Skinmed Jul / Aug by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

COMMENTARY Pseudoneoteleology and Lower Extremity Vascular Entities Lambert, Lambert, and Lee

ORIGINAL CONTRIBUTIONS Patch Testing in Children and Adolescents With Suspected Allergic Contact Dermatitis Meena, Garg, and Chander

Survey of Patient Satisfaction With Ingenol Mebutate Gel Treatment for Actinic Keratosis From a Community Dermatology Practice Schaefer

First-Line Fixed-Combination Psoriasis Treatment Is Associated With Lower Healthcare Costs Feldman, Levi, Pathak, Kakatkar, and Balkrishnan

REVIEW Dermatomyositis––Part 1: Definition, Epidemiology, Etiology and Pathogenesis, and Clinics Ramos-e-Silva, Pinto, Pirmez, Cuzzi, and Carneiro

Self Assessment Examination Lambert

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

July/August 2016 • Volume 14 • Issue 4 EDITORIAL CORE CURRICULUM A Visit From Our Friendly Hospital Footwear Dermatitis: Diagnosis and Regulators: Typhoid Mary on Steroids Management—Part III Lambert and Parish

North American Clinical Dermatologic Society

Sehgal, Rasool, Srivastava, Aggarwal, Dutt, and Verma

DEPARTMENTS HISTORICAL VIGNETTE Fowler’s Solution and the Evolution of the Use of Arsenic in Modern Medicine Ho and Lowenstein

NEW THERAPY UPDATE Adalimumab (Humira®) for Hidradenitis Suppurativa

Gupta, Cernea, Abramovits, and Vincent

July/August 2016 • Volume 14 • Issue 4

Cutaneous Collagenous Vasculopathy-Associated Benign Pigmented Purpura Heymann

Abdominal Elephantiasis Nostras Verrucosa: An Underrecognized Disorder Ho and Lowenstein

Recalcitrant Verrucae in Patients With DOCK8 Deficiency

Wang, Geng, Gendelman, Freeman, and Kim

BOOK REVIEW Dermoscopy of the Hair and Nails, Second Edition Butala

THE HEYMANN FILE A Birthday Wish in the Era of “Value-Based” Healthcare Heymann

COSMETIC SURGERY CAPSULE 7th Annual Cosmetic Surgery Forum 2015 Schlessinger

PHOTO CAPSULE Multiple Nonhealing Furuncles in a Traveler Returned From Belize Naga, Baruch, and Kao

case studies Adult Manifestation of HenochSchönlein Purpura Kemp, Studdiford, Osley, and Sahu

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TABLE OF CONTENTS July/August 2016 • Volume 14 • Issue 4

EDITORIAL

A Visit From Our Friendly Hospital Regulators: Typhoid Mary on Steroids ................................................. 248

W. Clark Lambert, MD, PhD; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARy

Pseudoneoteleology and Lower Extremity Vascular Entities ...................................................................... 251

W. Clark Lambert, MD, PhD; Peter C. Lambert, MD; Brian Lee, MD

ORIGINAL CONTRIBUTIONS

Patch Testing in Children and Adolescents With Suspected Allergic Contact Dermatitis ........................... 253

Surekha Meena, MD; Taru Garg, MD; Ram Chander, MD

Survey of Patient Satisfaction With Ingenol Mebutate Gel Treatment for Actinic Keratosis From a Community Dermatology Practice ................................................................................................. 259

Dale Schaefer, MD

First-Line Fixed-Combination Psoriasis Treatment Is Associated With Lower Healthcare Costs ................. 266

Steven R. Feldman, MD, PhD; Eugenia Levi, PharmD, BCPS; Prathamesh Pathak, BPharm, MS; Sonali Kakatkar, BSc, MMS; Rajesh Balkrishnan, PhD

B:11”

T:10.75”

S:10.25”

REVIEW Dermatomyositis––Part 1: Definition, Epidemiology, Etiology and Pathogenesis, and Clinics .................... 273

Marcia Ramos-e-Silva, MD, PhD; Ana Paula Frade Lima Pinto, MD; Rodrigo Pirmez, MD; Tullia Cuzzi, MD, PhD; Sueli Coelho da Silva Carneiro, MD, PhD

Self Assessment Examination ................................................................................................................... 280

W. Clark Lambert, MD, PhD

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Footwear Dermatitis: Diagnosis and Management—Part III ....................................................................... 281

Virendra N. Sehgal, MD; Farhan Rasool, MD; Govind Srivastava, MD; Ashok Aggarwal, MD; Taru Dutt, MD; Prashant Verma, MD

Departments Historical Vignette

Charles Steffan, MD, Section Editor

Fowler’s Solution and the Evolution of the Use of Arsenic in Modern Medicine ......................................... 287

Derek Ho, BS; Eve J. Lowenstein, MD, PhD

New Therapy Update

William Abramovits, MD; Aditya K. Gupta, MD, PhD, FRCPC, Section Editors

Adalimumab (Humira®) for Hidradenitis Suppurativa ................................................................................ 291

Aditya K. Gupta, MD, PhD, FRCPC; Maria Cernea, PhD; William Abramovits, MD; Kimberly Dawn Vincent, MD

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TABLE OF CONTENTS July/August 2016 2016 •• Volume Volume 14 14 •• Issue Issue 44 July/August

The Heymann File

Warren R. Heymann, MD, Section Editor

A Birthday Wish in the Era of “Value-Based” Healthcare .......................................................................... 295

Warren R. Heymann, MD

COSMETIC SURGERY CAPSULE

7th Annual Cosmetic Surgery Forum 2015 ................................................................................................ 297

Joel Schlessinger, MD

PHOTO CAPSULE

Multiple Nonhealing Furuncles in a Traveler Returned From Belize ........................................................... 301

Lina Naga, MD; Danielle Baruch, MD; Grace Kao, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Adult Manifestation of Henoch-Schönlein Purpura .................................................................................... 303

Daria Marley Kemp, MD, MEd; James Studdiford, MD; Katie Osley, MD; Joya Sahu, MD

Cutaneous Collagenous Vasculopathy-Associated Benign Pigmented Purpura ........................................... 308

Warren R. Heymann, MD

Abdominal Elephantiasis Nostras Verrucosa: An Underrecognized Disorder ............................................ 311

Derek Ho, BS; Eve J. Lowenstein, MD, PhD

Recalcitrant Verrucae in Patients With DOCK8 Deficiency.......................................................................... 315

Yen Tun Wang, MD; Bob Geng, MD; Samantha Gendelman, MD; Alexandra Freeman, MD; Christina Nam-Soo Kim, MD

BOOK REVIEW

Jennifer L. Parish, MD, Section Editor

Dermoscopy of the Hair and Nails, Second Edition ................................................................................... 319

Niraj Butala, MD

242

July/August 2016

Volume 14 • Issue 4

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

COPYEDITOR Elizabeth Holcomb eholcomb@skinmedjournal.com

MEDIA WEB DIRECTOR Joan Osgoodby joan@skinmedjournal.com

Composition Paul Bennett paul@skinmedjournal.com

Publishing PUBLISHER Art Kalaka

Associate Publisher James R. Adams jadams@skinmedjournal.com

Corporate President Arthur Kalaka akalaka@skinmedjournal.com

Copyright: © 2016 Pulse Marketing & Communications, LLC. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without the prior permission in writing from the Publisher. Requests should be addressed to the Permissions Editor at: Pulse Marketing & Communications, LLC, 4 Peninsula Avenue, Sea Bright, NJ 07760.

Chief Executive Officer Jo-Ann Kalaka-Adams jadams@skinmedjournal.com

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Abstracting & Indexing: The journal is indexed in Index Medicus/MEDLINE.

Chinese Society of Dermatology

Lebanese Dermatological Society

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243

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

July/August 2016

Volume 14 • Issue 4

EDITOR IN CHIEF

Lawrence Charles Parish, MD, MD (Hon) Philadelphia, PA

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

Eve J. Lowenstein, MD, PhD New York, NY

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

Venkataram Mysore, MD, FRCP (Hon, Glasgow) Bangalore, India

Robert J. Thomsen, MD Los Alamos, NM

Anthony V. Benedetto, DO Philadelphia, PA Brian Berman, MD, PhD Miami, FL

Anthony A. Gaspari, MD Baltimore, MD Michael Geiges, MD Zurich, Switzerland

Mark Bernhardt, MD Ft. Lauderdale, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel L. Cohen, MD Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Seung-Kyung Hann, MD, PhD Seoul, Korea

Joseph L. Pace, MD, FRCP Naxxar, Malta

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Art Papier, MD Rochester, NY

María Daniela Hermida, MD Buenos Aires, Argentina

Johannes Ring, MD, DPhil Munich, Germany

Warren R. Heymann, MD Camden, NJ

Roy S. Rogers III, MD Rochester, MN

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2016;14:245

Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Ronni Wolf, MD Rechovot, Israel Jianzhong Zhang, MD Beijing, China Matthew J. Zirwas, MD Columbus, Ohio

Andrew P. Lazar, MD Washington, DC

245

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INDICATION AND USAGE Enstilar® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. Apply Enstilar® to affected areas once daily for up to 4 weeks. Patients should discontinue use when control is achieved. Instruct patients not to use more than 60 g every 4 days. IMPORTANT SAFETY INFORMATION For topical use only. Enstilar® is not for oral, ophthalmic, or intravaginal use. Instruct patients to avoid use on the face, groin, or axillae, or if atrophy is present at the treatment site, and not to use with occlusive dressings, unless directed by a physician. The propellants in Enstilar® are flammable. Instruct patients to avoid fire, flame, or smoking during and immediately after using this product. Hypercalcemia and hypercalciuria have been observed with use of Enstilar®. If hypercalcemia or hypercalciuria develop, patients should discontinue treatment until parameters of calcium metabolism have normalized. Topical corticosteroids can produce reversible hypothalamicpituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. Risk factors include use of highpotency topical corticosteroids, use over a large surface area or on areas under occlusion, prolonged use, altered skin barrier, liver failure, and use in pediatric patients. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of Reference: 1. Enstilar® [prescribing information]. Parsippany, NJ: LEO Pharma Inc.; October 2015.

application, or substitute with a less potent steroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroidcontaining product at the same time may increase total systemic corticosteroid exposure. Adverse reactions reported in <1% of subjects treated with Enstilar® in clinical trials included application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Patients who apply Enstilar® to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. You may wish to limit or avoid use of phototherapy in patients who use Enstilar®. There are no adequate and well-controlled studies of Enstilar® in pregnant women. Enstilar® should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Because many drugs are excreted in human milk, caution should be exercised when Enstilar® is administered to a nursing woman. Do not use Enstilar® on the breast when nursing. The safety and effectiveness of Enstilar® in pediatric patients have not been studied. Please see Brief Summary on following page. *Must be 18 years of age or older to be eligible. For specific eligibility requirements and program restrictions, visit Enstilar.com or call 1-855-772-7224.

Enstilar ® (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064% for topical use Initial U.S. Approval: 2006 BRIEF SUMMARY: Please see package insert for full Prescribing Information. INDICATIONS AND USAGE Enstilar ® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Flammability The propellants in Enstilar ® Foam are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Hypercalcemia and Hypercalciuria Hypercalcemia and hypercalciuria have been observed with use of Enstilar ® Foam. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Enstilar ® Foam treatment of more than 4 weeks has not been evaluated. Effects on Endocrine System Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios. Use of more than one corticosteroid-containing product at the same time may increase total systemic corticosteroid exposure. Allergic Contact Dermatitis Allergic contact dermatitis has been observed with topical calcipotriene and topical corticosteroids. Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing. Risks of Ultraviolet Light Exposures Patients who apply Enstilar ® Foam to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The rates of adverse reactions given below were derived from three randomized, multicenter, prospective vehicle and/or active-controlled clinical trials in subjects with plaque psoriasis. Subjects applied study product once daily for 4 weeks, and the median weekly dose of Enstilar ® Foam was 24.8 g. Adverse reactions reported in <1% of subjects treated with Enstilar ® Foam included: application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis. Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing reports for local adverse reactions to topical steroids include atrophy, striae, telangiectasia, dryness, perioral dermatitis, secondary infection, and miliaria.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Pregnant women were excluded from the clinical studies conducted with Enstilar ® Foam. Enstilar ® Foam should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with Enstilar ® Foam. Enstilar ® Foam contains calcipotriene that has been shown to be fetotoxic and betamethasone dipropionate that has been shown to be teratogenic in animals when given systemically. Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Enstilar ® Foam is administered to a nursing woman. Instruct the patient not to use Enstilar ® Foam on the breast when nursing. Pediatric Use Safety and effectiveness of the use of Enstilar ® Foam in pediatric patients have not been studied. Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency with the use of topical corticosteroids. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients treated with topical corticosteroids. Local adverse reactions including striae have been reported with use of topical corticosteroids in pediatric patients. Geriatric Use Of the total number of subjects in the controlled clinical studies of Enstilar ® Foam in plaque psoriasis, 97 were 65 years or older, while 21 were 75 years or older. No overall differences in safety or effectiveness of Enstilar ® Foam were observed between these subjects versus younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. PATIENT COUNSELING INFORMATION [Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions For Use)] Inform patients of the following: • Instruct patients to shake before use. • Instruct patients not to use more than 60 g every 4 days. • Discontinue therapy when control is achieved unless directed otherwise by the physician. • Avoid use of Enstilar ® Foam on the face, underarms, groin or eyes. If this medicine gets on face or in mouth or eyes, wash area right away. • Wash hands after application. • Do not occlude the treatment area with a bandage or other covering unless directed by the physician. Instruct the patients not to use other products containing calcipotriene or a corticosteroid with Enstilar ® Foam without first talking to the physician. • Instruct patients who use Enstilar ® Foam to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.). Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam. • Enstilar ® Foam is flammable; avoid heat, flame, or smoking when applying this medication. •The foam can be sprayed holding the can in any orientation except horizontally. Manufactured by: Colep Laupheim GmbH & Co. KG Fockestraße 12 88471 Laupheim Germany (DE)

Distributed by: LEO Pharma Inc. 1 Sylvan Way, Parsippany, NJ 07054

July/August 2016

Volume 14 • Issue 4

Editorial

A Visit From Our Friendly Hospital Regulators: Typhoid Mary on Steroids W. Clark Lambert, MD, PhD;1 Lawrence Charles Parish, MD, MD (Hon)2

e have previously written about dirt and how it nearly consumed Victorian England,1 and we have also examined the use of gloves in striving for cleanliness2; however, there must be a limit to Uncle Sam and his disciples’ interference, as the story of the visit unfolds. Imagine if Typhoid Mary3 were still alive today. Background Recently, one of our (WCL) institutions was site visited by a powerful regulatory agency as part of a new program in which the institution as a whole was considered, not just individual residency training or patient delivery programs or even either being considered altogether.4 The site visitors were at pains to announce that this was not an evaluatory visit, and indeed by all appearances it was not, although they did notify us that someone would follow-up, if an egregious violation were discovered. We have not mentioned the agency by name, because this editorial is not about them; rather, it is about a phenomenon. Please allow us to explain. Despite the totally nonpejorative nature, and indeed intent, of the visitors or the agency that sent them, nor their completely professional and courteous behavior, the response of the institution may be gently described as exhibiting a panic mode. Not that we have anything to hide, far from it, but the prospect of a visit, any visit, by such an agency is daunting. Department chairs, residency program directors, faculty, residents, and others were assigned places to be and things to do. Importantly, none of this was paid for by the agency, which probably also charged a significant sum for the visit. Perhaps, it was all justified, perhaps, not. Something was learned from the experience, but it may not have been entirely the lesson intended.

The Visit Our part of the site visit consisted of, perhaps 25, faculty members sitting around a table and being asked a series of interesting but provocative questions. These were projected onto a screen and read aloud. We responded by using a handheld device that telegraphed our votes to the site visitor, who then projected our responses, nicely de-identified, on the screen. It was very cordial, friendly, and moderately informative. An area of particular focus was infection control and the importance of frequent hand washing. We were informed that a large number of hospitals, in excess of 250, had already been visited under this new program, with about 20 to 30 to go. At the end of it, WCL made a comment to the site visitor, based in part as a result of a two-term stint as chair of the institution’s Institutional Review Board (IRB) for Investigation Using Human Subjects5 that this highly structured review process, now even more structured as a result of this new type of site visit, may be counterproductive, even if each part seemed appropriate and proper. Such a large detailed structure tends to generate cracks through which important things may be missed. One of us (WCL) used to tell the IRB that if we were to try to catch every ant that tried to walk through the result might be that an elephant would pass by unmolested. The site visitor was appreciative, even very polite and professional, but responded that theirs was an excellent organization with extensive regulatory experience that would not allow this sort of thing to happen. The site visitor was then asked whether, with all this very proper emphasis on infection control, the handheld devices we all held were washed following each visit and also between groups of

From the Departments of Dermatology and Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ;1 and the Department of Dermatology and Cutaneous Biology and Director of the Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers-New Jersey Medical School, Room H576 Medical Science Building, Department of Dermatology, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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interviewees (there were several such sessions at each hospital). Oops!! It turns out no one had thought of that. The devices, although used repeatedly by hospital personnel at each institution, had not been cleaned—not once. An elephant indeed! The Results The agency in question is a splendid, well-intentioned group, but not a state or federal government agency, and thus susceptible to lawsuits. For this and other reasons, they are the last people on Earth one might expect to do a rash and dangerous thing, endangering innumerable people in many different cities; yet, this is exactly what they did, not because they were irresponsible, but because of the phenomenon mentioned earlier: being too cautious and creating too many barriers to prevent error.

Conclusions Over the next few weeks, most participants had thought of the inspection as merely one of the many intrusions that occur during the year. That was the case, until new regulations suddenly appeared. Any patient who was suspected of having an infection, and that includes those with stasis dermatitis, bullous pemphigoid, and even rosacea—yes, that is correct—because they might have cellulitis and are considered to be infected with a contagious disease. Anyone entering the room, even to deliver a newspaper, now must gown, wear masks, and don gloves to prevent spreading germs. And, so, cleanliness must be next to Godliness, after all: One “cannot be too careful,” or maybe too careful.6 References

On another level, this may be interpreted in an entirely different way. In addition to being overly cautious, the behavior of this agency is also self-serving. The more complex they make the regulatory process, the more money and power they accrue. Interestingly, there is really no limit to this process. What if they introduced yet another layer, and then another, to the regulatory activity they oversee? Who is to stop them? Also, imagine if an unusual infectious breakout were found to follow them around the country, leading to sickness and/or even death at multiple institutions. Imagine if this series of outbreaks continued, even after this was pointed out to them (they are accustomed to enforcing restrictions, not obeying them). Finally, imagine if the CDC or another agency sequenced DNA from the infectious organism responsible for each outbreak and found it to be identical. Just sayin’.

1 Parish LC. Dirt, dirt everywhere: nary a drop to clean. Skinmed. 2012;10:126–128. 2 Parish LC, Bernstein JM. There is more to infection control than just gloves in the dermatology office. Skinmed. 2014;12:9–10. 3 Marineli F, Tsoucalas G, Karamanou M, Androutsos G. Mary Mallon (1869-1938) and the history of typhoid fever. Ann Gastroenterol. 2013;26:132–134. 4 Flodgren G, Pomey MP, Taber SA, Eccles MP. Effectiveness of external inspection of compliance with standards in improving healthcare organisation behaviour, healthcare professional behaviour or patient outcomes. Cochrane Database Syst Rev. 2011;11:CD008992. 5 Homedes N, Ugalde A. The evaluation of complex clinical trial protocols: resources available to research ethics committees and the use of clinical trial registries—a case study. J Med Ethics. 2015;41:464–469. 6 Dhar S, Marchaim D, Tansek R, et al. Contact precautions: more is not necessarily better. Infect Control Hosp Epidemiol. 2014;35:213–221.

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A Visit From Our Friendly Hospital Regulators

July/August 2016

Volume 14 • Issue 4

COMMENTARY

Pseudoneoteleology and Lower Extremity Vascular Entities W. Clark Lambert, MD, PhD; Peter C. Lambert, MD; Brian Lee, MD “The best way to make a bad idea dangerous is to stop thinking about it.”––Philip Leder, MD

eleology is the interpretation of natural phenomena due to acts of a deity, rather than to natural causes. For example, parasitologists working in primitive environments sometimes find that villagers believe that they are sick because some god has been displeased, rather than that they have been infected by a parasite, making their work more difficult. Pseudoteleology is the belief that some emotional desire can, unaided, bring about a change in physical outcome, for example, a belief that one can move a boulder by intently staring at it. (Or that a student can learn the contents of a textbook just by spending time with it––think of students in a library asleep with their heads on their open textbooks.) Neopseudoteleology Neopseudoteleology is more subtle and more dangerous. It is the belief that reactions, especially reactions to disease or insults, seen in human (or animal) tissues, are inherently beneficial to the organism. Neopseudoteleology may affect our judgement subconsciously, as a critical but unexamined factor influencing our interpretation of events. For example, physicians believed for centuries that pus formation in wounds was a beneficial response (pus often occurred in wounds of healthy individuals who would later recover but not in terminal patients too ill to generate pus). This belief proved to be a serious obstacle for Joseph Lister (1827–1912) when he introduced aseptic surgery into medicine (and may have been the undoing of many surgeons who tried the procedure but lost their reputations as a result). Counterproductive Adaptations There are numerous examples of counterproductive adaptations in medicine, such as hypertrophy of the myocardium during heart fail-

See also Heymann WR. Cutaneous Collagenous VasculopathyAssociated Benign Pigmented Purpura, pages 308–309.

ure. The lower extremity, particularly the vasculature of the lower extremity, is an especially likely site for such counterproductive, and also counterintuitive, reactions. In addition, the lower extremity is a target area for peripheral-dependent edema caused by numerous systemic pathologies, including liver, kidney, and heart failure. Often, these pathologies occur together in the same patient. Stasis Dermatitis Stasis dermatitis is the most common of the pathologies that uniquely affect the lower extremities. In stasis dermatitis, the original insult is indeed caused by stasis of blood in the vasculature of the lower extremity; however, this quickly sets in motion a series of deleterious events that are self-perpetuating. In response to tissue oxygen deprivation, there is proliferation of blood vessels serving the region (Figure 1). The vessels thus created, however, have increased vessel wall thickness and increased tortuosity (Figure 1). This results in tissue perfusion actually decreasing in the region, even as the speed at which blood progresses through these vessels, as well as the volume of blood itself, increases. The reaction of tissue to this insult is not only counterproductive but it constitutes the major pathology. Stasis dermatitis is bad enough, but the tissue of the lower extremity is not yet done with its self-destructive binge. The tissue of the upper part of the dermis in the region, already underperfused and starved for oxygen, proceeds to do the one thing that will most markedly increase its need for oxygen and nutrients, as well as other benefits provided by tissue perfusion: undergo hypertrophy. The hypertrophy can have many forms, one of which is to lead to hypoxia that causes ulceration, as in ulcerated stasis dermatitis (Figure 1). Perhaps the most extreme form of this counterproductive hypertrophy is elephantiasis nostra, in which the lower extremities show massive acanthosis and hyperkeratinization in response to dependent edema and decreased tissue perfusion (Figure 2).

From the Departments of Dermatology and of Pathology and Laboratory Medicine, Rutgers – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers-New Jersey Medical School, Room H576 Medical Science Building, Department of Dermatology, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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Figure 2. Elephantiasis nostra. This symmetrical lesion occurred in a 29-year-old man with ankle edema caused by severe liver failure subsequent to hepatitis and alcoholism.

Figure 1. Stasis dermatitis. Note the ulceration and tortuous thick walled blood vessels in the dermis (hematoxylin and eosin stain, original magnification ×270).

