiacne agents. Br J Dermatol . 2001;145:19-27.
11 Verschoore M, Bouclier M, Czernielewski J, Hensby C. Topical retinoids: their uses in dermatology. Dermatol Clin . 1993;11:107-115.
12 Mills OHJr, Kligman AM. Treatment of acne vulgaris with topically applied erythromycin and tretinoin. Acta Derm Venereol . 1978;58:555.
13 Halder RM, Brooks HL, Callender VD. Acne in ethnic skin. Dermatol Clin . 2003 Oct;21(4):609-615. vii
14 Embil K, Nacht S. The Microsponge Delivery System (MDS): a topical delivery system with reduced irritancy incorporating multiple triggering mechanisms for the release of actives. J Microencapsul . 1996 Sep–Oct;13(5):575-588.
15 Martin B, Meunier C, Montels D, Watts O. Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation. Br J Dermatol . 1998;139(suppl 52):8-11.
16 Cove H, Holland KT. The effect of benzoyl peroxide on cutaneous micro-organisms in vitro. J Appl Bacteriol . 1983;54:379-382.
17 Cunliffe WJ, Holland KT. The effect of benzoyl peroxide on acne. Acta Derm Venereol . 1981;61(3):267-269.
18 Bojar RA, Cunliffe WJ, Holland KT. The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol . 1995;132:204-208.
19 Crawford WW, Crawford IP, Stoughton RB, Cornell RC. Laboratory induction and clinical occurrence of combined clindamycin and erythromycin resistance in Corynebacterium acnes. J Invest Dermatol . 1979 Apr;72(4):187-190.
20 Badreshia-Bansal S, Draelos ZD. Insight into skin lightening cosmeceuticals for women of color. J Drugs Dermatol . 2007;6(1):32-39.
21 Webster G. Combination azelaic acid therapy for acne vulgaris. J Am Acad Dermatol . 2000 Aug;43(2 Pt 3):S47-S50.
22 Gupta AK, Nicol K. The use of sulfur in dermatology. J Drugs Dermatol . 2004;3:427-431.
23 Espersen F. Resistance to antibiotics used in dermatological practice. Br J Dermatol . 1998;139:4-8.
24 Ochsendorf F. Minocycline in acne vulgaris: benefits and risks. Am J Clin Dermatol . 2010;11(5):327-341.
25 Eady EA, Jones CE, Tipper JL, Cove JH, Cunliffe WJ, Layton AM. Antibiotic resistant propionibacterium in acne: need for policies to modify antibiotic usage. BMJ . 1993;306:555.
26 Kurokawa I, Danby FW, Ju Q, Wang X, Xiang LF, Xia L, et al. New developments in our understanding of acne pathogenesis and treatment. Exp Dermatol . 2009 Oct;18(10):821-832.
27 Zaenglein AL, Thiboutot DM. Expert Committee Recommendations for Acne Management. Pediatrics . 2006 Sep;118(3):1188-1199.
28 Quarles FN, Brody H, Johnson BA, Badreshia S. Chemical peels in richly pigmented patients. Dermatol Ther . 2007 May–Jun;20(3):147-148.
29 Badreshia S, Verma S. Laser and light modalities in the treatment of acne vulgaris. The CSI Journal of Cosmetic Dermatology . Feb 2006;Vol 1:5-9.
30 Davis EC, Callender VD. A Review of acne in ethnic skin pathogenesis, clinical manifestations, and management strategies. J Clin Aesthet Dermatol . 2010 April;3(4):24-38.
31 Quarles FN, Johnson BA, Badreshia S, Vause SE, Brauner G, Breadon JY, et al. Acne vulgaris in richly pigmented patients. Dermatol Ther . 2007 May–Jun;20(3):122-127.
32 Poli F. Acne on pigmented skin. Int J Dermatol . 2007;46(Suppl 1):39-41.
33 Taylor SC, Cook-Bolden F, Rahman Z, Strachan D. Acne vulgaris in skin of color. J Am Acad Dermatol . 2002;46(2 Suppl Understanding):S98-S106.
34 Paul Kelly, Susan C. Taylor Dermatology for Skin of Color Chapter 12. The Structure and Function of Skin of Color, Sonia Badreshia-Bansal and Susan C Taylor . New York: McGraw-Hill; 2009.
35 Tsuruta D, Someda Y, Sowa J, Kobayashi H, Ishii M. Drug hypersensitivity syndrome caused by minocycline. J Cutan Med Surg . 2006;10(3):131-135.
36 Koldovsky O. Hormones in milk. Vitam Horm . 1995;50:77-149.
37 Hoyt G, Hickey MS, Cordain L. Dissociation of the glycaemic and insulinaemic responses to whole and skimmed milk. Br J Nutr . 2005;93:175-177.
38 Charakida A, Charakida M, Chu AC. Double-blind, randomized, placebo-controlled study of a lotion containing triethyl citrate and ethyl linoleate in the treatment of acne vulgaris. Br J Dermatol . 2007;157:569-574.
39 Treloar V, Logan AC, Danby FW, Cordain L, Mann NJ. Comment on acne and glycemic index. J Am Acad Dermatol . 2008;58:175-177.
40 Namazi MR. Further insight into the pathomechanism of acne by considering the 5-alpha-reductase inhibitory effect of linoleic acid. Int J Dermatol . 2004;43:701.
41 Danby FW. Acne and iodine: reply. J Am Acad Dermatol . 2007;56:164-165.
42 Danby FW. Diet and acne. Clin Dermatol . 2008;26:93-96.

Pomade acne
Pomades are comedogenic cosmetic and hair dressings used commonly to style African American hair. Pomades are oil-based products used to improved hair manageability, straighten curly hair or to mold hair into various shapes. The oils in pomades can cause follicular plugging, setting the stage for formation of comedones. In addition, other ingredients in pomades may irritate skin, contributing to inflammation. African Americans are common users of pomades, oils, or ointments to style or improve the manageability of their hair, which may lead to forehead, temple or scalp acne, called pomade acne or acne cosmetica ( Fig. 1.4 ). Pomade acne usually consists of comedones, papules, and pustules. One study showed half of Blacks with acne used hair oil or pomade. 1

Figure 1.4 Pomade acne on the forehead.
Treatment of pomade acne requires discontinuing or minimizing pomade use and substituting with silicone-based hair products. If a pomade is used to decrease scalp dryness, it should be applied 2.5 cm (1 inch) behind the hairline. When used to style or improve hair manageability, the pomade should be applied only to the distal ends of the hair to avoid contact with the scalp and hairline. Pomade acne will gradually clear if it is discontinued or if no contact is made with the skin. However, if pomade acne persists, it should be treated as described above for acne vulgaris.

Reference

1 Taylor SC, Cook-Bolden F, Rahman Z, Strachan D. Acne vulgaris in skin of color. J Am Acad Dermatol . 2002;46(2 Suppl Understanding):S98-106.


Steroid acne
Steroid acne presents as monomorphous papulo-pustules located predominantly on the trunk, extremities and face. Characteristically, it appears after the administration of topical or systemic corticosteroids, including intravenous and inhalation therapy. The eruption usually resolves after discontinuation of the corticosteroid and, in addition, may respond to the usual acne treatment regimens. In some African and Asian immigrant groups, use of corticosteroid-containing fade creams is common and acne is increasingly observed in adults using these depigmenting agents ( Fig. 1.5 ). Discontinuation of the corticosteroid will lead to resolution of the acne.

Figure 1.5 (A) Steroid acne resulting from long-term topicalclobetasol use. (B) and (C) Steroid containing fade creams.

Pediatric perspectives: Infantile acne
Candrice R Heath


First-Line Therapies

Observation (mild cases) C
Infantile acne: a retrospective study of 16 cases. Hello M, Prey S, Léauté-Labrèze C, et al. Pediatr Dermatol 2008; 25(4):434–438.
In this retrospective review of 16 cases (11 boys and 5 girls), the cheeks were the primary site of involvement. Cystic lesions were reported in 25% of the patients. Information regarding treatment was available for 15 patients; 3 of 15 resolved without treatment, 4 were treated with benzoyl peroxide, 5 with topical antibiotics and 7 with topical retinoids. Oral medications were used in 8 patients: 4 with zinc salts, 2 with macrolides and 2 with isotretinoin. The disease duration was between 9 and 42 months. Of the 8 patients who reached adolescence at the time of the review, only one developed severe adolescent acne. Of the 16 total cases reviewed, 9 reported scarring, generally atrophic.
Isotretinoin is only approved for children 12 years and older with nodulocystic acne, though there have been reports in the literature of use in younger age groups for recalcitrant cases.

Second-Line Therapies

Benzoyl peroxide (inflammatory acne) C Tretinoin (comedonal acne) C Topical antibiotic (erythromycin or clindamycin) C Adapalene gel 0.1% C
A clinical and therapeutic study of 29 patients with infantile acne . Cunliffe WJ, Baron SE, Coulson IH. Br J Dermatol 2001; 145(3):463–466.
In this retrospective review of 29 patients (24 boys and 5 girls) with infantile acne, 24% of the cases were mild, 62% were moderate and 14% of the cases were severe. Inflammatory acne occurred in 59% of the cases, while comedonal lesions in 17%, nodular lesions in 7% and a mixture of lesions was seen in 17%. The patients with mild acne were treated successfully with benzoyl peroxide, erythromycin and topical retinoids. All of the infants with moderate acne responded well with a combination of oral erythromycin and topical treatment, except 2 infants. The two erythromycin resistant cases were treated with trimethoprim. The majority of the infants treated with oral antibiotics were treated with oral therapy for 18 months or less. However 38% of the infants treated with oral antibiotics required over 24 months of treatment. The acne lasted between 6 and 40 months. One case was treated successfully with a 4-month course of isotretinoin. Five of the 29 patients were left with residual scarring.
Topical acne medications should be used very sparingly on the skin of infants to avoid irritation.
Adapalene gel 0.1% in the treatment of infantile acne: an open clinical study. Kose O, Koç E, Arca E. Pediatr Dermatol 2008; 25(3):383–386.
12 patients were treated with adapalene gel 0.1% once per day for 16 weeks. Clearance of lesions was achieved in 4 patients after 3 months of treatment and the remaining 8 patients cleared in 4 months. There was no residual scarring, however at a one-year follow-up evaluation, 3 patients had a few mild lesions.

Third-Line Therapies

Oral antibiotics (erythromycin) C
Oral tetracycline is not recommended in children under 8 years old due to decreased bone growth and tooth staining .

Pediatric perspectives: Neonatal acne (acne neonatorum)
Candrice R Heath
Although predominately a disease of adults and adolescents, acne may occur in newborns and infants. The acne that presents in newborns and infants is more common in males. Hyperactivity of the sebaceous glands stimulated by androgens has been the implicated cause of acne in both boys and girls in this group. Open and closed comedones predominate, but other inflammatory lesions may occur as well. Neonatal acne appears within the first few weeks of life. While infantile acne occurs in infants between 3 months and 6 months of age. When infantile acne occurs, it usually persists and may be severe.


First-Line Therapies

Observation C Daily Cleansing with Gentle Soap  
Acne neonatorum: a study of 22 cases. Katsambas AD, Katoulis AC, Stavropoulos P. Int J Dermatol 1999; 38(2):128–130.
22 patients (18 males and 4 females) with acne neonatorum were evaluated. The average age of onset was 3 weeks, with an average duration of 4 months. The cheeks were involved in 81.8% of the cases. Papules and pustules were the predominant lesion type in 72.7% and only 22.7% of the patients had comedones. A family history of acne was present in 3 cases. 18 patients were treated with a regimen of daily cleansing with soap and water. Benzoyl peroxide 5% gel was used in 3 patients and 1 patient was treated with benzoyl peroxide 5% gel combined with topical clindamycin alcohol solution. Though this is a self-limiting disorder, treatments hastened resolution.
Neonatal acne occurs within the first few weeks of life while infantile acne usually does not occur until 3 to 6 months of age.

Acne rosacea
Rosacea is a common skin disease characterized by vascular hyper-reactivity, facial flushing, erythema, and telangiectasias. The pathogenesis appears to be multifactorial. Demodex mites, normal inhabitants of the human hair follicle, are found in greater numbers in rosacea patients and are thus theorized to play a role in its pathogenesis. 1 - 3 However, more studies are needed to conclusively determine if Demodex truly is pathogenic. Also, inconclusive evidence suggests that Helicobacter pylori ( H. pylori ) is associated with the etiology of rosacea, as increased levels of H. pylori antibodies have been detected. 4, 5 However, many of the studies were not controlled.
Rosacea is most common in middle aged fair skinned individuals, but it can also be seen in individuals of any skin type.Data on the incidence of rosacea in different racial groups is variable and generally lacking. Rosacea appears to be more common in light skinned and Asian populations and less common in people who have darker skin. However, in ethnic skin, the diagnosis can be obscured due to skin hue, causing rosacea to appear more hyperpigmented and less erythematous in darker patients with resulting misdiagnosis. Although it is considered to be rare among Black patients, it may be more common than believed to be in the past. 6
There are four main subtypes of rosacea: vascular rosacea characterized by flushing and persistent central erythema ( Fig. 1.6 ); papulopustular rosacea characterized by central facial papules or pustules; phymatous rosacea with thickened, irregular, nodular skin, (referred to as rhinophyma when the nose is involved, Fig. 1.7 ); and ocular rosacea characterized by burning, stinging, or the sensation of a foreign body in the eye. Patients may present with one or a combination of symptoms and signs such as facial burning and stinging, edema, erythematous plaques, dryness, ocular manifestations, or phymatous changes. Extrafacial involvement may occur on the neck and the upper chest. Common rosacea triggers include hot and/or cold temperatures, wind, hot drinks, caffeine, exercise, spicy food, alcohol, stress, topical products that irritate the skin and decrease the stratum corneum barrier, or medications that cause flushing. Rosacea fulminans (pyoderma faciale) is a rare complication characterized by the development of nodules and abscesses with sinus tract formation accompanied by systemic signs. A rare caseating granulomatous variant of rosacea, called lupus miliaris disseminatus faciei, can manifest with inflammatory red-brown or flesh-colored papules distributed symmetrically across the upper part of the face, particularly around the eyes and the nose.

Figure 1.6 Rosacea with persistent central erythema in an Asian woman.

Figure 1.7 Rhinophyma in an Indian man.
Unlike with acne vulgaris, patients with rosacea generally do not report oily skin but instead they experience dryness and peeling. The absence of comedones and lack of scarring is another helpful distinguishing feature from acne vulgaris. Other cutaneous disorders that mimic rosacea include polycythemia vera, connective tissue diseases (e.g. lupus erythematous, dermatomyositis, mixed connective tissue disease), perioral dermatitis, seborrheic dermatitis, photosensitivity, mastocytosis, neuroendocrine tumor such as pheochromocytoma or carcinoid, long-term application of topical steroids, anticancer agents such as epidermal growth factor receptor inhibitor ( Fig. 1.8 ), contact dermatitis, and photosensitivity. Clues to an endocrinopathy include tachycardia, hypertension, sweats, hot flashes, or diarrhea.

Figure 1.8 Skin eruption induced by an epidermal growth factor receptor inhibitor
(Courtesy of Emmy Graber MD, Dave Adams MD, and Diane Thiboutot MD; Department of Dermatology, Penn State Milton S. Hershey Medical Center).
Rosacea is a challenging disease to treat and there are very few large well controlled studies. Additionally, vasodilation, a key component of rosacea, is unresponsive to therapy. However, avoiding triggers described above may help with symptoms. 7 - 9 Sunblock may have an effect on vasodilatation since exposure to ultraviolet radiation leads to destruction of collagen and the surrounding supportive connecting tissue, which contributes to vasodilation. 10, 11 Topical therapy includes the use of metronidazole for inflammatory rosacea with resulting slow, gradual response. Azelaic acid has been helpful in reducing erythema. Sodium sulfacetamide, as an adjunct to therapy, may improve severe disease. A combination of topical and oral therapy usually provides the best results for initial flares. Oral therapy consists of the tetracycline class of antibiotics administered over several weeks with a gradual taper for initial flares. Other options may include trimethoprim/sulfamethoxazole and ciprofloxacin but these may be limited by cost and resistant micro-organisms. In the most severe cases of rosacea with resistant inflammatory lesions and nodules or rhinophyma, isotretinoin therapy may be required. Persistent erythema may respond best with vascular lasers, which are the mainstay of rosacea therapy. Cosmetic improvement of rhinophyma may be produced by mechanical dermabrasion, surgical shave techniques, CO 2 laser or hot loop recontouring. Anecdotal evidence indicates treatment of rosacea with medications including beta-blockers, clonidine, naloxone, ondansetron, and selective serotonin reuptake inhibitors may improve cutaneous flushing.

First-Line Therapies

Oral antibiotics A Topical antibiotics A Topical metronidazole A Topical azelaic acid A Laser surgery B
There is evidence to support the use of topical metronidazole and azelaic acid in the maintenance of rosacea. For acute, inflammatory flares, oral antibiotics in combination with topical agents will result in improvement. Finally, laser therapy may help diminish the erythema associated with rosacea, but care must be exercised when treating ethnic patients.
American Acne & Rosacea Society rosacea medical management guidelines. Del Rosso JQ, Baldwin H, Webster G, American Acne & Rosacea Society. J Drugs Dermatol 2008; 7(6):531–533.
The pharmacologic agents discussed are inclusive of those that are FDA-approved based on phase 3 pivotal trials. The mainstay of treatment for inflammatory lesions has been oral antibiotics, but topical metronidazole also may be effective. Antibiotics are more effective for inflammatory lesions than for erythema and telangiectasia. Isotretinoin may be effective for inflammatory lesions, edema and rhinophyma and in some resistant cases, but its use is limited by side effects and teratogenecity.
Efficacy and safety of azelaic acid (15%) gel as a new treatment for papulopustular rosacea: results from two vehicle-controlled, randomized phase III studies. Thiboutot D, Thieroff-Ekerdt R, Graupe K. J Am Acad Dermatol 2003; 48(6):836–845.
Two multicenter, double-blind, randomized, parallel-group, vehicle-controlled studies were conducted enrolling 665 subjects (92.5% Caucasian, 0.75% African American, 5.75% Hispanic, 0.25% Asian, 0.75% Asian) with moderate papulopustular rosacea. Azelaic acid 15% gel yielded statistically significantly higher reductions in mean inflammatory lesion count with improvement in erythema and therapeutic success as compared to placebo within 12 weeks of treatment. In vitro investigations indicate that azelaic acid may exert an anti-inflammatory effect by scavenging or reducing the generation and/or release of proinflammatory reactive oxygen species by neutrophils (much like the effect of tetracyclines in rosacea).
Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. Tan JK, Girard C, Krol A, Murray HE, Papp KA, Poulin Y, Chin DA, Jeandupeux D. J Cutan Med Surg 2002; 6(6):529–534.
120 patients with moderate to severe rosacea were enrolled in a randomized, placebo-controlled, double-blind study. Study cream was applied twice daily to the entire face over a 12-week period. Treatment with metronidazole 1% cream with SPF 15 sunscreen resulted in significant improvement in inflammatory lesion count, erythema and telangiectasia scores, and investigator and patient global assessment scores compared with baseline and placebo.
Rosacea patients are prone to irritation, including from ingredients found in sunscreen. It is preferable to use physical blockers containing zinc oxide or titanium dioxide and/or ones that contain dimethicone or cyclomethicone to reduce possible contact dermatitis.
Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. Fowler JF Jr. J Drugs Dermatol 2007; 6(6):641–645.
This 16-week, randomized, double-blind, placebo-controlled study of an anti-inflammatory dose of doxycycline plus topical metronidazole gel 1% for mild to moderate rosacea is presented. At week 12, metronidazole was discontinued and patients continued on either placebo or doxycycline. Combination therapy significantly reduced inflammatory lesion counts as early as week 4 and through week 12 compared to topical metronidazole 1% gel monotherapy.
Long-pulsed (6-ms) pulsed dye laser treatment of rosacea-associated telangiectasia using subpurpuric clinical threshold. Jasim ZF, Woo WK, Handley JM. Dermatol Surg 2004; 30(1):37–40.
To examine the effect of long-pulsed PDL at subpurpuric clinical threshold in the treatment of rosacea-associated telangiectasia, 12 patients with rosacea-associated telangiectasia were recruited into the study. The 595-nm PDL at a pulse duration of 6 ms was titrated up to a fluence between 7 and 9 J/cm 2 to produce immediate purpura lasting only a few seconds. Pretreatment cooling was achieved by cryogen spray. Patients were evaluated 6–8 weeks after one PDL treatment. Two of 12 patients had more than 75% improvement, another two had 50–75% improvement, and five had 25–50% improvement. Overall, 9 (75%) of 12 patients had more than 25% improvement after a single treatment of PDL. None of the patients reported lasting post-treatment purpura or complications.
Caution must be taken when treating ethnic skin, especially with lasers containing cryogen spray due to possible risk of hyperpigmentation or hypopigmentation.

Second-Line Therapies

Topical calcineurin inhibitors A Topical sulfur C Topical antibiotics A Oral antibiotics (ampicillin, metronidazole) A
Supporting evidence of treatment with topical immunomodulators, benzoyl peroxide, and oral antibiotics has been varied.
Pimecrolimus 1% cream for the treatment of steroid-induced rosacea: an 8-week split-face clinical trial. Lee DH, Li K, Suh DH. Br J Dermatol 2008; 158(5):1069–1076.
This investigator-blided, split-face study evaluated the efficacy and safety of pimecrolimus 1% cream for the treatment of steroid-induced rosacea. Patients applied pimecrolimus 1% cream twice daily to a randomly allocated half face for the first 2 weeks, and then applied pimecrolimus 1% cream to both sides of the face for 6 more weeks. After 1 week of application, a statistically significant improvement in erythema was observed. Asian subjects (type IV) were included in the study but no mention was made regarding demographics. Some patients developed hyperpigmentation as papules and pustules resolved. This was most common in ethnic patients and was considered to be PIH.
Efficacy of pimecrolimus for the treatment of steroid induced rosacea is debated. Other case reports have concluded that rosaceiform eruption could be aggravated after tacrolimus or pimecrolimus treatment.
Combination sodium sulfacetamide 10% and sulfur 5% cream with sunscreens versus metronidazole 0.75% cream for rosacea. Torok HM, Webster G, Dunlap FE, Egan N, Jarratt M, Stewart D. Cutis 2005; 75(6):357–363.
In an investigator-blinded, randomized, parallel-group study at 6 sites, after 12 weeks of treatment with sodium sulfacetamide 10% and sulfur 5% cream with sunscreens, there was a significantly greater percentage reduction in inflammatory lesions compared with metronidazole 0.75% cream, as well as a significantly greater percentage of subjects with improved erythema. Seven subjects had poor tolerance to the sodium sulfacetamide 10% and sulfur 5% cream with sunscreens, possibly caused by a sulfa drug allergy.
Double-blind, randomized, vehicle-controlled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Breneman D, Savin R, VandePol C. Int J Dermatol 2004; 43(5):381–387.
This 12-week, double-blind, vehicle-controlled, randomized, prospective, parallel-group study in 53 patients with moderate to severe rosacea showed a difference in favor of benzoyl peroxide/clindamycin by the third week of treatment as compared to placebo. Severity scores for erythema, papules/pustules, and flushing/blushing decreased more with benzoyl peroxide/clindamycin than with vehicle. Application site reactions were reported in 14% of patients.
Caution must be taken in skin of color with topical agents that can cause irritant contact dermatitis, and subsequent post-inflammatory hyperpigmentation.
Comparison of efficacy of azithromycin vs doxycycline in the treatment of rosacea: a randomized open clinical trial. Akhyani M, Ehsani AH, Ghiasi M, Jafari AK. Int J Dermatol 2008; 47(3):284–288.
A randomized, open clinical trial was conducted in Iran to compare the efficacy of azithromycin with doxycycline in 77 rosacea patients who were randomized to receive either azithromycin 500 mg three times weekly (on Monday, Wednesday, and Saturday) in the first month, 250 mg three times weekly in the second month, and 250 mg twice weekly (on Tuesday, and Saturday) in the third month. The other group was given doxycycline 100 mg/day for the three months. Clinical assessment was made at baseline, at the end of first, second, third, and fifth months after treatment. Statistically significant improvement was obtained with both drugs. In the azithromycin group, 4 patients had diarrhea, while epigastric burning was seen in 2 patients using doxycycline. This study indicates that azithromycin is at least as effective as doxycycline in the treatment of rosacea.

