Skinmed - May/June, 2015 by jo-ann kalaka-Adams

Lebanese Dermatological Society

Lebanese Dermatological Society Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

Belarusian Society of Dermatovenereologists and Cosmetologists

African Association for Dermatology

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

May/June 2015 • Volume 13 • Issue 3 May/June 2015 • Volume 13 • Issue 3

EDITORIAL Cutaneous Adaptations and Subcutaneous Soft Tissue Alterations Following Mechanical Stress: The Coxsackie A6 Virus May Offer a Solution Lambert, De Marco, and Parish

COMMENTARY Patch: A Skin Lesion in Need of Definition Mahajan and Ranjan

ORIGINAL CONTRIBUTIONS Topical Nitroglycerine in Perniosis/Chilblains Verma

Oral Finasteride Presents With Sexual-Unrelated Withdrawal in Long-Term Treated Androgenic Alopecia in Men Perez-Mora,Velasco, and Bermúdez

Topical Minoxidil: Systematic Review and Meta-Analysis of Its Efficacy in Androgenetic Alopecia Gupta and Charrette

Cosmetic Regulations: A Comparative Study Suhag and Dureja

REVIEWS The Use of Traditional Chinese Medicine in Some Dermatologic Diseases: Part II—Autoimmune Bullous Disorders and Lichen Planus

Baroni, Ruocco, Russo, Piccolo, Geng, Zhou, Chen, and Gao

Self-Assessment Examination Lambert

Basal Cell Carcinoma Part I: Basal Cell Carcinoma Has Come of Age Deng, Marsch, and Petronic-Rosic

Self-Assessment Examination Lambert

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Attack of the Living Dead: Why You Need a GMS Stain With a PAS Stain to Detect Fungi in Dermatopathology Specimens Sharma, Weiss, Peters, and Lambert

NEW TO THE CLINIC 1% Ivermectin Cream (Soolantra) for the Treatment of Rosacea Scheinfeld

NEW THERAPY UPDATE XELJANZ (Tofacitinib) for Chronic Plaque Psoriasis

Gupta, Daigle, Abramovits, and Vincent

THE HEYMANN FILE Necrotic Carpal Tunnel Syndrome: A Standard Deviation From the Median Nerve

COMMON DISEASES: TREATMENT OPTIONS Dissecting Cellulitis Scheinfeld

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Onychomycosis Bernhardt

COSMETIC SURGERY CAPSULE 6th Annual Cosmetic Surgery Forum 2014 Top Resident Presentations December 3–6, 2014, Las Vegas, NV

case studies Weightlifter’s Nodule: A New Variant of Athlete’s Nodule

Jamie Goldberg, Campanelli, and Lee

Chromoblastomycosis Caused by Cladophialophora bantiana in a Renal Transplant Recipient From Delhi, India Verma, Karmakar, Pandhi, Singal, Yadav, and Khare

BOOK REVIEW Cutaneous Cryosurgery Parish

Heymann

CONTACT DERMATITIS CAPSULE Patch Testing Pearls: Solutions to Common Clinical Dilemmas Bonchak and Zirwas

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TABLE OF CONTENTS May/June 2015 • Volume 13 • Issue 3

EDITORIAL

Cutaneous Adaptations and Subcutaneous Soft Tissue Alterations Following Mechanical Stress: The Coxsackie A6 Virus May Offer a Solution................................................................................. 167

W. Clark Lambert, MD, PhD; Michael A. De Marco, BA; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARY

Patch: A Skin Lesion in Need of Definition ................................................................................................ 171

Vikram K. Mahajan, MD; Nitin Ranjan, MD

ORIGINAL CONTRIBUTIONS

Topical Nitroglycerine in Perniosis/Chilblains .......................................................................................... 176

Prashant Verma, MD

Oral Finasteride Presents With Sexual-Unrelated Withdrawal in Long-Term Treated Androgenic Alopecia in Men ...................................................................................................................... 179