Vascular Disorders Vascular disorders that affect the lower extremities are varied and complex, as is superbly reviewed by Heymann in this issue of the Journal.1 Much of this complexity would appear to be related to these pathophysiologic mechanisms unique to the lower extremity and acting in concert with pigment anomalies, which are also

influenced by these mechanisms. The study of such lesions and their underlying mechanisms is medical dermatology at its finest. Reference 1 Heymann WR. Cutaneous collagenous vasculopathyassociated benign pigmented purpura. SKINmed. 2016;14:308–309.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2016;14:251–252

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Original contribution

Patch Testing in Children and Adolescents With Suspected Allergic Contact Dermatitis Surekha Meena, MD; Taru Garg, MD; Ram Chander, MD Abstract Allergic contact dermatitis (ACD) in children is not uncommon. The reported rates of positive patch test in various series in children with suspected ACD varies from 32.6% to 67%. At present, patch testing is the only reliable test to identify various contact allergens in a suspected case of ACD. The aim of this study was to find out the common allergens responsible for ACD in children and adolescents. Patch testing was carried out with Indian Standard Series. Additional allergens were added wherever implicated from history. Seventy-four patients were recruited during the study period, of which analysis was performed in 70 patients. Thirty-eight (54.3%) patients had one or more positive patch test results. The most common allergen found to be positive was nickel sulfate. The clinically relevant reactions were found in 78.94% of patients. The relevance of positive patch test reactions were higher in children (3–9 years) compared with adolescents (10–19 years) and it was found to be statistically significant (P=.030). ACD is a significant health problem in children, compromising their quality of life, therefore age should not be a bar for performing patch testing to diagnose this clinical condition. (SKINmed. 2016;14:253–258)

llergic contact dermatitis (ACD) was once thought to be rare in children. This was attributed to the low frequency of patch tests performed on children (compared with adults) and to the fact that in clinical practice, manifestations of ACD in children had often been attributed to the morphological look-alikes such as atopic dermatitis or irritant contact dermatitis.1 It has been estimated that 20% of the pediatric population is affected by ACD.2 The most common allergens to cause ACD in children have historically been nickel, thimerosal, neomycin, rubber compounds, potassium dichromate, and fragrance.2 The most commonly incriminated allergen is nickel in children.3 ACD can be diagnosed clinically but the best method for confirmation to date is patch testing, which diagnose and also identify the allergens responsible for dermatitis.4 ACD acquired in childhood has important repercussions for patients and may affect decisions regarding future occupation in adulthood.5 There are various studies2,6,7 of allergens in children in the western literature; however, not much work has been performed in India. Therefore, an attempt has been made to study the common allergens responsible for causing ACD in this age group.

Material and Methods The study was conducted at the Department of Dermatology of a tertiary care center during the study period of November 2011 to March 2013. Prior ethical committee approval was obtained. Seventy-four patients with suspected ACD in the age group of 3 to 19 years were included in the study. Children taking immunosuppressive drugs or with known immunocompromised status, severe ACD, or active dermatitis at the site of patch testing were excluded. After receiving informed and written consent from parents/patients, demographic details, detailed history, and findings of clinical examination were recorded on the proforma. Patch testing was performed by the modified Finn chamber method utilizing the Indian Standard Series (ISS, 25 allergens), Indian Cosmetic and Fragrance Series (ICFS, 44 allergens,), and Indian Footwear Series (IFS, 24 allergens) manufactured by Chemotechnique Diagnostics (Vellinge, Sweden), and approved by Contact Dermatitis Forum of India. Patch testing with ISS was performed in all patients. In patients in whom allergy was strongly suspected to other allergens, patch testing with additional series/allergens, ie, IFS (15 patients), ICFS (three patients), or medicaments (four patients) was performed, after a minimum gap of 1 month. Two readings were taken, first at 48

From the Department of Dermatology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India Address for Correspondence: Taru Garg, MD, Department of Dermatology and STD, Lady Hardinge Medical College and Associated Hospitals, Connaught Place, Opposite Shaheed Bhagat Singh Marg, New Delhi, 110001, India • E-mail: tarugarg4@yahoo.co.in

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hours and then again at 96 hours after applying allergens. The scoring system recommended by the International Contact Dermatitis Research Group was followed for patch test reading. To know the relevance of positive patch test reaction, interpretation of the test results was performed in relation to the history (past or present) given by the patients regarding the exposure to the positive allergen. We considered results to be relevant if the positive patch test result putatively explained the patient’s present dermatitis or past disease. Statistical analysis was performed by using SPSS software version 20 (SPSS Inc, Chicago, IL). Means and standard deviations were calculated for continuous parameters. Chi-square test and proportion were used for qualitative data. P<.05 was taken as statistically significant.

Table I. Demographic Profile of the Study Population Patients, No. (%)

Male

37 (52.9)

Female

33 (47.1)

History of atopy (personal or family)

34 (48.57)

Seasonal variations Winter

4 (5.71)

Summer

15 (21.4)

Hobbies

Observations and Results

Painting

17 (24.3)

Sports

8 (11.4)

Table II. Common Allergens in Different Age Groups

Seventy patients completed the study protocol. Children aged up to 9 years comprised 37.14% of the study population while 62.86% of patients were adolescents (10–19 years). The mean age of the study patients was 11.36±3.89 years. Demographic profile and relevant history of the patients is depicted in Table I. Itching was the most common symptom present, in 95.7% of the study population, followed closely by eruptions (92.8 %) and redness (88.6%). Fissuring was the least common symptom, being present in 4.2% of patients. Dryness was the most common symptom in patients with ACD to cosmetics. Scaling, burning, and oozing were the other reported symptoms. Thirty-four (48.57%) patients had positive patch test reactions to allergens in ISS. This positivity rate increased from 48.57% to 54.3% after patch testing with additional allergens. Maximum positive patch test reactions (61.90%) were seen in the age group of 10 to 13 years, while minimum positive patch test reactions (50%) were seen in the age group of 3 to 5 years. Various allergens in different age groups are depicted in Table II. Women had more positive patch test reactions (60.60%) than men (48.65%). Nickel sulfate was the most common allergen found in women (n=7, 35%), while cobalt chloride had the highest positive patch test reactions (33.33%) in men. We analyzed the results at the following sites: site of direct contact with allergen, labeled as, site involved by specific allergen, hands, feet, face, and genitalia. The most common site showing positive patch test reactions by dermatitis was the site of contact with specific allergen, ie, site of tattooing (Figure 1), infraumbilical/ periumbilical region from jeans studs/belt buckle (Figure 2), earlobe from ear piercing, and wrist/forearm contact dermatitis from metal bangles (Figure 3). It was closely followed by contact dermatitis involving the foot (Figure 4). Hand and genitalia involvement was present in 5.7% patients each. Patients with dermatitis at the site involved by specific allergens had the highest number (100%) of clinically relevant positive patch test results. SKINmed. 2016;14:253–258

Demographic Profile

Age Group, y

Common Allergens

3–5

Cobalt chloride, gentamicin

6–9

Nickel sulfate, paraben mix, parthenolide, balsam of Peru

10–13

Nickel sulfate, cobalt chloride, neomycin, gentamicin, formaldehyde, para-tertiarybutylphenol formaldehyde resin, colophony

14–19

Nickel sulfate, cobalt chloride, neomycin, para-phenylenediamine, potassium dichromate, gentamicin, formaldehyde, paraben mix, wool alcohols, black rubber mix

Figure 1. Dermatitis at the site of tattooing (para-phenylenediamine).

Overall, the most common allergen was nickel sulfate (15.7%), with a 100% clinical relevance, followed by cobalt chloride (8.57%), with a 50% clinical relevance. Grade 3 positive patch test reaction was seen only with nickel sulfate; however, grade 2

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Figure 2. Periumblical dermatitis to jeans stud (nickel).

Figure 4. Footwear dermatitis (para-phenylenediamine, 4-Aminoazobenzene, and Disperse Orange 3).

Figure 3. Dermatitis at the site of metal bangles (nickel) in two sisters.

Figure 5. Patch test positivity to multiple allergens (paraphenylenediamine, 4-aminoazobenzene, and Disperse Orange 3).

positive reactions were seen with the multiple allergens nickel sulfate, cobalt chloride, para-phenylenediamine (PPD), benzocaine, para-tertiary-butylphenol formaldehyde resin (PTBPFR), and parthenolide. Patch test with IFS (n=15) and ICFS (n=7) showed positive patch test reactions in three patients each (Table III). Multiple positive patch test reactions were seen in seven patients (Table IV, Figure 5). Irritant reactions were seen in 12.8% of patients. The percentage of irritant reactions was slightly higher in women and in patients without a history of atopy (P=.666). Clinically relevant reactions were seen in 78.94% of patients. Relevant reactions were slightly higher in men (83.33%) and in patients with a history of atopy (P=.693). SKINmed. 2016;14:253â&#x20AC;&#x201C;258

Discussion ACD is often suspected in children; however, patch testing is not always performed for confirmation of diagnosis. We performed patch testing in all suspected cases of ACD to reveal the various allergens that caused it. The percentage of positive patch test reactions reported in the previous studies varied from 14.5% to 71%.8 In our study, 54.3% of patients had positive patch test reactions. Patch testing with additional allergens (IFS, ICFS, topical medicaments) increased the positivity from 48.57% to 54.3%. A similar observation was made in an earlier study, where patch testing was performed in

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Table III. Patch Test Results for Allergens According to Indian Standard Series, Indian Footwear Series, and Indian Cosmetic and Fragrance Series Allergens

Positive Results in Patients, No. (%)

Irritant Results in Patients, No. (%)

Potassium dichromate

1 (1.4)

0 (0)

Neomycin sulfate

3 (4.2)

0 (0)

Cobalt (II) chloride hexahydrate

6 (8.57)

2 (2.8)

Benzocaine

1 (1.4)

4-Phenylenediamine

3 (4.2)

0 (0)

Paraben mix

3 (4.2)

3 (4.3)

Nickel sulfate hexahydrate

11 (15.7)

1 (1.4)

Colophony

1 (1.4)

Gentamicin sulfate

3 (4.2)

0 (0)

Wool alcohol

2 (2.8)

0 (0)

Balsam Peru

1 (1.4)

0 (0)

Black rubber mix

2 (2.8)

0 (0)

4-Para-tertiary-butylphenol formaldehyde

3 (4.2)

1 (1.4)

Formaldehyde

2 (2.8)

0 (0)

Parthenolide

1 (1.4)

0 (0)

N,Nâ&#x20AC;&#x2122;-Diphenylguanidine

1 (6.6)

0 (0)

4-Aminoazobenzene

1 (6.6)

0 (0)

Disperse Orange 3

1 (6.6)

0 (0)

Disperse Blue 124

1 (6.6)

0 (0)

Gallate mix

1 (14.2)

0 (0)

Thimerosal

1 (14.2)

0 (0)

Cetrimide

2 (28.5)

0 (0)

Table IV. Positive Patch Test Reactions to Multiple Allergens Serial Number

Name of Allergens

Para-phenylenediamine,a 4-aminoazobenzene,a Disperse Orange 3a

Para-phenylenediamine,a benzocaine, black rubberb

Neomycin,a gentamicin,a wool alcohola

Neomycin,a cobalt,b gentamicina

Potassium dichromate,b nickel,a wool alcohola

Parabens,a parthenolidea

Gallate mix,a cetrimidea

Relevant. Nonrelevant.

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two separate sessions. If the first series of allergens did not reveal sensitization, a second tray of 15 substances was applied, thereby increasing the yield.9 The highest number (61.90%) of positive reactions was seen in the age group of 10 to 13 years in our study, in close concordance with a previous study.10 Opposing this, a previous study recorded that the higher the age group, the higher the prevalence of allergy.11 Most commonly, positive reactions had been observed with clinical presentation of dermatitis confined to the site of contact with specific allergens, as seen in this study.12 Nickel was the most common allergen, found to be positive in 15.7% of patients, with 100% relevance, in accordance with findings of previous studies.1,2,5,10,12–14 The second most common allergen in our study was cobalt chloride (8.57%), with 50 % relevance. A similar number of positive reactions (8%) to cobalt was also found in a previous study.12 In an Indian study, cobalt (23%) was recorded as the fourth most common allergen.11 Three (4.2%) patients showed positive patch test reactions to PPD. The source of allergy in two patients was black henna tattoos and in one patient there was history of hair dye use along with footwear dermatitis. Paraben mix had been reported earlier as the most common allergen in children (43%)11; however, this was not observed in our study (4.2%). Positive patch test reactions to topical antibiotics such as neomycin and gentamicin were observed in an equal number of patients (4.2%). Earlier, studies showed similar patterns for neomycin10; however, a higher percentage (10%) of positive patch test reactions to gentamicin was previously observed with a lower relevance (14.1%).11 Patch test reactions to formaldehyde (2.85%) were relevant in 50% of children. A previous study reported a higher percentage of sensitivity to formaldehyde (4.28%), with a lower relevance (33.3%).11 PTBP-FR was another allergen that showed positive patch test reactions (2.85%), with 50% relevance, which was in accordance with results from previous studies.11 Few studies have reported wool alcohol as one of the most common allergens in children6,10; however, we observed positive reactions to wool alcohol in 2.85% of patients. With IFS, three patients showed positive reactions to N,N’-diphenylguanidine (carbamates), 4-Aminoazobenzene, Disperse Orange 3, and Disperse Blue 124, which may be present in the rubber used for items such as gloves, balloons, socks, athletic shoes, and dyes used to color leather. Patients with positive reactions to thimerosal and cetrimide (ICFS) had facial dermatitis. Another patient with sensitivity to cetrimide had persistent genital dermatitis. Few previous studies have reported thimerosal to be the most frequent allergen in children.9,15

be caused by cross-sensitization between these two allergens.16 In one patient, in addition to PPD, allergens of IFS (4-Aminoazobenzene and Disperse Orange 3) were also found to be positive. We thought this was a relevant reaction as the patient had ACD at the site of a tattoo as well as foot wear dermatitis clinically; however, cross-reaction between these above-mentioned allergens has also been described in the literature.17 Similarly cross-reaction between neomycin and gentamicin has also been described.18 In previous studies, irritant reactions have been reported in children varying from 5.1% to 18.57%.11,19 We did not observe a very high number of irritant reactions (12.85%). It was most commonly caused by paraben mix (21.42%). Clinically relevant positive reactions were found in 78.94% patients, a percentage similar to earlier studies.1,6 Conclusions ACD should not be ignored as a clinical diagnosis in children and, when it is suspected, patch testing should be performed for the confirmation and identification of the causative allergen. Nickel sulfate remains the most common allergen in children. Allergens in the same concentrations as used for adults may be used; however, a battery of allergens can be individualized depending on the history of exposure and clinical presentation. References

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1 Jacob SE, Brod B, Crawford GH. Clinically relevant patch test reactions in children––a United States based study. Pediatr Dermatol. 2008;25:520–527. 2 Hammonds LM, Hall VC, Yiannias JA. Allergic contact dermatitis in 136 children patch tested between 2000 and 2006. Int J Dermatol. 2009;48:271–274. 3 Hand dermatitis due to contactants: special consideration. In: Rietschel RL, Fowler JF, eds. Fischer’s Contact Dermatitis. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1995:330. 4 Vender RB. The utility of patch testing children with atopic dermatitis. Skin Therapy Lett. 2002;7:4–6. 5 Clayton TH, Wilkinson SM, Rawcliffe C, et al. Allergic contact dermatitis in children: should pattern of dermatitis determine referral? A retrospective study of 500 children tested between 1995 and 2004 in one UK centre. Br J Dermatol. 2006;154:114–117. 6 Seidenari S, Giusti F, Pepe P, et al. Contact sensitization in 1094 children undergoing patch testing over a 7-year period. Pediatr Dermatol. 2005:22:1–5. 7 Lewis VJ, Statham BN, Chowdhury MM. Allergic contact dermatitis in 191 consecutively patch tested children. Contact Dermatitis. 2004;51:155–156. 8 Mortz CG, Andersen KE. Allergic contact dermatitis in children and adolescents. Contact Dermatitis. 1999;41:121–130.

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ORIGINAL CONTRIBUTION

9 Manzini BM, Ferdani G, Simonetti V, et al. Contact sensitization in children. Pediatr Dermatol. 1998;15:12–17. 10 Goon AT, Goh CL. Patch testing of Singapore children and adolescents: our experience over 18 years. Pediatr Dermatol. 2006;23:117–120. 11 Sarma N, Ghosh S. Clinico-allergological pattern of allergic contact dermatitis among 70 Indian children. Indian J Dermatol Venereol Leprol. 2010;76:38–44. 12 Beattie PE, Green C, Lowe G, et al. Which children should we patch test? Clin Exp Dermatol. 2007;32:6–11. 13 Roul S, Ducombs G, Taieb A. Usefulness of the European standard series for patch testing in children. A 3-year single-centre study of 337 patients. Contact Dermatitis. 1999;40:232–235. 14 Hogeling M, Pratt M. Allergic contact dermatitis in children: the Ottawa hospital patch-testing clinic experience, 1996 to 2006. Dermatitis 2008;19:86–89. 15 Heine G, Schnuch A, Uter W, et al. Frequency of contact allergy in German children and adolescents patch tested

between 1995 and 2002: results from the Information Network of Departments of Dermatology and the German Contact Dermatitis Research Group. Contact Dermatitis. 2004;51:111–117. 16 Practical aspects of patch testing. In: Rietschel RL, Fowler JF, eds. Fischer’s Contact Dermatitis. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2001:9– 33. 17 Beck MH, Wilkinson BM. Allergic contact dermatitis. In: Burns T, Breathnach SM, Cox N, Griffiths C, eds. Rook’s Textbook of Dermatology. 8th ed. Oxford, England: Blackwell; 2010:26.1–26.106. 18 Topical antimicrobial. In: Rietschel RL, Fowler JF eds. Fischer’s Contact Dermatitis. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:167–183. 19 Zug KA, McGinley-Smith D, Warshaw EM, et al. Contact allergy in children referred for patch testing: North American Contact Dermatitis Group data, 2001–2004. Arch Dermatol. 2008;144:1329–1336.

“Favus”. Moulage No. 206, made by Lotte Volger in 1923 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Original contribution

Survey of Patient Satisfaction With Ingenol Mebutate Gel Treatment for Actinic Keratosis From a Community Dermatology Practice Dale Schaefer, MD Abstract Actinic keratosis (AK) is a condition that can present as a discrete lesion or as areas of confluent lesions. It is generally treated either with cryosurgery or, less frequently, with patient-applied topical medications or photodynamic therapy. Topical therapies can offer benefits over cryosurgery, especially in patients with significant actinic damage. The long durations of topical treatment required and the persistence of associated local skin reactions (LSRs) may deter some patients from adhering to topical therapies and thus affect clinical outcomes. This study describes patient satisfaction with ingenol mebutate treatment for AK in a community dermatology practice in Austin, Texas. Patients were invited to participate in a survey to evaluate their level of satisfaction with the treatment. The patients completed a questionnaire on ease of use, tolerability, appearance of their skin after treatment, and their likelihood of repeat use of ingenol mebutate for AK. Overall, 42 patients completed the questionnaire. The majority of patients had a ≥10-year history of AK, had received prior cryosurgery, and had used topical therapies, most commonly fluorouracil. After treatment with ingenol mebutate, more than 90% of patients reported a good or excellent treatment experience and an improved appearance of their skin. Patients cited the brief 2- to 3-day treatment regimen, high efficacy for clearance of AK, and the rapid resolution of LSRs as factors in their satisfaction with treatment. (SKINmed. 2016;14:259–265)

ctinic keratosis (AK) is a common skin disease and a frequent dermatologic diagnosis in patients 45 years and older.1 The average patient with AK usually has multiple lesions,2–4 any of which may progress to squamous cell carcinoma (SCC). The prevailing opinion is that all AKs should be evaluated for treatment to reduce the risk of progression to more invasive disease.5–7 Lesion-directed cryosurgery is the most commonly used method to treat localized AK.8,9 It becomes less practical for patients who have numerous lesions in a contiguous area of skin,10 and it is associated with posttreatment hypopigmentation11 and recurrence of treated lesions.12 Topical field treatment can treat areas of skin with large numbers of lesions, but adherence can be problematic because of the requirements for multiple applications and long durations of treatment.10,13 Further, the associated local skin reactions (LSRs) may cause physical discomfort and be unsightly. Ingenol mebutate gel, 0.05% and 0.015%, is a topical treatment for AK that requires a brief, 2- or 3-day application regi-

men, depending on the area of the body being treated.14 Phase 3 studies of ingenol mebutate used as monotherapy15,16 and used sequentially after cryosurgery17,18 have demonstrated sustained clearance of AKs, with a good tolerability profile. We have used ingenol mebutate treatment in a community dermatology practice in Austin, Texas. We report here the results of a survey we conducted to assess the level of satisfaction with ingenol mebutate, as well as the response to therapy, among our patients. Methods Dermatology patients who had received ingenol mebutate gel treatment for AK were invited to participate in the survey. The survey questionnaire was prospectively administered during a clinic visit for a dermatologic evaluation from January 2014 to January 2015. Eligible patients underwent a clinical evaluation before and after treatment and provided informed consent at their clinic visit. The questionnaire assessed the patients’ attitudes about their treatment experience.

From Austin Dermcare, Austin, TX Address for Correspondence: Dale Schaefer, MD, Austin Dermcare, 3807 Spicewood Springs Road, Suite 200, Austin, TX 78759 • E-mail: dschaefermd@gmail.com

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A chart review captured the patients’ dermatologic history and results of clinical assessments performed before and after ingenol mebutate treatment. After treatment with ingenol mebutate, complete clearance of AK was recorded as 100% clearance. For patients who had AKs that remained after treatment, AK clearance was estimated as 75%, 50%, or 25% improvement, as compared with the start of treatment. Results

Patient satisfaction The survey questions are shown in Table III, along with a tally of the patient responses. Not all patients responded to all questions. Among those responding to the question about their experience with topical AK treatments in the past, most (17 of 22) cited “good” or “excellent” results; however, 13 of 23 responders indicated that the past medication was “difficult” or “somewhat difficult” to use, and 12 of 23 responders were unwilling to use that medication again in the future.

Baseline characteristics and past AK treatments The 42 patients who completed the questionnaire ranged in age from 38 to 84 years (average, 61.4 years; men, n=29). The majority had sustained significant sun damage, indicated by a 10-year or longer history of AK (n=25, 60%). Prior cryosurgery, recurrent AKs, hyperkeratotic AKs, and a history of nonmelanoma skin cancer were common (Table I).

Table I. Patient Dermatologic History (N=42) Characteristic

No.

Percentage

BCC

SCC

Treatment with ingenol mebutate

Both BCC and SCC

Approximately two thirds of the patients (n=28, 66%) used ingenol mebutate as monotherapy. Several patients (n=14, 33%) initially received cryosurgery to a subset of hyperkeratotic lesions and then received ingenol mebutate treatment approximately 2 weeks later. Cryosurgery was also used to treat lesions that persisted after topical treatment.

Melanoma

None

Initial diagnosis

Recurrent AKs

Most of the patients in the survey treated AKs on the face or scalp using ingenol mebutate gel 0.015% (Table II). The 0.05% gel was prescribed for seven (17%) patients to treat AKs on the scalp; this dosage was based on observed experience in the practice over several months that the 0.015% gel was less effective on the scalp than on the face. Therefore, men exclusively treating AKs on the scalp were prescribed the 0.05% formulation. The 0.05% gel was also prescribed for nine (21%) patients who were treating AKs on the trunk or extremities. Of these nine patients, five were treating AKs on the trunk or extremities after an initial course of therapy using the 0.015% gel for AKs on the face or scalp.

Hyperkeratotic AKs

Cryosurgery

Any topical treatment

Fluorouracil (multiple strengths)

Imiquimod (multiple strengths)

Diclofenac 3% gel

Photodynamic therapy (blue light)

Skin cancer history

AK history

Prior treatment

Abbreviations: AK, actinic keratosis; BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

Table II. Sites of Actinic Keratosis Treatment With Ingenol Mebutate Gel Among 42 Patients Treated Area

Ingenol Mebutate Regimen

Patients, No.

Face or scalp

0.015% once daily for 3 days

Scalp

0.05% once daily for 2 days

Trunk or extremities

0.05% once daily for 2 days

Face or scalp and trunk or extremities

Separate courses of each formulation, 0.015% and 0.05%

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Table III. Patient Satisfaction Questionnaire and Summed Responses From 42 Patients Question

Options

Responses No.