Third-Line Therapies

Topical retinoids
Oral antibiotics: trimethoprim/sulfamethoxazole, ciprofloxacin
Oxymetazoline
Photodynamic therapy
Demodex eradication: topical permethrim, oral ivermectin
H. pylori eradication
Oral isotretinoin
Topical steroid
Ketoconazole
Bifonazole
Ondansetron
Spironolactone
Octreotide


Commonly encountered pitfalls
The various forms of rosacea are more common than once believed in ethnic skin. The caseating granulomatous variant may be more common in Asian or Black patients and acne rosacea may be more common in Black patients than previously thought. However, rhinophyma has remained relatively uncommon in Japanese and reported in only 3 cases in African-Americans. 12 - 15 Ocular rosacea in Black patients has been found to range from blepharitis and conjunctival hyperemia to sight-threatening problems such as corneal neovascularization, thinning, ulceration, and perforation. 16
Treating rhinophyma is difficult due to the technical challenges of producing a good cosmesis. In Japan, almost all cases are located to the lower half of the nose, which is treated by full-thickness excision followed by application of either skin grafts or direct closure. 13 Laser therapy and dermabrasion, a commonly used treatment in the US for rhinophyma, should be used with caution in ethnic patients since risk of scarring and pigment dyschromias are high.

Special management & counseling considerations
Combination therapy with mild skin care products, vigilant use of sunblock, and maintenance medical therapy as well as vascular lasers may optimize treatment results. As discussed, care must be taken to avoid irritant contact dermatitis and post-inflammatory hyperpigmentation. The daily use of broad-spectrum sunblock is recommended for all patients, including ethnic patients in whom sunscreen use is low. A sunscreen that protects against both ultraviolet A and ultraviolet B rays should be selected. Physical blockers with micronized titanium dioxide and/or zinc oxide are well tolerated in ethnic skin but may produce a temporary white or purple skin hue. Green tinted sunscreens or cosmetics can provide coverage of erythema if present in patients with lighter skin hues. Patients should be encouraged to avoid astringents, toners, menthols, camphor, waterproof cosmetics requiring solvents to be removed, or products containing sodium lauryl sulfate which can irritate the skin. Dietary modulation should aim at avoidance of triggers.

References

1 Erbağci Z, Ozgöztaşi O. The significance of Demodex folliculorum density in rosacea. Int J Dermatol . 1998;37(6):421-425.
2 Forton F, Seys B. Density of Demodex folliculorum in rosacea: a case control study using standardized skin-surface biopsy. Br J Dermatol . 1993;128(6):650-659.
3 Bonnar E, Eustace P, Powell FC. The Demodex mite population in rosacea. J Am Acad Dermatol . 1993;28(3):443-448.
4 Rebora A, Drago F, Picciotto A. Helicobacter pylori in patients with rosacea. Am J Gastroenterol . 1994;89(9):1603-1604.
5 Utaş S, Ozbakir O, Turasan A, Utaş C. Helicobacter pylori eradication treatment reduces the severity of rosacea. J Am Acad Dermatol . 1999;40(3):433-435.
6 Rosen T, Stone MS. Acne rosacea in blacks. J Am Acad Dermatol . 1987;17(1):70-73.
7 Jansen T, Plewig G. Rosacea: classification and treatment. J R Soc Med . 1997;90:144-150.
8 Wilkin JK. Flushing reactions: consequences and mechanisms. Ann Intern Med . 1981;95:468-476.
9 Guarrera M, Parodi A, Cipriani C, Divano C, Rebora A. Flushing in rosacea: a possible mechanism. Arch Dermatol Res . 1982;272:311-316.
10 Wilkin JK. Rosacea. Pathophysiology and treatment. Arch Dermatol . 1994;130:359-362.
11 Plewig G, Jansen T. Rosacea. In: Freedberg IM, Eisen AZ, Wolff K, et al, editors. Dermatology in General Medicine . 5th ed. New York, NY: McGraw-Hill Health Professions Division; 1999:785-794.
12 Koffi-Aka V, Kouassi AA, D’Horpock FA, Boka NJ, Ehouo F. [Rhinophyma in a black African]. Rev Laryngol Otol Rhinol (Bord) . 2002;123(2):109-110.
13 Furukawa M, Kanetou K, Hamada T. Rhinophyma in Japan. Int J Dermatol . 1994;33(1):35-37.
14 Allah KC, Kossoko H, Yéo S, Richard Kadio M, Assi Djè Bi Djè V. [Rhinophyma in a black African male patient]. Rev Stomatol Chir Maxillofac . 2009 Dec;110(6):347-349.
15 Khoo CT, Saad MN. Rhinophyma in a negro: case report. Br J Plast Surg . 1980 Apr;33(2):161-163.
16 Browning DJ, Rosenwasser G, Lugo M. Ocular rosacea in blacks. Am J Ophthalmol . 1986;101(4):441-444.

Hidradenitis suppurativa
Hidradenitis suppurativa (HS) results from rupture of the hair follicle into the surrounding dermis, which leads to inflammation and subsequent abscess formation. 1 A familial form with autosomal dominance inheritance has been described. HS occurs around puberty and women are three times more likely to develop HS than men. It is common in Europeans and African-Americans.
HS is a debilitating disease characterized by chronic inflamed, swollen, painful nodules and sterile abscesses in apocrine gland-bearing sites including the axillae, groin, and inframmamary areas. Over time, recurrent boils lead to a hallmark of the disease, draining sinus tracts, fistulae, and subsequent hypertrophic scars ( Fig. 1.9 , Fig. 1.10 ). Often patients are afflicted with acne, pilonidal cysts, and scalp folliculitis, giving rise to the term follicular occlusion triad. 2 Exacerbating factors include being overweight, cigarette use, and moisture. Several complications can occur including scarring, contracture at the sites of lesions, urethral or rectal fistulas, squamous cell carcinomas, anemia secondary to chronic infection, and lymphedema from chronic inflammation and scarring. 3

Figure 1.9 Severe hidradenitis supparativa
(Courtesy of Dave Adams MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center).

Figure 1.10 Hidradenitis supparativa affecting the axilla
(Courtesy of Dave Adams MD; Department of Dermatology, Penn State Milton S. Hershey Medical Center).
Several treatments have been tried with varied success. Weight reduction, limiting friction and moisture from sweating by employing maneuvers such as wearing loose undergarments, using absorbent powders, antiseptic soaps, and topical aluminum chloride, are somewhat helpful. In early lesions, topical and intralesional corticosteroids or topical antibiotics such as clindamycin have proven to be beneficial. In acute cases, oral antibiotics may be necessary as a short- or long-term treatment option. Culture of exudates often reveal staphylococci, streptococci, pseudomonas, and/or anaerobic bacteria. Female patients presenting with HS should be screened for underlying polycystic ovary syndrome (PCOS) and insulin resistance. In severe cases, the best results occur with radical excision with primary closure or grafts. Although extensive surgery is usually considered the most effective curative therapy, there is little experience with this approach, with most being reports from European studies. An alternative has been the use of ablative laser treatment with secondary intention healing or radiation treatment. Systemic retinoids may reduce flares but have not been a reliable cure. Acitretin may have better results as compared to isotretinoin. Systemic corticosteroids often lead to dramatic improvement but results are not sustained upon discontinuation. Topical antibacterials containing benzoyl peroxide may be helpful to prevent or diminish relapses. Individual lesions are slow to heal, usually with drainage of pus. Remissions may last months to years and recurrences are common with progressive scarring and sinus tracts.

First-Line Therapies

Antibiotics A Surgical excision B
Topical treatment of hidradenitis suppurativa with clindamycin. Clemmensen OJ. Int J Dermatol 1983; 22(5):325–358.
This double-blind trial evaluated the efficacy of topical clindamycin in hidradenitis in 27 patients over 3 months. Clindamycin was superior to placebo. However, no difference was found for inflammatory nodules and abscesses at the second and third month evaluation. Topical clindamycin may be helpful prior to radical surgery or spontaneous remission.
Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients. Gener G, Canoui-Poitrine F, Revuz JE, Faye O, Poli F, Gabison G, Pouget F, Viallette C, Wolkenstein P, Bastuji-Garin S. Dermatology. 2009; 219(2):148–154.
This retrospective study evaluated the efficacy of a combination of systemic clindamycin (300 mg twice daily) and rifampicin (600 mg daily) in the treatment of patients with severe HS which was given for 10 weeks with success. The proposed mechanism of action was the antibacterial and anti-inflammatory effects of the two antibiotic agents. No data regarding long-term follow-up and recurrence was reported. This treatment regimen was aimed at being suspensive only, therefore, a maintenance treatment with tetracyclines or zinc gluconate was prescribed at the conclusion of the 10-week regimen.
Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa. Jemec GB, Wendelboe P. J Am Acad Dermatol 1998; 39(6):971–974.
46 patients with hidradenitis suppurativa were treated in a double-blind, double dummy controlled trial. Systemic therapy with tetracyclines 1 g daily did not produce better results than topical therapy with clindamycin twice daily after a minimum of 3 months of treatment. Abscesses were reduced during the first 3 months of treatment. Nodules only appeared to be reduced in number after 3 months of treatment. The time course suggests that nodules may be precursors to abscesses.
Surgical treatment of hidradenitis suppurativa: a retrospective study of 93 cases. Bordier-Lamy F, Palot JP, Vitry F. Ann Dermatol Venereol 2008; 135(5):373–379.
Of 93 French patients followed for a mean of 30 months, 209 anatomical sites were operated on with curative intent, using either limited or wide excision. The disease had been present for an average of 7.6 years before surgical treatment, with onset 7 years earlier in women. Surgery required hospitalization for an average duration of 6.6 days, caused complications in 21% of cases and was often perceived as difficult. Relapse in the operated areas occurred in 33% of cases and this was more frequent after limited excision. Nevertheless, 74% of patients were ultimately satisfied with their surgical treatment and most regarded surgery as the only effective therapy. Wide excision remains the mainstay of therapy in extensive forms of hidradenitis suppurativa.
Surgical treatment of hidradenitis suppurativa: a 10-year experience. Kagan RJ, Yakuboff KP, Warner P, Bemard P, Grange F. Surgery 2005; 138(4):734–740.
This study attempted to determine which factors have the greatest impact on outcome in order to develop an operative treatment algorithm. An algorithm for operative treatment was developed based on the extent of involvement, chronicity, and comorbid conditions. 57 patients had an average duration of symptoms of 6.7 years. 92 operative procedures were performed, 50% involved the axilla, 36% involved the perineum, and 14% involved the inguinal region. Excision and primary closure was used for localized disease and wide excision with or without skin grafting was used for diffuse disease. Definitive treatment involves excision of the involved apocrine tissue and should be individualized based on the stage and location of the disease.
Total surgical excision may be required in the gluteal region to prevent further complications including abscess, sinus tract formation, fistulization, and scarring. A multidisciplinary team approach is necessary and the patients often require an extensive hospital stay with aggressive wound care management.
Surgical treatment of hidradenitis suppurativa with gentamicin sulfate: a prospective randomized study. Buimer MG, Ankersmit MF, Wobbes T, Klinkenbijl JH. Dermatol Surg 2008; 34(2):224–247.
A prospective randomized study was performed showing gentamicin sulfate was useful in the surgical treatment of hidradenitis suppurativa. In the 76 patients in the study, gentamicin after primary excision of hidradenitis suppurativa reduced the number of complications 1 week post-operatively, including dehiscence, infection, and seroma. Furthermore, in 65% of the patients treated with gentamicin, the wound was completely healed within 2 months. No effect on the long-term recurrence rate was noted.

Second-Line Therapies

Oral corticosteroids E Oral isotretinoin B Hormonal therapy B Radical surgery B
Severe vulval apocrine acne successfully treated with prednisolone and isotretinoin. Fearfield LA, Staughton RC. Clin Exp Dermatol 1999; 24(3):189–192.
A case of a 34-year-old woman with severe vulval apocrine acne was successfully treated initially with prednisolone and then maintained with long-term isotretinoin. Long-term treatment with isotretinoin may be more successful than a 4–6 month treatment regime.
Long-term results of isotretinoin in the treatment of 68 patients with hidradenitis suppurativa. Boer J, van Gemert MJ. J Am Acad Dermatol 1999; 40(1):73–76.
This retrospective study assessed low-dose isotretinoin for 4–6 months in the treatment of 68 patients with mild-to-severe HS. In 23.5% of patients, the condition completely cleared during initial therapy and 16.2% maintained their improvement during the follow-up period. Treatment was more successful in the milder forms of HS. Monotherapy with isotretinoin for patients with HS usually has a limited therapeutic effect.
However, another recent study found no effect or even worsening with use of oral isotretinoin. It seems unclear if isotretinoin, which affects sebaceous glands would have an effect on apocrine glands involved in HS. The limited therapeutic effect may be due to absence of significant sebaceous gland involvement in HS, as measured by sebum excretion rates and histopathologic observation.
Hidradenitis suppurativa in 64 female patients: retrospective study comparing oral antibiotics and antiandrogen therapy. Kraft JN, Searles GE. J Cutan Med Surg 2007; 11(4):125–131.
As HS has been linked to a hyperandrogenic state, this retrospective study examined its association with PCOS. In 64 female HS patients, the prevalence of PCOS was 38.1%. Antiandrogen therapy was superior to oral antibiotic therapy.
Female patients presenting with HS should be considered for screening of underlying PCOS and insulin resistance.
A double-blind controlled cross-over trial of cyproterone acetate in females with hidradenitis suppurativa. Mortimer PS, Dawber RP, Gales MA. Br J Dermatol 1986; 115(3):263–268.
Ethinyloestradiol 50 micrograms/cyproterone acetate 50 mg in a reverse sequential regimen was compared with ethinyloestradiol 50 micrograms/norgestrel 500 micrograms in 24 female patients. Both treatments produced substantial improvement in disease activity. 12 patients cleared and have remained disease free for 18 months, 5 patients improved, four remained unchanged, while two deteriorated. Cyproterone acetate was not more effective than combination therapy, and both gave a similar reduction in free androgen index.
Cyproterone has been effective in some cases but high doses may be necessary which may raise safety issues.

Third-Line Therapies

Laser (CO 2 , Nd:Yag, Laser lipolysis)
Photodynamic therapy
Immunosuppressants
Infliximab
Etanercept
Cyclosporine
Adalimumab
Dapsone
Botulinum toxin
Electrosurgery
Zinc
Granulocyte colony stimulating factor


Commonly encountered pitfalls
Controversy exists whether African-Americans have a difference in the size, number, and morphology of apocrine glands. 4 African-Americans have been found to have a higher incidence of HS than those of European descent. Ingrown hairs may be a predisposing factor. Care must be taken with excision of lesions of HS due to the high risk of hypertrophic or keloidal scarring. Radical surgical excision may be limited in this patient population in whom keloid scarring is frequent. Further studies are required in ethnic populations.

Special management & counseling considerations
Unfortunately, none of the treatment modalities have a high success rate. It is important to note that cases of squamous cell carcimoma have been reported in longstanding HS. Despite its low incidence, squamous cell carcinoma remains the most serious complication and patients with darker skin are not exempt.

References

1 Balik E, Eren T, Bulut T, Büyükuncu Y, Bugra D, Yamaner S. Surgical approach to extensive hidradenitis suppurativa in the perineal/perianal and gluteal regions. World J Surg . 2009 Mar;33(3):481-487.
2 Deschamps ME, Payet S, Tournadre A, Soubrier M, Souteyrand P, D’Incan M. [Efficacy of infliximab in the treatment of follicular occlusion triad]. Ann Dermatol Venereol . 2010 Aug–Sep;137(8–9):546-550.
3 Tanaka A, Hatoko M, Tada H, Kuwahara M, Mashiba K, Yurugi S. Experience with surgical treatment of hidradenitis suppurativa. Ann Plast Surg . 2001;47:636-642.
4 Paul Kelly, Susan C. Taylor Dermatology for Skin of Color Chapter 12. The Structure and Function of Skin of Color, Sonia Badreshia-Bansal and Susan C Taylor . New York: McGraw-Hill; 2009.

Perioral dermatitis
Perioral dermatitis is a chronic papulo-pustular and eczematous facial dermatitis which occurs primarily in women. The etiology of perioral dermatitis is unknown. However, the use of topical steroids of any strength on the face often precedes the manifestation of the disease. Many patients abuse topical corticosteroid preparations, so reassurance and education regarding discontinuation of steroid is essential. Cosmetics, moisturizers, drooling, and toothpaste have also been implicated in the etiology. 1 - 5
Characteristic skin lesions are grouped perioral, perinasal, or perioribital red follicular papules, papulovesicles, and/or papulopustules, and is often termed periorificial dermatitis. Skin of color patients can, in addition, present with hyperpigmentation or hypopigmentation. Perioral dermatitis can resemble other conditions including rosacea and acne vulgaris.
Anti-inflammatory agents such as antibiotics and topical immunomodulators may help hasten resolution. The tetracycline class of antibiotics decreases the chemotactic response of neutrophils, inhibits granuloma formation, and inhibits protein kinase C. Photodynamic therapy has also been reported to be helpful in small clinical studies.

First-Line Therapies

Discontinuation of corticosteroids B Antibiotics B
Perioral dermatitis: etiology and treatment. Bendl BJ. Cutis 1976; 17(5):903–908.
95 patients with perioral dermatitis showed consistent clearing of the eruption with oral tetracycline in combination with a topical sodium sulfacetamide-sulfur-hydrocortisone lotion. When compared to 50 control patients, there were highly significant quantitative differences. Lubricating and moisturizing products play a part in the etiology of perioral dermatitis.
The use of topical agents containing hydrocortisone is not recommended for treatment of perioral dermatitis.
Topical cosmetics and perioral dermatitis. Dirschka T, Weber K, Tronnier H. J Dtsch Dermatol Ges 2004; 2(3):194–199.
75 patients with perioral dermatitis and 125 randomly selected control patients were compared, including history of atopic dermatitis. There were significant differences between the patient and control group in morning skin care regimens including the use of day creams. 25% of patients used topical corticosteroids which were initiated after the onset of the rash. There was a correlation also with history of atopic diseases. A possible interaction between external factors, such as cosmetics, and intrinsic factors, such as atopic dermatitis appears to contribute to perioral dermatitis, perhaps by subclinical repetitive irritation and overwhelming the reparative capacity of the epithelial barrier function.
Critical appraisal of reports on the treatment of perioral dermatitis. Weber K, Thurmayr R. Dermatology 2005; 210(4):300–307.
There were consistent results on a variety of therapeutic trials regarding treatment of perioral dermatitis. The most common and consistent treatment guidelines included use of oral tetracycline as first line agents, topical antibiotics and metronidazole as second line, and to a lesser extent, recommending no therapy with only spontaneous resolution. The discontinuation of topical corticosteroids and cosmetics is thought to be important. Perioral dermatitis is thought to be self-limited because it spontaneously clears in most patients within approximately 3 months.

Second-Line Therapies

Topical corticosteroids E Topical sulfur E Topical metronidazole B Topical calcineurin inhibitors B Photodynamic therapy B Topical azelaic acid D Oral isotretinoin E
Topical therapy for perioral dermatitis. Bikowski JB. Cutis 1983; 31(6):678–682.
Six patients with perioral dermatitis were successfully treated with a combination of erythromycin topical solution twice a day and topically applied hydrocortisone valerate cream. Hydrocortisone valerate cream, when used in a controlled, tapered regimen, seems to prevent acute rebound flare of perioral dermatitis from previous high-potency steroid use or abuse.
Low-potency topical corticosteroid in cases of exacerbation (if there is any) during the first 2 weeks after initiation of therapy may be used.
The multifunctionality of 10% sodium sulfacetamide, 5% sulfur emollient foam in the treatment of inflammatory facial dermatoses. Draelos ZD. J Drugs Dermatol. 2010 Mar; 9(3):234–236.
This uncontrolled, observational, prospective, open-label, single site, eight-week study enrolled 24 subjects (8 with rosacea, 8 with seborrheic dermatitis, 8 with acne vulgaris) to evaluate the safety and efficacy of this novel foam formulation. At 8 weeks, statistically significant improvement was seen in all conditions. Perioral dermatitis may have been overlapped with some of these subjects. Sodium sulfacetamide possesses anti-inflammatory and antibacterial properties while sulfur is a nonspecific antibacterial and antifungal.
Topical metronidazole in the treatment of perioral dermatitis. Veien NK, Munkvad JM, Nielsen AO, Niordson AM, Stahl D, Thormann J. J Am Acad Dermatol 1991; 24(2 Pt 1):258–260.
In a prospective, double-blind, randomized, multicenter trial, 108 patients were treated with twice-daily 1% metronidazole cream or tetracycline 250 mg orally twice daily over 8 weeks. Oral tetracycline was significantly more effective than topical metronidazole.
Perioral dermatitis in children – clinical presentation, pathogenesis-related factors and response to topical metronidazole. Boeck K, Abeck D, Werfel S, Ring J. Dermatology 1997;195(3):235–238.
This study investigated perioral dermatitis in children and the possible pathogenetic mechanisms to response with topical metronidazole 1% cream in 7 children. Pretreatment with topical corticosteroids, skin prick test with a panel of six common aeroallergens, and screening for gastrointestinal colonization with Candida albicans was performed. In all but one child, topical corticosteroids had been used in the face prior to the first presentation. An association with atopy or intestinal Candida colonization was not found. In all children, skin lesions resolved after 3 – 6 months and they remained symptom free for 2 years.
A randomized, double-blind, vehicle-controlled study of 1% pimecrolimus cream in adult patients with perioral dermatitis. Schwarz T, Kreiselmaier I, Bieber T, Thaci D, Simon JC, Meurer M. J Am Acad Dermatol 2008; 59(1):34–40.
A multicenter, randomized, double-blind, parallel-group study was performed in 112 adult patients with perioral dermatitis treated with pimecrolimus cream 1% twice daily or pimecrolimus vehicle until clearance was achieved up to 4 weeks. After 8 days of treatment, 40% of the patients treated with pimecrolimus experienced a marked improvement in their skin symptoms compared with 10% in the vehicle group, with no rebound over 8 weeks.
Photodynamic therapy for perioral dermatitis. Richey DF, Hopson B. J Drugs Dermatol 2006; 5(2 Suppl):12–16.
A split-face 21-patient study was conducted in which one side of the face was treated 4 times weekly with aminolevulinic acid photodynamic therapy (ALA-PDT). A protocol of 30-minute ALA incubation with blue light activation was used while the other side was treated with topical clindamycin. 66.7% of patients completed the study. The side treated with ALA-PDT achieved a mean clearance of 92.1% compared to 80.9% for the clindamycin-treated side. More studies are needed to confirm these results and to elucidate the mechanism of action.
Perioral dermatitis with histopathologic features of granulomatous rosacea: successful treatment with isotretinoin. Smith KW. Cutis. 1990 Nov; 46(5):413–415.
A young woman with granulomatous perioral dermatitis failed standard therapies. Her eruption cleared after a 20 week treatment of oral isotreinoin. Isotertinoin is only indicated for long-standing and refractory forms of perioral dermatitis.