Nicolas Perez-Mora, MD, PhD; Carlos Velasco, MD; Fernando Bermúdez, MBA

Topical Minoxidil: Systematic Review and Meta-Analysis of Its Efficacy in Androgenetic Alopecia .............................................................................................................................. 185

Aditya K. Gupta, MD, PhD, FRCPC; Andrew Charrette, MSc

Cosmetic Regulations: A Comparative Study ............................................................................................. 191

Jyoti Suhag, MPharm; Harish Dureja, PhD

REVIEW

The Use of Traditional Chinese Medicine in Some Dermatologic Diseases: Part II—Autoimmune Bullous Disorders and Lichen Planus .................................................................... 195

Adone Baroni, MD,PhD; Eleonora Ruocco, MD, PhD; Teresa Russo, MD; Vincenzo Piccolo, MD; Long Geng, MD, PhD;

Hongbo Zhou, MD, PhD; Hong-Duo Chen, MD; Xing-Hua Gao, MD, PhD

Self Assessment Examination ................................................................................................................... 204

W. Clark Lambert, MD, PhD

Basal Cell Carcinoma Part I: Basal Cell Carcinoma Has Come of Age........................................................ 206

Min Deng, MD; Amanda F. Marsch, MD; Vesna Petronic-Rosic, MD, MSc

Self Assessment Examination ................................................................................................................... 214

W. Clark Lambert, MD, PhD

Departments Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor

Attack of the Living Dead: Why You Need a GMS Stain With a PAS Stain to Detect Fungi in Dermatopathology Specimens ..................................................................................................... 217

Divya Sharma, BA; Amy Weiss, BA; Stephen Peters, MD; W. Clark Lambert, MD, PhD

161

TABLE OF CONTENTS May/June 2015 2015 •• Volume Volume 13 13 •• Issue Issue 33 May/June

New to the Clinic Noah Scheinfeld, MD, JD, Section Editor

1% Ivermectin Cream (Soolantra) for the Treatment of Rosacea ................................................................ 222

Noah Scheinfeld, MD, JD

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

XELJANZ (Tofacitinib) for Chronic Plaque Psoriasis .................................................................................. 227

Aditya K. Gupta, MD, PhD, FRCPC; Deanne Daigle, MSc; William Abramovits, MD; Kimberly Dawn Vincent, MD

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

Necrotic Carpal Tunnel Syndrome: A Standard Deviation From the Median Nerve ..................................... 231

Warren R. Heymann, MD

Contact Dermatitis Capsule Matthew J. Zirwas, MD, Section Editor

Patch Testing Pearls: Solutions to Common Clinical Dilemmas ................................................................. 234

Jonathan G. Bonchak, MD; Matthew J. Zirwas, MD

Common Diseases: Treatment Options Noah Scheinfeld, MD, JD, Section Editor

Dissecting Cellulitis .................................................................................................................................. 236

Noah Scheinfeld, MD, JD

History of Dermatology Society Newsletter Eve Lowenstein, MD, PhD, Section Editor

Onychomycosis.......................................................................................................................................... 240

Mark Bernhardt, MD

Cosmetic Surgery Capsule

6th Annual Cosmetic Surgery Forum 2014 Top Resident Presentations December 3–6, 2014, Las Vegas, NV............................................................................................................................................ 241

Noah Scheinfeld, MD, JD

case studies Vesna Petronic-Rosic, MD, MSc, Section Editor

Weightlifter’s Nodule: A New Variant of Athlete’s Nodule.......................................................................... 246

Jamie Goldberg, MD; Carmen Campanelli, MD; Jason B. Lee, MD

162

TABLE OF CONTENTS May/June 2015 • Volume 13 • Issue 3

Chromoblstomycosis Caused by Cladophialophora bantiana in a Renal Transplant Recipient From Delhi, India....................................................................................................................................... 251

Prashant Verma, MD; Somenath Karmakar, MD; Deepika Pandhi, MD; Archana Singal, MD, MNAMS; Pravesh Yadav, MD; Shashi Khare, MD

Book Review Jennifer L. Parish, MD, Section Editor

Cutaneous Cryosurgery.............................................................................................................................. 255

Lawrence Charles Parish, MD, MD (Hon)

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.