Percentage

1. How would you describe the results of your prior experience with a topical medication?

Excellent Good Not good No answer

5 12 5 20

12 19 12 48

2. How easy or difficult was it for you to use that topical medication?

Easy Somewhat difficult Difficult No answer

10 10 3 19

24 24 7 45

3. Would you use that topical medication again?

Yes No No Answer

11 12 19

26 28 45

4. How would you describe your experience with ingenol mebutate gel?

Excellent Good Not good No answer

25 16 1 0

60 38 2 0

5. Would you use ingenol mebutate gel again?

Yes No

41 1

98 2

6. How would you describe your skin appearance following ingenol mebutate gel treatment?

Excellent Better than before Same as before Worse No answer

12 17 2 0 1

29 64 5 0 2

7. How easy or difficult was it to use ingenol mebutate gel?

Easy Somewhat difficult Difficult No answer

35 5 2 0

83 12 5 0

8. Did you prefer ingenol mebutate gel over all other actinic keratosis treatments you have used in the past?

Yes No No answer

34 3 5

81 7 12

9. Would you ask for ingenol mebutate gel by name if treatment of actinic keratosis is indicated in the future?

Yes No No answer

36 6 0

84 14 0

10. Please indicate why you prefer ingenol mebutate gel over other actinic keratosis treatments.

Provide comments

10 (24%) no response 32 (76%) responded (Responses are discussed in the Results)

Nearly all patients (n=41, 98%) described their experience with ingenol mebutate as “excellent” or “good” and reported that they would use ingenol mebutate again. Most respondents indicated that their skin was better (n=27, 66%) or excellent (n=12, 29%) after treatment. Photographs of patients’ skin appearance before and after treatment are shown in Figures 1 and 2.

ments they had used previously. Reasons cited in the patients’ open-response comments were the 2- or 3-day treatment regimen, the ease of completing the prescribed doses, the early development of LSRs followed by rapid healing of the skin, less pain than with prior treatments, effective clearance of AKs, and the absence of cryosurgery-associated hypopigmentation.

Most patients (n=35, 83%) described ingenol mebutate as easy to use. Among the 37 patients who indicated a treatment preference, 34 patients preferred ingenol mebutate over other treat-

Patients commented that LSRs developed within the first day of treatment. This was consistent with reports from the phase 3 studies and information in the package insert.14,15 All patients

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A A

B Figure 1. Photographs of a man, aged 38 years, before and after treatment of the forehead with ingenol mebutate gel, 0.015%. (A) Before treatment. (B) Approximately 3 months after treatment.

were satisfied with the time course for healing of the treatment area, which occurred within 2 weeks after treatment completion. Patients who used the 0.05% gel to treat AKs on the scalp also indicated that the treatment was well tolerated and that they experienced a similar time course of recovery as seen with the 0.015% gel. One patient commented that fluorouracil was more effective than ingenol mebutate and did not find that the length of treatment with fluorouracil or its LSRs limited tolerability. Three patients found that the amount of medication in the single-dose tubes of ingenol mebutate was inadequate to treat their affected areas. After a satisfactory first treatment experience with ingenol mebutate, 16 of 42 patients have either completed or plan to comSKINmed. 2016;14:259â&#x20AC;&#x201C;265

C Figure 2. Photographs of a woman, aged 56 years, before and after treatment of the chest with ingenol mebutate gel, 0.05%. (A) Before treatment. (B) Three days after treatment initiation. (C) Three months after treatment completion.

plete a second course of treatment. Among 15 patients who used the 0.015% formulation to treat AKs on the face or scalp, five are repeating that treatment, four are treating AKs on the trunk or extremities with the 0.05% formulation, and six are treating

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the scalp with the 0.05% formulation. One patient who used ingenol mebutate gel, 0.05%, for AKs on the extremities is using it again to treat a different area on the extremities.

AK clearance At 2 months to 25 months following initiation of treatment, complete clearance was observed in 21 of 35 (60%) patients, and 75% clearance of lesions occurred in 8 of 35 (23%) patients (Figure 3). The single patient with limited (25%) clearance had treated facial AKs using only two of the three doses of the 0.015% gel because of concern over the rapid development of LSRs on days 1 and 2 of treatment. His skin healed promptly, however, and he retreated his facial AKs with the full complement of three doses.

Figure 3. Clearance of actinic keratosis on the face or scalp after three consecutive, once-daily applications of ingenol mebutate gel, 0.015%, for 35 patients. *The patient used only two applications of the 0.015% gel.

Among the seven patients who treated AKs on the scalp with two applications of the 0.05% gel, the proportion of AK lesions cleared was 100% in two patients, 75% in three patients, and 50% in two patients, at 2 months to 20 months after treatment. Results were available for four of the nine patients who treated trunk or extremity lesions with the 0.05% gel. At 2 months to 4 months after treatment, the proportion of AK lesions cleared from a variety of body sites was 100% on the arms (n=2), 100% on the chest (n=1), and greater than 75% on the back of the neck/upper back (n=1). Results were pending for five additional patients who had treated the arms, hands, and/or chest but who had not been evaluated at a follow-up visit. These patients were using the 0.05% gel after their initial treatment course with the 0.015% gel for AKs on the face or scalp.

Patients of particular interest The treatment experiences of four patients are described in Table IV. These descriptions highlight satisfaction with ingenol mebutate treatment among a diverse group of patients, including those with long-standing AK, a history of nonmelanoma skin cancer, dissatisfaction with prior topical treatments, no prior treatment, and concomitant dermatologic disease. Discussion Patients treated for AK with ingenol mebutate gel in a community dermatology practice in Austin, Texas, reported that the treatment was effective and well tolerated. Many of these patients had a long history of AK and a history of nonmelanoma skin cancer, which reflected a high degree of actinic damage. Their past AK treatment experience was dominated by cryosurgery, but more than 50% of the patients had used a prior topical treatment. The 2- or 3-day treatment period needed for ingenol mebutate was regarded as more acceptable than the longer SKINmed. 2016;14:259â&#x20AC;&#x201C;265

treatment courses involved with the topical AK therapies they had previously used. Nearly all patients found the appearance of their skin to be excellent or better after treatment, and they indicated that they would use ingenol mebutate if future treatment was required. Comparative studies of tolerability and satisfaction with AK topical treatments are limited, but reports suggest that patients prefer treatments that cause less irritation. For example, fluorouracil, as a 5% cream, was identified as being more irritating than the 0.5% cream19 and in comparison with diclofenac.20 A recent study used open-ended telephone inquiry and face-toface interviews with outpatients to gain their perspectives on AK treatments.21 Efficacy was a primary patient concern, but additional considerations included pain during the procedure, inflammatory reactions that could be worse than expected, long recovery times, interference with social activities, and posttreatment scarring.21 The patients we surveyed from our community dermatology practice identified a similar set of issues. The most important factors leading to patient satisfaction in our study were effective clearance of the AKs, the brief nature of the 2or 3-day treatment regimen, and the recovery time (within 2 weeks) associated with ingenol mebutate. Conclusions AK is typically a chronic condition in which new lesions appear over time.22 It is thus valuable to identify a treatment regimen that patients are most likely to use again. The patients in this community practice reported a high level of satisfaction with ingenol mebutate and a willingness to repeat the treatment as needed.

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Table IV. Patients of Particular Interest Patient 2 Female, 64 y AK and DSAP

Patient 8 Male, 43 y AK on difficult-to-

Patient 15 Male, 46 y Unrecognized AK

treat site

Patient 22 Male, 66 y Almost-confluent scalp AK

Presentation

15-y history of AK on arms Severe DSAP on arms and legs

9-y history of AK on back “Persistent red blotches” of neck and upper back on face of a few years’ History of BCC on back, duration neck, shoulder 7 AKs diagnosed >30 AKs on back of neck and upper back

19-y history of AK 16-y history of >25 BCCs

Prior treatment

Cryosurgery, fluorouracil, diclofenac

Cryosurgery, fluorouracil

None

Cryosurgery; no topicals

Current treatment

Ingenol mebutate 0.05% on arms, following cryosurgery to subset of AKs

Ingenol mebutate 0.05%

Ingenol mebutate 0.015%

Cryosurgery to subset of AKs Ingenol mebutate 0.05% in two treatment courses, separated by 6 mo

Outcome

Intense LSRs in a few areas 100% AK clearance at 3 mo Substantial improvement of DSAP

75% AK clearance on back of neck and upper back at 2 mo

100% AK clearance at 2 mo

75% AK clearance at 1 mo after the second treatment course One remaining AK, treated with cryosurgery

Patient satisfaction

Pleased with AK clearance Liked the 2-day regimen and DSAP improveWell-tolerated LSRs Preferred ingenol mebument tate vs past fluorouracil Will treat DSAP on legs with 0.05% gel

Liked the brevity of treatment Satisfied with appearance of skin

“Quick, easy, and effective treatment”

Abbreviations: AK, actinic keratosis; BCC, basal cell carcinoma; DSAP, disseminated superficial actinic porokeratosis; LSRs, local skin reactions.

Acknowledgments Data were organized and compiled by Caroline Schaefer. Editorial support was provided by Tanya MacNeil, PhD, from p-value communications and funded by LEO Pharma Inc. Disclosures Dr Schaefer is a speaker for AbbVie Inc., Aqua Pharmaceuticals, Celgene, Galderma Laboratories, L.P., LEO Pharma Inc., PuraCap Pharmaceuticals LLC, and Valeant Pharmaceuticals. References 1 Landis ET, Davis SA, Taheri A, Feldman SR. Top dermatologic diagnoses by age. Dermatol Online J. 2014;20:22368.

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2 Naldi L, Chatenoud L, Piccitto R, et al. Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the Prevalence of Actinic Keratoses Italian Study, 2003– 2004. Arch Dermatol. 2006;142:722–726. 3 Harvey I, Frankel S, Marks R, Shalom D, Nolan-Farrell M. Non-melanoma skin cancer and solar keratoses. I. Methods and descriptive results of the South Wales Skin Cancer Study. Br J Cancer. 1996;74:1302–1307. 4 Marks R, Ponsford MW, Selwood TS, Goodman G, Mason G. Non-melanotic skin cancer and solar keratoses in Victoria. Med J Aust. 1983;2:619–622. 5 Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115:2523– 2530.

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6 Czarnecki D, Meehan CJ, Bruce F, Culjak G. The majority of cutaneous squamous cell carcinomas arise in actinic keratoses. J Cutan Med Surg. 2002;6:207–209. 7 Mittelbronn MA, Mullins DL, Ramos-Caro FA, Flowers FP. Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma. Int J Dermatol. 1998;37:677– 681. 8 Balkrishnan R, Cayce KA, Kulkarni AS, et al. Predictors of treatment choices and associated outcomes in actinic keratoses: results from a national physician survey study. J Dermatolog Treat. 2006;17:162–166. 9 Halpern AC, Hanson LJ. Awareness of, knowledge of and attitudes to nonmelanoma skin cancer (NMSC) and actinic keratosis (AK) among physicians. Int J Dermatol. 2004;43:638–642. 10 Berman B, Cohen DE, Amini S. What is the role of fielddirected therapy in the treatment of actinic keratosis? Part 1: overview and investigational topical agents. Cutis. 2012;89:241–250. 11 Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol. 2004;43:687–692.

14 Picato (ingenol mebutate) gel 0.015%, 0.05% [package insert]. Parsippany, NJ: LEO Pharma Inc; 2012. 15 Lebwohl M, Swanson N, Anderson LL, et al. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366:1010–1019. 16 Lebwohl M, Shumack S, Stein Gold L, et al. Long-term follow-up study of ingenol mebutate gel for the treatment of actinic keratoses. JAMA Dermatol. 2013;149:666–670. 17 Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol mebutate 0.015% gel 3 weeks after cryosurgery of actinic keratosis: 11-week results. J Drugs Dermatol. 2014;13:154–160. 18 Berman B, Goldenberg G, Hanke CW, et al. Efficacy and safety of ingenol mebutate 0.015% gel after cryosurgery of actinic keratosis: 12-month results. J Drugs Dermatol. 2014;13:741–747. 19 Loven K, Stein L, Furst K, Levy S. Evaluation of the efficacy and tolerability of 0.5% fluorouracil cream and 5% fluorouracil cream applied to each side of the face in patients with actinic keratosis. Clin Ther. 2002;24:990–1000. 20 Smith SR, Morhenn VB, Piacquadio DJ. Bilateral comparison of the efficacy and tolerability of 3% diclofenac sodium gel and 5% 5-fluorouracil cream in the treatment of actinic keratoses of the face and scalp. J Drugs Dermatol. 2006;5:156–159.

12 Krawtchenko N, Roewert-Huber J, Ulrich M, et al. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007;157(suppl 2):34–40.

21 Esmann S, Jemec GB. Patients’ perceptions of topical treatments of actinic keratosis. J Dermatolog Treat. 2014;25:375–379.

13 Stockfleth E, Ferrandiz C, Grob JJ, et al. Development of a treatment algorithm for actinic keratoses: a European Consensus. Eur J Dermatol. 2008;18:651–659.

22 Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169:502–518.

Pogonology

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Volume 14 • Issue 4

Original contribution

First-Line Fixed-Combination Psoriasis Treatment Is Associated With Lower Healthcare Costs Steven R. Feldman, MD, PhD;1 Eugenia Levi, PharmD, BCPS;2 Prathamesh Pathak, BPharm, MS;3 Sonali Kakatkar, BSc, MMS;3 Rajesh Balkrishnan, PhD4 Abstract Treatment of psoriasis is associated with significant healthcare-related costs. A retrospective, observational study was conducted to investigate whether first-line treatment with calcipotriene/betamethasone dipropionate (CBD) fixed-combination topical products would lower the cost impact of psoriasis compared with using the fixed-combination product later in the course of treatment. Patients were classified as being initially treated with CBD combination products (cohort A, n=7307) or other topical psoriasis medications (cohort B, n=9670). We included only patients who, at some point after diagnosis, were prescribed a CBD fixed-combination product. During the 1-year followup, the mean±standard deviation values and number of total office visits and psoriasis-related office visits were significantly lower in cohort A (13.36±14.39; 2.79±7.60) than in cohort B (16.08±16.68; 4.25±10.23) (both P<.0001). Mean total healthcare costs were also significantly lower for cohort A ($7785.80±$15,255.60; median, $3411.30) than for cohort B ($11,757.20±$19,747.60; median, $5595.80) (P<.0001). Compared with other topical psoriasis medications, first-line treatment with CBD fixed-combination topical products was associated with fewer office visits and lower total healthcare costs. (SKINmed. 2016;14:266–272)

soriasis is a chronic inflammatory condition that affects 7.5 million Americans.1 It typically persists in cycles of exacerbation and remission requiring ongoing treat2 ment. Over a patient’s lifetime, these treatment costs can lead to a significant financial burden. A retrospective analysis of a large insurance claims database showed that the average incremental total direct and indirect costs associated with psoriasis were $11.25 billion annually (2006 US dollars), or approximately $1500 per patient per year.1,3

Most patients with psoriasis (80%) have mild to moderate disease. According to treatment guidelines, the majority of these patients can safely and effectively be treated with topical agents, including corticosteroids, vitamin D analogs, retinoids, coal tar, or a combination of these agents.4 An important advantage of vitamin D analogs is their potential to act in a corticosteroid-sparing manner.4 Consistent with this action, a fixed-combination suspension of calcipotriene and betamethasone dipropionate (CBD) is more effective in the treatment of mild to moderate

psoriasis of the trunk and limbs than either of the two components used alone.4,5 Clinicians use various strategies to control localized disease in individual patients. Their choices may be further informed by an understanding of the cost impact of the available therapies. We conducted a retrospective analysis of insurance claims to investigate the effect on healthcare costs of using CBD topical products as first-line therapy in plaque psoriasis, as compared with other first-line therapies. Methods Deidentified health insurance claims from January 1, 2006, to March 31, 2011, drawn from the Thomson Reuters MarketScan databases were used to retrospectively analyze healthcare costs of patients with psoriasis (International Statistical Classification of Diseases and Related Health Problems 9th Revision [ICD-9] diagnosis code 696.1x). All patients included in the analysis were

From the Department of Dermatology, Pathology & Public Health Sciences, Wake Forest Baptist Medical Center, WinstonSalem, NC;1 LEO Pharma Inc, Parsippany, NJ;2 Outcomes Incorporated, Livingston, NJ;3 and the Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA4 Address for Correspondence: Steven R. Feldman, MD, PhD, 4618 Country Club Road, Winston-Salem, NC 27104 • E-mail: sfeldman@wakehealth.edu

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diagnosed between January 1, 2007, and March 31, 2010. The date of the first prescription fill was used as the index date. We included only patients who, at some point after diagnosis, were prescribed a CBD fixed-combination product. Patient cohorts were constructed using a hierarchical approach, whereby patients with at least one prescription for CBD fixedcombination topical products and at least one prescription for any other topical psoriasis medication immediately following diagnosis were eligible to be classified sequentially. Cohort A was selected from eligible patients treated with CBD fixedcombination products immediately postdiagnosis, while cohort B was selected from eligible patients treated with any other topical psoriasis medication immediately postdiagnosis. Patients included in the analysis were enrolled continuously during the 1-year period prior to the index date (preindex period) and for the 1-year period following the index date, for a total of a 2-year assessment period. During the preindex period and prior to the initial psoriasis diagnosis, it was permissible for patients to have been prescribed medications commonly used for the treatment of psoriasis. Patient demographics and clinical characteristics were identified from the database. Demographic variables were defined as of the index date; these included age, sex, geographic region, health plan characteristic, employment status, comorbidities, disease severity, and psoriasis-related outpatient visits. Moderate to severe psoriasis was defined as psoriasis requiring the use of biologics, nonbiologic systemic medications, or phototherapy during the preindex period, at the index date, or both. Psoriasis-related outpatient visits were defined as any outpatient visit with a psoriasis diagnosis (ICD-9 code 696.1x). Total healthcare costs included pharmacy costs and the costs of inpatient and outpatient services. Statistical Analyses Univariate descriptive analyses were conducted to characterize the demographic measures of the study population. Statistically significant differences between cohort A and cohort B were assessed using the chi-square test for categorical variables and using t tests for continuous variables. A critical value of P<.05 was set a priori as indicative of a significant difference between cohorts. Multivariate analyses were conducted to study the association between healthcare costs and receipt of CBD therapy after a first psoriasis diagnosis. Model covariates included baseline demographic characteristics and clinical characteristics. A proxy for psoriasis severity, which was based on the use of biologics, nonSKINmed. 2016;14:266–272

biologic systemic agents, or phototherapy during the preindex period, was included in the model to account for baseline differences between the two cohorts. A generalized linear model with gamma distribution and log transformation was used for modeling cost. Results The overall sample consisted of 16,977 patients who had used CBD fixed-combination products during the study time period. After stratification by topical medication used after the index date, the cohort sizes were 7307 patients (43%) in cohort A and 9670 patients (54%) in cohort B. Both cohorts consisted of approximately 50% men and 50% women. The average age in both groups was 45 years, with approximately 60% of all patients aged 45 to 64 years. The majority of patients in both cohorts were active, full-time employees with healthcare insurance covered by a preferred provider program. Approximately 70% of patients were from the north central and south regions of the country (Table I). Demographically, the cohorts differed significantly with respect to disease severity and number of psoriasis-related outpatient visits during the preindex period (Table I). There were significantly more patients with psoriatic arthritis, diabetes, hypertension, and depression in cohort B than in cohort A. These baseline differences were adjusted for in a generalized linear model (see below). During the 1-year follow-up period, patients in cohort A had significantly fewer overall and psoriasis-related office visits than those in cohort B (13.36±14.39 vs 16.08±16.68; 2.79±7.6 vs 4.25±10.23; P<.0001 for both comparisons). The mean±standard deviation of total healthcare costs during the follow-up period were also lower for cohort A than for cohort B ($7785.8±$15,255.6 vs $11,757.2±$19,747.6; P<.0001) (Table II). The generalized linear regression model identified the covariates that were predictors of total healthcare costs and those that were not (Table III). Costs per patient reflected the entire cohort. In a generalized linear model that adjusted for baseline covariates, cohort A had significantly lower total healthcare costs than cohort B (β±standard error, 0.041±0.017; P=.02), consistent with the previous analysis. Although cohort A had lower total healthcare costs than cohort B, this cohort also had a higher percentage of patients with mild psoriasis than those in cohort B (Table I). Disease severity was among the variables adjusted for in our multivariate model; however, we cannot exclude the possibility that adjustments for disease severity were not fully captured. We thus performed an

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Table I. Demographic Characteristics of Patients Using CBD or Any Other Topical Medication for Psoriasis Immediately Following Diagnosis Variable

Cohort A (n=7307)

Cohort B (n=9670)

P Value

Mean age (SD), y

45.1 (12.7)

45.8 (12.4)

.0005

Age group, %

.0267

<18 y

3.9

3.4

18-34 y

15.6

14.7

35-44 y

22.4

21.5

45-54 y

30.7

31.2

55-64 y

27.4

29.1

Sex, %

.0005

Male

52.6

49.9

Female

47.4

50.1

Northeast

17.1

16.1

North central

29.1

25.9

South

41.8

43.7

West

11.0

13.6

Unknown

1.0

0.7

Geographic region, %

<.0001

Health plan type, %

<.0001

Comprehensive

2.2

2.6

Exclusive provider organization

1.2

Health maintenance organization

12.4

15.4

Preferred provider organization

68.2

64.0

Point of service

9.8

10.3

Point of service with capitation

1.1

1.3

Consumer-driven health plan

2.7

2.8

High-deductible health plan

0.7

0.6

Missing

1.8

1.7

Active full-time

49.2

53.5

Active part-time or seasonal

0.9

Early retiree

6.0

6.8

Retiree (status unknown)

0.9

1.0

Other/unknown

43.0

37.8

Psoriatic arthritis

3.0

8.0

<.0001

Diabetes

8.8

9.9

.0130

Heart disease

4.1

4.5

.1956

Atherosclerosis

0.9

.6714

Peripheral arterial disease

0.5

.9552

Hypertension

21.8

24.0

.0005

Employment status, %

<.0001

Comorbidities, %

Continued SKINmed. 2016;14:266â&#x20AC;&#x201C;272

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Table I. Demographic Characteristics of Patients Using CBD or Any Other Topical Medication for Psoriasis Immediately Following Diagnosis (Continued) Variable

Cohort A (n=7307)

Cohort B (n=9670)

P Value

Cerebrovascular disease

1.5

.7941

Depression

6.8

7.7

.0164

Obesity

2.7

.9544

Comorbidities, % (continued)

Psoriasis severity, %

<.0001

Mild

87.8

61.6

Moderate to severe

12.3

38.4

Psoriasis-related outpatient visits during preindex period, No. Mean (SD)

1.23 (3.96)

3.73 (8.67)

Median

<.0001

Abbreviations: CBD, calcipotriene and betamethasone dipropionate; SD, standard deviation.

Table II. Total Healthcare Costs During the 1-Year Follow-Up Period Variable

Cohort A (n=7307)

Cohort B (n=9670)

P Value

Mean (SD)

13.36 (14.39)

16.08 (16.68)

<.0001

Median

9.00

11.00

Mean (SD)

2.79 (7.60)

4.25 (10.23)

Median

1.00

Mean (SD)

$7785.80 ($15,255.60)

$11,757.20 ($19,747.60)

Median

$3411

$5596

Mean (SD)

$7,088.80 ($14,090.50)

$7,936.20 ($14,829.60)

Median

$3,171.00

$3,816.80

Any office visits, No.