Commonly encountered pitfalls
Ethnic patients are more likely to use topical bleaching agents on the face which may contain high potency corticosteroids, thus increasing their incidence of perioral dermatitis. All lightening creams should be assessed by the clinician, especially from Asian or African countries where lightening creams are more likely to be adulterated with potent corticosteroids. In the United States, lightening creams purchased in beauty supply stores should likewise be carefully evaluated. Discontinuation of lightening agents which contain potent corticosteroids is the treatment of choice, though a rebound phenomenon can occur. A taper of topical steroids may be considered.

Special management & counseling considerations
Since many cases are associated with the use of topical corticosteroids, withdrawal of this medication is the most important strategy, despite initial flares. In ethnic patients, as previously stated, use of bleaching agents should be discontinued if they are suspected of containing high potency corticosteroids. Patients should be advised to discard the bleaching agent as they may be tempted to reuse if uncomfortable symptoms associated with a rebound flare occur.

References

1 Manders SM, Lucky AW. Perioral dermatitis in childhood. J Am Acad Dermatol . 1992;27:688-692.
2 Cohen HJ. Perioral dermatitis. J Am Acad Dermatol . 1981;4:739-740.
3 Ferlito TA. Tartar-control toothpaste and perioral dermatitis. J Clin Orthod . 1992;26:43-44.
4 Kalkoff KW, Buck A. Etiology of perioral dermatitis. Hautarzt . 1977;28:74-77.
5 Held E, Ottevanger V, Petersen CS, Weismann K. Perioral dermatitis in children under steroid inhalation therapy. Ugeskr Laeger . 1997;159:7002-7003.
2 Bullous and Pustular Disorders

Janelle Vega, David A. Rodriguez

Bullosis diabeticorum 25
Bullous pemphigoid 26
Impetigo 29
Infantile acropustulosis 32
Pemphigus foliaceus 33
Pemphigus vulgaris 35

Bullosis diabeticorum
Bullosis diabeticorum (BD) is a relatively rare cutaneous complication of diabetes mellitus, characterized by the spontaneous development of tense bullae that may range up to several centimeters in size. BD usually arises on previously normal skin particularly on acral areas with the feet the most common location, ( Fig. 2.1 ), followed by the lower legs, hands and forearms. The blister is filled with clear, sterile fluid with a thick consistency. 1 Patients report rapid onset, with lesions often appearing ‘overnight.’ The lesions of BD heal without scarring in most cases. 2

Figure 2.1 Bullosis diabeticorum. A tense blister on the palm as well as desquamation at sites of previous bullae.
(From Bolognia; Dermatology 2e; Mosby, copyright Elsevier 2008.)
Diabetes mellitus is a common disease of individuals with skin of color, particularly those of Latin and African American decent. Although 30% of diabetic patients develop cutaneous manifestations of their disorder, BD occurs much less commonly, with an incidence of 0.16% per year in one series. 3, 4 Patients may have more than one episode during their lifetime. 5 In some cases, the development of BD heralds the onset of diabetes or insulin resistance. 6 The cause of BD is unknown, but it has been observed in patients with diabetic microangiopathy, neuropathy, nephropathy, and retinopathy. 7


Therapy
There are no studies regarding appropriate therapy for BD; some articles suggest that lesions will spontaneously resolve within 2–6 weeks; however, others suggest local care including de-roofing and treatment with antibiotics when necessary.
Incidence of bullosis diabeticorum – a controversial cause of chronic foot ulceration. Larsen K, Jensen T, Karlsmark T, Holstein PE. Int Wound J 2008; 5(4):591–596.
This single-center retrospective case series included 25 patients with BD; collectively, they experienced 35 episodes with 93 total bullae. The authors recommend de-roofing and drainage of the bullae, then the application of a non-adherent gauze. Patients were followed, received regular foot care and wore special shoes. Patients that had what appeared to be an infection were treated with appropriate antibiotics.

Commonly encountered pitfalls
Although much of the literature suggests that spontaneous resolution is the rule, some case series have reported subsequent chronic ulcers, osteomyelitis, and even amputation following bullosis diabeticorum. 8 Careful observation and close follow-up of these patients are required. Patients without a history of diabetes who are present with a lesion similar to BD should be fully evaluated for an existing endocrinopathy. 4

Special management & counseling considerations
In a study of the prevalence of diabetes in different ethnic groups, the authors found a significantly higher prevalence of BD in Hispanics, which was statistically significantly higher than in Blacks, and higher than Asians and Caucasian patients (Hispanics 334/1000; Blacks 296/1000; Asians 243/1000; Whites 184/1000). 9 Therefore, the prevalence of BD in clinical practice may be higher depending on the population one is treating.

References

1 Derighetti M, Hohl D, Krayenbühl BH, Panizzon RG. Bullosis diabeticorum in a newly discovered type 2 diabetes mellitus. Dermatology . 2000;200(4):366-367.
2 Aye M, Masson EA. Dermatological care of the diabetic foot. Am J Clin Dermatol . 2002;3(7):463-474.
3 Bernstein JE, Medenica M, Soltani K, Griem SF. Bullous eruption of diabetes mellitus. Arch Dermatol . 1979;115:324-325.
4 Larsen K, Jensen T, Karlsmark T, Holstein PE. Incidence of bullosis diabeticorum – a controversial cause of chronic foot ulceration. Int Wound J . 2008;5(4):591-596.
5 Basarab T, Munn SE, McGrath J, Russell JR. Bullosis diabeticorum. A case report and literature review. Clin Exp Dermatol . 1995;20:218-220.
6 Lopez PR, Leicht S, Sigmon JR, Stigall L. Bullosis diabeticorum associated with a prediabetic state. South Med J . 2009 May 7. [Epub ahead of print]
7 Anand KP, Kashyap AS. Bullosis diabeticorum. Postgrad Med J . 2004;80(944):354.
8 Tunuguntla A, Patel KN, Peiris AN, Zakaria WN. Bullosis diabeticorum associated with osteomyelitis. Tenn Med . 2004;97:503-504.
9 McBean AM, Li S, Gilbertson DT, Collins AJ. Differences in diabetes prevalence, incidence, and mortality among the elderly of four racial/ethnic groups: whites, blacks, hispanics, and asians. Diabetes Care . 2004;27(10):2317-2324.

Bullous pemphigoid
Bullous pemphigoid (BP) is an autoimmune blistering disorder equally affecting male and female patients between the ages of 60 and 80 years. IgG autoantibodies target hemidesmosomal proteins (BP230 [BPAg1] and BP180 [BPAg2]) and result in tense, fluid filled vesicles ( Fig. 2.2 ). 1 Often, the early phase of BP is urticarial, and patients may initially present with erythematous pruritic plaques, which evolve over time to form bullae. Common sites of involvement include flexural areas such as axillae, antecubital fossae, inner thighs, groin, lower trunk, and lower legs. The one year mortality for BP is 23%; however, when BP patients were matched with controls for age and comorbidities, there was no significant difference in mortality. It is likely that BP does not confer increased mortality to these patients, and mortality results from disease-independent factors. 2

Figure 2.2 Bullous pemphigoid. Classic presentation with multiple bullae arising on normal and erythematous skin. Several of the bullae have ruptured leaving circular erosions.
(Courtesy Dr. Henry Lim.)

First-Line Therapy

Systemic corticosteroids A Topical corticosteroids A
Patients with mild to moderate disease can be treated initially with high potency topical corticosteroids and systemic corticosteroids may be added if they are uncontrolled. 3 The need for high dose corticosteroids has not been established, and may confer an increased adverse event profile. Therefore, the dosage of corticosteroids may begin at 0.5–0.75 mg/kg/day.
Treatment of bullous pemphigoid with prednisolone only: 0.75   mg/kg/day versus 1.25   mg/kg/day. A multicenter randomized study. Morel P, Guillaume JC. Annales de Dermatologie et Vénéréologie 1984; 111:925–928.
In this randomized, multicenter study, patients received either 0.75 mg/kg/day or 1.25 mg/kg/day of prednisolone. There was no significant difference in clearance of lesions at 21 or 51 days with the two dosage regimens. However, there were more deaths in the 1.25 mg/kg/day group.
A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. Joly P, Roujeau JC, Benichou J, Picard C, Dreno B, Delaporte E and the Bullous Diseases French Study Group. N Engl J Med 2002; 346(5):321–327.
This multicenter, non-blinded, randomized trial of 341 participants who were randomized to receive potent topical corticosteroids (clobetasol propionate: 40g/d), or prednisone (1 mg/kg/d) for severe disease [>10 new blisters/day]; or 0.5 mg/kg/d for moderate disease [<10 new blisters/day]). Even in patients with severe disease, survival was higher for those using topical steroids (76%) versus those on oral steroids (58%, OR 0.44, 95% CI 0.24–0.83). Disease control was achieved within 3 weeks in 99% of the patients receiving topical steroids versus 91% of those on oral steroids.

Second-Line Therapy

Topical tacrolimus D Azathioprine A Mycophenolate mofetil A Tetracycline and nicotinamide C
Several case reports have demonstrated success of topical tacrolimus in the treatment of both localized and generalized BP. Its addition has allowed for tapering of prednisone. Topical tacrolimus may be a good therapeutic option for patients who cannot use topical steroids, do not improve with their use, or for patients with facial lesions. 4 One limitation to this therapy is its high cost particularly when compared to the price of topical corticosteroids.
Topical tacrolimus is a useful adjunctive therapy for bullous pemphigoid. Chu J, Bradley M, Marinkovich MP. Arch Dermatol 2003; 139:813–815.
This case series of two patients describes a 70-year-old woman on multiple medications including doxycycline, niacinamide, mycophenolate mofetil and prednisone (60 mg/d). Physicians were unable to taper prednisone without significant flare of the BP. Topical tacrolimus was added, and after 2 weeks, the area of application was clear of lesions. Over the next 4 weeks, she was weaned to 20 mg/d of prednisone without a flare. The second patient was a 58-year-old man, on multiple medications including prednisone (20 mg/d), tetracycline, and niacinamide was also able to be tapered off of prednisone three weeks after topical tacrolimus was added to the therapeutic regimen.
The addition of an immunosuppressive agent to a therapeutic regimen that includes an oral corticosteroid, allow the dosage of the corticosteroid to be reduces or discontinued, thus reducing possible adverse event from the corticosteroid.
A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid. Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler R, et al. Arch Dermatol 2007; 143(12):1536–1542.
In this prospective, multicenter, randomized, non-blinded clinical trial, patients were randomized to receive methylprednisolone (0.5 mg/kg/day) and azathioprine or mycophenolate mofetil. Clinical remission was achieved faster in patients in the azathioprine group (23.8 ± 18.9 days vs 42.0 ± 55.3 days), and lower total doses of methylprednisolone were used overall in this group (4967.0 ± 12 190.7 mg vs 5754.0 ± 9692.8 mg). Higher adverse effects were seen in the azathioprine group, with 24% of patients experiencing grade 3 or 4 adverse effects vs 17% of patients in the mycophenolate mofetil group. There was decreased liver toxicity in the mycophenolate mofetil group.
Nicotinamide and tetracycline therapy of bullous pemphigoid. Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D. Arch Dermatol 1994; 130:753–758.
In this randomized, non-blinded trial, a total of 20 patients were randomized to receive prednisone versus tetracycline (500 mg po qid) and nicotinamide (500 mg po tid). Only 18 of the 20 enrolled were treated, and 6 of these were randomized to the prednisone group. There were two complete responders in the tetracycline and nicotinamide group versus one complete responder in the prednisone group. At 10-month follow-up, there were only 5 participants able to be reached in the tetracycline group, all of whom were disease free after tapering. In the prednisone group, three patients were reached at follow-up, all of whom had flares on a steroid taper. Severe side effects in the prednisone group included death secondary to sepsis and in the tetracycline group included transient renal failure in patients with impaired renal function at the start of the trial.

Third-Line Therapy

Methotrexate C Intravenous immunoglobulin (IVIg) C Rituximab E
Low-dose methotrexate is a treatment option for BP patients who are able to tolerate the treatment or for those who have coexisting psoriasis. It has been demonstrated that methotrexate confers no difference in mortality as compared to prednisone alone.
A retrospective analysis of patients with bullous pemphigoid treated with methotrexate. Kjellman P, Eriksson H, Berg P. Arch Dermatol 2008; 144(5):612–616.
This was a retrospective study of 138 patients with bullous pemphigoid who received either methotrexate (median weekly dosage 5 mg/week), prednisone, methotrexate and prednisone, or topical glucocorticoids alone. Mild adverse effects occurred with methotrexate including gastrointestinal tract irritation, transient alveolitis, anemia, and increasing liver enzymes. There was a trend toward decreased mortality in the patients on low dose methotrexate, and no significant difference in survival in all groups. Two-year remission in the methotrexate alone group was better than the methotrexate plus prednisone group, and there were no clinical remissions in the prednisone alone group.
No randomized controlled trials have been performed on the use of IVIg in BP, but a consensus statement summarized the available data up until 2003 which seems promising. 5 It may be helpful to add IVIg when a patient has failed 6 weeks of prednisone at 1 mg/kg/day, and has failed therapy even with the addition of immunosuppressive agents for 10–12 weeks. Other indications for treatment are patients with severe side effects on corticosteroids or immunosuppressive agents or with contraindications to these agents. The addition of an immunosuppressive agent and IVIg may help resolution of BP by decreasing the burden of circulating autoantibodies, according to one case report.
Intravenous immunoglobulin therapy for patients with bullous pemphigoid unresponsive to conventional immunosuppressive treatment. Ahmed AR. J Am Acad Dermatol 2001; 45:825–835.
In this case series of 15 patients with severe BP refractory to high dose corticosteroids and immunosuppressive agents, requiring multiple hospitalizations, the patients received IVIg at 2 g/kg per cycle. All patients achieved remission, even after IVIg was discontinued. Time to effectiveness was a mean of 2.9 months and patients were treated for a mean of 24.4 months with IVIg. Oral prednisone was tapered over time.
The response to rituximab therapy, a CD 20 monoclonal antibody targeted at B cells, has been mixed, and although effective in some patients, deaths have been associated with its use. 6
Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Schmidt E, Seitz CS, Benoit S, Bröcker EB, Goebeler M. Br J Dermatol 2007; 156(2):352–356.
In this case series, 2 of the 7 patients had BP and were treated with intravenous rituximab weekly for one month at a dose of 375 mg/m 2 . One of the patients was a 2-year-old boy who developed a prolonged hypogammaglobulinemia and required parenteral feeding; the other patient died of nosocomial pneumonia. These patients had partial and complete remission of the BP.

Commonly encountered pitfalls
BP has an urticarial phase, which is commonly misdiagnosed as urticaria. It is important to include BP in the differential diagnosis of urticarial-like lesions. If treating an elderly patient with urticaria, it is also helpful to warn them if the lesions become blisters, that immediate reevaluation by their physician is required. 7

Special management & counseling considerations
Patients with bullous pemphigoid tend to be older and have more comorbidities. It may be prudent, wherever possible, to use the least toxic therapy (i.e. topical corticosteroids) to avoid any unwanted side effects. Mortality in this age group is high, and it is not desirous to add therapies that further increase it.

References

1 Suárez-Fernández R, España-Alonso A, Herrero-González JE, Mascaró-Galy JM. [Practical management of the most common autoimmune bullous diseases]. Actas Dermosifiliogr . 2008;99(6):441-455.
2 Parker SR, Dyson S, Brisman S, Pennie M, Swerlick RA, Khan R, et al. Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol . 2008;59(4):582-588.
3 Khumalo N, Kirtschig G, Middleton P, Hollis S, Wojnarowska F, Murrell D. Interventions for bullous pemphigoid. Cochrane Database Syst Rev 2005; (3):CD002292.
4 Ko MJ, Chu CY. Topical tacrolimus therapy for localized bullous pemphigoid. Br J Dermatol . 2003;149:1079-1081.
5 Czernik A, Bystryn JC. Improvement of intravenous immunoglobulin therapy for bullous pemphigoid by adding immunosuppressive agents: marked improvement in depletion of circulating autoantibodies. Arch Dermatol . 2008;144(5):658-661.
6 Hertl M, Zillikens D, Borradori L, Bruckner-Tuderman L, Burckhard H, Eming R, et al. Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases. J Dtsch Dermatol Ges . 2008;6(5):366-373.
7 Brodell LA, Beck LA. Differential diagnosis of chronic urticaria. Ann Allergy Asthma Immunol . 2008;100(3):181-188.

Impetigo
Impetigo, a superficial infection of the skin, is the most common cause of bacterial infections in children. 1 It is extremely contagious and can be transmitted by person-to-person contact as well as via fomites. Children with diseases that disrupt the epidermal barrier, such as atopic dermatitis, are especially prone to impetigo. 2, 3 Atopic dermatitis is a disorder that occurs frequently in children with skin of color ( Fig. 2.3 ). The bullous form of impetigo accounts for about one-third of cases, and is sometimes referred to as pyoderma. This form is almost always a result of Staphylococcus aureus infection, due to its ability to produce exfoliative toxins (ET-A, ET-B), which cleave cell-to-cell adhesions, specifically, desmoglein 1. 4 Occasionally, bullous impetigo can be caused by β-hemolytic streptococcus pyogenes . 5 Although bullae may appear anywhere on the skin, moist intertriginous areas on the trunk are the most common location. Lesions often resolve over several days.

Figure 2.3 Impetigo. Widespread impetigo in a Filipino child.
(From Johnson, Moy, White: Ethnic Skin – Medical and Surgical, Mosby, copyright Elsevier 1998.)
Although lesions may clear on their own, failure to treat impetigo appropriately can result in a variety of complications including septicemia, guttate psoriasis, staphylococcal scalded skin syndrome, and acute post-streptococcal glomerulonephritis (APGN). 6 APGN is a feared complication, which can occur in as many as 5% of cases of streptococcal bullous impetigo. 7

First-Line Therapy

Mupirocin A Fusidic Acid A Retapamulin A
Topical antibiotics are the first-line therapy for impetigo when the patient has limited involvement, and is otherwise well. Mupirocin, fusidic acid and retapamulin are superior to other topical antibiotics, and have minimal side effects given their route of administration. Additionally, the antibiotic concentration is highest in the area intended for treatment, and topical antibiotics are generally less expensive than oral antibiotics.
There is a paucity of high-quality trials evaluating the best therapy for patients with impetigo; however, there are meta-analyses that demonstrate that topical antibiotics are at least better than placebo, and evidence suggests that they may be superior to oral antibiotics, in uncomplicated cases. 8, 9
Mupirocin is the first line of treatment for impetigo in the United States. The mechanism of action of mupirocin, a derivative of Pseudomonas fluorescens , is the inhibition of transfer-RNA synthetase. A short course of 3–7 days is effective utilizing two to three times daily dosing. However, it is important to note that treatment for longer than 10 days should be avoided to prevent bacterial resistance. 10, 11
Mupirocin resistance . Patel JB, Gorwitz RJ, Jernigan JA. Clin Infect Dis 2009 Sep; 49(6): 935–941.
Low levels of resistance have emerged against mupirocin, especially in strains of methicillin-resistant Staphylococcus aureus (MRSA). This is related to its widespread use in the general population for skin infections, as well as to the use of mupirocin for elimination of nasal carriage of MRSA.
Topical mupirocin treatment of impetigo is equal to oral erythromycin therapy . Mertz PM, Marshall DA, Eaglstein WH, Piovanetti Y, Montalvo J. Arch Dermatol 1989; 125:1069–1073.
This investigator-blinded study of 75 impetigo patients with Staphylococcus aureus , Streptococcus pyogenes , or both, used topical mupirocin applied three times daily or oral erythromycin ethylsuccinate (30–50 mg/kg per day). Mupirocin treatment produced similar clinical results to oral erythromycin and was superior in the eradication of S. aureus , including antibiotic-resistant S. aureus . This study proved topical mupirocin to be a safe and effective alternative to oral antibiotic therapy in the treatment of impetigo.
Fusidic acid, which is not available in the United States, is an antibiotic derived from Fusidium coccineum that inhibits bacterial protein synthesis by interfering with ribosome function. 12 Resistance patterns to this topical antibiotic are also emerging.
Fusidic acid cream in the treatment of impetigo in general practice: a double blind randomised placebo controlled trial. Koning S, van Suijlekom-Smit LWA, Nouwen JL, Verduin CM, Bernsen RMD, Oranje AP, et al. BMJ 2002; 324:203–206.
This double-blind, randomized, placebo-controlled trial of fusidic acid cream in combination with povidone-iodine shampoo is compared to placebo. Patients in the fusidic acid group had a 55% clinical cure rate versus only 13% in the placebo group (OR 12.6, 95% confidence interval [5.0–31.5]).
A newly approved topical antibiotic for impetigo is retapamulin 1% cream, which has been shown to be superior to placebo in clinical trials. 13 The treatment course is similar to mupirocin (BID × 5 days). This antimicrobial is derived from Clitopilus passeckeraianus , and functions by inhibiting the 50S subunit of the bacterial ribosome, which ultimately inhibits protein synthesis. Although other antibiotics function against the 50S subunit, the mechanism of retapamulin is novel. 10 The benefit of the drug also lies in its success against strains of Staphylococcus aureus that are resistant to fusidic acid, methicillin and mupirocin. It has been shown in trials to be as effective as fusidic acid and oral cephalexin in the treatment of impetigo. 14 Its recent development and unique mechanism of action makes bacterial resistance intrinsically more unlikely. 15
Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial . Koning S, van der Wouden JC, Chosidow O, et al. Br J Dermatol 2008; 158(5):1077–1082 [Epub 2008 Mar 13].
In this randomized, double-blind, multicenter study retapamulin was tested vs placebo in a total of 213 patients. Retapamulin ointment had a success rate of 84.6% in contrast to placebo, which had a success rate of 52.1% (p < 0.001). The most common side effect was pruritus in the retapamulin group (6%). Retapamulin was felt to be a safe and effective treatment with minimal side effects in the treatment of impetigo.
Topical retapamulin ointment (1%) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial . Parish LC, Jorizzo JL, Breton JJ, Hirman JW, Scangarella NE, Shawar RM, et al. J Am Acad Dermatol 2006; 55:1003–1013.
This is a randomized, double-blind, double-dummy, non-inferiority trial, evaluating the efficacy and safety of retapamulin ointment 1% BID for 5 days in the treatment of secondarily infected dermatitis vs cephalexin 500 mg BID for 10 days. The study yielded results demonstrating that retapamulin was just as effective as cephalexin both clinically (85.9% vs 89.7% respectively) and in terms of microbiologic clearance (87.2% vs 91.8%). Of note is the fact that participants preferred topical treatment. The study concludes that topical retapamulin is just as effective in the treatment of secondary infected dermatitis as oral cephalexin.

Second-Line Therapy

Oral antibiotics B
When bullous impetigo is extensive, treatment with oral antibiotics may be a more practical option for patients. The oral route should also be considered if infection is complicated by systemic symptoms such as fever. It is important to be familiar with resistance patterns of Staphylococci in one’s community when deciding on an oral antibiotic. If no methicillin resistance is suspected or culture shows methicillin sensitive Staphylococcus aureus (MSSA), β-lactamase resistant penicillins, macrolides and 1st or 2nd generation cephalosporins (Gram-positive activity) are all viable treatment options. Treatment duration should span 10 days; the dosing varies according to the medication (see Table 2.1 ).