Psoriasis-related office visits, No. <.0001

Total costsa,b <.0001

Total costs, mild patients .0011

Abbreviation: SD, standard deviation. Includes pharmacy cost and cost of inpatient and outpatient services adjusted for 2011 US dollars using medical component of consumer price index. b A small portion of patients had zero costs: cohort A, 0.6%; cohort B, 0.3%. a

exploratory analysis to compare costs among the two cohorts using only patients who had mild psoriasis (no use of systemic agents in the preindex period). Total costs were again found to be lower for cohort A than for cohort B ($7088.8±$14,090 vs $7936.2±$14,829.6; P=.0011) (Table II). SKINmed. 2016;14:266–272

Discussion This retrospective study showed that patients who initiated therapy with CBD fixed-combination topical products as first-line therapy following an initial psoriasis diagnosis had significantly fewer total office visits and psoriasis-related office visits than pa-

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Table III. Regression Model Results for Healthcare Costs Odds Ratio

95% CI

P Value

1.0413

1.0064–1.0775

.0200

18–34 y

1.1995

1.0997–1.3083

<.0001

35–44 y

1.3102

1.2041–1.4257

<.0001

45–54 y

1.4715

1.3542–1.5990

<.0001

55–64 y

1.6349

1.5010–1.7808

<.0001

1.0066

.7969–1.0373

.6681

North central

1.0616

1.0130–1.1125

.0122

West

1.0035

.9612–1.0477

.8750

Unknown

1.0421

.9849–1.1026

.1521

South

.9667

.8190–1.410

.6891

Exclusive provider organization

.8251

.6982–.9750

.0240

Health maintenance organization

.8179

.7349–.9103

.0002

Preferred provider organization

.9212

.8266–1.0266

.1374

Point of service

.8531

.7715–.9433

.0020

Point of service with capitation

.7232

.6124–.8539

.0001

Consumer-driven health plan

.7750

.6779–.8860

.0002

High-deductible health plan

.7565

.6100–.9381

.0110

Missing

.9240

.7957–1.0731

.3003

Active part-time or seasonal

.8419

.7184–.9866

.0333

Early retiree

1.0406

.9731–1.1127

.2440

Medicare-eligible retiree

.9812

.7678–1.2538

.8796

Retiree (status unknown)

1.0489

.9002–1.2221

.5406

COBRA continuee

1.0961

.7954–1.5105

.5748

Long-term disability

1.2036

.8514–1.7014

.2942

Surviving spouse/dependent

.7099

.4753–1.0600

.0939

Other/unknown

.9939

.9615–1.0274

.7192

Psoriatic arthritis

1.2350

1.1568–1.3186

<.0001

Diabetes

1.3059

1.2391–1.3763

<.0001

Heart disease

1.0999

1.0187–1.1875

.0148

Atherosclerosis

.9574

.7481–1.2254

.7297

Peripheral arterial disease

.8448

.6155–1.1597

.2968

Hypertension

1.1110

1.0700–1.1537

<.0001

Cerebrovascular disease

1.0035

.8855–1.1372

.9560

Key independent variable CBD after first diagnosis Age group (reference: <18 y)

Sex (reference: male) Geographic region (reference: northeast)

Plan type (reference comprehensive)

Employment status (reference: active full-time)

Comorbidities (reference: no comorbid disease)

Continued SKINmed. 2016;14:266–272

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Table III. Regression Model Results for Healthcare Costs (Continued) Odds Ratio

95% CI

P Value

Comorbidities (reference: no comorbid disease) (continued) Depression

1.3055

1.2327–1.3827

<.0001

Obesity

1.4045

1.2804–1.5407

<.0001

1.4252

1.3699–1.4827

<.0001

Psoriasis severity (reference: mild)

Abbreviations: CBD, calcipotriene and betamethasone dipropionate; CI, confidence interval; COBRA, Consolidated Omnibus Budget Reconciliation Act.

tients who used CBD topical products only as a later-line treatment. The economic analyses showed that total mean healthcare costs were approximately $4000 lower for patients in the CBD fixed-combination products cohort during the 1-year follow-up period, as compared with patients not treated initially with CBD topical products, even after results were adjusted for differences in baseline covariates. Study Limitations This study has several limitations. Although the use of a retrospective claims-based database allowed us to evaluate a large sample of patients across the United States with psoriasis who used topical medications, we assessed only a limited volume of the data available, and the regional distribution of the database patients did not represent that of the overall US population. It is possible that the approach of comparing patients treated with CBD initially in cohort A with those who received CBD only later in cohort B may have selected for patients who required a treatment change in cohort B, thereby selecting those patients who had more visits and higher costs. In addition, because the study was not randomized and controlled, sample biases may have contributed to the differences observed across the cohorts. For example, the percentage of patients with mild disease was higher in cohort A than in cohort B. Adjustment for disease severity in our multivariate model may not have fully captured the full cost impact associated with disease severity. Exploratory analysis, however, using only patients with mild psoriasis again found that cohort A had lower costs than cohort B, indicating that cost differences between the two cohorts cannot be fully explained by differences in disease severity. Topical combination therapy is commonly used in dermatologic practice to enhance treatment efficacy in patients with psoriasis. Multiple intervention studies support the use of CBD fixed-combination topical therapy in patients with localSKINmed. 2016;14:266–272

ized plaque psoriasis.5,6 In addition, CBD fixed-combination topical products are well tolerated.5-7 In this study, the lower frequency of office visits with CBD fixed-combination topical products could be the result of better treatment efficacy as compared with other topical agents, and use of these agents could provide a means for lower overall treatment costs related to psoriasis. Unfortunately, claims data do not provide a direct measure of psoriasis severity, so this hypothesis could not be directly tested by our approach. Conclusions Topical CBD fixed-combination products offer a once-daily regimen with efficacy and tolerability in the treatment of scalp and body plaque psoriasis. Analysis of a claims-based database found that first-line use of CBD fixed-combination topical products for the treatment of psoriasis was associated with lower healthcare utilization and cost among patients who received CBD at some point during their treatment and a 1-year follow-up period. Acknowledgment Editorial support was provided by Benjamin Dale, PhD, of p-value communications. Disclosures This study was sponsored by LEO Pharma Inc. Dr Feldman received financial support for his involvement as an investigator in this study, is a speaker/consultant, and has conducted research for AbbVie, Amgen, Galderma Laboratories, L.P., and Janssen. Eugenia Levi was an employee of LEO Pharma Inc. at the time of the study. Outcomes Incorporated received financial support from LEO Pharma Inc. for data collection and analysis. Both Prathamesh Pathak and Sonali Kakatkar are employees of Outcomes Incorporated. Rajesh Balkrishnan is a consultant for Outcomes Incorporated.

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References 1 National Psoriasis Foundation. Psoriasis statistics, prevalence, severity, age of onset and psoriasis research. https://www.psoriasis.org/cure_known_statistics. 2015. Accessed May 6, 2015. 2 Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826–850. 3 Fowler JF, Duh MS, Rovba L, et al. The impact of psoriasis on health care costs and patient work loss. J Am Acad Dermatol. 2008;59:772–780. 4 Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic

arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60:643–659. 5 Menter A, Gold LS, Bukhalo M, et al. Calcipotriene plus betamethasone dipropionate topical suspension for the treatment of mild to moderate psoriasis vulgaris on the body: a randomized, double-blind, vehicle-controlled trial. J Drugs Dermatol. 2013;12:92–98. 6 Kragballe K, Noerrelund KL, Lui H, et al. Efficacy of once-daily treatment regimens with calcipotriol/ betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris. Br J Dermatol. 2004;150:1167–1173. 7 Mason AR, Mason J, Cork M, Dooley G, Hancock H. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev. 2014;28:CD005028.

Historical Diagnosis and treatment Diagnosis and treatments have advanced over the past century. This feature depicts conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic Skin Clinic by, Dr S. I. Rainforth.

(Continued on page 294)

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Dermatomyositis––Part 1: Definition, Epidemiology, Etiology and Pathogenesis, and Clinics Marcia Ramos-e-Silva, MD, PhD;1 Ana Paula Frade Lima Pinto, MD;1 Rodrigo Pirmez, MD;1 Tullia Cuzzi, MD, PhD;2 Sueli Coelho da Silva Carneiro, MD, PhD1,3 Abstract Dermatomyositis is an inflammatory autoimmune disorder that affects the skin, muscles, and blood vessels. The prevailing clinical manifestations are intense erythema, typically around the eyes and dorsum of the hands, accompanied by proximal muscle weakness. There is one clinical form, called amyopathic dermatomyositis, which lacks muscular symptoms and laboratory evidence of muscle damage. (SKINmed. 2016;14:273–279)

Etiology and Pathogenesis

virus, human immunodeficiency virus (HIV), and human T-cell lymphotropic virus (HTLV). Nonviral pathogens such as Toxoplasma gondii have been noted4; however, repeated attempts to confirm persistent myotropic viral infection and other agents were unsuccessful.3,4 Drugs described as triggers include D-penicillamine, hydroxyurea, statins, nonsteroidal anti-inflammatory drugs, phenytoin, and alfuzosin. Association with neoplasia in the adult form is well established.

It is believed that dermatomyositis is derived from an autoimmune process triggered by environmental factors in genetically predisposed individuals.

Skin lesions can also be precipitated or exacerbated by exposure to UV light, both UV-A and UV-B radiation, and natural sources.3,4

Individual susceptibility is related to genetic predisposition. This group presents a higher incidence of HLA-B8, HLA-B14, HLA-DR3, HLA-DRw52, and HLA-DQA1 histocompatibility antigens. When drug-induced, it is associated with HLA-B18, HLA-B35, and HLA-DR414 and, in juvenile dermatomyositis, with HLA-B8, HLA-DR3, and HLA-DQA1*0501.4

Dermatomyositis (DM) suggests primary involvement of the microcirculation with secondary ischemic alterations of the muscular fibers. The physiopathologic impact of microcirculatory alterations has been explored by an increasing number of researchers.5 The humoral mechanism of dermatomyositis is the basis of muscular microangiopathy, with CD4+ cells, B cells, immunoglobulin deposits, and complement, differing from polymyositis, in which CD8+ cells act directly against a specific muscular antigen.4 It is believed that the disease begins when antibodies directed against endothelial cells activate the C3 com-

ermatomyositis is the rarest form among collagenoses and there is no accurate study that determines its occurrence. It generally affects adults older than 40 years and children between the ages of 5 and 12 years.1 There is no typical geographical distribution and it is four times more frequent in black women.2 Familial occurrence is rare.3

Among the precipitating factors, infectious agents and drugs have been reported. Viral infections related to the disease include hepatitis B, influenza A, coxsackie 9, picornavirus, echo-

From the Sector of Dermatology and Post-Graduation Course in Dermatology,1 and Sector of Pathology,2 HUCFF/UFRJ and School of Medicine, Federal University of Rio de Janeiro, Brazil; and the Sector of Dermatology, HUPE/UERJ and School of Medicine, University of the State of Rio de Janeiro, Brazil3 Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, Rua Dona Mariana 143/C-32, Botafogo 22280-020, Rio de Janeiro, Brazil • E-mail: ramos.e.silva@dermato.med.br

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plement, which, when activated, leads to the formation of C3b, C4b, and the membrane attack complex fragments. They are detected early in the serum and deposited in the capillaries, leading to necrosis, inflammation, infarction, endofascicular hypoperfusion, and sometimes perifascicular atrophy. The generated hypoperfusion seems to be the cause of capillary arterialization observed in dermatomyositis. Reperfusion of ischemic areas leads to ischemia-reperfusion syndrome, causing additional lesions as a result of oxidative stress. Furthermore, there is evidence that the damage caused by this process is also able to activate the complement’s cascade.5 Muscular injury produces a coordinated cellular reaction. At the beginning, a degranulation of resident mastocytes and release of tumor necrosis factor α (TNF-α) and other previously formed proinflammatory mediators occur. Following, there is an accumulation of neutrophils, which also releases TNF-α. About 8 hours after the injury, monocytes arise, with continuous infiltration of neutrophils and mastocytes. After 24 to 48 hours, macrophages become the main cells in the scenario, remaining for days until their progressive disappearance.5 In juvenile dermatomyositis, the pathogenic process occurs either by vasculopathy, leading to tissue ischemia and necrosis, or by leukocytoclastic vasculitis.6 In addition to the immune response, nonimmune mechanisms, including endoplasmic reticulum response to stress, activation of nuclear factor κB, and autophagy, may take part in the genesis of muscle involvement in dermatomyositis.5

Clinical findings on dermatomyositis and polymyositis have been reported in patients infected with coxsackievirus, parvovirus B19, Epstein-Barr, HIV, and HTLV 1. Clinics

Cutaneous manifestations Cutaneous and muscular symptoms are simultaneously present at the beginning of the clinical picture in 60% of patients with classic dermatomyositis. Manifestations in the skin precede those in muscles in about 30% of cases, while the opposite occurs in 10%.3 Onset of symptoms is usually preceded by general symptoms such as low fever, malaise, headache, asthenia, and arthralgia, as well as a sensation of skin burning and photosensitivity. The pathognomonic signs of dermatomyositis are erythematousviolaceous papules or macules, with or without edema, on the dorsum of the interphalangeal and/or metacarpophalangeal joints, called Gottron papules or Gottron sign (Figures 1 and 2). These can demonstrate a central depression, resulting in an atrophic, whitish appearance, with desquamation and associated telangiectasias. Patella, olecranon, and medial malleolus can also display lesions similar to Gottron sign. Other characteristic clinical findings include edema and violaceous erythema around the eyes, with or without edema of the eyelids (heliotrope) (Figure 3); telangiectasias and periungual erythema, with or without cuticular dystrophy and cuticular bleeding, confluent symmetrical and pruritic macular erythema that can affect the fingers’ extensor surface, forearms, neck, upper chest (shawl sign), central area of the face, shoulders, forehead,

Figure 2. Gottron papules, erythematous papules, and periungual erythema on the hand of a child. (Courtesy of Tania Cestari, MD.)

Figure 1. Gottron papules on the fingers of a teenager. SKINmed. 2016;14:273–279

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Figure 3. Heliotrope: violaceous erythema and edema around the eyes.

Figure 5. Periungual erythema and telangiectasia observed with a dermoscope.

Figure 4. Periungual erythema.

Figure 6. Pruritic macular erythema on the upper chest and part of the shawl sign.

scalp, and lateral regions of hips and thighs; and hyperkeratosis on the ulnar side of the fingers, presenting an aspect similar to a mechanic’s hands (Figures 4–9).

Poikilodermatomyositis consists of round violaceous erythema

Pruritus, which can be very intense, is a clinical symptom that may help in the differential diagnosis with other diseases, especially lupus. Patients also complain of burning and pain in the lesions.3,7

frequently in the upper chest, neck (V sign), buttocks, poste-

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associated with hypopigmentation and hyperpigmentation, telangiectasias, and superficial atrophy and may be seen more rior shoulder, and back (Figure 10). It is an indicator of chronic disease.3

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Figure 9. Erythema and edema on the cheeks and infraorbital area in a young girl. (Courtesy of Tania Cestari, MD.)

Figure 7. Pruritic macular erythema on the neck.

Figure 10. Poikilodermatomyositis: hyperpigmentation and areas of superficial atrophy on the neck, ear, and cheek.

Figure 8. Pruritic macular erythema on the arm. SKINmed. 2016;14:273–279

Skin calcification (calcinosis) is the most characteristic sequel in juvenile DM and occurs in one third of children (Figures 11– 14). The calcification is dystrophic, meaning that it occurs in areas where there is previous tissue injury with normal serum levels of calcium and phosphorus, thus being a secondary phenomenon. Mineralization occurs after muscle damage with calcium release and hydroxyapatite accumulation. Other related factors are the genetic polymorphisms that result in increased expression of proteins involved in bone mineralization, such as osteo-

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Figure 11. Calcinosis on the elbow.

Figure 13. Calcinosis in various fingers (same patient as Figures 12 and 14).

Figure 12. Calcinosis with ulcer on the finger.

Figure 14. X-ray of calcinosis on various fingers (same patient as Figures 12 and 13).

pontin, and TNF 308A promoter gene polymorphism, which determines increase of TNF production by mononuclear cells.6 The most common areas for skin calcification are the elbows, knees, and fingers, although it can affect any part of the body. Four types of clinical features can be described: (1) small nodules or superficial hardened plaques, (2) subcutaneous periarticular nodules (circumscribed calcinosis), (3) larger nodules that extend into deeper tissues such as muscle and fascia (universal calcinosis); and (4) severe calcification of the subcutaneous tissue with exoskeleton patterns. Patients may experience intense pain, ulcers, muscle atrophy, and joint contracture. It usually arises in patients 1 to 3 years after onset of the disease, although there SKINmed. 2016;14:273â&#x20AC;&#x201C;279

are reports of occurrences 50 years after diagnosis. Some studies have associated the late diagnosis and beginning of treatment, as well as corticosteroid doses lower than 2 mg/kg/d, with the higher incidence of calcinosis.8 Rare findings include noncicatricial alopecia, vesicles and bullae, erythroderma, and livedo reticularis. Linear erythematous lesions on the trunk and extremities are known as flagellate dermatitis and are related to the development of the disease. Panniculitis is a rare presentation of dermatomyositis. Patients may present with indurated erythematous nodules or plaques, sometimes followed by ulceration.9

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Ulcers, which indicate bad prognosis, are due to leukocytoclastic vasculitis, and intense atrophy can also be seen over areas of secondary poikiloderma.3 Muscular manifestations Muscular symptoms typically arise as progressive proximal muscle weakness with slow evolution from weeks to months. Patients report muscle pain and difficulty in performing daily activities such as climbing stairs, getting up from a chair, combing hair, and lifting objects. Facial musculature is not affected, although there may be impairment of respiratory and pharyngeal muscles leading to conduction dysphagia and respiratory symptoms. The distal muscles are later affected, entailing impairment of fine movements, such as buttoning shirts and writing, among others. If these symptoms are observed in the beginning of the disease, other myopathies must be considered.10 Esophageal involvement occurs in 15% to 50% of patients. It appears in the form of high dysphagia and reflects the weakness of the striated muscles of the pharynx or proximal esophagus. It correlates with the disease activity and generally shows good response to corticosteroids; however, it is a sign of severe disease with bad prognostics.11 The amyopathic form is defined by a dermatomyositis compatible skin biopsy without clinical and laboratory evidence of muscular involvement for 6 months or more. Some patients present with subclinical myositis detected by magnetic resonance imaging or histopathology. These patients are classified as having hypomyopathic dermatomyositis. Pulmonary manifestations In general, any muscular inflammatory disease may involve the lungs in the form of interstitial lung disease (ILD).12 Approximately 35% to 40% of all DM patients present with pulmonary symptoms during the course of the disease.7 Pulmonary disease causes deterioration of quality of life and tends to follow an independent course, even if the muscular and cutaneous manifestations respond positively to treatment.12 The pathogenic mechanism is not well understood. There are indications that the process begins with a cellular inflammatory reaction that progresses to an irreversible proliferation of fibrous tissue. Other potentially related factors are viral infections (coxsackie, influenza, echovirus, HIV, HTLV, parvovirus B19), which serve as triggers for the inflammatory response.12 It is known that the positivity of antisynthetase antibodies indicates greater risk for developing lung disease. SKINmed. 2016;14:273â&#x20AC;&#x201C;279

There are no differences between the symptoms of ILD that accompany DM and those from other etiologies. Dyspnea, dry cough, fatigue, and intolerance to physical exercise are the most common complaints. Digital clubbing may occur in later stages. Pulmonary manifestations may precede muscular symptoms in a few cases and may present as acute, subacute, or chronic. Patients with amyopathic dermatomyositis tend to develop acute pulmonary disease with poor response to treatment.13 It is necessary to distinguish whether pulmonary complaints are the result of the involvement of respiratory muscles or of the lung parenchyma itself through imaging examinations (high-resolution computed tomography) and respiratory function tests. Infiltrates mocking dull glass, pulmonary nodules, alveolar honeycombing, and bronchiectasis may be observed under traction, in accordance with the extension of the process. Results from respiratory function tests show a restrictive pattern with reduced diffusing capacity and may be used to monitor the treatment.12 Arthritis Nonerosive arthritis in the knees, elbows, wrists, and small joints of the hands can be seen in 20% to 65% of juvenile dermatomyositis cases, and may be a prominent symptom.7 Cardiovascular manifestations Cardiac involvement in DM is rare but can be considered a fatal cause. Subclinical involvement is more common than the clinically manifested heart disease. Conduction abnormalities, such as atrioventricular blockage, prolongation of the PR interval, and ventricular extrasystoles, are most frequently found. Myocarditis, congestive heart failure, and coronary artery disease may also occur less frequently. It is believed that cardiovascular manifestations are caused by the inflammation of muscular fibers and subsequent fibrosis, either of the cardiomyocytes and the conduction system nerve fibers. It is recommended that patients undergo at least one electrocardiogram for screening cardiac involvement. The manifestations do not seem to follow the disease activity and can occur even with adequate immunosuppressive therapy.14 Conclusions Although not as common as the other collagenoses, DM affects individuals over 40 years of age and between 5 and 12 years of age, sometimes causing very severe disabilities in these groups. A correct clinical diagnosis at the beginning of the disease will permit a laboratory investigation and early treatment, improving the prognosis and minimizing the sequels which are often incapacitating.

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References 1 Duarte AA. Dermatomiosite. In: Ramos-e-Silva M, Castro MCR. eds. Fundamentos de Dermatologia. Rio de Janeiro: Atheneu; 2010:1287–1291. 2 Carneiro SC. Dermatomiosite. In: Azulay D, Azulay R. Dermatologia. 5th ed. Rio de Janeiro: Guanabara Koogan; 2008:494–496. 3 Sontheimer RD, Costner MI. Dermatomyositis. In: Wolff K, Goldsmith LA, Katz S, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGrawHill; 2007:1536–1552. 4 Ortigosa LC, Reis VM. Dermatomyositis. An Bras Dermatol. 2008;83:247–259. 5 Gherardi RK. Pathogenic aspects of dermatomyositis, polymyositis and overlap myositis. Presse Med. 2011;40(4 pt 2):e209–e218.

8 Tugnet N, Rees DH. Calcinosis in juvenile dermatomyositis. Postgrad Med J. 2010;86:510. 9 Carneiro S, Alvim G, Resende P, et al. Dermatomyositis with panniculitis. Skinmed. 2007;6:46–47. 10 Khan S, Christopher-Stine L. Polymyositis, dermatomyositis, and autoimmune necrotizing myopathy: clinical features. Rheum Dis Clin North Am. 2011;37:143– 158. 11 Callen JP, Wortmann RL. Dermatomyositis. Clin Dermatol. 2006;24:363–373. 12 Connors GR, Christopher-Stine L, Oddis CV, Danoff SK. Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest. 2010;138:1464– 1474.

6 Rosa Neto NS, Goldenstein-Schainberg C. Juvenile dermatomyositis: review and update of the pathogenesis and treatment. Rev Bras Reumatol. 2010;50:299–312.

13 Mukae H, Ishimoto H, Sakamoto N, et al. Clinical differences between interstitial lung disease associated with clinically amyopathic dermatomyositis and classic dermatomyositis. Chest. 2009;136:1341–1347.

7 Sontheimer RD. Dermatomyositis: an overview of recent progress with emphasis on dermatologic aspects. Dermatol Clin. 2002;20:387–408.

14 Lundberg E. The heart in dermatomyositis and polymyositis. Rheumatology (Oxford). 2006;45 suppl 4:iv18– iv21.

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question choose the single best lettered response, unless directed otherwise. 1. Of the collagenoses (i.e., collagen diseases; collagen vascular diseases; connective tissue diseases), the least common is: a. Combined connective tissue disease. b. Dermatomyositis. c. Lupus erythematosus. d. Rheumatoid arthritis. e. Scleroderma. 2. Dermatomyositis: a. Generally affects adults over forty years of age. b. Generally affects children between the ages of 2 and 5 years. c. Generally spares Black females. d. Is more common in Brazil and other Portuguese speaking countries. e. Has a familial occurrence in Brazil and other Portuguese speaking countries.

Cardiac involvement in dermatomyositis: Is common in children with early onset disease. Is most commonly due to conduction anomalies. Is most commonly due to congestive heart failure. Is most commonly due to coronary artery disease. Is most commonly due to myocarditis.

5. Signs associated with dermatomyositis include: (Choose as many as apply; all, some, or none of the choices may be correct.) a. The Gottron papule(s) (Gottron sign). b. The heliotrope sign. c. The shawl sign. d. The V sign. e. The raccoon sign seen following a proctoscopic examination.

ANSWERS TO EXAMINATION: 1. b, 2. a, 3. b, 4. b, 5. a, b, c, d

3. In adults, dermatomyositis myopathy suggests (that): a. Amyotrophic dermatomyositis is present. b. Primary involvement of the microcirculation with secondary ischemia of the muscle fibers. c. Primary involvement of the muscle fibers with secondary ischemia of the microcirculation. d. Primary involvement of both the microcirculation and the muscle fibers together. e. Primary involvement of the kinin system with secondary involvement of the microcirculation and secondary ischemia of the muscle fibers.