Table 2.1 Oral therapy for impetigo

Third-Line Therapy

Erythromycin B
Erythromycin should be used as third-line therapy because of gastrointestinal side effects, and studies that demonstrate that it may be inferior to topical mupirocin.
Topical mupirocin treatment of impetigo is equal to oral erythromycin therapy. Mertz PM, Marshall DA, Eaglstein WH, Piovanetti Y, Montalvo J. Arch Dermatol 1989; 125:1069–1073.
This investigator-blinded study of 75 impetigo patients with Staphylococcus aureus , Streptococcus pyogenes , or both, used topical mupirocin applied three times daily or oral erythromycin ethylsuccinate (30–50 mg/kg per day). Mupirocin treatment produced similar clinical results to oral erythromycin and was superior in the eradication of S. aureus , including antibiotic-resistant S. aureus . This study proved topical mupirocin to be a safe and effective alternative to oral antibiotic therapy in the treatment of impetigo.


Commonly encountered pitfalls
As with all contagious conditions, crowded living areas, low-income housing, impaired access to health care, lack of appropriate sanitation and homelessness will increase a patient’s risk of developing impetigo. Therefore, it is imperative to maintain a high index of suspicion in these patients. 16 The risk for acquiring community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is increased in these same conditions. Thus, in treating some patients with ethnic skin, it is crucial to obtain cultures of bullous lesions or treat presumptively for CA-MRSA. 17

Special management & counseling considerations
MRSA infection is an increasing problem in the treatment and management of dermatologic diseases. Infection with resistant strains should be treated according to the Infectious Disease Society of America (IDSA) practice guidelines. For CA-MRSA, doxycycline, minocycline, and trimethoprim-sulfamethoxazole are viable treatment options, whereas for more serious infection, systemic therapy with vancomycin, linezolid, clindamycin or daptomycin can be employed. 18 Tigecycline is a new glycylcycline antibiotic that has shown efficacy comparable with that of vancomycin and can be used in hospital settings. 19
Simple practices such as handwashing and general good hygiene have also been shown to decrease transmission of impetigo. 20

References

1 Darnstadt GL. Cutaneous bacterial infections. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics . Philadelphia: WB Saunders; 2000:2028-2030.
2 Kiken DA, Silverberg NB. Atopic dermatitis in children, part 1: epidemiology, clinical features, and complications. Cutis . 2006;78(4):241-247.
3 Koning S, Verhagen AP, van Suijlekom-Smit LW, Morris A, Butler CC, van der Wouden JC. Interventions for impetigo. Cochrane Database Syst Rev 2004; CD003261.
4 Amagai M, Matsuyoshi N, Wang ZH, Andl C, Stanley JR. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat Med . 2000;6:1275-1277.
5 Lin JJ, Wu CT, Hsia SH, Chiu CH. Bullous impetigo: a rare presentation in fulminant streptococcal toxic shock syndrome. Pediatr Emerg Care . 2007;23:318-320.
6 Hedrick J. Acute bacterial skin infections in pediatric medicine: current issues in presentation and treatment. Pediatr Drugs . 2003;5(Suppl 1):35-46.
7 Oumeish I, Oumeish OY, Bataineh O. Acute bacterial skin infections in children. Clin Dermatol . 2000;18:667-678.
8 George A, Rubin G. A systematic review and meta-analysis of treatments for impetigo. Br J Gen Pract . 2003;53:480-487.
9 Mertz PM, Marshall DA, Eaglstein H, Piovanetti Y, Montalvo J. Topical mupirocin treatment of impetigo is equal to oral erythromycin therapy. Arch Dermatol . 1989;125:1069-1073.
10 Gelmetti C. Local antibiotics in dermatology. Dermatol Ther . 2008;21(3):187-195.
11 Patel JB, Gorwitz RJ, Jernigan JA. Mupirocin resistance. Clin Infect Dis . 2009;49(6):935-941.
12 Mason BW, Howard AJ. Fusidic acid resistance in community isolates of methicillin susceptible Staphylococcus aureus and the use of topical fusidic acid: a retrospective case-control study. Int J Antimicrob Agents . 2004;23:300-303.
13 Koning S, van der Wouden JC, Chosidow O, Twynholm M, Singh KP, Scangarella N, et al. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial. Br J Dermatol . 2008;158(5):1077-1082. [Epub 2008 Mar 13]
14 Parish LC, Jorizzo JL, Breton JJ, Hirman JW, Scangarella NE, Shawar RM, et al. Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial. J Am Acad Dermatol . 2006;55:1003-1013.
15 Shawar R, Scangarella-Oman N, Dalessandro M, Breton J, Twynholm M, Li G, et al. Topical retapamulin in the management of infected traumatic skin lesions. Ther Clin Risk Manag . 2009;5(1):41-49. [Epub 2009 Mar 26]
16 Feldman SR, Vallejos QM, Whalley LE, Quandt SA, Brooks T, Cabral G, et al. Blistering eruption in a Latino migrant farmworker. J Agromedicine . 2007;12(4):81-85.
17 Cohen PR. Community-acquired methicillin-resistant Staphylococcus aureus skin infections: implications for patients and practitioners. Am J Clin Dermatol . 2007;8(5):259-270.
18 Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis . 2005;41(10):1373-1406. [Epub 2005 Oct 14]
19 Huang V, Cheung CM, Kaatz GW, Rybak MJ. Evaluation of dalbavancin, tigecycline, minocycline, tetracycline, teicoplanin and vancomycin against community-associated and multidrug-resistant hospital-associated methicillin-resistant Staphylococcus aureus . Int J Antimicrob Agents . 2010;35:25-29. [Epub 2009 Nov 8]
20 Luby SP, Agboatwalla M, Feikin DR, Painter J, Billhimer W, Altaf A, et al. Effect of handwashing on child health: a randomised controlled trial. Lancet . 2005;366(9481):225-233.

Infantile acropustulosis
Recurrent, acral pruritic, vesiculopustules during infancy characterizes this rare disorder. It is most commonly seen in boys with skin types IV–VI. The onset of lesions is within the first 6 months of age which regress within 1–2 weeks, and recur monthly. 1 The frequency of recurrence and duration of lesions wanes until they resolve, usually around 3 years of age. Infantile acropustulosis most commonly occurs on the palms and soles, dorsa of hands and feet ( Fig. 2.4 ), and between the digits. Rarely, these lesions occur in an axial distribution. Although this disease resolves spontaneously, extreme pruritus causes significant discomfort, difficulty sleeping, and excoriations, which can become secondarily infected. 2

Figure 2.4 Infantile acropustulosis with multiple pustules on the foot of an African-American child.
(Courtesy of Valarie Callander, MD.)

First-Line Therapies

Topical corticosteroids B Oral antihistamines E
Studies have shown that medium to high potency corticosteroids for a brief time are safe and effective in treating pruritus. If needed, the corticosteroids can be used with wet wraps to help increase their efficacy. 3 Supplementation with oral antihistamines, usually at sedating doses, is also effective in alleviating the symptoms. 4 Although the pustules are sterile, treatment with oral antibiotics has been reported to be helpful, likely due to their anti-inflammatory properties. Secondarily infected lesions should be treated with antibiotics and topical antibiotics are usually adequate.
Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids. Mancini AJ, Frieden IJ, Paller AS. Pediatr Dermatol 1998; 15(5):337–341 [PubMed PMID: 9796580].
This is a retrospective study of 21 patients diagnosed with infantile acropustulosis, in which the history of scabies and prior treatment for scabies was analyzed. In 14 of 21 patients, there was a history of scabies, but only 2 of whom had evidence of scabies on microscopic analysis. All patients were treated with topical corticosteroids ranging from class I to VI with no adverse events.

Second-Line Therapies

Dapsone D
Dapsone, a potent inhibitor of neutrophil chemotaxis, at a dose of 2 mg/kg/day, is thought to be the most effective oral medication for infantile acropustulosis, but should be reserved for cases refractory to treatment. Potential severe side effects including aplastic anemia, methemoglobinemia, and peripheral motor neuropathy precludes wide-spread use. There have been no randomized controlled trials, and support for its use is basis of multiple case series and case reports. 5, 6
Atypical acropustulosis in infancy. Truong AL, Esterly NB. Int J Dermatol 1997; 36(9):688–691.
A 20-month-old girl with lesions on the feet, extending to the legs, chest and scalp, was treated for infantile acropustulosis with dapsone therapy initially at 1 mg/kg/day, and then increased to 2 mg/kg/day. Dapsone was tapered over 11 months with no recurrence of disease.


Commonly encountered pitfalls
The primary differential diagnosis for infantile acropustuloss includes infestation with Sarcoptes scabeii , given the acral location, pruritus, and similar clinical presentation (see Table 2.2 ). Patients with scabies may have burrows interdigitally or on the wrists, in addition to close family members with similar symptoms. 7 Microscopic confirmation of the diagnosis can be performed with mineral oil immersion revealing eggs, scybala and/or mites. Some authors believe that acropustulosis of infancy represents a hypersensitivity to prior scabies infestation, which resolves over time. Other studies have demonstrated that although many patients have been diagnosed with and treated for scabies, few of these patients had histologic confirmation of infection. 3
Table 2.2 Differential diagnosis of neonatal pustular disorders Non-infectious causes Infectious causes Erythema toxicum neonatorum Bacterial • Bullous impetigo Infantile acropustulosis • Pseudomonas aeruginosa Transient neonatal pustular melanosis   Neonatal acne Viral Miliaria pustulosa • Herpes simplex Ofuji’s disease (eosinophilic folliculitis) • Varicella zoster Incontinentia pigmenti Fungal Congenital self-healing Langerhans cell histiocytosis • Candidiasis (Congenital or neonatal) • Pityrosporum folliculitis   Parasitic   • Scabies
Adapted from: Van Praag MC, Van Rooij RW, Folkers E, Spritzer R, Menke HE, Oranje AP. Diagnosis and treatment of pustular disorders in the neonate. Pediatr Dermatol 1997; 14:131–43.

Special management & counseling considerations
If dapsone is being considered for treatment of severe infantile acropustulosis, the presence of glucose-6-phosphate dehydrogenase (G6PD) deficiency must be considered as it has a higher prevalence in patients of African or Mediterranean descent. It is these very patients who are more commonly affected by acropustulosis of infancy. Therefore, it is important to screen for G6PD enzyme deficiency prior to instituting therapy to avoid a hemolytic crisis. 8

References

1 Mancini AJ, Frieden IJ, Paller AS. Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids. Pediatr Dermatol . 1998;15(5):337-341.
2 Child FJ, Fuller LC, Higgins EM, Du Vivier AW. A study of the spectrum of skin disease occurring in a black population in south-east London. Br J Dermatol . 1999;141(3):512-517.
3 Braun-Falco M, Stachowitz S, Schnopp C, Ring J, Abeck D. Infantile acropustulosis successfully controlled with topical corticosteroids under damp tubular retention bandages. Acta Derm Venereol . 2001;81(2):140-141.
4 Vignon-Pennamen MD, Wallach D. Infantile acropustulosis. A clinicopathologic study of six cases. Arch Dermatol . 1986;122(10):1155-1160.
5 Truong AL, Esterly NB. Atypical acropustulosis in infancy. Int J Dermatol . 1997;36(9):688-691.
6 Kahn G, Rywlin AM. Acropustulosis of infancy. Arch Dermatol . 1979;115:831-833.
7 Kamal R, Shahab A, Loo D. Bullous scabies. J Am Acad Dermatol . 2003;49:346-350.
8 Minucci A, Giardina B, Zuppi C, Capoluongo E. Glucose-6-phosphate dehydrogenase laboratory assay: How, when, and why? IUBMB Life . 2009;61(1):27-34.

Pemphigus foliaceus
Pemphigus foliaceus (PF) is an autoimmune blistering disorder similar to pemphigus vulgaris. The antigen in this disorder is desmoglein 1, a component of desmosomes primarily present in skin and in lesser quantity in mucosal surfaces. Therefore, clinical disease is expressed only in the skin, with sparing of the mucosa. This disease shares a common antigen with staphylococcal scalded skin syndrome and bullous impetigo, and as such, shares clinical and histologic findings with these disorders. Subcorneal vesicles characterize the disorder but because of the superficial nature of the vesicle, they are rarely seen intact. Clinically, patients have disseminated red, scaly plaques ( Fig. 2.5 ).

Figure 2.5 Pemphigus foliaceus.
(Courtesy Dr. Henry Lim.)
The sporadic form of PF can be seen anywhere in the world. Its incidence in North America and Europe is 1 in 10 and it is as common as pemphigus vulgaris. 1 In contrast, the endemic form of PF, known as fogo selvagem , is present in up to 3% of the population in some rural areas of Brazil, Colombia, Peru and Tunisia. 2, 3 Patients with endemic PF tend to be younger than those with sporadic PF (teenage and 20s). In addition to genetic susceptibility (HLA Class II DR4, DR 14 and DR 1 alleles), environmental factors influence the development of fogo selvagem . 4 There is a seasonal variation with higher incidence during the rainy season. It has been associated with crowded living conditions in underdeveloped areas, with decreasing incidence as an area becomes urbanized. Interestingly, there is a high prevalence of bed bugs and kissing bugs in the homes of patients with endemic PV, and their homes are usually near rivers, which is why the black fly ( Simulium spp.) is also suspected in transmission. 5, 6

First-Line Therapy

Topical corticosteroids C
For severe, extensive disease, systemic treatment is the same as for pemphigus vulgaris. In this section, we will discuss topical therapy for PF. Topical corticosteroids are the first-line and the most common therapy for limited cutaneous disease. There are no large studies regarding the use of topical steroids. One group suggests using the levels of desmoglein 1 antibodies to guide initial treatment with topical corticosteroids only (in the case of low levels), instead of immediately starting systemic treatment. 7 Mild pemphigus may be treated with topical agents initially until relapse requires systemic therapy.
The treatment of mild pemphigus vulgaris and pemphigus foliaceus with a topical corticosteroid . Dumas V, Roujeau JC, Wolkenstein P, Revuz J, Cosnes A. Br J Dermatol 1999; 140(6):1127–1129.
In this case series of seven patients with pemphigus vulgaris and pemphigus foliaceus (mild), patients were treated with clobetasol propionate cream 0.05% twice daily with no systemic treatment. Within 2 weeks, all cutaneous lesions resolved in the 7 patients, and with in one month, mucosal lesions likewise resolved. Three of the patients required systemic treatment within 2–11 months, however 4 of them were maintained only on topical agents for at least 19 months.

Second-Line Therapy

Tacrolimus D
Tacrolimus is a topical immunomodulator, which binds to immunophilins and decreases downstream transcription of inflammatory pathways, specifically, IL-2 and IL-2 receptors in T-lymphocytes. Case reports describe its use in pemphigus foliaceus. One case report was of a split-face trial of tacrolimus 0.1% ointment compared with clobetasone butyrate in which equivalent efficacy was demonstrated. 8, 9 Tacrolimus may be beneficial in areas where one wants to avoid secondary side effects of topical corticosteroid use, such as telangiectasias.
Equal efficacy of topical tacrolimus and clobetasone butyrate in pemphigus foliaceus. Cohen SN, Lim RP, Paul CJ, Abdullah A. Int J Dermatol 2006; 45(11):1379.
Case report of a 71 year old woman with pemphigus foliaceus, on dapsone 100 mg daily, with atrophy and telangiectasias from long-term application of topical corticosteroids. The patient used twice daily tacrolimus ointment 0.1% on one side, and clobetasone butyrate on the other side. After one month, the patient had resolution of the lesions on both sides of the face, with some post-inflammatory changes. Tacrolimus caused mild irritation but otherwise both treatments were tolerated well.

Third-Line Therapy

Topical epidermal growth factor A
Accelerating effects of epidermal growth factor on skin lesions of pemphigus vulgaris: a double-blind, randomized, controlled trial . Tabrizi MN, Chams-Davatchi C, Esmaeeli N, Noormohammadpoor P, Safar F, Etemadzadeh H, et al. J Eur Acad Dermatol Venereol 2007; 21(1):79–84.
This randomized, double-blind, controlled study in which each patient acted as their own control, evaluated silver sulfadiazine cream alone versus epidermal growth factor. Patients healed a median of 6 days earlier on EGF cream (p = 0.0003) as compared to the comparitor, and did not have any side effects.


Special management & counseling considerations
Patients with resolving PF may develop hyperpigmentation in areas of resolved lesions, but in some cases, the hyperpigmentation may extend to uninvolved areas. In Brazil, this change in skin color was referred to as aurora da cura (the dawn of healing), and was considered a sign of remission. Patients described their skin color as changing from white to mulatto, mulatto to black, and Blacks became gray-blue in color. 10 It is important to discuss this color change with patients, as it may be unexpected and severe in patients with ethnic skin.

References

1 Meyer N, Misery L. Geoepidemiologic considerations of auto-immune pemphigus. Autoimmun Rev . 2010;9:A379-A382. [Epub 2009 Nov 3]
2 Warren SJ, Lin MS, Giudice GJ, Hoffmann RG, Hans-Filho G, Aoki V, et al. The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research. N Engl J Med . 2000 Jul 6;343(1):23-30.
3 Uzun S, Durdu M, Akman A, Gunasti S, Uslular C, Memisoglu HR, et al. Pemphigus in the Mediterranean region of Turkey: a study of 148 cases. Int J Dermatol . 2006 May;45(5):523-528.
4 Tron F, Gilbert D, Mouquet H, Joly P, Drouot L, Makni S, et al. Genetic factors in pemphigus. J Autoimmun . 2005 Jun;24(4):319-328.
5 Eaton DP, Diaz LA, Hans-Filho G, Santos VD, Aoki V, Friedman H, et al. Comparison of black fly species on an American reservation with a high prevalence of fogo selvage to neighboring disease-free sites in the state of Mato Grosso do Sul, Brazil. J Med Entomol . 1998;35:120-131.
6 Sagi L, Sherer Y, Trau H, Shoenfeld Y. Pemphigus and infectious agents. Autoimmun Rev . 2008 Oct;8(1):33-35. [Epub 2008 Aug 14]
7 Aoyama Y, Tsujimura Y, Funabashi M, Sato M, Kamiya H, Kitajima Y. An experience for ELISA for desmoglein 1, suggesting a possible diagnostic help to determine the initial therapy for pemphigus foliaceus. Eur J Dermatol . 2000;10(1):18-21.
8 Gach JE, Ilchyshyn A. Beneficial effects of topical tacrolimus on recalcitrant erosions of pemphigus vulgaris. Clin Exp Dermatol . 2004;29(3):271-272. [PubMed PMID: 15115509]
9 Cohen SN, Lim RP, Paul CJ, Abdullah A. Equal efficacy of topical tacrolimus and clobetasone butyrate in pemphigus foliaceus. Int J Dermatol . 2006 Nov;45(11):1379.
10 Hans-Filho G, Aoki V, Rivitti E, Eaton DP, Lin MS, Diaz LA. Endemic pemphigus foliaceus (fogo selvagem) – 1998. The Cooperative Group on Fogo Selvagem Research. Clin Dermatol . 1999;17(2):225-235.

Pemphigus vulgaris
Pemphigus vulgaris is a mucocutaneous bullous disorder caused by acquired autoantibodies targeted against desmosomes, specifically, desmoglein 3 (Dsg3), and less commonly desmoglein 1 (Dsg1). It occurs in people from all backgrounds, however, it seems to have a higher incidence in patients of Jewish descent and in Hispanic New Mexicans. The lesions of pemphigus vulgaris are characterized by flaccid bullae containing clear fluid that easily rupture with resulting erosions ( Fig. 2.6 A and B ). The eroded areas may be extensive and secondary bacterial infections may develop. Eroded areas may form crusts and granulation tissue with resulting vegetating lesions ( Fig. 2.6C ).

Figure 2.6 Pemphigus vulgaris. (A) Characteristic flaccid bullae of pemphigus vulgaris with rupture and secondary bacterial infection. (B) Ruptured bullae and erosions in a patient of Indian decent. (C) Ulcerated lesions of pemphigus vulgaris.
(Courtesy Dr. Sonia Badreshia-Bansal.)

First-Line Therapy
Corticosteroids:
Oral B Intravenous, pulsed C Oral, pulsed A
The mortality associated with pemphigus vulgaris reached nearly 75% before the use of systemic corticosteroids commenced in the 1950s. 1 This inexpensive therapy is considered to be first-line treatment, although the best, most effective schedule and route of administration has not been determined conclusively. 2 A starting dose of 1 mg/kg/day is thought to be safe and effective, as higher doses are coupled with an increase in unwanted side effects. 3 Induction of remission can be expected in 21 days, although complete healing may take up to 8 weeks under normal circumstances. Pemphigus vulgaris patients may be the only ones who can be considered for intravenous, pulsed corticosteroid therapy. 4 Pulsed intravenous corticosteroids (250–1000 mg of methylprednisolone) have been used for 1—5 consecutive days with intent to induce quicker remission; however sample sizes in these trials are small and most patients had recalcitrant disease. However, this method requires continuous cardiac monitoring and hospitalization. Oral pulse therapy with 300 mg of dexamethasone was evaluated in a small, randomized controlled trial; however, this did not show any benefit as compared to controls receiving standard oral therapy. 5
Treatment of pemphigus vulgaris and pemphigus foliaceus: experience with 71 patients over a 20-year period . Fernandes NC, Perez M. Rev Inst Med Trop S Paulo 2001; 43:33–36.
This retrospective case series of 41 patients with pemphigus vulgaris compared the use of high dose prednisone (>120 mg/day) versus the use of 1–2 mg/kg/day (maximum of 120 mg) for 4–6 weeks with subsequent tapering, and looked at initial response, morbidity and mortality rate. The response to therapy and mortality in both groups was similar (no significant difference); however, patients on the higher dose therapy developed unwanted side effects more often (infections, diabetes, Cushing’s syndrome, psychosis, cataracts, aseptic necrosis of the femur and peptic ulcer disease).
Treatment of pemphigus vulgaris with brief, high-dose intravenous glucocorticoids. Werth VP. Arch Dermatol 1996; 132(12):1435–1439.
This small series evaluated 15 patients with severe pemphigus vulgaris, 8 of whom received intravenous methylprednisolone pulse therapy for 2–5 days, 1 received two courses of pulse therapy, and 6 controls received no intravenous therapy. 44% of the patients on intravenous therapy achieved complete remission as compared to none in the control group, and these patients used about half the mean maintenance doses of corticosteroid therapy after the intravenous pulsed course.
Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS Trial . Mentink LF, Mackenzie MW, Tóth GG, Laseur M, Lambert FP, Veeger NJ, et al. Arch Dermatol 2006; 142:570–576.
This multicenter, randomized, double-blind, placebo-controlled clinical trial of 20 patients with new onset pemphigus vulgaris or controlled disease with active flares, 11 of whom received 300 mg of oral dexamethasone supplementation in addition to tapered doses of 80 mg/day of prednisolone and azathioprine 3 g/day. No significant difference was observed between the control and the intervention group as measured by which patients were able to discontinue systemic therapy (8/11 of pulsed dexamethasone and 9/9 of control group).