4. a. b. c. d. e.

From the Departments of Pathology and Dermatology, Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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Core curriculum Virendra N. Sehgal, MD, Section Editor

Footwear Dermatitis: Diagnosis and Management—Part III Virendra N. Sehgal, MD;1 Farhan Rasool, MD;1 Govind Srivastava, MD;1 Ashok Aggarwal, MD;1 Taru Dutt, MD;1 Prashant Verma, MD2 Footwear dermatitis is an entity with clear clinical features, and the confirmation of its diagnosis is vital. The authors review several tools used for its diagnosis to facilitate appropriate and timely management. (SKINmed. 2016;14:281–286)

ootwear dermatitis is a time-old entity that was relegated to the background for many years. Its revival, therefore, is considered relevant to comprehend the various facets of the disorder, which have been discussed in parts I and II of this three-part series.1,2 Accordingly, we define the tools used to establish its etiology and ultimately alleviate its symptoms and signs through appropriate management. Diagnosis Diagnosis of footwear dermatitis involves a detailed history, examination, and patch testing to identify the offending allergens. History taking is an important step towards diagnosis. It is used to enquire in detail about the types of footwear used by the patient and duration of their use. Exacerbation of dermatitis coinciding with the wearing of shoes and remission induced by the removing of the shoes favor the clinical diagnosis of contact allergy.3,4 A history of recurrence of dermatitis is often noted in the summer and rainy seasons.5,6 It is often helpful to inquire about use of any topical medications on the feet as they may cause sensitization.7,8 The pattern of dermatitis that corresponds with footwear, characteristic morphology, and relative sparing of insoles and interdigital space suggest footwear allergy.

Patch testing is a well-established procedure for the diagnosis of contact allergic dermatitis.9 If used properly, it can be of great value both in the diagnosis and management of contact dermatitis.10 With patch testing, the contact sensitivity to suspected allergens is elicited by exposure to the allergens under controlled conditions.10 During the past few decades, much effort has been put into standardization of allergens, vehicles, concentrations, patch test materials, tapes, and scoring of test reactions, with the method considered reliable and accurate.11 A series of studies have demonstrated good reproducibility of patch testing.12–14 Special types of units are available for patch testing such as the Al-test, Finn Chambers, and thin-layer rapid-use epicutaneous (TRUE) test.15

Al-test patch The Al-test patch consists of a cellulose disc, fastened onto a polythene-coated aluminum backing, available in rolls.10 The allergens used can either be aqueous- or petroleum-based. The patches are fixed with adhesive tape to the skin. The disadvantage of the Al-test unit is that a relatively small number of patches can be applied at one time because of the large size of these patches.10

Finn Chambers The Finn Chambers patch is made of stiff aluminum and has a diameter of 80 mm and a depth of 0.5 mm mounted on a scan-

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India, Skin Institute, and the School of Dermatology, Greater Kailash, New Delhi;1 and the Department of Dermatology and STD, University College of Medical Sciences, University of Delhi and Associated GTB Hospital, Delhi, India2 Address for Correspondence: Virendra N. Sehgal, MD, Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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por tape.10 Petroleum-based allergens are applied onto the disc (~15 µl) and liquid-based allergens are applied with the help of a filter paper on the disc.15 The advantage of these chambers is the tight apposition to the skin, which localizes the reaction to the test site and allows the use of porous hypoallergenic tape. The above test methods are perceived to be time-consuming, and their accuracy is adequate only in the hands of dermatologists trained in patch testing.16

TRUE test The True test is a ready-to-use patch test system and represents a new generation of patch test.16,17 In this system, allergens are incorporated in hydrophilic gels, coated on waterimpermeable sheet of polyester, and dried to a thin film. The gel occluded with plastic ensures optimal contact with the skin, and subsequent permeation enables high allergen bioavailability. The advantage of the TRUE test system is offers consistent panel-to-panel quality and stability, which ensures reproducibility of the test. Consistent location of each test in the panel also ensures correct identification of the allergens. The disadvantage of this test is that it is available only as a standard series of 24 allergens.16 The back is the most preferred site of application as both allergic and irritant reactions are most easily provoked on the upper back, possibly because of additional effects of pressure on the back18 and stronger percutaneous absorption.19 The patches should be removed after 48 hours and readings should be observed 1 hour after removal.20 A single secondday reading may not only lead to labeling of some marginal irritants as allergens but poorly absorbed allergens may also be missed.21 Therefore, all patients should be evaluated for delayed reactions on the seventh day.22 If only one reading is possible, then reading on the fourth day is optimal.23 Interpretation of results requires experience and expertise and it is often not possible to distinguish between allergic and irritant reactions on clinical grounds alone20; however, no infiltration, lack of itching, and a sharp delineation corresponding to the margin of the test patch points to an irritant reaction. Some irritants provoke a “soap effect,” a spot of red, brownish, or normalcolored skin with a glistening finely wrinkled surface.9,20 Patch test with metals may provoke a papular or pustular reaction, especially in patients with atopic dermatitis.24 Difficulties in evaluation are particularly common with substances brought in by the patient for testing.25 Reactions of an allergic nature are erythematous and commonly infiltrated with minute papules or vesicles, which, in severe reSKINmed. 2016;14:281–286

actions, may coalesce into bullae. The infiltration causes a thickening in the dermis that is palpable and can be distinguished from surface changes in the epidermis.20 The reaction may extend beyond the margin of the patch test and there is usually some itching. Once they have developed, positive allergic reactions persist for several days.9 The strength of the reaction depends on various factors such as barrier function of the epidermis, the presence or absence of sweating, the atmospheric humidity, test materials employed, proper technique, and reactivity of the individual.15 Grading may be performed according to the following criteria of the International Contact Dermatitis Research Group: • Doubtful reactions (+/–) • Weak positive reaction (+) • Strong positive reaction (++) • Extreme positive reaction (+++) • Irritant reaction Fisher and Rystedt 24 found that doubtful reactions were relevant in 1% to 5%, 1+ were relevant in 20%, 2+ were relevant in 80% to 90%, and 3+ were relevant in 95% to 100% of cases. Rietschel25 proposed that nonpapulovesicular patch test reactions consisting of slightly palpable erythema and edema be called Janus or double-faced reactions, and stated that these reactions may or may not be relevant. Mitchell26,27 used the term angry back to describe a regional phenomenon caused by the presence of a strongly positive reaction, a state of hyperreactivity in which other patch test sites become reactive, especially marginal irritants. Calnan28 used the term status eczematous to describe the same phenomenon. Mitchell and Maibach29 broadened the term angry back to excited skin syndrome, suggesting entire skin hyperactivity, not just the back. This phenomenon was extensively studied by researchers who noted an increase in the number of positive reactions of challenges in close proximity to strong reactions, wherein 44.3% of these reactions were lost on retesting.30 Investigators31 noted that skin which is repeatedly inflamed or is extensively involved in dermatitis often becomes hyperactive; however, other investigators32 did not find any such reactions while patch testing nickel-sensitive patients. These reactions are often nonreproducible, suggesting a false-positive result. Causes of false-positive reactions may be caused by excessive concentration of the test substance, impure substance (contaminants), irritant vehicles, excess allergen applied, uneven dispersion, current or recent dermatitis at patch test site, current dermatitis at

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distant sites, pressure effect of hard materials, adhesive tape reactions, or “angry back” reaction.20,25 A negative result, however, does not exclude the possibility of contact dermatitis. 25 Standard screening series include only statistically common allergens and it is possible that the patient may be sensitive to certain rare or new sensitizers. Reasons for false-negative reactions may be inadequate concentration of the test substance, inappropriate vehicle or degradation of the patch test substance, poor adhesion of patches, brief duration of contact, failure to perform delayed readings, and influence of topical or systemic corticosteroids.20,33

Patch test allergens for shoe dermatitis Patch testing with standard screening series may detect up to 80% of cases of footwear dermatitis caused by different allergens.34 Adding shoe allergens in the series will increase the yield.5,6,35 The following is a list of relevant antigens associated with footwear dermatitis. Leather chemicals Potassium dichromate Formaldehyde Glutaraldehyde Rubber chemicals 2-Mercaptobenzothiazole Mercapto mix Thiuram mix Black rubber mix Dibutylthiourea Diphenylguanidine N-Cyclohexyl-2-benzothiazyl sulfenamide Plastics Hydroquinone monobenzylether Dioctyl phthalate Dyes 4-Phenyldiamine base 4-Aminobenzene Glues Para-tertiary butylphenol Colophony Dodecyl mercaptan Metals Nickel sulphate Cobalt chloride SKINmed. 2016;14:281–286

Management and Prevention of Footwear Dermatitis

Therapeutic measures Treatment of acute episodes of footwear dermatitis does not differ from treatment of contact dermatitis on other parts of the body.36,60 Wet compresses with Burow’s solution, application of steroid-containing lotions and creams, oral antihistamines, and occasional short courses of systemic steroids are usually effective.36 Systemic antibiotics may need to be administered for secondary bacterial infection. Chronic lichenified dermatitis is best treated by application of steroid-containing creams under thin plastic film occlusion at night.37 Patient empowerment through education to assist in avoidance of the implicated allergens and the type of footwear causing the dermatitis is the primary goal and the cornerstone of management.6,7,38,39 Avoidance of these allergens, however, is often difficult to implement, which ultimately results in presentation of shoe dermatitis.7 Once a diagnosis of footwear dermatitis has been confirmed, management goals include alleviation of pruritus and treating the inflammation. Treatment should begin by applying moist compresses to enhance the drying of welllocalized, acute weeping lesions.37 Cool moist soaks applied for 5 to 10 minutes, followed by air drying may significantly reduce drainage from the affected foot.37 Moisturizing emollients have been prescribed to treat shoe dermatitis, providing both occlusion and humectance.37 The occlusive effects of emollients provides a sealant layer on the surface of the skin to reduce water loss. On the other hand, the humectant effect is one of increasing the “water-holding capacity” of the stratum corneum and therefore increasing skin hydration. The prescribing and application of topical steroids is a medical standard of care in the treatment of shoe dermatitis.40 Corticosteroids are known to interfere with inflammatory response. Once the selection of a topical corticosteroid agent is considered, the clinician must decide on the most appropriate delivery system. Thus, the choice of vehicle in a topical formulation is important.41 An advantage of using creams or oil-in-water emulsions is that they are absorbable and may facilitate drying of oozing.40 Water-miscible creams may be more appropriate for moist or weeping lesions. An ointment is a water-in-oil emulsion and is considered to be the most effective hydrating agent.37 Ointments are the most effective vehicle for treating thick, fissured, lichenified, and dry, scaly eruptions.36 Gels are most effective when applied to hairy areas.40 Although topical corticosteroids are well tolerated for short-term use, long-term widespread use can result in adverse effects grouped into four

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categories: cutaneous changes, cutaneous infections and infestations, eye effects, and systemic effects.40 Therefore, alternative therapeutic interventions for treating shoe dermatitis may be considered. Topical immune modulators have been investigated as a treatment option for inflammatory skin disorders.41 Both tacrolimus ointment and pimecrolimus cream act by inhibiting the protein calcineurin, which subsequently prevents the dephosphorylation of the nuclear factor of activated transcription factor.41 This causes signal transduction pathways to be blocked and inflammatory cytokine production inhibition. These agents should be considered when conventional therapies have failed.41 Systemic therapy may be reserved for severe and chronic allergic contact shoe dermatitis. Systemic treatment may include the use of the following oral agents: H1 antihistamines, systemic corticosteroids, azathioprine, methotrexate, and mycophenolate mofetil.37 Oral antihistamines have an effect on severe pruritus by competing with free antihistamines for binding H1 receptor sites. The most common antihistamines used to treat allergic contact dermatitis include cetirizine, hydroxyzine, diphenhydramine, chlorpheniramine, and loratadine. Systemic corticosteroid therapy has demonstrated high efficacy in the treatment of acute allergic dermatitis by dramatically improving skin inflammation; however, it also causes the same adverse effects as topical steroids. In an attempt to avoid adverse effects from repeated dosing of corticosteroids in patients with chronic dermatitis, steroid-sparing systemic immunosuppressant therapy has been investigated.37,40

Preventive Measures The foremost part of treatment of shoe dermatitis is the avoidance of the sensitizer (allergen) once it is known. The dermatologist can offer expertise in footwear by providing education to their patients regarding the selection of footwear without materials that may cause shoe dermatitis. Substitute products made of different materials that do not cause allergic reaction may lessen the likelihood of future episodes of shoe dermatitis. Investigators42 treated a 54-year-old man, a sugar refinery worker experiencing severe and incapacitating dermatitis of both feet caused by protective rubber boots, by recommending a protective polyvinyl chloride work boot along with a heavy-duty sock to absorb sweat and reduce friction inside the boot. Within 3 weeks it was noted that the dermatitis had completely resolved and there was no recurrence during the follow-up period of 6 months.

shoe dermatitis can use special types of shoes prepared from nonsensitizing substances.44–46 For adults and older adolescents, hypoallergic shoes made of vegetable-tanned leather or that contain no rubber or formaldehyde can be offered.44 The use of hypoallergic shoes is limited by the fact that they must be made to order and take 6 to 8 weeks for delivery. Moreover, the price of these shoes is higher than that for ordinary footwear. Measures to control sweating may also be helpful for the patients who have shoe dermatitis.47 Medicated powders such as tannic acid powder administered either once or twice a day can help control foot perspiration and may prevent shoe dermatitis.48 Changing socks two or three times a day and wearing different shoes for work and home may prove beneficial in preventing footwear dermatitis.47 Investigators49 described successful treatment of allergic contact dermatitis in a 50-year-old construction worker with “barrier socks.” They reported an improvement in their patient’s quality of life as well as a comparative reduction in costs. These findings were further validated by a more recent study50 in which the therapeutic efficacy of allergen-proof fabric socks (a three-layer fabric designed to provide a physical barrier to allergens and irritants as well as high perspirability) in patients who were sensitized to shoe allergens was demonstrated. Good clinical results showing improvement in symptoms and recovery from foot eczema after 2 months of treatment was remarkable. The best results were observed in patients (6 of 9 patients) who followed the protocol strictly, wearing the socks every time they wore shoes. Finally, a light application of a steroid-containing aerosol spray each morning is also beneficial.50 References

Therapeutic goals can be achieved by offering an educational initiative to patients to avoid redyed shoes.5,7,39,43 Patients with SKINmed. 2016;14:281–286

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1 Sehgal VN, Rasool F, Srivastava G, Aggarwal A, Verma P. Footwear dermatitis: pathogenesis—part I. Skinmed. 2012;10:291–297. 2 Sehgal VN, Rasool F, Srivastava G, Aggarwal A, Verma P. Footwear dermatitis: historical background, epidemiology, clinical connotation—part II. Skinmed. 2014;12:360–364. 3 Shatin H, Reisch M. Dermatitis of the feet due to shoes. AMA Arch Derm Syphilol. 1954;69:651–666. 4 Fisher AA. Some practical aspects of the diagnosis and management of shoe dermatitis. AMA Arch Derm. 1959;79:267–274. 5 Saha M, Srinivas CR, Shenoy SD, et al. Footwear dermatitis. Contact Dermatitis. 1993;28:260–264. 6 Rani Z, Hussain I, Haroon TS. Common allergens in shoe dermatitis: our experience in Lahore, Pakistan. Int J Dermatol. 2003;42:605–607. 7 Priya KS, Kamath G, Martis J, et al. Foot eczema: the role of patch test in determining the causative agent using standard series. Indian J Dermatol. 2008;53:68–69.

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core curriculum 26 Mitchell JC. The angry back syndrome: eczema creates eczema. Contact Dermatitis. 1975;1:193–194.

8 Rietschel RL, Fowler JF Jr. Textile and shoe dermatitis. In: Rietschel RL, Fowler JF Jr, eds. Fisher’s Contact Dermatitis. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:305–319.

27 Mitchell JC. Multiple concomitant positive patch test reactions. Contact Dermatitis. 1977;3:315–320.

9 Wahlberg JC. Patch testing. In: Rycroft RJG, Menne T, Frosch PJ, Benezera C, eds. Textbook of Contact Dermatitis. 2nd ed. Berlin, Germany: Springer Verlag; 1995:241–267.

28 Calnan CD. The use and abuse of patch tests. In: Maibach HI, ed. Occupational and Industrial Dermatology. 2nd ed. Chicago, IL: Yearbook Medical Publishers; 1982:28–31.

10 Adams RM. Patch testing—a recapitulation. J Am Acad Dermatol. 1981;5:629–640.

29 Mitchell JC, Maibach HI. The angry back syndrome: the excited back syndrome. Semin Dermatol. 1982;1:9.

11 Fisher TI, Hansen J, Kieilgard B, et al. The science of patch test standardization. In: Maibach HI, ed. Immunology and Allergy Clinics of North America (Urticaria and the Exogenous Dermatoses). Philadelphia, PA: W.B. Saunders Company; 1989:417–433.

30 Bruynzeel DP, Nieboer C, Boorsma DM, Scheper RJ, van Ketel WG. Allergic reactions “spillover” reactions, and T-cell subsets. Arch Dermatol Res. 1983;275:80–85.

12 Belsito DV, Storrs FJ, Taylor JS, et al. Reproducibility of patch tests: a United States multicenter study. Am J Contact Dermat. 1992;3:193–200. 13 Breit R, Agathos M. Quality control in epicutaneous testing—reproducibility in the right-left comparison. Hautarzt. 1992;43:417–421. 14 Bousema MT, Geursen AM, van Joost T. High reproducibility of patch tests. J Am Acad Dermatol. 1991;24:322– 323. 15 Fischer T. The art of patch testing. Contact Dermatitis. 1990;23:221–223. 16 Fischer TI, Maibach HI. The thin layer rapid use epicutanoeus test (TRUE-test), a new patch test method with high accuracy. Br J Dermatol. 1985;112:63–68.

31 Kligman AM, Epstein W. Updating the maximization test for identifying contact allergens. Contact Dermatitis. 1975;1:231–239. 32 Andersen KE, Lidén C, Hansen J, Vølund A. Dose-response testing with nickel sulphate using the TRUE test in nickel-sensitive individuals. Multiple nickel sulphate patch-test reactions do not cause an “angry back”. Br J Dermatol. 1993;129:50–56. 33 Bruynzeel DP. Contact dermatitis research groups. In: Frosch PJ, Menne T, Lepoittevin JP, eds. Contact Dermatitis. 4th ed. Berlin, Germany: Springer Verlag; 2006:903–906. 34 Lazzarini R, Duarte I, Marzagao C. Contact dermatitis of the feet. A study of 53 cases. Dermatitis. 2004;15:125– 130.

17 Fischer T, Maibach HI. Easier patch testing with TRUE test. J Am Acad Dermatol. 1989;20:447–453.

35 Olumide Y. Contact dermatitis in Nigeria. (IV). Dermatitis of the feet. Contact Dermatitis. 1987;17:142– 145.

18 Magnusson B, Hersle K. Patch test methods. II. Regional variations of patch test responses. Acta Derm Venereol. 1965;45:257–261.

36 Cohen DE, Heidary N. Treatment of irritant and allergic contact dermatitis. Dermatol Ther. 2004;17:334– 340.

19 Cronin E, Stoughton RB. Percutaneous absorption. Regional variations and the effect of hydration and epidermal stripping. Br J Dermatol. 1962;74:265–272.

37 Jacob SE, Castanedo-Tardan MP. Pharmacotherapy for allergic contact dermatitis. Expert Opin Pharmacother. 2007;8:2757–2774.

20 Beck MH, Wilkinson SM. Contact dermatitis. In: Burns T, Breathnach S, Cox N, Griffith C, eds. Rook’s Textbook of Dermatology. 7th ed. Oxford, England: Blackwell Science Ltd; 2004:20.1–20.124.

38 Smith RG. Shoe dermatitis: a practical guide for the pedorthist. Curr Pedorthics. 2007;39:6–12.

21 Rietschel RL, Adams RM, Maibach HI, Storrs FJ, Rosenthal LE. The case of patch test reading beyond day 2. Notes from the lost and found department. J Am Acad Dermatol. 1988;18:42–45. 22 Mitchell JC. Day 7 (D7) patch test reading valuable or not? Contact Dermatitis. 1978;4:139–141. 23 Macfarlane AW, Curley RK, Graham RM, Lewis-Jones MS, King CM. Delayed patch test reactions at day 7 and 9. Contact Dermatitis. 1989;20:127–132. 24 Fischer T, Rystedt I. False-positive, follicular and irritant patch test reactions to metal salts. Contact Dermatitis. 1985;12:93–98. 25 Practical aspects of patch testing. In: Rietschel RL, Joseph FF, eds. Fisher’s Contact Dermatitis. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:1–7.

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39 Nardelli A, Taveirne M, Drieghe J, et al. The relation between the localization of foot dermatitis and the causative allergens in shoes: a 13-year retrospective study. Contact Dermatitis. 2005;53:201–206. 40 Smith RG. A review of topical corticosteroids. Podiatry Manage. 2006;25:207–216. 41 Bornhövd E, Burgdorf WH, Wollenberg A. Macrolactam immunomodulators for topical treatment of inflammatory skin diseases. J Am Acad Dermatol. 2001;45:736– 743. 42 Mathias CG, Maibach HI. Polyvinyl chloride work boots in the management of shoe dermatitis in industrial workers. Contact Dermatitis. 1979;5:249–250. 43 Handa S, Sharma SC, Sharma VK, Kaur S. Footwear dermatitis: clinical patterns and contact allergens. Indian J Dermatol Venereol Leprol. 1991;57:174–177. 44 Fisher AA. Allergen replacements in allergic dermatitis. Int J Dermatol. 1977;16:319–328.

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45 Srinivas CR, Sundaram VS, Selvaraj K. Reducing the allergenic hexavalent chromium in leather to hypoallergenic trivalent chromium for prevention of leather dermatitis. Indian J Dermatol Venereol Leprol. 2007;73:428–429. 46 Nishioka K, Murata M, Ishikawa T, Kaniwa M. Contact dermatitis due to rubber boots worn by Japanese farmers, with special attention to 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline (ETMDQ) sensitivity. Contact Dermatitis. 1996;35:241–245. 47 Adams RM. Shoe dermatitis. Calif Med. 1972;117:12– 16.