Second-Line Therapy

Azathioprine A Cyclophosphamide A Mycophenolate mofetil A
Immunosuppressive cytotoxic drugs are used in pemphigus as steroid-sparing agents, in an effort to reduce negative side effects of high dose corticosteroid use.
Azathioprine sodium is a purine analogue that inhibits RNA and DNA synthesis. Its active metabolite, mercaptopurine, is deactivated by thiopurine methyltransferase (TPMT), an enzyme which shows variable activity amongst individuals. Common toxicities include gastrointestinal discomfort (nausea, diarrhea), as well as bone marrow toxicities, especially in people with low levels of enzyme activity. 6
When used in conjunction with corticosteroids, azathioprine has been shown to be slightly more effective than corticosteroids alone in the treatment of pemphigus vulgaris, and is superior as a steroid-sparing agent when compared to mycophenolate mofetil, and pulse therapy cyclophosphamide (both in conjunction with corticosteroids). 7, 8
Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris . Chams-Davatchi C, Esmaili N, Daneshpazhooh M, Valikhani M, Balighi K, Hallaji Z, et al. J Am Acad Dermatol 2007; 57(4):622–628.
This is a randomized, controlled study, with four treatment arms, and a total of 120 patients, evaluating the use of prednisolone alone, prednisolone plus azathioprine, prednisolone plus mycophenolate mofetil, and prednisolone plus intravenous cyclophosphamide pulse therapy. The study demonstrated that prednisolone plus azathioprine was more effective than either mycophenolate mofetil or cyclophosphamide in reducing the total amount of corticosteroids use after a year of treatment (only significant for prednisolone plus mycophenolate mofetil). However, there was no difference in its efficacy in controlling disease activity.
Cyclophosphamide is a nitrogen mustard derivative that suppresses the immune system by cross-linking DNA (cell cycle independent). Its most common complication, hemorrhagic cystitis, is caused by the accumulation of acrolein (a toxic metabolite). Acrolein is a carcinogen that increases the risk of developing transitional cell carcinoma. This risk is especially high in patients who receive low doses of cyclophosphamide over long periods of time as compared to patients who receive pulse-dose therapy of this medication. Infertility in men and women is also a concern. 9
Cyclophosphamide has been evaluated as an adjunctive therapy to corticosteroids in pemphigus vulgaris, with outcomes similar to azathioprine in efficacy (as above). Pulsed therapy and chronic low dose cyclophosphamide in conjunction with corticosteroids have similar results in terms of efficacy, but a lower risk of malignancy when used as pulse therapy. 10, 11
Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, et al. Am J Clin Dermatol 2007; 8(2):85–92.
This retrospective study with long-term follow-up evaluated 101 patients with moderate to severe pemphigus vulgaris and divided patients into four different treatment regimens: oral prednisone at an initial dose of 100 mg (1.1–1.5 mg/kg) per day as monotherapy; prednisone combined with azathioprine at a dose of 100 mg (1.1–1.5 mg/kg) per day; cyclosporine (ciclosporin) at a dose of 2.5–3 mg/kg/day; or cyclophosphamide at a dose of 100 mg (1.1–1.5 mg/kg) per day. Time to clinical and immunologic remission was shortest in the cyclophosphamide group as compared to all other groups (4.9 ± 6.9 months; 23 ± 17 months respectively). The proportion of patients who remained disease free after 5 years was also significantly larger, and those patients who did relapse did so after a longer disease-free period. The authors conclude that cyclophosphamide at a dose of 1.1–1.5 mg/kg/day should be the adjuvant drug of choice in the treatment of moderate to severe pemphigus vulgaris.
Mycophenolic acid (MPA) was isolated from Penicillium stoloniderum as a fermentation product; its morpholinoethyl ester form is what is known as Mucophenolate mofetil (MMF) which has better bioavailability and tolerability than MPA. This antimetabolite inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required for the de novo synthesis of purines. B and T lymphocytes, which depend on this pathway for DNA synthesis, are most affected. Patients on MMF develop gastrointestinal side effects in a dose-dependent manner (20% at 2 g/day), however hematologic side effects are not as common (< 5%). 9, 12
MMF has been used both as adjuvant therapy and as monotherapy in the treatment of pemphigus vulgaris, although time to remission seems to be longer in the latter. 8, 13 As a steroid-sparing agent, it appears to be less effective than azathioprine and cyclophosphamide; however, it does seem to be more effective in inducing remission than azathioprine. 14
A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler R, et al. Arch Dermatol 2006; 142(11):1447–1454.
This is a small, randomized prospective, multicenter, non-blinded trial of 41 patients with pemphigus vulgaris and pemphigus foliaceus which compared azathioprine and mycophenolate mofetil as adjuvants to corticosteroids. MMF was more effective than azathioprine in conjunction with methylprednisolone in the induction of complete remission (95% vs 72% respectively), and was similar to azathioprine in terms of its steroid-sparing effects. Patients in the MMF group had fewer grade 3 toxicities and no grade 4 toxicities when compared to azathioprine.
Efficacy and safety of long-term mycophenolate sodium therapy in pemphigus vulgaris. Baskan EB, Yilmaz M, Tunali S, Saricaoglu H. J Eur Acad Dermatol Venereol 2009; 23:1432–1434 [Epub 2009 Mar 17].
A small non-blinded trial compared the safety and effectiveness of MMF (1440 mg/day) as monotherapy and in combination with oral prednisolone (70–100 mg/day) in 6 patients. Complete remission was achieved in two patients on combination therapy, partial remission in two patients with monotherapy, and two patients did not respond. Patients receiving combination therapy had a faster response than those on monotherapy.

Third-Line Therapy

Intravenous immunoglobulin A Rituximab D
The mechanism of action of IVIg is not well understood, but it is thought to decrease activation of complement and cytokine expression via Fc receptors. The advantage of IVIg is that unlike other adjuvant therapy, it does not immunosuppress patients. 15
A randomized double-blind trial of intravenous immunoglobulin for pemphigus. Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, et al; Pemphigus Study Group. J Am Acad Dermatol 2009; 60(4):595–603.
This is a randomized, double-blind, multicenter, placebo controlled clinical trial which enrolled 61 patients with relatively resistant pemphigus vulgaris and pemphigus foliaceus. Patients were either in the placebo group, the 200 mg/kg/day of IVIg, or 400 mg/kg/day group. Evaluation of efficacy was based on time to recurrence of disease after treatment, pemphigus activity score, and ELISA scores of desmoglein 1 and 3. Patients responded to IVIg in a dose-dependent manner (p < .001), which included increased time to relapse (p < .001), decreased disease activity at 43 and 85 days (p < .05, p < .01), and decreased ELISA levels (p < .001).
Rituximab is a chimeric, monoclonal IgG1 antibody which targets CD20 antigen, located on B-cells. After binding, it induces antibody and complement dependent cell cytotoxicity as well as apoptosis, thereby resulting in decreased circulating levels of CD20+ B cells for 6–12 months. Its use in bullous disorders has increased, prompting a consensus on usage from experts in Germany, Austria and Switzerland. The panel of experts believes that patients with failure to respond after at least three months with standard treatments (steroids ± immunosuppressants) or patients who cannot use standard therapies due to underlying conditions, are candidates for rituximab. Patients with underlying active hepatitis, tuberculosis, HIV infection with CD 4+ < 250, severe heart failure or allergy to mouse proteins should not be considered for treatment. 16, 17, 18
Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature . Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Arch Dermatol 2007; 143(8):1033–1038.
This case series reviews the treatment of pemphigus vulgaris in 10 patients (severe mucocutaneous disease; recalcitrant disease; adverse side effects of steroids) and 2 patients with pemphigus foliaceus. This was one of the largest series to date and most patients were on a standardized dose of oral prednisone (40 mg/day); 4 patients required additional immunosuppressants for control. They underwent four total intravenous treatments with 375 mg/m 2 once weekly. Patients responded to therapy within an average of 6–10 weeks, 9 had complete remission within 6 months of rituximab infusion, and one of the patients required an additional dose after 6 months. Only three of the patients required immunosuppressive treatment in addition to corticosteroids as maintenance.


Commonly encountered pitfalls
The highest incidence of pemphigus vulgaris has been seen in Ashkenazi Jews; Hispanic New Mexicans have a four-fold rate of PV as compared to the general population of non-Hispanics. Evidence suggests that the New Mexican Hispanics are descendants of Jews who emigrated during the inquisition in the 15th and 16th centuries. The importance of this lies in the need to have a higher index of suspicion for pemphigus vulgaris in Hispanics from the Southwest, and to be aware that they may have an increased incidence of other diseases seen most commonly in Ashkenazi Jews given their ancestry. 19

Special management & counseling considerations
In deciding which agent to use for pemphigus vulgaris, it is helpful to take into account the patient’s age, as the risk of malignancy increases with increased exposure to certain medications. It is also important to consider the patient’s desire to have children as some medications, such as azathioprine, can cause permanent infertility. ELISA levels of Dsg1 and Dsg3 levels parallel disease activity, and may be used to monitor response to treatment and adjustment of medication doses. 20, 21

References

1 Bystryn JC. Adjuvant therapy of pemphigus. Arch Dermatol . 1984;120(7):941-951.
2 Harman KE, Albert S, Black MM. Guidelines for the management of pemphigus vulgaris. Br J Dermatol . 2003;149:926-937.
3 Fernandes NC, Perez M. Treatment of pemphigus vulgaris and pemphigus foliaceus: experience with 71 patients over a 20 year period. Rev Inst Med Trop Sao Paulo . 2001;43(1):33-36.
4 Werth VP. Treatment of pemphigus vulgaris with brief, high-dose intravenous glucocorticoids. Arch Dermatol . 1996;132(12):1435-1439.
5 Mentink LF, Mackenzie MW, Tóth GG, Laseur M, Lambert FP, Veeger NJ, et al. Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial. Arch Dermatol . 2006 May;142(5):570-576.
6 Firooz A, Ghandi N, Hallaji Z, Chams-Davatchi C, Valikhani M, Karbakhsh Davari M. Role of thiopurine methyltransferase activity in the safety and efficacy of azathioprine in the treatment of pemphigus vulgaris. Arch Dermatol . 2008 Sep;144(9):1143-1147.
7 Chams-Davatchi C, Esmaili N, Daneshpazhooh M, Valikhani M, Balighi K, Hallaji Z, et al. Randomized controlled open-label trial of four treatment regimens for pemphigus vulgaris. J Am Acad Dermatol . 2007 Oct;57(4):622-628. [Epub 2007 Jun 21]
8 Beissert S, Werfel T, Frieling U, Böhm M, Sticherling M, Stadler R, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol . 2006 Nov;142(11):1447-1454.
9 Pan TD, McDonald CJ. Comprehensive dermatologic drug therapy. In: Wolverton SE, editor. Comprehensive dermatologic drug therapy . Cytotoxic agents: WB Saunders; 2001:180-204.
10 Saha M, Powell AM, Bhogal B, Black MM, Groves RW. Pulsed intravenous cyclophosphamide and methylprednisolone therapy in refractory pemphigus. Br J Dermatol . 2009 Nov 18. [Epub ahead of print]
11 Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, et al. Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol . 2007;8(2):85-92.
12 Orvis AK, Wesson SK, Breza TSJr, Church AA, Mitchell CL, Watkins SW. Mycophenolate mofetil in dermatology. J Am Acad Dermatol . 2009;60(2):183-199.
13 Baskan EB, Yilmaz M, Tunali S, Saricaoglu H. Efficacy and safety of long-term mycophenolate sodium therapy in pemphigus vulgaris. J Eur Acad Dermatol Venereol. . 2009;23:1432-1434. [Epub 2009 Mar 17]
14 Martin LK, Werth V, Villanueva E, Segall J, Murrell DF. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev 2009 Jan 21; (1):CD006263.
15 Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, et al. Pemphigus Study Group. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol . 2009 Apr;60(4):595-603.
16 Hertl M, Zillikens D, Borradori L, Bruckner-Tuderman L, Burckhard H, Eming R, et al. Recommendations for the use of rituximab (anti-CD20 antibody) in the treatment of autoimmune bullous skin diseases. J Dtsch Dermatol Ges . 2008 May;6(5):366-373. [Epub 2008 Jan 14]
17 Cianchini G, Corona R, Frezzolini A, Ruffelli M, Didona B, Puddu P. Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol . 2007;143(8):1033-1038.
18 Schmidt E, Goebeler M, Zillikens D. Rituximab in severe pemphigus. Ann. NY Acad Sci . 2009;1173:683-691.
19 Bordenave K, Griffith J, Hordes SM, Williams TM, Padilla RS. The historical and geomedical immunogenetics of pemphigus among the descendants of Sephardic Jews in New Mexico. Arch Dermatol . 2001 Jun;137(6):825-826.
20 Amagai M, Komai A, Hashimoto T, Shirakata Y, Hashimoto K, Yamada T, et al. Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br J Dermatol . 1999 Feb;140(2):351-357.
21 Daneshpazhooh M, Chams-Davatchi C, Khamesipour A, Mansoori P, Taheri A, Firooz A, et al. Desmoglein 1 and 3 enzyme-linked immunosorbent assay in Iranian patients with pemphigus vulgaris: correlation with phenotype, severity, and disease activity. J Eur Acad Dermatol Venereol . 2007 Nov;21(10):1319-1324.
3 Collagen Vascular Diseases

Sumayah J. Taliaferro, Erica Chon Davis, Valerie D. Callender

Dermatomyositis 39
Livedoid vasculopathy 44
Lupus 47
Chronic cutaneous lupus 47
Subacute cutaneous lupus erythematosus (SCLE) 52
Systemic lupus erythematosus 53
Scleroderma 58
Localized scleroderma (morphea) 58
Systemic sclerosis 61

Dermatomyositis
Dermatomyositis is an idiopathic myopathy involving inflammation of proximal muscles and characteristic cutaneous findings. When the cutaneous findings occur without the typical muscle weakness and muscle enzyme levels are normal over a 2-year period, the condition is referred to as amyopathic dermatomyositis or dermatomyositis sine myositis. Polymyositis, which is thought to be related to dermatomyositis, is an inflammatory myopathy typified by muscle inflammation and weakness in the absence of skin involvement. The relationship between dermatomyositis and polymyositis is currently somewhat controversial as new evidence suggests different pathogenetic mechanisms. 1, 2
The etiology of dermatomyositis remains unclear, but is presumed to be of autoimmune origin. Experts speculate that a viral infection of the muscles is a precipitating cause. Other triggers include malignancy and medications. These stimulate an immune-mediated inflammatory response in genetically predisposed individuals. Ninety-five percent of patients have positive serum antinuclear autoantibodies.
While dermatomyositis can develop at any age, it tends to have a bimodal age distribution, most commonly occurring in children between the ages of 5 and 15 and adults between the ages of 40 and 60. Women are affected more than men with an approximate female to male ratio of 6 to 1. The incidence of dermatomyositis ranges from 2 to 7 cases per million. Overall, the incidence of dermatomyositis appears to be increasing.
The characteristic cutaneous findings of dermatomyositis include malar erythema and poikiloderma in the V neck distribution. A hallmark feature is the presence of erythematous-violaceous patches over the upper eyelids, known as a ‘heliotrope’ rash. Another pathognomonic sign is the presence of Gottron’s papules, which are erythematous-violaceous papules and plaques over the knuckles, elbows, and knees ( Fig. 3.1 ). Both of these cutaneous signs often appear hyperpigmented in skin of color patients. Periungual and cuticular changes also occur, most commonly nailfold telangiectasia. Inflammation and weakness affect the proximal muscles. Soreness and stiffness of the muscles is common. Patients may report difficulty climbing stairs, walking, and rising from a sitting position. Up to 40% of patients may initially present with skin disease without muscle involvement. 3 In dermatomyositis, muscle and skin disease may occur concurrently or one may precede the other.

Figure 3.1 Gottron’s papules over the proximal interphalangeal joints in a dermatomyositis patient.
While characteristic skin findings and muscle weakness are definitive features, dermatomyositis is ultimately a multisystem disease. Cardiac and pulmonary complications are not uncommon. 4 Specifically, interstitial lung disease and pneumomediastinum are potential pulmonary complications. 5 The presence of Jo-1 antibody has been associated with interstitial lung disease in dermatomyositis. One study showed that Anti-Jo-1 and other myositis associated autoantibodies were equally distributed among whites, African-Americans, Mexican-Americans, and Japanese. 6 Systemic symptoms can be severe and include arthralgias, dysphagia, dyspnea, and palpitations.
Juvenile dermatomyositis typically presents with slow-onset, but progressive muscle weakness develops. Cutaneous features may be delayed. Calcinosis and lipodystrophy are complicating features of some patients with longstanding childhood dermatomyositis. 7 A recent study identified the novel autoantibody, anti-p140 in association with calcinosis in juvenile dermatomyositis. 8 Contractures leading to long-term disability may occur in severe disease. The association with malignancy is not seen in juvenile dermatomyositis.
A concerning feature of dermatomyositis in adults is its association with malignancy. Frequently it may herald the onset of malignancy that might otherwise go unnoticed and result in late detection. Approximately one-fourth of cases of dermatomyositis in adults occur in the presence of an occult malignancy. Certain malignancies occur more frequently. These include ovarian, lung, pancreatic, colon, non-Hodgkin’s lymphoma, and breast cancer. 9 The presence of cutaneous leukocytoclastic vasculitis may be a sign of malignancy in dermatomyositis, and thus should prompt thorough systemic evaluation. 10
Drug-induced dermatomyositis is now well-described. Hydroxyurea is a known precipitating cause of dermatomyositis. Other sources of possible drug-induced dermatomyositis include d -penicillamine, non-steroidal anti-inflammatory medications, and lipid-lowering medications. 11
When dermatomyositis is suspected, serum aldolase and creatine kinase levels should be checked. Confirmation of muscle disease with electromyogram and muscle biopsy is also recommended. Magnetic resonance imaging (MRI) and ultrasound imaging have been useful in determining extent of muscle involvement and aiding in the identification of specific muscles to biopsy. Some patients with amyopathic dermatomyositis have been shown to have mild muscle inflammation identified on MRI that is not evident clinically. Work-up for systemic disease should include a thorough evaluation of the cardiac, pulmonary and gastrointestinal systems. A chest X-ray, esophageal motility test, pulmonary function test, and electrocardiogram are recommended. In adults, evaluation for the presence of malignancy should also ensue, starting with routine labwork and basic age-appropriate cancer screening tests. Some experts recommend computed tomographic (CT) scans of the chest, abdomen, and pelvis. Women should be screened for ovarian cancer. 12

First-Line Therapies
For cutaneous disease:
Sunscreens   Topical corticosteroids E Antimalarials C Cyclophosphamide E
For muscle disease:
Systemic corticosteroids C Methotrexate C Azathioprine A, E (Polymyositis) A (Dermatomyositis) E
Dermatomyositis: comparative studies of cutaneous photosensitivity in lupus erythematosus and normal subjects. Dourmishev L, Meffert H, Piazena H. Photodermatol Photoimmunol Photomed. 2004; 20:230–234.
Ultraviolent light may play a prominent role in the pathophysiology of dermatomyositis, in which the characteristic skin findings occur on mostly sun-exposed areas. The authors found that photosensitivity was a frequent sign in dermatomyositis and sought to demonstrate this in a scientific manner by measuring the minimal erythema dose (MED). In this study, the MED was reduced in dermatomyositis and lupus patients compared to healthy controls. The subjects were Caucasian with skin types II and III. The authors indicate that photosensitivity should be one of the major criteria for the diagnosis of dermatomyositis as in lupus.
Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. Woo TY, Callen JP, Voorhees JJ, Hanno R, Hawkins C. J Am Acad Dermatol. 1984; 10:592–600.
The cutaneous manifestations of dermatomyositis are frequently more resistant to treatment with corticosteroids and other immunosuppressives. In this open clinical trial of seven patients, all patients with cutaneous lesions responded well with the addition of hydroxychloroquine.
Complete resolution of dermatomyositis with refractory cutaneous vasculitis by intravenous cyclophosphamide pulse therapy. Tsujimura S, Saito K, Tanaka Y. Intern Med 2008; 47:1935–1940.
This case report demonstrates the effective use of cyclophosphamide without systemic corticosteroids in the treatment of cutaneous ulcerations and vasculitis in a complicated case of dermatomyositis in a 43-year-old male.
Dermatomyositis; a dermatology-based case series. Dawkins MA, Jorizzo JL, Walker FO, Albertson D, Sinal SH, Hinds A. J Am Acad Dermatol. 1998; 38:397–404.
In this study, a retrospective analysis of the clinical features of sixty-five patients during a ten-year period was performed. The authors paid special attention to the patients’ response to systemic corticosteroids. Twenty-one of the patients were enrolled in a prospective, uncontrolled trial of prednisone treatment with slow tapering. Prednisone was dosed at 1 mg/kg/day and reduced gradually to one-half the initial dose during a six-month period. Prednisone dose was slowly lowered and discontinued during a period that ranged from twenty to sixty-three months. Findings indicate that treatment with high-dose prednisone followed by slow tapering is effective.
Efficacy of early treatment of severe juvenile dermatomyositis with IV methylprednisolone and methotrexate . Al-Mayout S, Al-Mazyed A, Bahabris S. Clin Rheumatol 2000; 19:138–141.
In this small trial of 12 children with severe juvenile dermatomyositis, methotrexate and IV methylprednisolone were found to be an effective treatment combination. The study suggests that this treatment combination may prevent complications such as calcinosis.
Treatment of dermatomyositis with methotrexate. Zieglschmid-Adams ME, Pandya AG, Cohen SB, Sontheimer RD. J Am Acad Dermatol 1995; 32:754–757.
This article reports five pediatric cases (ages four to twelve) of severe dermatomyositis in which the patients improved with adjuvant therapy with either methotrexate alone or combined therapy with methotrexate and azathioprine. All patients were on systemic steroids. The dose of methotrexate ranged from 2–3 mg/kg administered every two weeks. The dose of azathioprine was 50 mg daily, but was increased to 125 mg daily in the twelve-year old boy reported in the fifth case.
Prednisone and azathioprine for polymyositis: long-term follow-up . Bunch TW. Arthritis Rheum 1981; 24:45–48.
The initial study of a double-blind placebo-controlled trial published the previous year by the same author indicated no statistically significant improved effect with the addition of azathioprine. However, it observed muscle function for a limited period of time. Results of this follow-up study showed a long-term beneficial effect of azathioprine in combination with prednisone.