48 Fisher AA. Prevention of shoe dermatitis by controlling hyperhidrosis with tannic acid. Cutis. 1973;12:493– 494. 49 Borghesan F, Bellotti M. Use of new “barrier socks” in contact allergic dermatitis. Eur Ann Allergy Clin Immunol. 2007;39:202–203. 50 Corazza M, Baldo F, Ricci M, Sarno O, Virgili A. Efficacy of new barrier socks in the treatment of foot allergic contact dermatitis. Acta Derm Venereol. 2011;91:68– 69.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2016;14:281–286

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HISTORICAL VIGNETTE Charles Steffan, MD, Section Editor

Fowler’s Solution and the Evolution of the Use of Arsenic in Modern Medicine Derek Ho, BS;1 Eve J. Lowenstein, MD, PhD1,2

While arsenic has been used medicinally and as a poison for thousands of years, Fowler’s solution, an arsenic compound, has had a fascinating history in medicine during the past 200 years. The use of Fowler’s solution was first described and published as a treatment for malaria and syphilis in the late 1700s. Many clinical applications for Fowler’s solutions have been studied and utilized over the years, but toxicities have limited its utility. Even so, arsenic trioxide, chemically related to Fowler’s solution, was approved by the US Food and Drug Administration for treating acute promyelocytic leukemia. The history of Fowler’s solution, its applications and uses, and benefits and risks are discussed. (SKINmed. 2016;14:287–289)

he use of arsenic has a long history in medicine and its roots stem from our founding fathers in medicine. It has been documented that Hippocrates used realgar (As2S2) as a remedy for ulcers and Dioscorides used orpiment (As2S3) as a depilatory.1 During the Middle Ages, arsenic was often used as a homicidal and suicidal agent. It was referred to as “king of poisons” and the “poison of kings” because of its strong potency and frequent use to eliminate members of the ruling class.2 Arsenic remained a popular poison for many years and for many reasons. It was readily available, odorless, and undetectable in food and beverages. Many visible symptoms of acute arsenic poisoning including nausea, vomiting, diarrhea, and abdominal pain could easily be confused with other common diseases at the time, such as cholera and pneumonia. There was also no reliable analytical method for detecting or measuring arsenic until 1832, when chemist James Marsh developed a test that allowed for the detection of arsenic and prosecution of murderers who used this agent.3 To this day, arsenic is still used as a poison. For example, a recent arsenic poisoning incident occurred in 2003 at a church meeting in Maine where arsenic was detected in coffee.4 Dr Thomas Fowler, a graduate of Edinburgh University in the United Kingdom, first published his formula in the Medical Reports on the Effects of Arsenic in 1786. Fowler’s solution, a 1% potassium arsenic solution KH2AsO3, was designed as an im-

proved drug after studying the patented medicine known as “Tasteless Ague and Fever Drop” created by Thomas Wilson in 1771.5 Fowler’s solution is an oral solution introduced to treat ague (fever), malaria, chorea, and syphilis. Local farmers began using Fowler’s solution on livestock to improve skin texture and prevent parasite infestations.6 Fowler’s solution gained wider acceptance in 1809 as it made its first appearance in the London Pharmacopoeia. It was widely used for the next 100 years as one of the only effective treatments against infections, critical at a time in Europe when syphilis and African Sleeping Sickness were a concern. By 1911, medical textbooks worldwide described Fowler’s solution as a cure-all for improving chorea, Hodgkin disease, asthma, psoriasis, general metabolism, oxygen uptake by tissues, and blood counts in anemic patients. Arsenic’s use was further popularized by Dr Paul Ehrlich, a Nobel laureate, physician, and founder of chemotherapy who introduced Salvarsan (an organoarsenic compound) in 1910 for the treatment of syphilis and trypanosomiasis.7 It was referred to as the “magic bullet” for syphilis and was used until penicillin became prevalent in the 1940s; however, this “magical” drug had a high prevalence of adverse effects. The US Navy published a report in 1947 after administering more than 2.5 million doses of arsenic to its soldiers for syphilis, with more than 1300 unwanted adverse reactions reported in the same 21-year time period.8

From the Department of Dermatology, SUNY Health Science Center,1 and Brookdale University Hospital,2 Brooklyn, NY Address for Correspondence: Eve J. Lowenstein, MD, PhD, Department of Dermatology, SUNY Downstate Medical Center, 8th Floor, 450 Clarkson Avenue, Box 46, Brooklyn, NY 11230 • E-mail: evlow13@yahoo.com

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Worrisome Toxicities Because of arsenic’s naturally poisonous properties, its usage was debated and physicians across the globe slowly moved away from prescribing Fowler’s solution. In the 1940 edition of The Pharmacological Basis of Therapeutics, arsenic was described as a “protoplasmic poison but with some limited medical uses.”9 Its usage for psoriasis continued throughout the first half of the 20th century, however, and even made another appearance for asthma treatment in the 1950s.10 Dr Gay from Mississippi formulated a recipe from combining Fowler’s solution with other drugs and achieved positive results with asthma patients.11 Although it was promising for some time, it quickly fell out of favor because of its cutaneous carcinogenicity. Fowler’s solution continued to be included in the 1960 edition of Wintrobe’s Hematology and the 1970 edition of Britain’s Pharmacopoeia.12 Its listing continued through 1989’s 11th edition of the Merck Index, which advocated Fowler’s solution as a treatment for psoriasis and severe asthma.13 During the past 100 years, the toxicities of arsenic have been proven, with hepatotoxicity and carcinogenicity primarily limiting its utility. In a 1990 case series involving patients with noncirrhotic portal hypertension, eight of 47 patients had intake arsenic from Fowler’s solution for treating psoriasis. Arsenic poisoning may cause vasculopathy to the intrahepatic portal venules and obliterate circulation.14 Angiosarcoma of the liver has been reported after chronic intake (15 years) of Fowler’s solution.15 The use of Fowler’s solution and chronic arsenic intoxication are also known to result in squamous cell carcinomas of the skin, as well as cutaneous markers of chronic arsenicism such as confetti-like hypopigmentation and Mee’s lines of the nails.16,17 The documented latency for the carcinogenicity of arsenic has been reported to be anywhere between 13 to 22 years, contributing to the delayed recognition of this relationship. New Hopes for Leukemia Patients

Currently, because of its toxic nature, arsenic is under heavy government regulation since its approval by the FDA for treating leukemia; however, arsenic is still available for purchase over the Internet for research purposes. For example, chemical companies such as Sigma-Aldrich sells 125 g of As2O3 for $309.5.30 In addition, common household rat poisons contain arsenic, although poisoning from it is less prevalent as a result of the addition of denatonium, which makes the poison taste bitter. Fowler’s solution is no longer recommended for treating psoriasis, as safer and more effective treatments are available. An online search for Fowler’s solution today no longer promotes it as beneficial in the treatment of psoriasis. Conclusions

A modified variant of Fowler’s solution is still in use today as a therapeutic modality in the management of leukemia. Arsenic in low doses is antiproliferative but not myelosuppressive as are conventional cytotoxic chemotherapeutic agents. Arsenic induces apoptosis and partial cytodifferentiation of leukemia cells and inhibits angiogenesis.18 In 1865, Dr Abraham Lissauer from Germany published the first successful treatment for chronic myelogenous leukemia (CML) with Fowler’s solution for improving anemia, splenomegaly, and leukocytosis.19 In 1931, 66 years after Lissauer’s findings, Dr Claude Forkner also reported sustained control of white blood cell counts, anemia, and splenomegaly in CML20; however, in 1937, Dr KanSKINmed. 2016;14:287–289

del reported chronic arsenic poisoning in five of six patients treated for CML using Fowler’s solution.21 A decline in arsenic usage for treating CML immediately followed and did not pick up again until 1996, when a series of papers demonstrated the efficacy, pharmacokinetics, and mechanism of arsenic trioxide for acute promyelocytic leukemia (APL).22 Soon after, Soignet carried out a similar set of procedures in the United States.23 Twelve patients with relapsed APL responded to intravenous arsenic trioxide supplied from China. Despite the fact that the drug had already been registered in China, a patent application for this drug was filed in the United States.24,25 The US Food and Drug Administration officially approved arsenic trioxide injectable drug for the treatment of relapsed or refractory APL in 2000.26 Since all the original work was performed in China, production and supply of intravenous arsenic trioxide continued manufacture in Harbin, Beijing, and Taipei. A few years later, oral arsenic trioxide for APL was approved, as it was shown to be safer and required less dosage per treatment.27 The oral formula was also cheaper, more convenient for patients, and could be used with outpatients on a prolonged basis.28 In a 2010 study, arsenic trioxide performed better than chemotherapy alone for postremission therapy.29

Arsenic continues to haunt us in the modern day with reports of population poisonings through well water contamination in South America and India. Deadly at high concentrations, but highly effective in myelogenous leukemia, and after centuries of use and abuse, this chemical continues to draw the attention of the medical community. Fowler’s solution has played a major role in the history of arsenic medicaments. References

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1 Goodman L. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996.

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2 Vahidnia A, van der Voet GB, de Wolff FA. Arsenic neurotoxicity—a review. Toxicol. 2007;26:823–832. 3 Marsh J. Separation of 1837;II:307–314.

arsenic. Am J Pharmacy.

4 Zernike K. Arsenic Case Is Considered Homicide, Maine Police Say. The New York Times. 2003. 5 Cullen W. Is Arsenic an Aphrodisiac?: The Sociochemistry of an Element. Cambridge, England: RSC Publishing; 2008. 6 Au WY. A biography of arsenic and medicine in Hong Kong and China. Hong Kong Med J. 2011;17:507–513. 7 Aronson SM. Arsenic and old myths. R I Med. 1994;77:233–234. 8 Burton OL, Justyn GW, Anderson LT. Toxic effects of arsenical compounds as employed in the treatment of syphilis in the United States Navy 1945. US Nav Med Bull. 1947;47:180–197. 9 Goodman L, Gilman, A. The Pharmacological Basis of Therapeutics. Vol 11. New York, NY: McGraw-Hill; 2006. 10 Whorton JC. The Arsenic Century: How Victorian Britain was Poisoned at Home, Work, and Play. Oxford, England: Oxford University Press; 2010. 11 Gay FS, Gay ED. The Gay treatment of asthma. Miss Doct. 1951;29:142–144. 12 Scheindlin S. The duplicitous nature of inorganic arsenic. Mol Interv. 2005;5:60–64. 13 Budavari S. The Merck Index. 11th ed. Arsenic trioxide. Kenilworth, NJ: Merck & Co., Inc; 1989. 14 Nevens F, Fevery J, Van Steenbergen W, et al. Arsenic and non-cirrhotic portal hypertension. A report of eight cases. J Hepatol. 1990;11:80–85. 15 Lander JJ, Stanley RJ, Sumner HW, Boswell DC, Aach RD. Angiosarcoma of the liver associated with Fowler’s solution (potassium arsenite). Gastroenterology. 1975;68:1582–1586. 16 Jackson R, Grainge JW. Arsenic and cancer. Can Med Assoc J. 1975;113:396–401. 17 Cuzick J, Evans S, Gillman M, Price Evans DA. Medicinal arsenic and internal malignancies. Br J Cancer. 1982;45:904–911.

18 Waxman S, Anderson KC. History of the development of arsenic derivatives in cancer therapy. Oncologist. 2001;6 suppl 2:3–10. 19 Lissauer A. Zwei Falle von Leucaemie. Berl kiln Wochenschr. 1865;2:403–404. 20 Forkner C, Scott, MT. Arsenic as a therapeutic agent in chronic myelogenous leukemia. JAMA. 1931;97:3–5. 21 Kandel E, Leroy G. Chronic arsenical poisoning during the treatment of chronic myeloid leukemia. Arch Intern Med. 1937;60:846–866. 22 Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–3360. 23 Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341– 1348. 24 Cyranoski D. Arsenic patent keeps drug for rare cancer out of reach of many. Nat Med. 2007;13:1005. 25 Warrell RP Jr. Reply to ‘Arsenic patent keeps drug for rare cancer out of reach for many’. Nat Med. 2007;13:1278. 26 Antman KH. Introduction: the history of arsenic trioxide in cancer therapy. Oncologist. 2001;6 suppl 2:1–2. 27 Siu CW, Au WY, Yung C, et al. Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety. Blood. 2006;108:103–106. 28 Firkin F. Oral administration of arsenic trioxide in the treatment of acute promyelocytic leukaemia and accelerated phase chronic myeloid leukaemia: an Australian single-centre study. Intern Med J. 2012;42:948–952. 29 Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751– 3757. 30 Arsenic(III) oxide, ACS reagent (primary standard). As2O3. Sigma-Aldrich. 2016; http://www.sigmaaldrich.com/ catalog/product/sial/311383?lang=en&region=US. Accessed August 22, 2016.

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Hydrate Your Way to Healthy Skin

Hydrate. Nourish. Restore. Repair.

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July/August 2016

Volume 14 • Issue 4

New Therapy Update William Abramovits, MD; Aditya K. Gupta, MD, PhD, FRCPC, Section Editors

Adalimumab (Humira®) for Hidradenitis Suppurativa Aditya K. Gupta, MD, PhD, FRCPC;1,2 Maria Cernea, PhD;2 William Abramovits, MD;3–5 Kimberly Dawn Vincent, MD6

idradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by red, swollen nodules, sinuses, and fistulas, most often involving such intertriginous regions as the axillae, upper portion of the thighs, inframammary folds, and intergluteal area.1 Tunnels can form between the painful nodules, which progressively expand to abscesses and subsequently rupture, causing suppuration.1 Histologically, HS presents with initial follicular occlusion, which may result in perifolliculitis, infundibulum rupture, nodule and abscess development, scarring, and formation of sinus tracts.2 Treatment options for this debilitating disease offer unsatisfactory results or are off-label therapies. HS has a large negative impact on patients’ quality of life.3,4 For these reasons, new treatment options for HS are needed. Adalimumab (Humira®; AbbVie Inc, North Chicago, IL) is an anti-inflammatory medication that inhibits tumor necrosis factor α.5 The FDA approved adalimumab for treatment of HS in September 2015.5,6 Phase II Studies In a prospective, randomized, double-blind, placebo-controlled study of adalimumab (a subcutaneous [SC] dose of 80 mg at baseline followed by 40 mg every other week [QOW] for 12 weeks), participants with HS experienced significant improvement in HS severity after 6 weeks of treatment (P=.024); however, this effect did not last the entirety of the treatment period (12 weeks).7,8 Adalimumab was generally well tolerated, with a greater proportion of participants experiencing adverse events (AEs) in the adalimumab group compared with the placebo group with regard to mild infections (67% vs 17%, P=.063).8 In a phase II,

randomized, double-blind, placebo-controlled study of 154 participants, 17.6% of participants dosed every week (QW; 40 mg, SC), 9.6% of participants dosed every other week (40 mg, SC), and 3.9% of participants in the placebo group achieved clinical response (an HS Physician’s Global Assessment score of clear, minimal, or mild with at least a two-grade improvement relative to baseline) at week 16.9 AEs were experienced by 71% of participants receiving adalimumab QW, 64% of participants receiving adalimumab QOW, and 59% of participants receiving placebo. Injection site reactions were common in both adalimumab- and placebo-treated patients (20% and 14%, respectively) and headache was a frequently reported AE.9 The results from two phase III clinical trials evaluating the safety and efficacy of adalimumab in the treatment of moderate to severe HS have recently been published and are summarized below. Phase III Trials

PIONEER I trial (NCT01468207) A phase III randomized, double-blind study was undertaken to evaluate the efficacy and safety of adalimumab in the treatment of moderate to severe HS.10 The study was divided into two treatment periods (Figure 1). During period 1, participants were assigned to receive placebo (QW for 12 weeks; n=152) or adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg QW from week 4 to 12; n=153). During period 2, participants who received placebo during the initial treatment period were assigned to receive adalimumab (40 mg QW; n=145) from week 12 to 35, while participants who received adalimumab during the initial treatment period were re-randomized to receive either

From the Department of Medicine, University of Toronto School of Medicine, Department of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc., London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center, Dallas, TX;3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School, Dallas, TX;4 the Dermatology Treatment and Research Center, Dallas, TX;5 and Belle Meade Dermatology, Nashville, TN6 Address for Correspondence: Aditya K. Gupta, MD, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Primary and Secondary Efficacy Outcomes for Adalimumab Phase III Clinical Trials (at Week 12) PIONEER I10

PIONEER II11

Adalimumab

Placebo

P Value

Adalimumab

Placebo

P Value

41.8%

26.0%

.003

58.9%

27.6%

<.001

Participants with baseline Hurley stage II who achieved abscess and AN counts of 0, 1, or 2

28.9%

28.6%

51.8%

32.2%

.01

Participants achieving at least 30% reduction and at least 1 unit reduction from baseline in NRS30 (in participants with baseline skin pain ≥3)

27.9%

24.8%

45.7%

20.7%

<.001

Change from baseline in modified Sartorius scorea

–24.4

–15.7

–28.9

–9.5

<.001

Primary outcome Participants achieving HiSCR response Secondary outcomes

Abbreviations: AN, inflammatory nodule; HiSCR, hidradenitis suppurativa clinical response; NS, not significant; NRS30, Patient’s Global Assessment of Skin Pain (range from 0 [no skin pain] to 10 [severe skin pain]. a Modified Sartorius Score: used to quantify severity of hidradenitis suppurativa in 12 body areas, with points awarded for nodules (2 points), abscesses (4 points), fistulas (4 points), scars (1 point), other findings (1 point), and longest distance between two lesions (2–6 points).

placebo (n=49), adalimumab (40 mg QW; n=48), or adalimumab every other week (40 mg QOW; n=48) from week 12 to 35. The mean age of the patients was 37 years, with women comprising 64% of the participants. The primary outcome measure was the percentage of participants achieving HS clinical response (HiSCR) at week 12. This response was defined as at least a 50% reduction in abscess and inflammation nodule (AN) count with no increase in abscess count or draining fistula count at week 12 relative to baseline. Data are presented by baseline Hurley stage (stage I: single or multiple abscess formation without sinus tracts or scarring; stage II: one or more discrete recurrent abscesses with sinus tract formation and scarring; and stage III: multiple, diffuse interconnected sinus tracts and abscesses). At week 12, significantly more patients in the adalimumab group achieved HiSCR response compared with participants in the placebo group (41.8% vs 26%, P=.003; Table I). There was no significant difference between the placebo and adalimumab groups in the secondary efficacy measure outcomes at week 12 (Table I). The frequency of AEs and serious AEs are shown in Table II. The most common AEs were nasopharyngitis and upper respiratory tract infection. The study was discontinued by one patient (n=154) in the placebo group and no patients (n=153) in the adalimumab group during the initial treatment period. A total of six patients (n=145) in the placebo/adalimumab QW group, SKINmed. 2016;14:291–294

one patient (n=49) in the adalimumab QW/placebo group, two patients (n=48) in the adalimumab QW/adalimumab QOW group, and one patient (n=48) in the adalimumab QW/adalimumab QW group discontinued the study as a result of AEs.

PIONEER II trial (NCT01468233) A phase III randomized, double-blind study was undertaken to evaluate the efficacy and safety of adalimumab in the treatment of HS.11 The study was divided into two treatment periods (Figure 1). During period 1, participants were assigned to receive placebo (QW for 12 weeks; n=163) or adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg QW from week 4 to 12; n=163). During period 2, participants who received adalimumab during the initial treatment period were re-randomized to receive placebo (n=51), adalimumab (40 mg QW n=51), or adalimumab (40 mg QOW; n=53), from week 12 to 35. Patients who received placebo during the initial treatment period continued to receive placebo during the second period (n=151). The mean age of the patients was 35.5 years, with women comprising 68% of the overall participants. At week 12, the percentage of patients achieving the primary outcome of HiSCR response was significantly higher in the adalimumab group compared with the placebo group (58.9% vs 27.6%, P<.001; Table I). For secondary measure outcomes, significantly more patients in the adalimumab group with baseline Hurley stage II achieved an AN

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Table II. Percentage of Patients in Phase III Clinical Trials Reporting AEs and Serious AEs10,11 Period 1

Period 2

Placebo

ADA

Placebo/ Placebo

Placebo/ADA QW

ADA QW/ Placebo

ADA QW/ ADA QW

ADA QW/ ADA QOW

PIONEER I

53.3

41.8

46.9

61.2

50.0

58.3

PIONEER II

47.2

40.5

31.8

52.9

47.2

41.2

PIONEER I

3.3

2.0

3.5

4.1

6.25

2.1

PIONEER II

3.7

1.8

4.6

0.0

3.77

3.92

AEs

Serious AEs

Abbreviations: ADA, adalimumab; AE, adverse event; QOW, every other week; QW, every week.

Figure. Timeline for adalimumab (Ad.) studies (PIONEER I and II). Ew indicates every week; eow, every other week.

count of 0, 1, or 2, a 30% reduction and at least 1 unit reduction from baseline in NRS30, and had a significant change from baseline to week 12 in the modified Sartorius score (Table I). The frequency of AEs and serious AEs are shown in Table II. The most common AEs were nasopharyngitis and upper respiratory tract infection. The study was discontinued by five patients (n=163) in the placebo group and three patients (n=163) in the adalimumab group during the initial treatment period. A total of three patients (n=151) in the placebo group, no patients (n=51) in the adalimumab QW/placebo group, two patients (n=53) in the adalimumab QW/adalimumab QOW group, and one patient (n=51) in the adalimumab QW/adalimumab QW group discontinued the study as result of AEs. SKINmed. 2016;14:291â&#x20AC;&#x201C;294

Conclusions Limited treatment options of systemic antimicrobials, retinoids, and surgical approaches, including abscess drainage, laser, and cryosurgery have had suboptimal efficacies for HS; however, recent results from phase II and III studies indicate adalimumab to be a safe and effective treatment option for HS. Compared with placebo, 12 weeks of adalimumab treatment significantly diminishes the pain and associated symptoms of HS, nodule count, and abscesses, with only mild to moderate AEs. Adalimumab appears to be an effective new treatment to reduce symptoms and complications associated with HS. When to discontinue its use for a given patient remains unclear. Although HS is not a common condition, it is one that requires more awareness and future research into therapeutic options.

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References 1 Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012;366:158–164. 2 von Laffert M, Helmbold P, Wohlrab J, et al. Hidradenitis suppurativa (acne inversa): early inflammatory events at terminal follicles and at interfollicular epidermis. Exp Dermatol. 2010;19:533–537. 3 Wolkenstein P, Loundou A, Barrau K, Auquier P, Revuz J; Quality of Life Group of the French Society of Dermatology. Quality of life impairment in hidradenitis suppurativa: a study of 61 cases. J Am Acad Dermatol. 2007;56:621–623. 4 Matusiak L, Bieniek A, Szepietowski JC. Hidradenitis suppurativa markedly decreases quality of life and professional activity. J Am Acad Dermatol. 2010;62:706– 708, 708.e1. 5 Haslund P, Lee RA, Jemec GB. Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors. Acta Derm Venereol. 2009;89:595–600. 6 Harde V, Mrowietz U. Treatment of severe recalcitrant hidradenitis suppurativa with adalimumab. J Dtsch Dermatol Ges. 2009;7:139–141.

7 Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002;301:418–426. 8 Miller I, Lynggaard CD, Lophaven S, et al. A double-blind placebo-controlled randomized trial of adalimumab in the treatment of hidradenitis suppurativa. Br J Dermatol. 2011;165:391–398. 9 Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med. 2012;157:846–855. 10 Clinical Trials (NCT01468207). A Phase 3 Multicenter Study of the Safety and Efficacy of Adalimumab in Subjects With Moderate to Severe Hidradenitis Suppurativa—PIONEER I. 2015. https://clinicaltrials.gov/ct2/ show/study/NCT01468207?term=NCT01468207&rank =1&sect=X543a987016. Accessed June 16, 2016. 11 Clinical Trials (NCT01468233). A Phase 3 Multicenter Study of the Safety and Efficacy of Adalimumab in Subjects With Moderate to Severe Hidradenitis Suppurativa—PIONEER II. 2015. https://clinicaltrials.gov/ct2/ show/study/NCT01468233?term=NCT01468233&ra nk=1. Accessed June 16, 2016.

Historical Diagnosis and treatment: epithelioma

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Volume 14 • Issue 4

The Heymann File Warren R. Heymann, MD, Section Editor

A Birthday Wish in the Era of “Value-Based” Healthcare Warren R. Heymann, MD

am blessed that my 95-year-old mother is in reasonable health with a keen intellect. She’s a prolific reader, politically engaged, and still independent in mind, body, and spirit.

She has fought medical ageism on several occasions. At age 88, after her granddaughter’s graduation from George Washington University, she fell and fractured several cervical vertebrae. She had the good fortune of doing so in front of the GWU Medical Center, home of an expert group of spinal orthopedists. They preferred that she wear a head brace rather than have surgery at her age. She said “I’d rather be dead than live with that contraption. Do the surgery.” She convalesced quickly. At 90, she perforated her bowel secondary to Clostridium difficile, necessitating a colostomy. “When does this get reversed?” she asked the surgeon. Upon learning that colostomies are not usually reversed in nonagenarians, she demanded that the surgeon perform the procedure. “I’ll be damned to live with this bag—no way!” Again, she survived beautifully, and we are all looking forward to celebrating her 95th birthday next week. My mother doesn’t have a death wish—she just wants to live her life as she sees fit. As dermatologists, we frequently confront management decisions for elderly patients, arguably mostly regarding nonmelanoma skin cancers. “Dr Heymann, what would you do if it were your mother?” is a common question. I tell patients that they should be asking me another question first: “Do you love your mother?” My response to that question might alter my recommendation! Then I tell them that, yes, of course I love my mother, and I am fortunate that she can make her own medical decisions, based on the facts.