Second-Line Therapies
For cutaneous disease:
Tacrolimus   (topical) D (oral) E Methotrexate C Mycophenolate mofetil C Intravenous immunoglobulin A
For muscle disease:
Cyclophosphamide D Chlorambucil D Mycophenolate mofetil C Cyclosporine B Intravenous immunoglobulin A
Topical tacrolimus 0.1% ointment for refractory skin disease in dermatomyositis: a pilot study. Hollar CB, Jorizzo JL. J Dermatolog Treat. 2004; 15:35–39.
A few case reports indicate the usefulness of topical tacrolimus for cutaneous lesions of dermatomyositis. In this report six patients with resistant cutaneous manifestations of dermatomyositis showed improvement after six to eight weeks of treatment with topical tacrolimus 0.1% ointment. Dramatic improvement was observed in two of the patients, a moderate response was noted in one, and three of the patients had minimal improvement.
Treatment of refractory juvenile dermatomyositis with tacrolimus. Hassan J, van der Net JJ, van Royen-Kerkhof A. Clin Rheumatol 2008; 27:1469–1471.
Three patients with severe juvenile dermatomyositis, on systemic corticosteroids, were treated with oral tacrolimus (target serum level 10 µg/l, therapeutic range 5–15 µg/l). There was marked improvement of the cutaneous eruptions, improvement in physical activity, and overall decrease in disease that allowed for tapering of systemic corticosteroids. Side effects of oral tacrolimus include gastrointestinal symptoms, hypertension, nephrotoxicity and neurotoxicity, but no adverse effects were noted in the patients reported here. It is felt that oral tacrolimus may have beneficial effects in refractory cases of juvenile dermatomyositis, particularly those with extensive cutaneous manifestations.
Low dose methotrexate administered weekly is an effective corticosteroid-sparing agent for the treatment of the cutaneous manifestations of dermatomyositis . Kasteler JS, Callen JP. J Am Acad Dermatol 1997; 36:67–71.
The authors found that low-dose methotrexate administered weekly was effective in treating the cutaneous disease of dermatomyositis. The treatment with methotrexate frequently allowed for a lower dose of systemic steroids or discontinuation of corticosteroid therapy. Thirteen patients were reviewed in this retrospective analysis. The dose of methotrexate ranged from 2.5 to 30 mg weekly (average maximal dose of 7.5 mg per week). Methotrexate was tolerated well with minimal toxicity.
Immunomodulatory treatment for dermatomyositis. Callen JP. Curr Allergy Asthma Rep 2008; 8:348–353.
Treatment of muscle disease in dermatomyositis requires high-dose systemic steroids. The use of a steroid-sparing adjunctive agent is also recommended for early control of disease. Recommended treatments include methotrexate, azathioprine, mycophenolate mofetil, and intravenous immunoglobulin. The author suggests use of methotrexate as a first-line agent due to its effectiveness for muscle and skin disease with a starting dose of 5–7.5 mg/week orally or intravenously. Weekly increases of 2.5 or 5 mg/week are recommended until a dose of 25–30 mg/week is reached. The suggested azathioprine dose is 2 mg/kg/day. Mycophenolate mofetil is reported to be beneficial at a dose of 2–3 g/day. IVIg is effective with an infusion dose of 2 g/kg/mo. Clinical improvements are usually noted after 3–4 months with IVIg, but long-term intermittent therapy may be required.
Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety . Riley P, Maillard SM, Wedderburn LR, Woo P, Murray KJ, Pilkington CA. Rheumatology (Oxford). 2004; 43:491–496.
In this review, ten out of twelve patients with severe refractory juvenile dermatomyositis showed a significant improvement in muscle function and strength as well as skin disease severity after treatment with cyclophosphamide. The mean cumulative dose was 4.6 g/m 2 . The few reported complications included lymphopenia, herpes zoster infections, and alopecia, which were reversible. It was noted that the dreaded possible long-term complications (malignancy, infertility, gonadal failure) tend to occur at doses higher than the doses required to treat dermatomyositis.
Chlorambucil: an effective corticosteroid-sparing agent for patients with recalcitrant dermatomyositis . Sinoway PA, Callen JP. Arthritis Rheum. 1993; 36:319–324.
This is a report of five patients with recalcitrant dermatomyositis who showed improved clinical response after treatment with oral chlorambucil (4 mg/day). The patients were treated with chlorambucil after discontinuation of azathioprine or methotrexate. Three of the patients were treated with prednisone and chlorambucil concomitantly. The patients experienced improvement after four to six weeks of beginning chlorambucil. Chlorambicil was well-tolerated. Two patients experienced leucopenia, but no other major side effects were noted. The muscle disease improved in these patients but the cutaneous disease did not.
Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis . Edge JC, Outland JD, Dempsey JR, Callen JP. Arch Dermatol. 2006; 142:65–69.
This was a small open-label retrospective chart review of twelve patients with refractory cutaneous lesions of dermatomyositis. Improvement was noted in ten out of twelve patients. Doses of mycophenolate mofetil ranged from 500 mg to 1 g twice a day. The majority of patients tolerated mycophenolate mofetil well. One patient developed B-cell lymphoma of the central nervous system and another developed abnormal liver enzymes with resolution upon discontinuation of the medication.
Several case studies indicate that mycophenolate mofetil is an effective adjuvant therapy for dermatomyositis. However, patients should be monitored carefully for side effects. High rates of opportunistic infections have been reported in some studies while others indicate minimal risk.
Cyclosporin A versus methotrexate in the treatment of polymyositis and dermatomyositis. Vencovsky J, Jarosova K, Machaecek S, Studynkova J, Kafkova J, Bartunkova J, et al. Scand J Rheumatol 2000; 29:95–102.
This study looked at 36 patients with either dermatomyositis (20) or polymyositis (16) who were treated with both methotrexate and prednisone or cyclosporine A and prednisone. The dose of cyclosporine was 3 to 3.5 mg/kg/day. Oral methotrexate dose ranged from 7.5 mg to 15 mg weekly. Improvement in clinical features and laboratory indicators was demonstrated in the group treated with either methotrexate or cyclosporine without significant difference.
A controlled trial of high-dose IV immunoglobulin infusions as treatment for dermatomyositis. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. N Eng J Med 1993; 329:1993–2000.
In this double-blind, placebo-controlled study, fifteen patients who continued to receive prednisone (mean daily dose of 25 mg) were randomized to receive one infusion of immune globulin (8) or placebo (7) monthly for three months. Immune globulin was administered as 2 g per kilogram divided into two doses of 1 g/kg each. Patients treated with immune globulin showed significant improvement. Maximal improvement occurred in most of the patients between the second and third month.
Subcutaneous immunoglobulin administration: an alternative to intravenous infusion as adjuvant treatment for dermatomyositis? Schleinitz N, Jean E, Benarous L, Mazodier K, Figarella-Branger D, Bernit E, et al. Clin Rheumatol 2008; 27:1067–1068.
This is a case report of a patient with dermatomyositis who displayed clinical improvement with use of subcutaneous immunoglobulin instead of the standard intravenous form. The patient was treated with a monthly dose of 1.7 g/kg of subcutaneous immunoglobulin. Offering the advantage of at-home administration, subcutaneous immunoglobulin may provide a more convenient adjunctive treatment for dermatomyosits in some patients.
Safety of intravenous immunoglobulin in the treatment of juvenile dermatomyositis: adverse reactions are associated with immunoglobulin A content. Manlhiot C, Tyrrell PN, Liang L, Atkinson AR, Lau W, Feldman BM. Pediatrics 2008; 121:626–630.
Intravenous immunoglobulin has been found to be effective in treating juvenile dermatomyositis, particularly cases refractory to systemic steroid treatment. This study confirmed that intravenous immunoglobulin is a safe treatment alternative for juvenile dermatomyositis, but children tend to have a lower tolerance of intravenous immunoglobulin containing high amounts of immunoglobulin A. Thus, selection of immunoglobulin type is important when treating children with dermatomyositis with this agent.
Successful treatment of dermatomyositis during pregnancy with intravenous immunoglobulin monotherapy. Williams L, Chang PY, Park E, Gorson KC, Bayer-Zwirello L. Obstet Gynecol 2007; 109:561–563.
Dermatomyositis, while rare during pregnancy, is associated with poor fetal outcome without proper treatment. Corticosteroids, the mainstay of treatment, can lead to adverse events due to the high doses required. This case report demonstrates the safe and effective use of intravenous immunoglobulin in the treatment of dermatomyositis in a young white primigravida at 4 weeks gestation. Intravenous immunoglobulin was administered monthly at a dose of 1 g/kg/day for 2 consecutive days. Intravenous immunoglobulin may provide a nice treatment alternative with few adverse effects yielding good maternal and fetal outcome.

Third-Line Therapies

Dapsone E Diltiazem E Etanercept E Infliximab D Total Body Irradiation E Rituximab E Leflunomide E
Cutaneous involvement of dermatomyositis can respond to dapsone therapy. Cohen JB. Int J Dermatol 2002; 41:182–184.
Two patients with dermatomyositis who remained refractory despite treatment with prednisone and antimalarials improved dramatically after the addition of dapsone. Dapsone may be a good choice of adjunctive therapy for dermatomyositis.
Regression of calcinosis during diltiazem treatment of juvenile dermatomyositis. Oliveri MB, Palermo R, Mautalen C, Hubscher O. J Rheumatol 1996; 23:2152–2155.
This case report describes a child with severe dystrophic calcifications despite treatment with methylprednisolone, methotrexate, and later azathioprine. Pronounced regression of calcinosis was observed during treatment with diltiazem (2 mg/kg/day).
Etanercept is effective in the treatment of polymyositis/dermatomyositis which is refractory to conventional therapy including steroids and other disease modifying agents. Saadeh CK. Arthritis Rheum 2000; 43:S193.
Four patients responded well to etanercept after failing corticosteroids and other immunosuppressives. No side effects were reported. Etanercept may be useful in the treatment of patients who remain refractory to conventional therapy.
Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Riley P, McCann LJ, Maillard SM, Woo P, Murray KJ, Pilkington CA. Rheumatology (Oxford) 2008; 47:877–880.
Five patients with juvenile dermatomyositis who were refractory to other medications showed further improvement with infliximab, an anti-TNF-alpha monoclonal antibody. Starting dose was 3 mg/kg, but dose and frequency were tailored to individual response. High levels of TNF-alpha have been identified in patients with juvenile dermatomyositis and calcinosis.
Response to total body irradiation in dermatomyositis. Kelly JJ, Madoc-Jones H, Adelman LS, Andres PL, Munsat TL. Muscle Nerve. 1988; 11:120–123.
When patients with severe resistant dermatomyositis become too ill to tolerate immunusuppressives or have to discontinue immunosuppressives due to complications, other treatment options become necessary. The authors report two cases of dermatomyositis successfully treated with irradiation. Thrombocytopenia in one patient was the only reported side effect. *
Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients. Cooper MA, Willingham DL, Brown DE, French AR, Shih FF, White AJ. Arthritis Rheum 2007; 56:3107–3111.
This is a retrospective review of four pediatric patients with juvenile dermatomyositis treated with rituximab, an anti-CD20 monoclonal antibody. Three of the four patients showed an improved clinical response with rituximab.
Rituximab for the treatment of the skin manifestations of dermatomyositis: a report of 3 cases. Dinh HV, McCormack C, Hall S, Prince HM. J Am Acad Dermatol 2007; 56:148–153.
This is a report of three patients with dermatomyositis who were achieving good therapeutic responses for muscle disease but inadequate control of the cutaneous manifestations. The patients showed improvement of cutaneous disease with rituximab, a monoclonal anti-CD20 antibody.
Leflunomide as adjuvant treatment of dermatomyositis. Boswell JS, Costner MI. J Am Acad Dermatol 2008; 58:403–406.
This is a report of three cases of recalcitrant dermatomyositis that were treated effectively with the addition of leflunomide, a novel immunomodulatory medication used to treat rheumatoid arthritis. All three patients initially failed treatment with other immunosuppressives which included methotrexate and hydroxychloroquine, but cleared when leflunomide (20 mg/day) was added to their therapeutic regimen. Leflunomide may be a safe and effective adjuvant treatment in difficult cases of dermatomyositis.


Special management & counseling considerations
Systemic oral corticosteroids are the mainstay of treatment for dermatomyositis. The recommended initial dose is 0.5–1.5 mg/kg/day, followed by a slow taper to one half the starting dose over 6 months with a goal of stopping therapy in 2 years. Corticosteroids should not be continued indefinitely. Many patients need a 2–3-year duration of systemic steroids but some patients respond well earlier and can discontinue therapy as soon as 14 months.
Dermatologic manifestations of dermatomyositis can be difficult to treat. Even after muscle disease is adequately suppressed, the skin eruption may remain refractory to treatment and require additional therapy. Aggressive sun protection with physical barriers and sunscreen must be emphasized. Topical corticosteroids are recommended as first-line treatment. Hydroxychloroquine can be added as a systemic treatment in more difficult cases. It has been noted, however, that patients with dermatomyositis may not respond as dramatically to antimalarial therapy or tolerate it as well as patients with lupus erythematosus. Mycophenolate mofetil has been shown to effectively treat the skin manifestations of dermatomyosistis.
Calcinosis is a complicating feature frequently seen in children with dermatomyositis. Early aggressive treatment with high dose corticosteroids may prevent calcinosis. 13 Physical therapy should be a part of the treatment plan in children to prevent contractures and long-term disability from muscle weakness.
Patients of Asian ancestry may have more severe pulmonary disease and should be screened and treated early for pulmonary complications. 14, 15

References

1 Grundtman C, Malmstrom V, Lundberg IE. Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies. Arthritis Res Ther . 2009;9:208.
2 Mammen AL. Dermatomyositis and polymyositis:clinical presentation, autoantibodies, and pathogenesis . Annals of the New York Academy of Sciences; 2009. p. 24
3 Gerami P, Schope JM, McDonald L, Walling HW, Sontheimer RD. A systematic review of adult – onset clinically amyopathic dermatomyositis (dermatomyositis sine myositis). A missing link within the spectrum of idiopathic inflammatory myopathies. J Am Acad Dermatol . 2006;54:597-613.
4 Lundberg IE. The heart in dermatomyositis and polymyositis. Rheumatology (Oxford) . 2006;45(Suppl 4):iv18-iv21.
5 Fathi M, Lundberg IE, Tornling G. Pulmonary complications of polymyositis and dermatomyositis. Semin Respir Crit Care Med . 2007;28:451-458.
6 Arnett FC, Targott IN, Mimori T, Goldstein R, Warner NB, Reveille JD. Interrelationship of major histocompatability complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis. Arthritis Rheum . 1996;39:1507-1518.
7 Ramanan AV, Feldman BM. Clinical outcomes in juvenile dermatomyositis. Curr Opin Rheumatol . 2002;14:658-662.
8 Gunawardena H Autoantibodies to 140-kd protein in JDM are associated with calcinosis. Arthritis Rheum . 2009;60:1807-1814.
9 Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, Airio A, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet . 2001;357:96-100.
10 Hunger RE, Durr C, Brand CU. Cutaneous leukocytoclastic vasculitis in dermatomyositis suggests malignancy. Dermatology . 2001;202:123-126.
11 Seidler AM, Gottlieb AB. Dermatomyositis induced by drug therapy: a review of case reports. J Am Acad Dermatol . 2008;59:872-880.
12 Callen JP. Collagen vascular diseases. J Am Acad Dermatol . 2004;51:427-439.
13 Fisler RE, Liang MG, Fuhlbrigge RC, Yalcindag A, Sundel RP. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol . 2002;47:505-511.
14 Morinishi Y, Oh-ishi T, Kabuki T, Joh K. Juvenile dermatomyositis: clinical characteristics and the relatively high risk of interstitial lung disease. Mod Rhuematol . 2007;17:413-417.
15 Kameda H, Takeuchi T. Recent advances in the treatment of interstitial lung disease in patients with polymyositis/dermatomyositis. Endocr Metab Immune Discord Drug Targets . 2006;6:409-415.

Livedoid vasculopathy
Livedoid vasculopathy (LV), also known as atrophie blanche, livedo vasculitis, livedo reticularis with summer ulceration, and segmental hyalinizing vasculitis, is a chronic cutaneous syndrome characterized by painful ulcerations, white stellate scars with surrounding telangiectasia and reticulated erythema over the distal lower extremities. 1 The prevalence of LV in the general population is estimated to be 1–5%; 2 however, there are no data on the disease prevalence among different racial/ethnic populations. This disease predominantly affects young to middle-aged women and can be divided into primary or idiopathic form and secondary form, in which LV is associated with a variety of conditions such as chronic venous insufficiency and coagulation disorders like factor V Leiden mutation and antithrombin III deficiency. 3, 4 LV can also be found with livedo reticularis.
Although the exact pathogenesis of LV remains largely unclear, it is believed to involve fibrin thrombi formation focally within dermal blood vessels. Histologic analysis demonstrates segmental hyalinization of superficial dermal vessel walls as well as deposition of fibrin into the vessel lumen (fibrin plugs) leading to epidermal necrosis. 5, 6 There is also intimal proliferation and a paucity of lymphocytic infiltrates and extravasated red blood cells surrounding these vessels. 7 Although late-stage lesions demonstrate the presence of IgM, IgG, and C3, this is believed to be a secondary immunologic response not the primary pathologic event. 8 Although it was initially thought to be a vasculitis, the lack of neutrophilic infiltration and nuclear fragments in LV argues in favor of LV being a vasculopathy rather than a vasculitis. 8
The most prominent and characteristic feature of livedoid vasculopathy is atrophie blanche scarring. Lesions typically begin as purpuric papules over the distal lower extremities that progress to form painful superficial ulcers, which are typically slow to heal. The ulcers eventually heal to form atrophic, porcelain white scars in a stellate pattern surrounded by telangiectasia and retiform purpura. 1 There have been case reports in the literature describing the presentation of LV in African-American, Hispanic, and Asian patients. 9 - 11 The presentation and course of the disease appears to be similar between Caucasian and non-Caucasians.


Management strategy
Livedoid vasculopathy remains a difficult disease entity to treat. Since LV is believed to involve thrombus formation and alterations in coagulation and fibrinolysis, there is increased interest in antithrombotic, anticoagulation, and fibrinolytic therapies. Drucker 12 demonstrated platelet hyperaggregation in nearly all patients included in the study and normalization of platelet function and a resolution of symptoms after treatment with aspirin and dipyridamole. Anticoagulation has also been used to treat LV alone or in combination with fibrinolytic agents like tissue plasminogen activator.
Although there is little evidence of inflammation histologically in LV, there has also been some success with the use of steroids like danazol. Other therapies that have shown some efficacy in treating LV include intravenous immunoglobulins, hyperbaric oxygen therapy, pentoxifylline, psoralen-UVA, sulfasalazine, prostanoids, and nifedipine. 1 However, large-scale studies are needed to further prove the safety and efficacy of these treatments.

First-Line Therapies

Local wound care   Aspirin B Dipyridamole B
Atrophie blanche: a clinicopathological study of 27 patients . Yang LJ, Chan HL, Chen SY, Kuan YZ, Chen MJ, Wang CN, et al. Changgeng Yi Xue Za Zhi 1991; 14:237–245.
The authors studied 27 patients with LV. All patients were initially treated with aspirin and dipyridamole and 48% of patients responded well. Seventy percent of those patients who did not initially improve with aspirin and dipyridamole responded to the addition of or change to heparin. All patients experienced relapse but 50% were disease free for up to 2 years.
Antiplatelet therapy in atrophie blanche and livedo vasculitis . Drucker CR, Duncan WC. J Am Acad Dermatol 1982; 7(3):359–363.
Seven patients with LV underwent platelet function studies before and 3 weeks after treatment with aspirin and dipyridamole. Before treatment, all seven patients showed abnormalities in platelet function (adhesiveness 6/7, aggregation 3/7) but results normalized after therapy. Improvement in ulcerations occurred in all patients as well as decreased pain, increased activity, and decreased formation of new ulcers. Two patients relapsed after therapy was stopped but improved after the medications were restarted. The authors also noted that 5 of 7 patients developed wound infections after starting aspirin and dipyridamole, which they felt was possibly coincidental or due to a shift in the treatment strategy from an emphasis on local wound care to oral medications.

Second-Line Therapies

Pentoxifylline C Tissue plasminogen activator C Heparin E Warfarin E
Livedo vasculitis. Therapy with pentoxifylline. Sams WM Jr. Arch Dermatol 1988; 124:684–687. Erratum in: Arch Dermatol 1989; 125:368.
Eight patients with refractory LV were treated either with pentoxifylline alone or pentoxifylline in combination with aspirin and dipyridamole (3 patients). Three patients experienced complete healing of all lesions, four patients showed partial improvement, and one had no response. Patients were followed for up to 58 months and the majority of patients did experience relapse although new ulcers were typically small.
Tissue plasminogen activator for treatment of livedoid vasculitis . Klein KL, Pittelkow MR. Mayo Clin Proc 1992; 67(10):923–933.
Six patients with refractory LV were successfully treated with tissue plasminogen activator (t-PA). There was a high incidence of anticardiolipin antibodies, lupus anticoagulants, increased levels of plasminogen activator inhibitor, and low levels of endogenous t-PA activity among this group of patients. Multiple previous treatment strategies had failed; therefore, t-PA was started with a significant and rapid improvement in the non-healing ulcers in 5 out of 6 patients. One patient experienced re-thrombosis of the dermal vessels. This patient underwent another course of t-PA with the addition of anticoagulation with subsequent healing of the leg ulcers.
Idiopathic atrophie blanche: treatment with low-dose heparin . Heine KG, Davis GW. Arch Dermatol 1986; 122:855–856.
The authors report the case of a 59-year-old patient with LV for more than 20 years. Previous treatment with systemic corticosteroids and bilateral sympathectomy failed. After 3 months of minidose heparin therapy, the patient had complete healing of all ulcers and stopped treatment. No relapses occurred within 6 months of stopping heparin. The authors note that the risk of hemorrhage is minimal given that clotting time increases only slightly after minidose heparin use.
A case of livedoid vasculopathy associated with factor V Leiden mutation: successful treatment with oral warfarin . Kavala M, Kocaturk E, Zindanci I, Turkoglu Z, Altintas S. J Dermatol Treat 2008; 19(2):121–123.
The authors report the case of a 19-year-old man with LV of 4 years duration. Physical exam and diagnostic work-up revealed atrophie blanche and a factor V Leiden gene mutation. The patient was started on oral warfarin with significant clinical improvement. The authors also note that the patient was originally diagnosed with livedo vasculitis and was treated as such with long-term systemic corticosteroid therapy, which eventually led to surgery for femur necrosis. This highlights the importance of redefining the disease entity as a vasculopathy not a vasculitis and the impact on treatment options.

Third-Line Therapies

Danazol C Intravenous immunoglobulin C Psoralen-UVA (PUVA) C Sulfasalazine C Prostanoids C Nifedipine E Hyperbaric oxygen C
Low-dose danazol in the treatment of livedoid vasculitis . Hsiao GH, Chiu HC. Dermatology 1997; 194(3):251–255.
The authors conducted a study of six patients with LV and found low-dose danazol to be effective in the treatment of this disease. All patients noted improvement in ulcer healing, pain relief, and a halt in disease progression. There were no unacceptable side effects.
Pulsed intravenous immunoglobulin therapy in livedoid vasculitis: an open trial evaluating 9 consecutive patients . Kreuter A, Gambichler T, Breuckmann F, Bechara FG, Rotterdam S, Stucker M, et al. J Am Acad Dermatol 2004; 51(4):574–579.
Open, non-controlled clinical trial of nine patients with LV treated with IVIg. Seven patients were refractory to previous therapies. There was significant (p < 0.001) and rapid improvement in all patients based on three clinical parameters: erythema, ulceration, and pain. All but one patient had complete healing of the ulcers. Two patients were continued on systemic immunosuppressive drugs but these were stopped at the second cycle of IVIg. Side effects were minimal.
Livedoid vasculitis responding to PUVA therapy . Lee JH, Choi HJ, Kim SM, Hann SK, Park YK. Int J Dermatol 2001; 40(2):153–157.
Eight South Korean patients with LV (including 4 with livedo reticularis also) were treated with PUVA. Half of the patients had failed previous treatments including prednisolone, aspirin, and pentoxifylline. After completion of PUVA therapy, all patients experienced complete healing of ulcerations within 10 weeks with minimal side effects. There was also significant pain relief and no new ulcerations. No data on relapses noted.
Sulfasalazine in atrophie blanche . Bisalbutra P, Kullavanijaya P. J Am Acad Dermatol 1993; 28(2 Pt 1):275–276.
Clinical study of 8 patients with refractory LV successfully treated with sulfasalazine. All patients experienced prior treatment failures with aspirin, cyclophosphamide, prednisone, pentoxifylline, and nifedipine. After initiating treatment with sulfasalazine, ulcerations began healing within 1–2 weeks and complete healing was noted within 8 weeks in 7 of 8 patients. Sulfasalazine was discontinued in one patient after experiencing facial edema 2 days after starting the medication. After cessation of treatment, patients were followed for 6–10 months and only 1 patient experienced relapse within 6 months.
Successful treatment of livedo vasculitis with beraprost sodium: a possible mechanism of thrombomodulin upregulation . Tsutsui K, Shirasaki F, Takata M, Takehara K. Dermatology 1996; 192(2):120–124.
In this study, the authors demonstrated a decreased expression of thrombomodulin, which is upregulated by prostacyclin, on endothelial cells in patients with LV. Therefore, four patients with this disease were treated with beraprost sodium, a prostacyclin analog. These patients were initially treated with beraprost sodium alone then continued on a maintenance regimen of low-dose aspirin with beraprost sodium at half the original dose with good clinical responses in all four patients.
Nifedipine treatment of idiopathic atrophie blanche . Purcell SM, Hayes TJ. J Am Acad Dermatol 1986; 14(5 Pt 1):851–854.
This is a case report of a 13-year-old patient with idiopathic LV. Previous treatment strategies including aspirin and dipyridamole failed. The patient was then started on nifedipine with good resolution of symptoms. Relapse occurred when treatment was discontinued.
Livedoid vasculopathy: long-term follow-up results following hyperbaric oxygen therapy. Juan WH, Chan YS, Lee JC, Yang LC, Hong HS, Yang CH. Br J Dermatol 2006; 154:251–255.
Clinical study of 8 patients with idiopathic LV treated with 100% oxygen in a hyperbaric chamber. Patients received between 5 and 20 treatments based on the number and severity of ulcerations. In addition, all patients received a combination of aspirin, dipyridamole, and pentoxifylline for 1 month once all hyperbaric oxygen treatments were completed. Patients reported decreased pain, increased ambulation, and resolution of ulcers in 3.4 weeks. However, 6 of 8 patients experienced relapse as early as 6 months after initiating therapy but had improvement after undergoing additional sessions.

Commonly encountered pitfalls
Atrophie blanche must be distinguished from other similar-looking lesions. Malignant atrophic papulosis is a systemic thrombotic disease affecting the central nervous system, gastrointestinal tract, and skin. Lesions typically begin on the trunk or extremities as a crop of small erythematous papules and eventually form a porcelain white scar with central depression and occasionally a rim of telangiectasias. 1 Skin symptoms usually precede CNS or GI symptoms.

Special management & counseling considerations
Although the terms livedoid vasculopathy and atrophie blanche have been used interchangeably, some believe that the term ‘atrophie blanche’ is a morphological term describing the atrophic, porcelain white scar in a stellate pattern. 13 Atrophie blanche is not pathognomonic for LV and various conditions like venous stasis, cutaneous small-vessel vasculitis, and antiphospholipid syndrome can present with atrophie blanche-like lesions. 1 Therefore, a thorough diagnostic work-up for collagen vascular diseases among others is indicated for patients who present with atrophie blanche.

References

1 Piette W. Cutaneous manifestations of microvascular occlusion syndromes. In: Bolognia J, Jorizzo JL, Rapini RP, editors. Dermatology . 2nd edn. New York: Mosby Elsevier; 2008:331-345.
2 Maessen-Visch MB, Koedam MI, Hamulyak K, Neumann HA. Atrophie blanche. Int J Dermatol . 1999;38:161-172.
3 Hegemann B, Helmbold P, Marsch WC. Livedoid vasculitis with ulcerations: the role of antithrombin III deficiency and its therapeutic consequences. Arch Dermatol . 2002;138(6):841-842. Erratum in: Arch Dermatol 2002; 138(9):1212
4 Kavala M, Kocaturk E, Zindanci I, Turkoglu Z, Altintas S. A case of livedoid vasculopathy associated with factor V Leiden mutation: successful treatment with oral warfarin. J Dermatol Treat . 2008;19(2):121-123.
5 Gray HR, Graham JH, Johnson W, Burgoon CFJr. Atrophie blanche: periodic painful ulcers of lower extremities. Arch Dermatol . 1966;93:187-193.
6 Barnhill RL, Nousari CH, Xu X, Barksdale SK. Vascular diseases. In: Elder DE, Elenitsas R, Johnson BLJr., Murphy GF, Xu X, editors. Lever’s Histopathology of the Skin . 10th edn. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:205-234.
7 Kern AB. Atrophie blanche: report of two patients treated with aspirin and dipyridamole. J Am Acad Dermatol . 1982;6:1048-1053.
8 Browning CE, Callen JP. Warfarin therapy for livedoid vasculopathy associated with cryofibrinogenemia and hyperhomocysteinemia. Arch Dermatol . 2006;142:75-78.
9 Kawakami T, Kawasaki K, Mizoguchi M, Soma Y. Therapeutic effect of lipoprostaglandin E1 on livedoid vasculitis associated with essential cryoglobulinaemia. Br J Dermatol . 2007;157(5):1051-1053. [Epub 2007 Aug 24]
10 Gupta AK, Goldfarb MT, Voorhees JJ. The use of sulfasalazine in atrophie blanche. Int J Dermatol . 1990;29(9):663-665.
11 Purcell SM, Hayes TJ. Nifedipine treatment of idiopathic atrophie blanche. J Am Acad Dermatol . 1986;14(5 Pt 1):851-854.
12 Drucker CR, Duncan WC. Antiplatelet therapy in atrophie blanche and livedo vasculitis. J Am Acad Dermatol . 1982;7(3):359-363.
13 Leonard A, Pomeranz MK, Franks AG. A case of livedoid vasculopathy in a 22 year-old man. J Drugs Dermatol . 2004;3(6):678-679.

Lupus

Chronic cutaneous lupus


Discoid lupus erythematosus
Discoid lupus is one of the most common forms of cutaneous lupus. Discoid lupus has a female predominance, but the ratio (3:2 to 3:1) between men and women is not as large as that observed with systemic lupus (8:1). All races are affected by discoid lupus, but some data suggests a higher prevalence among African-Americans. African-Americans with cutaneous lupus present more commonly with discoid lupus, nephritis, and anti-Sm and anti-RNP antibodies. 1 Only 5–10% of patients with chronic cutaneous lupus develop systemic lupus erythematosus.
Characterized by disfiguring patches that have a predilection for the upper body, discoid lupus is divided into two groups: localized and widespread. It is considered localized when the skin lesions are confined to the head and neck areas and designated as widespread when other body areas are affected. The lesions of discoid lupus are generally easy to identify. Classically, an eruption may begin with an erythematous scaly papule or plaque that expands to form a hypopigmented center and hyperpigmented peripheral border ( Fig. 3.2 ). Full central depigmentation frequently occurs in older plaques causing significant disfigurement. The characteristic histologic findings are interface dermatitis and dilation of follicular openings with keratin plugs (follicular plugging).

Figure 3.2 Early discoid lupus lesion with a hypopigmented center and violaceous, hyperpigmented, irregular peripheral border in a patient with Fitzpatrick skin type IV.
Several case reports have described the development of squamous cell skin cancer in longstanding plaques of discoid lupus in African-American patients. 2 Plaques on the scalp are common and frequently lead to alopecia ( Figs. 3.3 , 3.4 ). Photosensitivity is generally present in patients with discoid lupus, but many patients, particularly patients of color, may be unaware of it.

Figure 3.3 Depigmentation in a chronic DLE plaque with ‘burn out’ scarring alopecia.

Figure 3.4 African-American patient with an acute DLE lesion showing peripheral hyperpigmentation, central depigmentation and alopecia. Note the erythematous base.

Hypertrophic lupus erythematosus
The plaques of hypertrophic lupus erythematosus are characterized by thick scales. This form of chronic cutaneous lupus presents with verrucous plaques that tend to occur at sites of trauma.

Lupus panniculitis/lupus profundus
Lupus profundus is classified as a variant of chronic cutaneous lupus that primarily involves subcutaneous fat. Lupus profundus is characterized by painful erythematous nodules and indurated plaques that tend to heal with atrophy and scars.

Lupus tumidus
First described by Gougerot and Bournier in 1930, lupus tumidus is a rare form of chronic cutaneous lupus that classically presents with indurated erythematous-violaceous plaques without scale or follicular plugging. The lesions occur most commonly on sun-exposed areas–typically the head and neck region. Patients with lupus tumidus are highly photosensitive. Most patients show no underlying systemic involvement. Lupus tumidus is distinct histologically from other forms of cutaneous lupus by the absence of alterations of the dermal–epidermal junction and epidermis. Other histologic features include a superficial and deep perivascular and periadnexal lymphohistiocytic infiltrate with dense interstitial mucin deposition. Direct immunoflourescence is frequently negative.

Diagnosis and work-up
The diagnosis of chronic lupus erythematosus is made based on clinical findings followed by confirmation with a skin biopsy. When the diagnosis of discoid lupus is made, an investigation to exclude systemic lupus should also ensue. Recommended laboratory tests include a complete blood count with differential, metabolic panel, urinalysis, erythrocyte sedimentation rate, antinuclear antibodies (ANA), and anti-Ro (SSA), and anti-La (SSB) antibodies.

Management strategy
While there are numerous case reports and a few pertinent randomized controlled trials on effective treatments for chronic cutaneous lupus, very few randomized, double-blind, placebo-controlled trials for medications have been conducted.
Topical steroids are first-line therapy for chronic cutaneous lupus. Though few randomized controlled trials have been performed, there is a longstanding history of successful treatment with corticosteroids by clinicians worldwide. One randomized trial reported in the Cochrane Database did show greater efficacy of fluocinonide cream over hydrocortisone. In patients who are refractory to potent topical corticosteroids, intralesional injections of corticosteroids have been found to be effective.

First-Line Therapies

Sunscreen C Topical corticosteroids B Intralesional corticosteroids B Topical immunomodulators B
Evaluation of the capacity of sunscreens to photoprotect lupus erythematosus patients by employing the photoprovocation test. Stege H, Budde MA, Grether-Beck S, Krutmann J. Photodermatol Photoimmunol Photomed 2000; 16:256–259.
Broadband sunscreens have been shown to suppress the induction of skin lesions in patients with cutaneous lupus exposed to UV irradiation. In this double-blind comparative study of 11 patients who were photoprovoked, the sunscreen containing a combination of both UVB and UVA protector ingredients, specifically mexoryl, showed the highest and most beneficial protective effect. All patients with discoid lupus should be counseled to avoid prolonged exposure to sunlight and other artificial sources of light.
Drugs for discoid lupus erythematosus. Jessop S, Whitelaw DA, Delamere FM. Cochrane Database of Systematic Reviews 2009(4): CD002954.
In a crossover study of 12 weeks duration, fluocinonide 0.05% cream was found to be more effective than hydrocortisone 1% cream for the treatment of discoid lupus. Twenty-seven percent of patients using fluocinonide cleared completely or displayed excellent improvement compared to 10% of those using hydrocortisone.
Chronic cutaneous lupus erythematosus. Callen JP. Arch Dermatol. 1982; 118:412–416.
The clinical, laboratory, and therapeutic data of 62 patients with active discoid lupus were reviewed. Of the 40 patients treated with intralesional corticosteroids, 35 noted improvement.
Tacrolimus vs clobetasol propionate in the treatment of facial cutaneous lupus erythematosus: a randomized, double-blind, bilateral comparison study. Tzung TY, Liu YS, Chang HW. Br J Dermatol 2007; 156:191–192.
In the only randomized controlled trial on the treatment of cutaneous lupus erythematosus with topical immunomodulators, no significant difference was seen in the efficacy of tacrolimus 0.1% ointment and clobetasol propionate 0.05% ointment. This was a double-blind bilateral comparison study with 20 patients. Clinical outcomes were measured on a 4-week twice-daily application of tacrolimus to one side of the face and application of 0.05% clobetasol to the other side of the face. Severity of lesions was assessed based on clinical signs of erythema, desquamation, and induration. All 18 patients who completed the study showed improvement based on the rating scales over a 4-week period. Weekly microdermabrasion was performed to increase penetration of tacrolimus to the cutaneous lupus lesions. Telangiectasia was noted as a side effect of topical clobetasol in 11 patients (61%). A major limitation of the study is the small sample size. Also, it is difficult to interpret degree of lesion improvement and clearance with either agent for the patients in the study.
Pimecrolimus 1% cream for cutaneous lupus erythematosus. Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stucker M, Bader A, et al. J Am Acad Dermatol 2004; 51:407–410.
Eleven patients with cutaneous lupus erythematosus were treated with pimecrolimus 1% cream under semi-occlusive conditions twice daily for 3 weeks. Significant regression of skin lesions was observed in all patients after treatment. There was a 57% improvement on clinical severity score (p < 0.001). Pimecrolimus could be an effective and safe treatment option for cutaneous lupus erythematosus.

Second-Line Therapies

Antimalarials A Systemic retinoids B Dapsone C
Patients with cutaneous lupus erythematosus who smoke are less responsive to antimalarial treatment . Jewell ML, McCauliffe DP. J Am Acad Dermatol 2000; 42:983–987.
Antimalarial medications, particularly hydroxychloroquine, are considered for discoid lupus patients that topical therapy alone is unsuccessful and when long-term management is required. In this retrospective analysis, patients with discoid lupus who smoked appeared to be less responsive to antimalarial treatment than those who did not smoke.
Lupus erythematosus tumidus: response to antimalarial treatment in 36 patients with emphasis on smoking. Kreuter A, Gaifullina R, Tigges C, Kirschke J, Altmeyer P, Gambichler T. Arch Dermatol 2009; 145:316–319.
In this retrospective, single-center study, the effectiveness of antimalarial treatment of lupus tumidus was evaluated in 36 patients. Patients were treated with either hydroxychloroquine or chloroquine. Overall, treatment with antimalarial medications showed a significant reduction in cutaneous lupus disease severity score. Sixty-one percent of patients exhibited complete or almost complete clearance of skin lesions. There was no significant difference in efficacy between hydroxychloroquine and chloroquine. Smokers had a lower reduction in skin lesions. Smoking cessation should be encouraged in patients with lupus undergoing treatment with antimalarial medications.
Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine. Ruzicka T, Sommerburg C, Goerz G, Kind P, Mensing H. Br J Dermatol 1992; 127:513–518.
This randomized double-blinded study demonstrated the efficacy of acitretin and hydroxychloroquine in the treatment of cutaneous lupus erythematosus. Successful improvement and clearing of lesions occurred in approximately 50% of patients in each treatment group. An increase in side effects was noted in the acitretin group.
Hypertrophic lupus erythematosus treated successfully with acitretin as monotherapy . Al-Mutairi N, Rijhwani M, Nour-Eldin O. J Dermatol 2005; 32:482–486.
Patients with hypertrophic lupus erythematosus, a rare subset of chronic cutaneous lupus erythematosus, have thick verrucous lesions which are chronic and frequently refractory to treatment. This case reports the successful treatment of hypertrophic cutaneous lupus on the hands, feet and legs with acitretin in patients who previously failed topical steroids and antimalarials.
Efficiency of acitretin in treatment of cutaneous lupus erythematosus . Ruzicka T, Meurer M, Bieber T. Arch Dermatol 1988; 124:897–902.
In this study, twenty patients with cutaneous lupus erythematosus (DLE and SCLE) were treated with an initial dose of acitretin 50 mg daily. The dose was adjusted according to response and tolerability (range of 10–75 mg). Fifteen patients responded well. Half of those patients showed more improvement with acitretin than with previous therapies used including corticosteroids and antimalarials.
Isotretinoin for refractory lupus erythematosus . Shornick JK, Formica N, Parke AL. J Am Acad Dermatol 1991; 24:49–52.
Six patients with cutaneous manifestations of lupus erythematosus were treated with isotretinoin, 1 mg/kg/day. The cutaneous lesions were resistant to previous treatment with systemic corticosteroids and antimalarial therapy. Treatment with isotretinoin resulted in rapid clinical improvement in all cases. Unfortunately, recurrences occurred rapidly when the drug was discontinued. Side effects were minimal and easily controlled by adjustments in dose or by the use of lubricants.
Dapsone in the treatment of cutaneous lupus erythematosus. Lindskov R, Reymann F. Dermatologica 1986; 172:214–217.
While the authors of this article concur that hydroxychloroquine remains the drug of choice for systemic treatment of cutaneous lupus erythematosus, dapsone is felt to be a suitable alternative treatment for those refractory to other therapies. In this retrospective analysis, out of 33 patients with chronic discoid lupus treated with dapsone who were observed in the study, almost 50% had a significant improvement in skin disease.

Third-Line Therapies

Cytotoxic agents C Thalidomide B Gold B Clofazamine B Phenytoin C Sulfasalazine D Interferon alpha-a E Topical Imiquimod E Efulizumab E
Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Wenzel J, Brahler S, Bauer R, Bieber T, Tuting T. Br J Dermatol 2005; 153:157–162.
Efficacy of low-dose methotrexate was demonstrated in 42 out of 43 (98%) patients with cutaneous lupus erythematosus who were refractory to first-line treatments. Seven patients had to discontinue treatment due to side effects which were not life-threatening and resolved upon discontinuation of the medication. Careful patient selection and close attention to potential side effects are recommended.
Azathioprine. An effective corticosteroid-sparing therapy for patients with recalcitrant cutaneous lupus erythematosus or with recalcitrant cutaneous leukocytoclastic vasculitis. Callen JP, Spencer LV, Burruss JB, Holtman J. Arch Dermatol 1991; 127:515–522.
Four of six patients with recalcitrant cutaneous lupus demonstrated improvement after use of azathioprine. Five of six patients with leukocytoclastic vasculitis improved. Due to the significant side effects observed the authors recommended use only in severe disease when more conventional treatments fail.
Clofazimine in the treatment of discoid lupus erythematosus. Mackey JP, Barnes J. Br J Dermatol 1974; 91:93–96.
Noting similarities in the mechanisms of immunosuppression of chloroquine and clofazimine (both taken up by macrophages and interrupting phagocytosis), the authors of this study conducted an open trial to observe response of discoid lupus to clofazimine. Seventeen of twenty-six patients went into remission. Doses ranged from 100 mg dosed three times a week to 200 mg daily. Optimal dose appeared to be 100 mg daily. Relapse occurred after treatment in some cases, but these patients responded after a second course. Improvement continued months after withdrawal of the medication in 6 patients. The lasting effect is attributed to absorption and deposition of clofazimine in the subcutaneous fat as well as storage in the reticuloendothelial cells.
Phenytoin in the treatment of discoid lupus erythematosus. Rodriguez-Castellanos MA, Barba Rubio J, Barba Gomez JF, Gonzalez Mendoza A. Arch Dermatol 1995; 131:620–621.
Patients with discoid lupus were observed for response to treatment with phenytoin dosed at 100 mg three times a day. Ninety percent (9 patients) with disseminated disease had an excellent response. The patients who were treated with phenytoin showed improvement from the fourth to the sixth week of treatment. Side effects were minimal and treatable. However, 6 patients developed erythema multiforme, urticarial reactions, myalgia, muscle weakness and paresthesia and were discontinued from the study.
Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a series of 65 Brazilian patients. Coelho A, Souto MI, Cardoso CR, Salgado DR, Schmal TR, Waddington Cruz M, et al. Lupus 2005; 14:434–439.
Thalidomide is very effective in the treatment of cutaneous lupus. However, the side effects, such as teratogenicity and neuropathy, limit its utility. This study observed the clinical efficacy of long-term low-dose thalidomide in 65 patients with lupus erythematosus with a special focus on the incidence of side effects. Nearly 99% of patients showed complete or partial improvement with thalidomide treatment. The notable adverse effects were drowsiness and neuropathy. Drowsiness was observed in 77% of the patients and neuropathy occurred in 43%.
Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens. Cuadrado MJ, Karim Y, Sanna G, Smith E, Khamashta MA, Hughes GR. Am J Med 2005; 118:246–250.
The safety and efficacy of various doses of thalidomide was observed in patients who were unresponsive to other systemic treatments for cutaneous lupus. The doses used were 100 mg daily, 50 mg daily, or 50 mg every other day. Eighty-one percent of patients responded to treatment with thalidomide, with 60% of those experiencing complete remission. Nine patients (19%) had no response. Twenty-seven percent developed peripheral neuropathy. The other side effects observed included drowsiness, constipation, abdominal pain, and amenorrhea. Interestingly, there was no significant difference in response based on dose. Also of note, side effects did not appear to be dose-dependent.
Treatment of chronic discoid lupus erythematosus with an oral gold compound (auranofin ). Dalzial K, Going G, Cartwright PH, Marks R, Beveridge GW, Rowell NR. Br J Dermatol 1986; 115:211–216.
Twenty-three patients with discoid lupus were treated with auranofin for 1 year with an average dose of 3 mg twice daily. Lesions completely resolved in 4 patients and 15 showed notable improvement. Gold is rarely employed for current therapy for discoid lupus, but if used, patients should be monitored for side effects which include gastrointestinal symptoms such as nausea and diarrhea, drug eruption, thrombocytopenia, and proteinuria.
Treatment of discoid lupus erythematosus with sulfasalazine. 11 cases. Delaporte E, Catteau B, Sabbagh N, Gosselin P, Breuillard F, Doutre MS, et al. Ann Dermatol Venereol 1997; 124:151–156.
Of the 11 patients with discoid lupus treated with sulfasalazine in this case series, 7 were considered complete responders; 1 patient responded partially; 3 patients failed treatment. While sulfasalazine is not a first-line agent, it can be considered in refractory cases of chronic cutaneous lupus. Sulfasalazine can cause photosensitivity so should be used with caution in patients with SLE.
Response of discoid and subacute cutaneous lupus erythematosus to recombinant interferon alpha 2a. Nicolas JF, Thivolet J, Kanitakis J, Lyonnet S. J Invest Dermatol 1990; 95:142S–154S.
Some cases of discoid lupus have been successfully treated with systemic interferon alpha 2a. In this study, patient response was rapid and impressive, but relapse occurred in all study patients after withdrawal of the medication.
A case of generalized discoid lupus erythematosus: successful treatment with imiquimod cream 5 %. Gul U, Gonul M, Cakmak SK, Kilic A, Demiriz M. Adv Ther 2006; 23:787–792.
In this case report from Turkey, a 44-year-old male with discoid lupus on the face, scalp, ears, and limbs was treated successfully with imiquimod 5% cream. Imiquimod was applied to the lesions once a day three times a week. Clearance and major regression of lesions occurred after 20 applications.
Efalizumab in the treatment of discoid lupus erythematosus. Usmani N, Goodfield M. Arch Dermatol 2007; 143:873–877.
Refractory cases of discoid lupus will often require cytotoxic immunosuppressive therapy. Efulizumab, a monoclonal antibody against CD11a, a subunit of the leukocyte-functioning antigen 1, is presented as a novel therapeutic alternative for resistant cases. Good response was observed in 12 out of 13 patients after a mean of 5 weeks. One patient with poor response had severe headaches and was withdrawn from the study. No long-term follow-up results were reported.

Special management & counseling considerations
Alopecia is a common associated finding in patients with discoid lupus who have scalp involvement. Management is aimed at decreasing inflammation and treating the underlying discoid lupus plaques as soon as possible to prevent permanent scarring and follicular dropout. The incidence of alopecia areata is also increased in patients with lupus erythematosus. 3 Treatment with intralesional corticosteroids can provide hair regrowth and in many cases provide rapid improvement of alopecia occurring directly over discoid plaques on the scalp.
Discoid lupus is characterized by atrophy in later stages. Thus, use of potent topical corticosteroids requires a delicate balancing act of using the dose that is most effective for treatment yet avoids exacerbation of atrophic changes.
All patients with discoid lupus, and African-Americans in particular, should be monitored for squamous cell carcinoma that could arise in chronic lesions of discoid lupus erythematosus. Skin cancer is less common in African-Americans than other racial groups. Discoid lupus, however, appears to be a predisposing factor for the development of squamous cell skin cancer in black skin. Malignant change is observed more commonly in men. The malignant change is in many cases associated with solar damage. Occurrence of metastases of squamous cell skin cancer has been observed in discoid lupus, regardless of race. Clinicians should maintain a low threshold for biopsying suspicious lesions of discoid lupus, particularly those which are hyperkeratotic or poorly healing. In addition, those patients with DLE who have been found to have a squamous cell skin cancer should be monitored, as the potential for metastasis may be greater than in squamous cell cancers arising in normal skin. 4
Some evidence suggests that smokers with discoid lupus have more severe disease. Furthermore, patients with cutaneous lupus who smoke appear to be less responsive to antimalarial treatment. 5 Smoking cessation should be an integral part of the treatment plan for chronic cutaneous lupus in smokers.