Options for Treating BCC Using basal cell carcinomas (BCCs) as a paradigm, I suggest reading the excellent article by Wiznia and Federman,1 which explores treatment options for BCCs in the elderly. Their key points are: (1) treatment options may be considered based on tumor characteristics. A morpheaform BCC near the eye would be approached very differently than a superficial BCC of the arm; (2) there is a wide range of therapeutic options, including standard surgery, Mohs surgery, destructive modalities such as electrodessication and curettage or cryosurgery, topical chemotherapy with imiquimod or 5FU, hedgehog inhibitors including vismodegib (or sonidegib), photodynamic therapy, or radiation; and (3) observation may be a reasonable option based on the BCC type, location, and life expectancy of the patient.1 I applaud the author’s conclusion that “given the wide range of therapeutic options for basal cell carcinoma, treatments can be tailored to achieve patients’ goals of care within their anticipated life expectancy.”1 Deciding on Appropriate Practices As America grays, medicine is under pressure to develop best practices to reflect outcomes, costs, and “value.” Variability in how practitioners manage disease may affect cost and outcomes. According to Soni and colleagues:2 Variation in clinical practice is substantial and is associated with poorer health outcomes, increased costs, and disparities in care. Substantial attention has been given to

From the Division of Dermatology, Departments of Medicine and Pediatrics, Cooper Medical School of Rowan University, Marlton, NJ Address for Correspondence: Warren R. Heymann, MD, Division of Dermatology, Departments of Medicine and Pediatrics, Cooper Medical School of Rowan University, Departments of Medicine and Pediatrics, Division of Dermatology, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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reducing unnecessary differences in practice patterns. Despite these efforts, practice variation has been difficult to overcome. Challenges to reducing variation include heterogeneity and gaps in clinicians’ knowledge; economic incentives for undesired clinical behaviors; concerns about malpractice risk; physicians’ value of autonomy and personal preference; inadequate communication and decision support tools; and imbalances between clinical demand and resource capacity. Another fundamental barrier to practice standardization is that good clinical practice must sometimes vary to reflect a patient’s specific social, environmental, and biological situation. Sometimes a standard practice would not be best for a given patient. Hence, efforts to legislate or establish policies governing care have been limited because they impede the common sense that there are nearly always exceptions to a given rule.

copy. A forthcoming evaluation of outcomes and costs will assess the success of the program. Intellectually, I concur with the need for evidence and appropriate algorithms to provide optimal care to the largest population possible. Emotionally, as a physician who sees one patient at a time, my Pavlovian reflex is to shudder at the concept of the loss of decision-making ability. When is the last time you were pleased to complete a prior authorization for a drug or imaging study? Would my mother have been able to have her spinal surgery or her colostomy reversed based on EP criteria? If not, would she have been able to appeal those decisions? The Birthday Wish

The authors detail their experience setting up “expected practices” (EPs) in the Los Angeles Department of Health Services, which they describe as being “resource-limited” and having a predominance of Medicaid patients. Twenty-five specialty-primary care work groups were established to define the EPs. They state: “The term ‘expected practice’ is used because it is expected that physicians and other health care professionals will follow this standard approach except in rare cases with a compelling justification to deviate based on a specific patient’s clinical situation.”

Here is a birthday wish for my mother (and all of us)—may we face the coming heathcare challenges with intelligence, grace, and compassion. Let us learn to make the best decisions for all populations, with ultimate respect and appropriate decisions for the individual. I love you, Mom! References

More than 120 EPs were established on topics ranging from rheumatoid arthritis, hepatitis C, and indications for colonos-

1 Wiznia LE, Federman DG. Treatment of basal cell carcinoma in the elderly: what nondermatologists need to know. Am J Med. 2016;129:655–660. 2 Soni SM, Giboney P, Yee HF Jr. Development and implementation of expected practices to reduce inappropriate variations in clinical practice. JAMA. 2016;315:2163– 2164.

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Volume 14 • Issue 4

Cosmetic Surgery Capsule

7th Annual Cosmetic Surgery Forum 2015 December 2–5, 2015, Las Vegas, NV

ver the past 7 years, Cosmetic Surgery Forum has been privileged to sponsor over 400 residents to attend and present papers on subjects pertaining to both cosmetic and medical dermatology. We are delighted to offer the top seven papers of the 2015 conference below. The topics range from surgical innovations to new uses of cosmeceuticals.

with sirolimus and vincristine produced an excellent response. Consensus treatment of KH utilizes vincristine, although sirolimus has also shown efficacy. Improved function and aesthetics are attainable goals.

We especially appreciate the collaboration with our partner, SKINmed, and its editorial team.

Sanja Galeb, MD;1 Nicole Langelier, MD, MBE;2 Julie A. Woodward, MD2

Cosmetic Surgery Forum Course Director—Joel Schlessinger, MD

Department of Internal Medicine, Duke University Medical Center,1 and the Department of Oculoplastic, Reconstructive, and Aesthetic Surgery, Duke Eye Center,2 Durham, NC

Severe Case of Kaposiform Hemangioendothelioma in a Newborn

Amy M. Cherof, MD; Sophie D. Liao, MD The University of Colorado School of Medicine, Denver, CO

Who is Performing My Procedure?

1-day-old girl presented with a severe vascular lesion of the face and neck with a violaceous hue and firm edema. Magnetic resonance imaging revealed an extensive infiltrative venous anomaly of the head, neck, and face, consistent with kaposiform hemangioendothelioma (KH). The baby also had Kasabach-Merritt phenomenon, circulatory overload, and a critical airway. She was treated with intravenous methylprednisolone with minimal response; however, further treatment

inimally invasive cosmetic procedures can have devastating complications. Unfortunately, regulation of medical spas varies by state and often do not have clear rules on patient safety issues. Our study, which evaluated the transparency of medical spas and business oversight in North Carolina, revealed that the majority of medical spas are directed by physicians who have not completed formal training in cosmetic surgery or dermatology. In addition, a large portion of state-registered corporations are not active corporations monitored by the North Carolina Medical Board. Oversight should involve physicians, who can actively address this rapidly expanding market. An Analysis of Pre- and Post-Operative Photography in Facial Aesthetic Surgery Morgan R. Godin, MD; Landon C. Meekins, MD; Betsy Colon-Acevedo, MD; Tanya T. Khan, MD; Julie A. Woodward, MD

Duke University Eye Center Oculoplastic and Reconstructive Surgery, Durham, NC

tandardized photography should be an integral part of valuating postoperative results. In part 1, three Internet searches for “blepharoplasty before and after,” “face lift before and

Address for Correspondence: Joel Schlessinger, MD, Skin Specialists, 2802 Oak View Drive Suite 100 Omaha, NE 68144 • E-mail: skindoc@lovelyskin.com

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after,” and “laser resurfacing before and after” were conducted to identify 300 sets of images from physician websites. In part 2, 107 sets of images from laser company websites were obtained. All images were graded for standardization of flash and position (including angle and magnification). Results showed that 51.3% of images on physician websites failed at least one component of analysis (flash or position), and images from laser company websites had a 35% fail rate for at least one component.

Mycobacterium chelonae, a rapid-growing nontuberculous mycobacteria (NTM). NTM organisms are found in the environment and rarely complicate cosmetic procedures, including fillers, neuromodulators, laser resurfacing, tattoos, liposuction, and pedicures. Patients often require prolonged antimicrobials to clear these indolent infections, and, in this case, 5 months of linezolid and azithromycin combination therapy was required. When routine therapy fails to stop an infection, tissue cultures of postprocedure lesions are indicated. New Nevi Secondary to Afamelanotide Dennis P. Kim, MD; Brandon Coakley, MD; Anne Marie McNeil, MD From the Department of Dermatology, University of California at Irvine College of Medicine, Irvine, CA

Blepharoplasty and Laser Resurfacing Complicated by Nontuberculous Mycobacterial Infection Jolene R. Jewell, MD; Julie A. Woodward, MD Department of Dermatology, Duke University School of Medicine, Durham, NC

healthy woman underwent bilateral blepharoplasty and lower lid CO2 laser resurfacing. An erythematous papular eruption developed postoperatively, which was refractory to routine antimicrobial therapy. Tissue culture revealed

SKINmed. 2016;14:297–299

74-year-old woman presented to our outpatient clinic for skin cancer screening. Ten months ago, she had used afamelanotide, an injectable tanning agent, purchased through the Internet. She noted an increase in generalized, homogenous pigmentation, along with a dark spot near the injection site. Histopathologic study revealed a lentiginous junctional nevus. Melanocyte-stimulating hormone (MSH) analogs, such as afamelanotide, can complicate the presentation and diagnosis of pigmented lesions. There have been reports of MSH analog– associated eruptive nevi and melanomas, although a causal relationship has not been established.

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Cosmetic Surgery Capsule

Evaluating the Effectiveness and Tolerability of Oral Polypodium Leucotomos in Patients With Melasma

The Buried Hybrid Mattress for Crescentic Defects Wesley Wu, MD;1 Arianne Chavez-Frazier, MD;2 Tri Nguyen, MD3

Lucy Martin, MD; Alexis Stephens, DO; Caroline Caperton, MD; Nidhi Avashi, MD; Heather Woolery-Lloyd, MD

University of Florida College of Medicine, Fort Lauderdale, FL

elasma has a significant impact on health-related quality of life. Polypodium leucotomos (PL) is an antioxidant used in oral form to provide systemic photoprotection and may benefit patients with melasma. Twenty-one healthy patients with epidermal melasma were randomized to receive either oral PL or placebo twice daily plus sunscreen for 12 weeks. Improvement was measured with Melasma Area and Severity Index (MASI) scores and the Melasma Quality of Life Scale (MELASQOL) in participants taking oral PL. The PL group had significantly improved MASI scores (5.7 to 3.3; P<.05), and MELASQOL parameters improved in 59% of PL patients. PL is well-tolerated and effective in patients with melasma and can be utilized as adjunctive treatment.

Department of Dermatology, Baylor College of Medicine,1 the University of Texas Health Science Center,2 and Texas Surgical Dermatology,3 Houston, TX

rescentic defects are wounds of uneven lengths that frequently co-occur in dermatologic surgery. We describe a hybrid buried horizontal and vertical mattress to reduce wound length discrepancy. On the longer wound edge, a buried suture is placed horizontally deep in the dermis. On the shorter side, the throw is oriented vertically and is positioned at the midpoint of the opposing horizontal suture. The edges are approximated after the suture is tied and buried. This technique brings together wound edges of different lengths while eliminating the need for standing cone excision.

Horizontal suture

Vertical suture

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Volume 14 • Issue 4

PHOTO CAPSULE

Multiple Nonhealing Furuncles in a Traveler Returned From Belize Lina Naga, MD; Danielle Baruch, MD; Grace Kao, MD

Figure 1. Erythematous, firm nodule with a central punctum and hemorrhagic crust on the right hand of our patient.

35-year-old man presented with four nonhealing insect bites 2 weeks following his honeymoon in Belize. He had acquired numerous bug bites that subsequently cleared, leaving four residual lesions that were progressively enlarging and becoming more painful. He had received 1 week of oral doxycycline from his primary care physician without improvement. He denied fever or chills. Physical examination revealed three erythematous, firm nodules each with a central punctum and hemorrhagic crust on the scalp and one on the right hand (Figure 1). Given his recent travel to an area endemic for human botflies, cutaneous myiasis was suspected. A 6-mm dermal punch was used to excise the skin over the punctum of each nodule, and a botfly larva was exposed and removed from each site (Figure 2). Sutures were placed to repair the defects, and the lesions resolved without complications. Dermatobia hominis is the most common cause of cutaneous myiasis diagnosed in travelers returning to the United States.1 Patients infested with D hominis present with an erythematous nodule with a central aperture and symptoms of pain, pruritus, a sensation of movement, and serosanguinous discharge.2 Diagnosis is primarily clinical and requires a high index of suspicion and particular attention to travel history. References 1 Safdar N, Young DK, Andes D. Autochthonous furuncular myiasis in the United States: case report and literature review. Clin Infect Dis. 2003;26:e73–e80.

Figure 2. Expulsion of botfly larvae after dermal punch on the scalp of our patient.

2 Hohenstein EJ, Buechner SA. Cutaneous myiasis due to Dermatobia hominis. Dermatology. 2004;208:268–270.

From the Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD Address for Correspondence: Danielle Baruch, MD, Department of Dermatology, University of Maryland School of Medicine, 1901 South Charles Street, #230, Baltimore, MD 21230 • E-mail: dpsbaruch@gmail.com

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July/August 2016

Volume 14 • Issue 4

CASE STUDY Vesna Petronic-Rosic, MD, MSc, Section Editor

Adult Manifestation of Henoch-Schönlein Purpura Daria Marley Kemp, MD, MEd;1 James Studdiford, MD;2 Katie Osley, MD;1 Joya Sahu, MD1

A 51-year-old man initially presented to the hospital with a 2-week history of constipation, intermittently diffuse abdominal pain, nausea, vomiting, and productive cough. Results from chest x-ray and obstruction series appreciated a right lower lobe opacity and small right pleural effusion. The patient met sepsis criteria and was empirically covered for community-acquired pneumonia with vancomycin, piperacillin-tazobactam, moxifloxacin, and tobramycin. His hospital course was complicated by oliguria, acute kidney injury with a normal renal ultrasound, and transaminitis with a negative hepatitis panel. After clinical improvement, he was discharged on 2 additional days of levofloxacin to complete a 7-day antibiotic course. (SKINmed. 2016;14:303–306)

our days after discharge, the patient developed a pruritic eruption on his lower extremities. Two days later, he again presented to the hospital with symptoms of volume overload and a worsening dermatitis. The patient admitted poor compliance with his heart failure medications. Physical examination revealed a nonblanching palpable purpuric eruption on his dependent regions (Figure 1), lower extremity edema, bibasilar crackles, and mild upper abdominal tenderness on palpation. Laboratory findings exhibited proteinuria, hematuria, and elevated C-reactive protein and erythrocyte sedimentation rate (ESR). Platelet levels and complement levels were within normal range. Antinuclear antibody (ANA) and cytoplasmic antineutrophil cytoplasmic autoantibody (ANCA) and perinuclear ANCA were negative. Initially, the patient’s dermatitis was thought to be a drug-induced vasculitis. Dermatology was consulted, and two punch biopsies taken from the patient’s thigh demonstrated leukocytoclastic vasculitis with neutrophils in a perivascular and interstitial pattern, nuclear dust, extravasation of red blood cells, and fibrinoid necrosis of the superficial blood vessels (Figure 2). Direct immunofluorescence (DIF) revealed prominent 3+ IgA granular staining of blood vessels in the papillary dermis (Figure 3). These DIF findings of perivascular IgA staining, along with his histopathologic and clinical manifestations, supported the diagnosis of Henoch-Schönlein purpura (HSP), rather than drug-induced vasculitis.

The patient currently refuses any treatment for his HSP and is to continue to follow-up with cardiology and nephrology. Discussion HSP is a multisystem inflammatory vasculitis that affects small vessels with IgA-dominant immune complex deposits typically involving the gut, skin, and glomeruli. It is commonly associated with arthritis and arthralgias. The first known case was described in 1801 by William Heberden (1710–1801) of a 5-year-old boy with the four disease hallmarks of HSP: purpura, abdominal pain, joint pain, and renal involvement. Johann Schönlein (1793–1864) initially illustrated the relationship between joint pain and purpuric dermatitis in 1837. Later, his student, Henoch, reported the additional symptoms of nephritis, bloody diarrhea, and colicky abdominal pain in 1874 and 1899.1,2 Although HSP is mainly a disease of childhood, it can occur at any age and has been described in adults. The mean age of onset in adults is 50 years,2,3 with an equal male to female prevalence.2 The disease commonly occurs in the winter,4 often after a respiratory infection; however, no single primary etiologic agent has been identified.5 In adults with no precipitating factors, respiratory and gastrointestinal (GI) tract malignancies have been linked.6 The prognosis of HSP is generally good, but long-term outcomes depend predominantly on the degree of renal involvement, which can be more likely and more severe in adults and older children.1,4

From the Department of Dermatology and Cutaneous Biology,1 Sidney Kimmel Medical College at Thomas Jefferson University, and Department of Family and Community Medicine,2 Sidney Kimmel Medical Collage at Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Daria Marley Kemp, MD, MEd, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University Hospital, 833 Chestnut St, Suite 740, Philadelphia, PA 19107 • E-mail: daria.kemp@jefferson.edu

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Figure 1. Nonblanching purpuric eruption on the lower extremities (left), posterior aspects of the arms (middle), and lower part of the back (right) of our patient.

Figure 3. Direct immunofluorescence revealing prominent 3+ IgA granular staining of blood vessels in the papillary dermis.

Figure 2. Histochemical staining representing leukocytoclastic vasculitis with neutrophils in a perivascular and interstitial pattern, nuclear dust, extravasation of red blood cells, and fibrinoid necrosis of the superficial blood vessels with fibrin deposition. (H&E stain, original magnification ×20.)

Clinical manifestations of petechiae and palpable purpura are caused by IgA immune complexes deposited in endothelial walls, leading to damage of these vessels. Development of GI hemorrhage occurs when immune complexes accumulate in the intestinal wall vessels.4 Nephritis manifests when these complexes affect the renal mesangium, which results in mild proliferative to severe crescentic glomerulonephritis.4,5 The purpuric lesions initially may be urticarial or maculopapular and within 1 or 2 days are well defined and no longer blanchable. Patients can display clusters of 2- to 10-mm petechial lesions that coalesce to palpable purpura,1,4,5 typically in dependent areas that are subject SKINmed. 2016;14:303–306

to pressure.4 Upper extremity involvement is more often seen in adults.7 Cutaneous lesions gradually fade over 2 weeks, but may reappear in intervals of days to weeks.1 Renal involvement is the most serious sequela displayed in 20% to 40% of childhood cases and 50% to 85% of adult cases, with 90% and 40%, respectively, occurring within the first month of HSP onset.2 The risk of renal insufficiency development is 5% to 15% in children and 30% in adults.3 As our case demonstrates, disease course features, such as GI and arthritic symptoms, may precede the onset of purpura by up to 1 to 2 weeks;5,8 however, nephritis rarely does and may be delayed weeks to months after the onset of other symptoms. HSP is primarily a self-limited illness that resolves within 4 weeks. Recurrences can occur in up to one third of patients, who typically reach resolution within 4 months.5

304

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CASE STUDY on renal disease.11,12 Studies have been mixed in the use of corticosteroids. A meta-analysis examining supportive care vs use of systemic corticosteroids found that systemic corticosteroid use at time of diagnosis decreased the odds of developing persistent renal disease and reduced the mean duration of abdominal pain.12,13 A Cochrane review found no significant reduction in serious kidney disease at 6 to 12 months after onset of HSP in children treated with prednisone for 14 to 28 days at disease onset compared with supportive or placebo therapy.12,14 For adult and pediatric patients with GI and joint involvement, factor XIII substitution therapy can potentially help alleviate associated symptoms.10 Patients with severe disease may benefit from a renal biopsy to guide diagnosis and therapy.4 Short-term and long-term prognosis will be related to the severity of GI involvement and renal insufficiency, respectively.5

Table. Diagnostic Criteria for Henoch-Schönlein Purpura American College of Rheumatology, 1990 At least two or more of the following: • Palpable purpura without thrombocytopenia • Age 20 years or younger at disease onset • Bowel angina • Histologic changes showing granulocytes in arteriole or venule walls International Consensus Conference, 2006 Presence of palpable purpura in addition to at least one or more of the following: • Diffuse abdominal pain • Biopsy showing predominant IgA deposition • Arthritis/arthralgia • Renal involvement (hematuria and/or proteinuria)

Diagnosis can be difficult as there is no definitive test. Clinical manifestations, especially palpable purpura in the absence of thrombocytopenia4, can peak concerns and a skin biopsy can provide useful information, particularly if patients do not display a classic rash distribution. Laboratory findings can help identify a predisposing factor, such as antistreptolysin O titers; exclude other diseases with a negative ANCA; or recognize complications, such as renal involvement with hematuria with or without proteinuria and red blood cell casts.9 A complete blood cell count should display a normal platelet count and may reveal anemia secondary to nephritis or GI bleeding.7,9 A mild leukocytosis is commonly present.7 Patients typically have normal complement levels and normal or a minimally elevated ESR. Results from serologic rheumatology tests, including rheumatoid factor and ANA, are negative. Elevated IgA levels are supportive of HSP, as more than 50% of cases display an increase.9 Findings from coagulation tests are normal; yet, patients may exhibit decreased factor XIII activity, which can indicate disease severity of GI and joint involvement.9,10 Patients with active HSP also have high concentrations of von Willebrand factor antigen. This is nonspecific as it is present in other vasculitides with endothelial injury.9

Conclusions HSP is commonly a disease of childhood but can occur at any age from infancy to adulthood. The four hallmark features include palpable purpura, abdominal pain, joint pain, and renal involvement. Cutaneous lesions may not always be the presenting sign. The prognosis of HSP is generally good, but the longterm outcomes depend primarily on the degree of renal involvement, which can be more likely and severe in adults. Acknowledgments John L. Farber, MD, Department of Pathology, Thomas Jefferson University Hospital, provided the pathology studies and histologic photos. References

In 1990, a subcommittee of the American College of Rheumatology defined the criteria for the classification of HSP with the sensitivity of 87.1% and a specificity of 87.7%.8 The criteria were modified in 2005 by the International Consensus Conference9 (Table5,8,9). Supportive treatment is commonly used in treating HSP, because spontaneous resolution occurs in about 94% of children and 89% of adults.4 Treatment options have mainly been studied in children, including those discussed here. Dapsone may decrease the duration of purpuric dermatitis but appears to have no effect SKINmed. 2016;14:303–306

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1 Gedalia A. Henoch-Schönlein purpura. Curr Rheumatol Rep. 2004;6:195–202. 2 Fervenza FC. Henoch-Schönlein purpura nephritis. Int J Dermatol. 2003;42:170–177. 3 Phillebout E, Thervet E, Hill G, et al. Henoch-Schölein purpura in adults: outcome and prognostic factors. J Am Soc Nephrol. 2002;13:1271–1278. 4 Reamy BV, Williams PM, Lindsay TJ. Henoch-Schönlein purpura. Am Family Physician. 2009;80:697–704. 5 Saulsbury FT. Henoch-Schönlein purpura. Cur Opin Rheumatol. 2001;13:35–40. 6 Linskey KR, Kroshinsky D, Mihm MC, et al. Immunoglobulin-A–associated small vessel vasculitis: a 10-year experience at the Massachusetts General Hospital. J Am Acad Dermatol. 2011;66:813–822. 7 Kang Y, Park JS, YJ Ha, et al. Differences in clinical manifestations and outcomes between adult and child patients with Henoch-Schönlein purpura. J Korean Med Sci. 2014;29:198–203.

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8 Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum. 1990;33:1114–1120.

11 Igbal H, Evans A. Dapsone therapy for Henoch-Schönlein purpura: a case series. Arch Dis Child. 2005;90:985–986.

9 Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936–941.

13 Weiss PF, Feinstein JA, Luan X, et al. Effects of corticosteroid on Henoch-Schönlein purpura: a systemic review. Pediatrics. 2007;120:1079–1087.

10 Matayoshi T, Omi, Sakai N, et al. Clinical significance of blood coagulation factor XIII activity in adult HenochSchönlein purpura. J Nippon Med Sch. 2013;80:268– 278.

14 Chartapisak W, Opastirakul S, Hodson EM, et al. Interventions for preventing and treating kidney disease in Henoch-Schönlein purpura (HSP). Cochrane Database Syst Rev. 2009;3:CD005128.

12 Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. 3rd ed. Philadelphia, PA: Elsevier; 2012:393.

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MEDIA PARTNER

July/August 2016

Volume 14 • Issue 4

CASE STUDY

Cutaneous Collagenous Vasculopathy-Associated Benign Pigmented Purpura Warren R. Heymann, MD

A 68-year-old woman presented with an asymptomatic eruption predominantly on the proximal pretibial region of the right lower extremity, which had been present for many months. Her medical history was remarkable for diabetes and hypothyroidism. Physical examination demonstrated “cayenne pepper”–like brown macules, scattered petechiae, and multiple minute, blanching telangiectasias (Figure 1) that were more evident on dermatoscopy (Figure 2). The clinical differential diagnosis included a benign pigmented purpura (BBP; Schamberg type), telangiectasia macularis eruptiva perstans, cutaneous T-cell lymphoma, essential telangiectasia, and cutaneous collagenous vasculopathy (CCV). Results from complete blood cell count, hepatic profile, and serum tryptase were normal. Findings from skin biopsy demonstrated ectatic papillary dermal vessels with hyalinized walls (accentuated by a periodic acid-Schiff stain), a sparse superficial perivascular mononuclear infiltrate, extravasated erythrocytes, and focal siderophages (Figure 3). The diagnosis of CCV with an associated BPP was confirmed. (SKINmed. 2016;14:308–309)

CV is an idiopathic microangiopathy of the superficial vasculature characterized by marked thickening of the walls of the dermal blood vessels displaying reduplication of the basement membrane on periodic acid-Schiff–diastase stain and deposition of hyanline collagenous material.1 Immunohistochemical stains are positive for collagen IV and decreased or absent actin. The etiology of CCV is unknown, although intravascular obstruction from local thrombosis has been hypothesized. Other factors, such as genetic susceptibility, chemical or environmental exposure, metabolic or hormonal influences, and infectious etiologies, have all been proposed as etiologic factors. While diabetes mellitus has been reported in several cases, such as our patient, it is not essential for the diagnosis of CCV.2 Although the disorder is usually seen in patients older than 50 years of age, it was recently described in a 16-year-old woman.3 Morphologic variants of BPP eruptions include Schamberg disease, the eczematid-like purpura of Doucas and Kapetanakis, pigmented purpuric lichenoid dermatosis of Gougerot and Blum, lichen aureus, and purpura annularis telangiectoides of See also Lambert, WC et al. Pseudoneoteleology and Lower Extremity Vascular Entities, pages 251–252.

Majocchi.4 The patient’s presentation was most consistent with the Schamberg type. Histologically, Schamberg BPP displays a perivascular mononuclear infiltrate with extravasation of erythrocytes and hemosiderin deposition but no fibrinoid necrosis of vessels. The etiology of BPPs is unknown, although cell-mediated immunity, immune complexes, capillary fragility, gravitational forces, venous hypertension, focal infection, clothing, contact allergens, and drugs have all been considered incriminating factors.4 The recently proposed pathogenesis of CCV is the result of repeated endothelial cell injury (regardless of the cause). While some patients have intravascular microthrombi, all patients demonstrate reduplication of the basement membrane, activation of veil cells, and subsequent reparative perivascular fibrosis.2 Presumably, this impairs the vessel’s integrity, allowing for extravasation of erythrocytes that clinically correlates with BPP. CCV was first described in 2000.6 Subsequently, the clinicalpathologic spectrum of the disorder has been refined. This patient demonstrates how CCV may be associated with BPP. It remains to be determined whether this is a distinct form of BPP or just a sequela of a long-standing capillilaritis.

From the Departments of Medicine and Pediatrics, Division of Dermatology, Cooper Medical School of Rowan University, Marlton, NJ Address for Correspondence: Warren R. Heymann, MD, Cooper Medical School of Rowan University, Departments of Medicine and Pediatrics, Division of Dermatology, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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Figure 3. A skin biopsy demonstrating ectatic papillary dermal vessels with hyalinized walls, a sparse superficial perivascular mononuclear infiltrate, extravasated erythrocytes, and focal siderophages (hematoxylin and eosin stain).

Conclusions

Figure 1. Right lower extremity with “cayenne pepper” macular hyperpigmentation, petechiae, and minute telangiectasias. (The patient also had a biopsy and a distinct traumatic erosion unrelated to the eruption).

When evaluating patients with BPP, it should first be determined whether the lesions blanch. Dermatoscopy assists in assessing whether lesions are telangiectasias or petechiae. A biopsy is required to secure the diagnosis of CCV-associated BPP. Further studies are necessary to elucidate the precise pathomechanism(s) of this entity. Acknowledgments Drs Mario DiLeonardo and Judith Kim (Dermpath Diagnostics, Newtown Square, PA) provided the photomicrograph. References 1 Burdick LM, Losher S, Somach SC, Billings SD. Cutaneous collagenous vasculopathy: a rare cutaneous microangiopathy. J Cutan Pathol. 2012;39:741–746. 2 Salama SS. Cutaneous collagenous vasculopathy: a new case series with clinicopathologic and ultrastructural correlation, literature review, and insight into the pathogenesis. Am J Dermatopathol. 2015;37:368–375. 3 Lloyd BM, Pruden SJ 2nd, Lind AC, Berk AC. Cutaneous collagenous vasculopathy: report of the first pediatric case. Pediatr Dermatol. 2011;28:598–599. 4 Sharma L, Gupta S. Clinicoepidemiological study of pigmented purpuric dermatoses. Indian Dermatol Online J. 2012;3:17–20. 5 Torrelo A, Requena C, Mediero IG, Zambrano A. Schamberg’s purpura in children: a review of 13 cases. J Am Acad Dermatol. 2003;48:31–33. 6 Salama S, Rosenthal D. Cutaneous collagenous vasculopathy with generalized telangiectasia: an immunhistochemical and ultrastructural study. J Cutan Pathol. 2000;27:40–48.

Figure 2. Dermatoscopy demonstrating telangiectasias and focal hyperpigmentation.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 12th World Congress of the International Academy of Cosmetic Dermatology May 4-6, 2017, Bengaluru, India Abstract deadline: January 10, 2017 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, or cosmetic (or combined) in nature. The author, whose abstract receives the highest score during the review process, will be awarded a scholarship by the IACD to present the full paper at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, January 10, 2017, and should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thought-out, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been or is in consideration for publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31st, 2017. The applicant must be in training at the time of the Congress presentation. All applicants will receive e-mail notice of the Resident Case Report Review Committeeâ&#x20AC;&#x2122;s decision by February 5, 2017. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor and Interim Chair The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

July/August 2016

Volume 14 • Issue 4

CASE STUDY

Abdominal Elephantiasis Nostras Verrucosa: An Underrecognized Disorder Derek Ho, BS;1 Eve J. Lowenstein, MD, PhD1,2

Case 1 A 60-year-old African American man presented with a medical history of morbid obesity (weighing more than 550 lb), benign prostatic hyperplasia, hyperlipidemia, gynecomastia, atrial fibrillation, hypertension, chronic obstructive pulmonary disease, psoriasis, sleep apnea, and cardiomegaly. His size has limited his ability to clean himself properly. He experiences chronic and recurrent skin irritation and cellulitis possibly secondary to intertriginous superinfection, lymphedema, and venous stasis. On examination, his abdomen showed heavy skinfolding with hyperpigmentation, cobblestone and velvety changes, thickening and fibrotic induration of the skin, focal areas of redness, and tenderness on palpation (Figure 1A and 1B). These findings are consistent with a clinical picture of chronic elephantiasis nostras verrucosa (ENV) and lipodermatosclerosis (LDS). He has had numerous hospitalizations for recurrent cellulitis in the abdomen and lower limbs during the past 8 years. He is currently residing in a weight-loss facility and is managing skin care using topical nystatin powder and periodic topical triamcinolone ointment. (SKINmed. 2016;14:311–313)

ase 2 A 53-year-old Caucasian man presented with a medical history of morbid obesity (weighing more than 250 lb), asthma, diabetes, and hyperlipidemia. On examination, he has swollen, woody lower aspects of the legs and testicular enlargement secondary to chronic lymphedema. His abdomen has pebbling, fibrosis, and thickening of the skin (Fig-

ure 2A and 2B). He has been hospitalized multiple times for abdominal wall cellulitis. Results from ultrasonography showed significant venous insufficiency of his legs from incompetent saphenofemoral valves. He recently started using compression stockings and doing exercises that include leg elevations and walking to enhance venous and arterial circulation.

Figure 1. The patient’s abdomen exhibiting hyperpigmentation and a classic elephantiasis nostras verrucosa cobblestone appearance (A). Scarring from recurrent abdominal cellulitis and focal, red nodular changes are noted (B).

From SUNY Health Science Center Department of Dermatology,1 and Brookdale University Hospital,2 Brooklyn, NY Address for Correspondence: Eve J. Lowenstein, MD, PhD, SUNY Downstate Medical Center, Department of Dermatology, 8th Floor, 450 Clarkson Avenue, Box 46, Brooklyn, NY 11230 • E-mail: evlow13@yahoo.com

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Figure 2. The abdominal panniculus covers up the scrotum and thigh when the patient is in the upright position (A). Pebbling and thickening of the skin and mild redness are noted (B).

Discussion ENV is a rare end-stage chronic scarring dermatosis typically described on the lower extremities. Both a functional and aesthetic problem, abdominal ENV is rarely described in the medical literature. We describe two morbidly obese men with fibrotic thickening and cobblestoned skin of the abdominal region, findings consistent with both chronic LDS and chronic ENV. Both patients have a history significant for recurrent abdominal cellulitis and severe lymphedema of the lower aspects of the legs. Multiple etiological factors have been implicated in ENV, which includes lymphatic obstruction, recurring infections, and obesity. In reviewing the English language literature, only 10 reported cases of abdominal ENV could be identified (Table).1–8,10 Given the increasing prevalence of obesity in our society and review of recent literature, however, the actual number of cases could be significantly higher. This review serves to increase physicians’ awareness of this disorder. ENV is a rare dermatologic situation that can arise in the context of chronic lymphedema. Classic ENV findings include hyperkeratosis, dermal fibrosis, and a cobblestone-like appearance. Risk factors include morbid obesity, congestive heart failure, and chronic venous insufficiency.9 Recurrent cellulitis is also highly correlated with ENV. According to a 2-year retrospective review of ENV patients, chronic venous insufficiency was present in 71% of the cases and many symptoms came up concurrently with stasis dermatitis and LDS.10 In that same study, ENV of the abdominal region accounted for about 10% of the cases (2 of 21 patients), with the majority localized in the lower extremities.10 This suggests that abdominal ENV may be underrepresented in SKINmed. 2016;14:311–313

the current medical literature or is an underrecognized phenomenon that needs to be diagnosed with better criteria. Aside from venous and lymphatic insufficiency, an alternative cause of ENV includes filarial elephantiasis caused by tropical parasites.11 Neither of our two patients traveled to tropical areas endemic for filarial elephantiasis. ENV can present similarly with chronic LDS, or, as is likely the case in the two patients presented here, ENV and chronic LDS may overlap. Chronic LDS is a chronic fibrotic disorder that most often follows an acute cellulitis-like phase. Chronic LDS presents with skin tightening that may progress into the classic “inverted champagne bottle” appearance of the lower portion of the leg. Doppler studies demonstrate lymphatic obstruction and pooling of blood in localized areas. LDS is highly correlated with obesity,12 and weight management is currently one of the most effective treatments. In our two cases, both patients were morbidly obese, experienced significant venous and lymphatic insufficiency, and had recurring episodes of cellulitis. These factors are consistent with previous literature examining the etiology of ENV and LDS. Both patients had symptomatic lymphedema of the legs prior to abdominal involvement. If the condition is severe enough for abdominal ENV to occur, it is highly likely that the lower portion of the legs are involved, as well. Only two cases of abdominal ENV in men have been previously reported in the literature.4,8 It is possible that ENV is more common in women secondary to the known role estrogen plays in the pathogenesis of venous insufficiency.

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Table. Reported Cases of Abdominal Elephantiasis Nostras Verrucosa in the English Medical Literature Author

Year

Age

Sex

Location

Relevant Risk Factors

2016

Male

United States

Morbid obesity, recurrent abdominal and leg cellulitis, congestive heart failure, chronic obstructive pulmonary disease

2016

Male

United States

Morbid obesity, asthma, diabetes, hyperlipidemia

Dean10

2011

N/A

United States (2 patients)

N/A

Berngard8

2011

Male

United States

Morbid obesity, congestive heart failure, bilateral leg edema

Buyuktas7

2010

Female

Turkey

Morbid obesity, cellulitis of the leg, abdominal lesions

Sarma6

2008

Female

India

Morbid obesity, congestive heart failure, diabetes, chronic obstructive pulmonary disease

Boyd4

2004

Male

United States

Morbid obesity, diabetes, chronic obstructive pulmonary disease, congestive heart failure

Hanna5

2004

Female

Canada

Multiple abdominal cellulitis

Bull3

1993

Female

United Kingdom

Congestive heart failure, chronic bronchitis, cellulitis or acute lipodermatosclerosis on both lower portions of the legs

Rudolph1

1973

Female

United States

Morbid obesity, skin thickening on both legs, numerous small lesions on feet

Chernosky2

1966

Female

United States

Morbid obesity

Abbreviation: N/A, not available.

Conclusions We have descrbed two cases of ENV and chronic LDS manifested on abdominal skin. Morbid obesity, venous and lymphatic insufficiency, recurrent cellulitis, and congestive heart failure may contribute to the development of this condition. While 10% of the ENV cases involved the abdominal region in one review,10 review of the medical literature showed a total of only 10 cases in the past 50 years. This suggests that abdominal ENV might be an underrecognized or misdiagnosed entity. With the occurrence of the current obesity epidemic, physicians should recognize, diagnose, and treat this complication of obesity. References 1 Rudolph RI, Gross PR. Elephantiasis nostras verrucosa of the panniculus. Arch Dermatol. 1973;108:832–834. 2 Chernosky ME, Derbes VJ. Elephantiasis nostras of the abdominal wall. Arch Dermatol. 1966;94:757–762. 3 Bull RH, Mortimer PS. Acute lipodermatosclerosis in a pendulous abdomen. Clin Exp Dermatol. 1993;18:164–166. 4 Boyd J, Sloan S, Meffert J. Elephantiasis nostrum verrucosa of the abdomen: clinical results with tazarotene. J Drugs Dermatol. 2004;3:446–448.

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5 Hanna D, Cloutier R, Lapointe R, et al. Abdominal elephantiasis: a case report. J Cutan Med Surg. 2004;8:229– 232. 6 Sarma PS, Ghorpade A. Elephantiasis nostras verrucosa on the legs and abdomen with morbid obesity in an Indian lady. Dermatol Online J. 2008;14:20. 7 Buyuktas D, Arslan E, Celik O, et al. Elephantiasis nostras verrucosa on the abdomen of a Turkish female patient caused by morbid obesity. Dermatol Online J. 2010;16:14. 8 Berngard SC, Narayanan V. Elephantiasis nostras verrucosa of the pannus. J Gen Intern Med. 2011;26:810. 9 Baird D, Bode D, Akers T, et al. Elephantiasis Nostras Verrucosa (ENV): a complication of congestive heart failure and obesity. J Am Board Fam Med. 2010;23:413– 417. 10 Dean SM, Zirwas MJ, Horst AV. Elephantiasis nostras verrucosa: an institutional analysis of 21 cases. J Am Acad Dermatol. 2011;64:1104–1110. 11 Bennuru S, Nutman TB. Lymphatics in human lymphatic filariasis: in vitro models of parasite-induced lymphatic remodeling. Lymphat Res Biol. 2009;7:215–219. 12 Miteva M, Romanelli P, Kirsner RS. Lipodermatosclerosis. Dermatol Ther. 2010;23:375–388.

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Volume 14 • Issue 4

CASE STUDY

Recalcitrant Verrucae in Patients With DOCK8 Deficiency Yen Tun Wang, MD;1 Bob Geng, MD;2 Samantha Gendelman, MD;2 Alexandra Freeman, MD;3 Christina Nam-Soo Kim, MD1

An 18-year-old Caucasian man presented with extensive recalcitrant verrucae on his trunk and extremities that were unresponsive to cryotherapy, salicylic acid, topical imiquimod, CO2 laser, candida antigen, and intralesional bleomycin. He had a diagnosis of hyperimmunoglobulin E syndrome until 2011, when he was determined to have DOCK8 immunodeficiency after genetic testing at the National Institutes of Health. In addition to verrucae, he had a personal history of eczematous dermatitis, osteomyelitis, molluscum infections, cutaneous abscesses, recurrent pneumonia, and severe food allergy. (SKINmed. 2016;14:315–317)

n examination, he had scaly erythematous patches on the face, thin verrucous pink papules on the chest and forearms (Figure 1), hypopigmented macules coalescing into patches on the abdomen and back, and extensive malodorous verrucous flesh-colored plaques on his hands, legs, and feet (Figure 2). He also developed a small fluctuant mass on his medial thigh with minimal inflammation, consistent with a skin abscess (Figure 3). His recent serum mmunoglobulin E (IgE) level was markedly elevated at 4450 mg/mL. Results of functional testing of lymphocyte activity revealed an adequate response to mitogens and candida but deficient cytotoxic activity of natural killer (NK) cells alone (7% lysis in patient vs 26% lysis in control at 50:1 effector:target ratio) and with interleukin 2 augmentation (18% lysis in patient vs 50% lysis in control). The patient is being treated symptomatically with debridement of large painful verrucae until his bone marrow transplant, and is undergoing immune evaluation for potential IgE replacement. Figure 1. Pink flat verrucae on right forearm.

Discussion In 2009, the loss-of-function DOCK8 mutation was discovered and found to be responsible for the clinical findings seen in patients previously categorized as having atypical hyper-IgE syndrome.1 Initially viewed as an autosomal-recessive Job syndrome, DOCK8 deficiency is now considered a separate entity: a combined immunodeficiency syndrome that features cutaneous viral infections, eczematous dermatitis, and typically elevated IgE levels.2

Patients with DOCK8 deficiency typically develop respiratory tract infections, atopic dermatitis, viral infections, bacterial skin infections, mucocutaneous candidosis, and allergic disease.3 They are also at an increased risk for malignancy and autoimmunity.4 Extensive recalcitrant cutaneous viral infections, most commonly herpes simplex virus, human papillomavirus (HPV), molluscum contagiosum, and varicella-zoster virus are charac-

From the Divisions of Dermatology1 and Clinical Immunology and Allergy,2 Ronald Reagan UCLA Medical Center, Los Angeles, CA, and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD3 Address for Correspondence: Yen Tun Wang, MD, 200 UCLA Medical Plaza, Suite 450, Los Angeles, CA 90095 • E-mail: jywanga@gmail.com

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Figure 2. A large wart on the patient’s thumb (a) and extensive warts on the patient’s legs (b).

complete resolution of their molluscum and herpes zoster infections, and others have had resolution of warts (personal communication).8 In addition to undergoing stem cell transplantation within the next year, our patient is currently undergoing evaluation of humoral immune function to determine whether he is a candidate for IgE replacement, which may attenuate his sinopulmonary and cutaneous viral infections.9

Figure 3. Skin abscess on the patient’s right medial thigh.

teristic. Patients often have large flat and verrucous warts from HPV infection.5 This phenomenon is thought to occur because DOCK8 has a role in the formation of the lytic immunologic synapse in NK cells.6 Because NK cells play an important role in antiviral defense, decreased NK cell cytotoxicity and potency from DOCK8 deficiency will lead to an inadequate response to viruses. HPV and molluscum infections generally do not respond to conventional therapies, but there are some anecdotal reports of response to interferon-α therapy.7 Our patient’s main complaint was recalcitrant warts that were worsening despite multiple therapies. Two patients who have undergone allogeneic hematopoietic stem cell transplantation had SKINmed. 2016;14:315–317

For eczematous dermatitis, topical antiseptics or antimicrobial soaps can minimize colonization of eczematized skin by Staphylococcus aureus. Topical corticosteroids can be helpful for achieving moderate control but may also exacerbate cutaneous viral infection.1 For increased malignancy risk, especially squamous cell carcinomas and lymphomas, close monitoring is required.3 It is currently unclear whether DOCK8 may have tumor-suppressing effects and whether stem cell transplantation will therefore lead to a lower risk for malignancy.10 The risk of allogeneic stem cell transplantation must be carefully weighed against symptoms of the disease. Conclusions The root cause of the cutaneous findings seen in DOCK8 deficiency may lie in NK cell dysfunction, which is responsible for activity against viruses and tumors. Some studies have shown that, while topical steroids, antibacterial washes, and systemic antimicrobials may be effective for the dermatitis, the cutaneous viral infections can be recalcitrant to almost all outpatient therapies. Allogeneic bone marrow transplantation is recommended for this condition because of the high risk of malignancy and early mortality, and has been shown to cause regression of viral infections.

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References 1 Su H. DOCK8 (Dedicator of cytokinesis 8) deficiency. Curr Opin Allergy Clin Immunol. 2010;10:515–520. 2 Renner ED, Puck JM, Holland SM, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004;144:93–99. 3 Chu EY, Freeman AF, Jing H, et al. Cutaneous manifestations of DOCK8 deficiency syndrome. Arch Dermatol. 2012;148:79–84. 4 Freeman AF, Holland SM. Clinical manifestations of hyper IgE syndromes. Dis Markers. 2010;29:123–130. 5 Leiding JW, Holland SM. Warts and all: human papillomavirus in primary immunodeficiencies. J Allergy Clin Immunol. 2012;130:1030–1048. 6 Mizesko MC, Banergee PP, Monaco-Shawver L, et al. De-

fective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency. J Allergy Clin Immunol. 2013;131:840–848. 7 Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361:2046–2055. 8 Gatz SA, Benninghoff U, Schutz C, et al. Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation. Bone Marrow Transplant. 2011;46:552–556. 9 Lin JH, Wang KY, Kraft S, Roberts RL. Resolution of warts in association with subcutaneous immunoglobulin in immune deficiency. Pediatr Dermatol. 2009;26:155–158. 10 Takahashi K, Kohno T, Ajima R, et al. Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer. Int J Oncol. 2006;28:321–328.

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Volume 14 • Issue 4

Book Review Jennifer L. Parish, MD, Section Editor

Dermoscopy of the Hair and Nails, Second Edition Niraj Butala, MD

s the field of dermoscopy continues to broaden, resources such as this book play an increasingly larger role in every day practice. The second edition of Dermoscopy of the Hair and Nails (by Antonella Tosti [Boca Raton, FL: CRC Press; 2016, 220 pages, $125.95]) is valuable in expanding the scope of the field. Not only have new photographs been added, but the addition of the nails to this update greatly enhances the utility of this text in daily practice. Direction As a senior dermatology resident, I approached this book having been trained in dermoscopy but with plenty of room for improvement. The book is aimed toward trainees and practicing dermatologists, and covers basic and mildly advanced dermoscopy of the hair and nails. The text is divided into 18 chapters related to the hair and 10 to the nails. One chapter is dedicated to basic techniques and tools, covering various brand name devices and their ability to take photos and videos, in addition to their magnification capability. Another chapter is dedicated to canines and felines, which was fascinating although somewhat unexpected. The Chapters Although a thorough history and examination may occasionally elicit a diagnosis, a biopsy and laboratory work are often needed to secure this, and dermoscopy can help guide clinicians diagnostically. Aside from distinguishing often clinically overlapping alopecia states, dermoscopy may be utilized in determining biopsy sites. Often, dermoscopes are relegated to the evaluation of dysplastic nevi or subtle nonmelanoma skin cancers; however, the ability to use these devices for hair and nail disorders, while not novel, is certainly a meaningful addition to the dermatologist’s armamentarium.

The chapters on scarring and nonscarring alopecias are useful for the practicing dermatologist, and I found them particularly enlightening. The nail chapters are excellent. The authors cover dermoscopy of the nail plate, the proximal nail fold, and the hyponychium, and discuss a wide variety of nail pathologies. Specifically, the authors’ overview of the usefulness of dermoscopy of the hyponychium is insightful and full of clinical pearls. Other notable topics that are covered well include dermoscopy of darker skin patients. Baseline and inflammatory color profiles may look different in persons of color, and this topic was handled very well. Overall, the book was excellent. The pictures were representative and consistently outstanding. A small, if unavoidable, difficulty I encountered was the overlapping clinical findings in many diseases. Variable hair diameter sizes, telangiectasias, and black and yellow dots are common to many disorders, highlighting the challenge of dermoscopy in this rapidly evolving field. Although the chapter on canines and felines was interesting, it felt misplaced in a book otherwise devoted to human dermoscopy. Those minor critiques aside, the pearls of wisdom were abundant, and I am a better dermatologist for having read this book. Recommendations Generally, this is a very worthwhile addition as a supplemental text for any dermatologist interested in broadening their dermoscopic skills. I see myself keeping and referring to this text once I am in practice and look forward to using its clinical pearls daily. For those just learning about dermoscopy, another text that serves as a primer would, however, be more appropriate.

Reviewed by Niraj Butala, MD, Division of Dermatology, Cooper Medical School of Rowan University, 3 Cooper Plaza, Suite 504, Camden, NJ 08103 • E-mail: Butala-niraj@cooperhealth.edu

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