References

1 Cooper GS, Parks CG, Treadwell EL, St Clair EW, Gilkeson GS, Cohen PL, et al. Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States. Lupus . 2002;11:161-167.
2 Caruso WR, Stewart ML, Nanda VK, Quismorio FP. Squamous cell carcinoma of the skin in black patients with discoid lupus erythematosus. J Rheumatol . 1987;14:156-159.
3 Werth VP, White WL, Sanchez MR, Franks AG. Incidence of alopecia areata in lupus erythematosus. Arch Dermatol . 1992;128:368-371.
4 Presser SE, Taylor R. Squamous cell carcinoma in blacks with discoid lupus erythematosus. J Am Acad Dermatol . 1981;4:667-669.
5 Jewel ML, McCauliffe DP. Patients with cutaneous lupus erythematosus who smoke are less responsive to antimalarial treatment. J Am Acad Dermatol . 2000;42:983-987.

Subacute cutaneous lupus erythematosus (SCLE)
Subacute cutaneous lupus (SCLE) is a variant of cutaneous lupus described in 1979 by Sontheimer, Thomas, and Gilliam. While not uncommon among people of color, SCLE more frequently affects Caucasian females between the ages of 15 and 40. Like other forms of cutaneous lupus, SCLE occurs in genetically predisposed individuals. Development of SCLE has been linked to certain HLA subtypes, such as HLA-B8, HLA-DR3, HLAw52, and HLA-DQ1. Most patients are positive for anti-Ro (SS-A) antibodies. The pathophysiology, while incompletely understood, involves the alteration of autoantibodies, epidermal cytokines, and adhesion molecules by ultraviolet light which leads to keratinocyte apoptosis.
Reactions generally begin with a papular eruption with mild pruritis. Patients present clinically with erythematous papules that coalesce to form a psoriasiform pattern or polycyclic annular arrangement with light scale in a symmetrical distribution. The typical locations for an SCLE skin eruption are sun-exposed areas – face, neck, upper back, and upper anterior chest. Unlike discoid lupus, scarring is not a feature. Patients may, however, have residual hyperpigmented and hypopigmented changes and telangiectasia. Follicular plugging is generally absent, unlike in discoid lupus; 50–71% of patients have antibodies to Ro/SSA. It is estimated that 10–15% of patients with subacute cutaneous lupus erythematosus develop internal disease over time. Approximately 50% of patients with SCLE exhibit four or more criteria for the systemic lupus classification, but internal disease is generally less severe. Approximately one-half of patients have joint involvement, mostly symmetrical arthralgias affecting small joints such as the hands and wrists. Overlapping symptoms of Sjogren’s syndrome may occur. These patients may have dry eyes (keratoconjunctivitis) and dry mouth (xerostomia). Annular erythema of Sjogren’s syndrome has been classified as a distinct entity in Japanese and Polynesian patients. However, many experts consider this condition to be a variant of subacute cutaneous lupus. A variant of SCLE in which patients present with a combination of erythema multiforme-like lesions, discoid lupus plaques, and chilblains has been described as Rowell’s syndrome.
Several medications have been reported to induce the onset of subacute cutaneous lupus erythematosus. The most common medications include terbinafine, hydrochlorothiazide, griseofulvin, calcium channel blockers, and non-steroidal anti-inflammatory drugs.
While there are no pathognomonic histologic findings, typical features are similar to other forms of cutaneous lupus. Superficial and deep inflammatory infiltrates are present along with interface changes. However, epidermal atrophy is a more common feature in SCLE than in the other forms of cutaneous lupus.
The differential diagnosis of SCLE includes other annular erythemas, such as erythema annulare centrifugum and granuloma annulare. Cutaneous SCLE can also appear clinically similar to dermatophytosis, psoriasis, and eczema.

First-Line Therapies

Sunscreens C Topical corticosteroids E Antimalarials D Systemic retinoids B
Use of sunscreens to protect against ultraviolet-induced lupus erythematosus. Herzinger T, Plewig G, Rocken M. Arthritis Rheum 2004; 50:3045–3046.
Sunscreens providing protection against both UVA and UVB are very effective in protecting against UV-induced lupus erythematosus.
The association of the two antimalarials chloroquine and quinacrine for treatment-resistant chronic and subacute cutaneous lupus erythematosus. Feldman R, Salomon D, Saurat JH. Dermatology 1994; 189:425–427.
Fourteen patients who had not responded to single antimalarial treatment with either chloroquine or hydroxychloroquine were treated with a combination of chloroquine 100 mg 3×/day and quinacrine 65 mg 3×/day. All 5 patients with SCLE cleared completely and 5 out of 9 patients with chronic lupus erythematosus improved significantly or completely. In patients who are not responding as well as expected on antimalarial therapy, the combination of chloroquine and quinacrine may provide a better outcome. Close monitoring of side effects and potential eye complications should not be overlooked.

Second-Line Therapies

Dapsone E Antibiotics E Systemic retinoids B Immunosuppressive agents D
Annular subacute cutaneous lupus erythematosus responsive to dapsone. McCormack LS, Elgart ML, Turner ML. J Am Acad Dermatol 1984; 11:397–401.
This is a case report of two patients with annular subacute cutaneous lupus erythematosus successfully treated with dapsone. Treatment with dapsone prevented new lesions and led to marked improvement with eventual resolution of skin lesions. Dose of dapsone ranged from 50 to 100 mg daily. Patients sustained improvement over 8–12 months. A maintenance dose of 25 mg/day was required in one patient.
Low dose dapsone in the treatment of subcutaneous lupus erythematosus. Fenton DA, Black MM. Clin Exp Dermatol 1986; 11:102–103.
This is a report of a 58-year-old male with a 3-year history of subacute cutaneous lupus erythematosus who failed treatment with potent topical corticosteroids and systemic mepacrine. The patient had complete clearance of lesions after 3 weeks of low-dose dapsone (25 mg daily).
Long-term cefuroxime axetil in subacute cutaneous lupus erythematosus. A report of three cases. Rudnicka L, Szymanska E, Walecka I, Slowinska M. Dermatology 2000; 200:129–131.
Based on the observation of complete clearance of subacute cutaneous lupus in three patients treated with cefuroxime axetil, the authors suggest that this cephalosporin medication may be a good alternative medication to consider in the treatment of SCLE. The patients were treated with cefuroxime axetil 500 mg for 30–60 days. An obvious limitation of the study is the small number of patients reported and a condition which may improve on its own regardless of treatment.
Efficiency of acitretin in treatment of cutaneous lupus erythematosus . Ruzicka T, Meurer M, Bieber T. Arch Dermatol 1988; 124:897–902.
Azathioprine. An effective corticosteroid-sparing therapy for patients with recalcitrant cutaneous lupus erythematosus or with recalcitrant cutaneous leukocytoclastic vasculitis. Callen JP, Spencer LV, Burruss JB, Holtman J. Arch Dermatol 1991; 127:515–522.
Four out of six patients with recalcitrant cutaneous lupus demonstrated improvement after use of azathioprine. Five of six patients with leukocytoclastic vasculitis improved. Due to the significant side effects observed the authors recommended use only in severe disease when more conventional treatments fail.
Mycophenolate sodium for subacute cutaneous lupus erythematosus resistant to standard therapy. Kreuter A, Tomi NS, Weiner SM, Huger M, Altmeyer P, Gambichler. Br J Dermatol 2007; 156:1321–1327.
In this prospective, non-randomized, open pilot study, 10 patients who were resistant to standard therapy were treated with oral mycophenolate sodium 1440 mg daily for 3 months. Clinical improvement was achieved in all patients and no serious side effects were seen.

Third-Line Therapies

Clofazimine E Phenytoin B IVIg C Capacitabine E Cytokine therapy D Interferon C
Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus . Goodfield M, Davison K, Bowden K. J Dermatolog Treat 2004; 15:46–50.
IVIg is felt to be a possible alternative treatment for subcutaneous lupus erythematosus in patients who are refractory to other therapies. The dose of IVIg started with 1g/kg × 2, followed by 400 mg/kg monthly until disease resolution or for 6 months. Approximately 75% of patients (5 patients) had complete or near complete clearing of their skin disease. Two patients had partial improvement and 3 patients had limited response. The treatment was well-tolerated with an overall good safety profile. Of note, 1 patient developed acute cutaneous vasculitis in this study.
Response of discoid and subacute cutaneous lupus erythematosus to recombinant interferon alpha 2a . Nicolas JF, Thivolet J, Kanitakis J, Lyonnet S. J Invest Dermatol 1990; 95:142S–145S.
Eight out of ten patients with subacute cutaneous lupus responded to treatment with interferon alpha 2a in this study. However, all patients subsequently relapsed after withdrawal of the medication. Further study will clarify the possible role of interferon alpha 2a in the treatment of SCLE.

Special management & counseling considerations
SCLE may be less responsive to antimalarial treatment. Systemic retinoid treatments, however, may actually yield a better response in SCLE than other types of cutaneous lupus. In some cases, combinations of antimalarials may need to be carefully implemented and other alternative treatments started earlier.

References

1 Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med . 1985;103:49-51.
2 Callen JP, Hughs AP, Kulp-Shorten C. Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine. Arch Dermatol . 2001;137:1196-1198.
3 Srivastava M, Rencic A, Diglio G, Santana H, Bonitz P, Watson R, et al. Drug-induced, Ro/SSA-positive cutaneous lupus erythematosus. Arch Dermatol . 2003;139:45-49.

Systemic lupus erythematosus
Lupus erythematosus is the prototypic autoimmune disease with a wide spectrum of clinical manifestations. Given its multitude of cutaneous manifestations, dermatologists frequently play an integral role in the management of patients with lupus erythematosus. Systemic lupus erythematosus (SLE) has been reported to occur in one in 10 000 Caucasian males, one in 1000 Caucasian females, and one in 250 African-American females. The cause of this ethnic and gender difference remains unclear, but there is evidence to suggest socioeconomic status, inequities in access to healthcare, and hormonal factors may play a major role. There are also widely variable regional differences in the epidemiology of SLE. While systemic lupus has the highest prevalence among African-American women, it is interesting to note that systemic lupus does not have a strikingly high prevalence on the African continent. The prevalence of cutaneous lupus in the United States varies between 17 and 48 cases/100,000 persons and the trend has been increasing over recent years. 1
The etiology of lupus is complicated by the heterogeneous nature of the disease and its variable clinical presentation. The American College of Rheumatology developed criteria for the classification of SLE ( Table 3.1 ). 2 Major research efforts have shed light on the pathogenetic mechanisms of lupus, but not culminated in complete understanding. Immunological mechanisms combined with genetic and environmental influences play a role. A major paradigm of the pathogenesis involves cross reactions to a self antigen occurring in genetically susceptible individuals. This instigates an autoimmune response followed by a phenomenon known as epitope spreading whereby there is expansion of the autoimmune response leading to organ damage. 3 Many of the clinical manifestations of lupus are a result of damage from circulating immune complexes on various tissues and the direct effects of autoantibodies.
Table 3.1 American College of Rheumatology 1982 revised criteria for classification of systemic lupus erythematosus * Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis (Non-erosive arthritis involving 2 or more peripheral joints) Serositis (Pleurisy, pleural effusion, pericarditis, pericardial effusion) Renal disorder (Proteinuria greater than 3+ or 0.5 g/day, or cellular casts) Neurologic disorder (Seizures or psychosis not due to other underlying factors) Hematologic disorder (Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia) Immunologic disorder (Positive anti-DNA antibody, positive anti-Smith antibody, or false positive serologic test for syphilis) Abnormal anti-nuclear antibody titer
* One meets the criteria for diagnosis of SLE if four or more of the 11 criteria listed are present.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271–1277.
Lupus is a polygenic disorder, as no one specific gene is responsible for the disease. In fact, over 30 susceptibility genes have been identified for SLE. The combination of genes has geographic, racial, and ethnic variability. Certain HLA types are also associated with lupus, most commonly HLA-DR2, DR3, DR4, and DR8. 4 Genetic deficiency of complement factors C1q, C2, and C4 have been demonstrated in patients with lupus.
Studies have shown a delayed expression of inducible nitric oxide synthase, an enzyme regulating the production of nitric oxide, which is an important regulator of apoptosis. Aberrant expression of nitric oxide synthase has been found in the epidermis of patients with cutaneous lupus erythematosus. Compared to healthy controls, skin lesions from patients with cutaneous lupus have been found to have a significant increase in apoptotic keratinocytes after ultraviolet irradiation. 5
Lupus commonly presents in young healthy-appearing women with complaints of fatigue and arthralgia. The most common presenting symptom is arthralgia (62%), followed by cutaneous manifestations (20%). Constitutional symptoms of fever, malaise, anorexia, and weight loss are common as well. The most frequent cutaneous manifestations of lupus include photosensitivity, malar rash, oral ulcerations, and alopecia ( Figs. 3.5 - 3.9 ). Approximately 10% of patients with SLE develop urticaria and this appears to occur more often in those with an atopic diathesis. Other cutaneous findings include cutaneous vasculitis, Raynaud’s phenomenon, and livido reticularis. Subsets of cutaneous lupus are covered in detail in prior sections of the chapter.

Figure 3.5 Malar rash of systemic lupus erythematosus.

Figure 3.6 Photosensitivity rash over the face of a SLE patient with skin phototype V. A common presentation of this disease is a diffuse reticulated hyperpigmentation of the skin.

Figure 3.7 Photosensitivity rash in SLE.

Figure 3.8 Dorsal surface of the hand with SLE photosensitivity rash.

Figure 3.9 Photosensitivity rash over the neck in SLE.
Lupus nephritis occurs in 30% of patients with SLE and is associated with high morbidity and mortality. Musculoskeletal manifestations include arthralgias, true inflammatory arthritis, and myalgias as well as myositis with elevated muscle enzymes. Patients must also be monitored for complications such as osteopenia, osteoporosis, and even avascular necrosis of the femoral head which may develop as sequelae of long-term corticosteroid therapy. Pulmonary features include pleurisy, acute pneumonitis, and chronic interstitial lung disease. Lupus patients are at increased risk for pulmonary embolism and pulmonary hypertension. SLE can also involve the cardiovascular system. Many lupus patients develop chest discomfort and dyspnea due to pericardial inflammation and effusions. Myocardial disease and endocarditis (Libman–Sacks endocarditis) are other potential cardiovascular complications of lupus. The central nervous system may also be affected in SLE. Cognitive dysfunction, CNS vasculitis, and visual changes are potential neurologic complications. 6
Race is a major predictor of clinical manifestations of SLE. Differences in clinical and laboratory features between ethnicities have been demonstrated as well. Renal manifestations occur more commonly in African-American and Hispanic patients compared to Caucasians with SLE. An increase in cardiac involvement, discoid lupus, and lymphadenopathy has also been demonstrated in African-Americans while a decrease in photosensitivity and malar rash occurs in this group. Anti-Sm and Anti-RNP occur more frequently in African-Americans. 7 - 10 A study of patients from Pakistan showed less cutaneous, arthritic, and renal involvement, but higher neuropsychiatric symptoms. 11 Of patients living in Malaysia, it appears that the ethnic Chinese have a higher prevalence of SLE (with a high prevalence of renal disease) than the Indian and Malay patients. 12 A small study of a Vietnamese population in California in the United States demonstrated a relatively high prevalence of anti-RNP antibody and features of overlap syndrome. 13 A study of patients in Saudi Arabia showed that SLE manifests similarly to patients in other Arab countries and Caucasians. The 5-year survival rate (98%) was similar to that of western countries and the 10-year survival rate (97%) higher than most places. The most common manifestations were hematologic abnormalities, arthritis, mucocutaneous symptoms, and malar rash. 14
Before making a diagnosis of systemic lupus it is important to exclude the possibility of a drug-induced lupus-like syndrome. Procainamide, hydralazine, isoniazid, minocycline, doxycycline, quinidine, and methyldopa are well-known causes of lupus-like syndrome; 80–90% of patients with drug-induced lupus-like syndrome have antibodies to histone.

Specific investigations
The antinuclear antibody (ANA) is the gold standard screening test for SLE. While ANA has low specificity, it is positive in 96% of those with SLE. The pattern of immunofluorescence is helpful. A speckled pattern is non-specific, but a homogeneous or rimmed pattern is suggestive of lupus. When the ANA is positive, testing for other serologies that are more specific to lupus is recommended. Specifically, positive double-stranded DNA (ds-DNA) antibodies are highly suggestive of SLE; 50% of patients with SLE have autoantibodies to double stranded DNA. Elevated levels of anti-ds-DNA may correlate with the degree of activity of lupus and level of nephritis.
Low serum complement levels, specifically C3 and C4 are seen in patients with SLE. This finding is associated with the level of inflammation and correlates with disease activity.
Creatinine and blood chemistries, along with urinalysis are appropriate to monitor for renal involvement. An electrocardiogram and chest X-ray may be warranted to monitor for cardiac disease and pulmonary complications, respectively.

First-Line Therapies

NSAIDS B Systemic corticosteroids A Antimalarials A Clofazimine A Topical corticosteroids A
Celecoxib for systemic lupus erythematosus: case series and literature review of the use of NSAIDS in SLE. Lander SA, Wallace DJ, Weisman MH. Lupus 2002; 11:340–347.
This retrospective review of medical records from 50 patients with systemic lupus erythematosus treated with celecoxib (200–400 mg/day for 1–9 months) by a community-based rheumatologist revealed a good safety profile and moderate efficacy in the treatment of SLE.
The effect of moderate-dose corticosteroids in preventing severe flares in patients with serologically active, but clinically stable, systemic lupus erythematosus. Findings of a prospective, randomized, double-blind, placebo-controlled trial. Tseng CE, Buyon JP, Kim M, Belmont HM, Mackay M, Diamond B, et al. Arthritis Rheum 2006; 54:3623–3632.
A total of 154 patients qualified for this trial. During a period of clinical stability, 41 of the 154 patients developed a serologic flare (defined as elevation of C3a level by 50% and anti-dsDNA levels by 25%). These 41 patients were then randomized to placebo or treatment with prednisone (30 mg daily for 2 weeks, 20 mg daily for 1 week, and 10 mg daily for 1 week). Four of twenty-one patients in the prednisone group developed a mild to moderate flare. Seven of twenty patients in the placebo group experienced at least one flare. All severe flares occurred in the placebo group.
A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian hydroxychloroquine study group. N Eng J Med 1991; 324:150–154.
In this 6-month, randomized, double-blind, placebo-controlled study, the authors looked at the effect of discontinuing hydroxychloroquine in 47 patients with clinically stable SLE. Results showed that patients with stable SLE who are maintained on hydroxychloroquine were less likely to develop a flare.
Hydroxychloroquine in pregnant patients with systemic lupus erythematosus. Parke A, West B. J Rheumatol 1996; 23:1715–1718.
The safety of hydroxychloroquine was observed in 8 pregnant patients on the medication. Flares of SLE can have a detrimental effect on the fetus during pregnancy. Due to the increased risk of a lupus flare upon discontinuation of hydroxychloroquine during pregnancy, the authors of this study concede that it is safer to continue hydroxychloroquine rather than to discontinue the drug because of pregnancy alone.
Double-blind, randomized, controlled clinical trial of clofazimine compared with chloroquine in patients with systemic lupus erythematosus. Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EI. Arthritis Rheum 2005; 52:3073–3078.
Sixteen patients received clofazimine at 100 mg/day and 17 patients received chloroquine diphosphate at 250 mg/day for 6 months. Twenty-seven patients completed the study. No significant difference was noted in response between the two groups. Twelve patients in the clofazimine group and 14 patients in the chloroquine group (82%) had complete or nearly complete clearance of lesions. The authors concluded that clofazimine proved to be as effective as chloroquine in the treatment of systemic lupus. However, it was noted that 5 patients in the initial clofazimine group dropped out due to a severe lupus flare compared to only 1 patient in the chloroquine group. This raised the question of whether clofazimine could possibly trigger a lupus flare.
Tacrolimus vs clobetasol propionate in the treatment of facial cutaneous lupus erythematosus: a randomized, double-blind, bilateral comparison study. Tzung TY, Liu YS, Chang HW. Br J Dermatol 2007; 156:191–192.

Second-Line Therapies

Topical immunomodulators C
Immunosuppressants:
Methotrexate A Azathioprine B Cyclosporin C
Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation. Tzellos TG, Kouvelas D. Eur J Clin Pharmacol 2008; 64:337–341.
This review article included 5 studies that demonstrated the efficacy of tacrolimus and pimecrolimus in the initial cutaneous lesions of SLE.
Pimecrolimus 1% cream for cutaneous lupus erythematosus. Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stucker M, Bader A, et al. J Am Acad Dermatol 2004; 51:407–410.
Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. Carneiro JR, Sato EI. J Rheumatol 1999; 26:1275–1279.
In this study, methotrexate was found to be effective in controlling cutaneous and joint disease in patients with SLE. Results were observed after 6 months of methotrexate dosed 15–20 mg/week.
Azathioprine therapy for patients with systemic lupus erythematosus. Abu-Shakra M, Shoenfield Y. Lupus 2001; 10:152–153.
Azathioprine has been recommended in SLE patients who have recurrent flares or require a maintenance dose of 15 mg or higher of prednisone. It is used for lupus nephritis in combination with systemic steroids. Azathioprine has been found to be effective in the treatment of cutaneous lupus and in SLE patients with pneumonitis, thrombocytopenia, and hemolytic anemia.
Cyclophosphamide for the treatment of systemic lupus erythematosus. Takada K, Illei GG, Boumpas DT. Lupus 2001; 10:154–161.
Due to evidence in controlled trials, cyclophosphamide has become the standard of treatment for moderate to severe lupus nephritis. Combining pulse cyclophosphamide with pulse methylprednisolone further improved efficacy without an increase in toxicity.
Patients should be monitored cautiously while on cyclophosphamide for signs of toxicity and bone marrow suppression. Intravenous pulse therapy is associated with fewer side effects. Mesna is recommended for protection against bladder carcinoma and cystitis. Some patients may want to consider sperm or ovum banking in the event of infertility.
Cyclosporin A in the treatment of systemic lupus erythematosus: results of an open clinical study. Manger K, Kalden R, Manger B. Br J Rheum 1996; 35:669–675.
Sixteen patients who had inadequate control of disease were treated with cyclosporin A (3–5 mg/kg) for an average of 30 months. Three patients had to discontinue treatment due to side effects (an elevated creatine level and a nephritis flare). Ten patients showed significant reduction of proteinuria. All 3 patients with thrombocytopenia and all 3 patients with leukocytopenia showed improvement of platelet count and leukocytes, respectively. The most frequent side effects were hypertension, alteration of renal function, and hypertrichosis. Overall, cyslosporin was well-tolerated over an extended period of time and effective in controlling disease activity in patients with SLE.
Cyclosporin is an effective treatment for SLE, but given the high prevalence of renal involvement in SLE, its potential nephrotoxic effects may limit its use.
Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a series of 65 Brazilian patients.

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