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Lebanese Dermatological Society

163

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

May/June 2015

Volume 13 • Issue 3

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ Vesna Petronic-Rosic, MD, MSc

Meridian, MS Marcia Ramos-e-Silva, MD, PhD

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Andrew P. Lazar, MD Washington, DC

Virendra N. Sehgal, MD Delhi, India

Robert L. Baran, MD Cannes, France

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

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Riccarda Serri, MD Milan, Italy

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 I. 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 Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea

Julian Trevino, MD Dayton, OH

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Graham Turner, PhD, CBiol, FSB Port Sunlight, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

Snejina Vassileva, MD, PhD Sofia, Bulgaria

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

Art Papier, MD Rochester, NY

Daniel Wallach, MD Paris, France

Johannes Ring, MD, DPhil Munich, Germany

Michael A. Waugh, MB, FRCP Leeds, UK

María Daniela Hermida, MD Buenos Aires, Argentina

Roy S. Rogers III, MD Rochester, MN

Wm. Philip Werschler, MD Spokane, WA

Warren R. Heymann, MD Camden, NJ

Donald Rudikoff, MD New York, NY

Joseph A. Witkowski, MD Philadelphia, PA

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Robert I. Rudolph, MD Wyomissing, PA

Ronni Wolf, MD Rechovot, Israel

Camila K. Janniger, MD Englewood, NJ

Vincenzo Ruocco, MD Naples, Italy

Jianzhong Zhang, MD

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2015;13:164

164

Beijing, China Matthew J. Zirwas, MD Columbus, Ohio

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BRIEF SUMMARY This summary contains important information about EPIDUO (EP-E-Do-Oh) gel. It is not meant to take the place of your doctor’s instructions. Read this information carefully before you start using EPIDUO gel. Ask your doctor or pharmacist if you do not understand any of this information or if you want to know more about EPIDUO gel. For full Prescribing Information and Patient Information please see the package insert. WHAT IS EPIDUO GEL? EPIDUO gel is a prescription medicine for skin use only (topical) used to treat acne vulgaris in people 9 years of age or older. Acne vulgaris is a condition in which the skin has blackheads, whiteheads, and pimples.

The most commonly reported side effects when using EPIDUO gel include erythema, scaling, dryness, application site irritation, stinging and burning. Depending upon the severity of these side effects, patients should be instructed to use a moisturizer, reduce the frequency of the application of EPIDUO gel, or discontinue use. Tell your doctor right away if these side effects continue for longer than 4 weeks or get worse, you may have to stop using EPIDUO gel. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of EPIDUO gel. For more information, ask your doctor or pharmacist.

WHO IS EPIDUO GEL FOR? EPIDUO gel is for use in people 9 years of age and older. It is not known if EPIDUO gel is safe and effective for children younger than 9 years old.

You are encouraged to report negative side effects of prescription drugs to the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also contact GALDERMA LABORATORIES, L.P. at 1-866-735-4137.

Do not use EPIDUO gel for a condition for which it was not prescribed. Do not give EPIDUO gel to other people, even if they have the same symptoms you have. It may harm them.

HOW SHOULD I USE EPIDUO GEL? • Use EPIDUO gel exactly as your doctor tells you to use it. EPIDUO gel is for skin use only. Do not use EPIDUO gel in or on your mouth, eyes, or vagina. • Apply EPIDUO gel 1 time a day. • Do not use more EPIDUO gel than you need to cover the treatment area. Using too much EPIDUO gel or using it more than 1 time a day may increase your chance of skin irritation.

WHAT SHOULD I TELL MY DOCTOR BEFORE USING EPIDUO GEL? Before you use EPIDUO gel, tell your doctor if you: • have other skin problems, including cuts or sunburn. • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if EPIDUO gel can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if EPIDUO gel passes into your breast milk and if it can harm your baby. Talk to your doctor about the best way to feed your baby if you use EPIDUO gel. Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. • Especially tell your doctor if you use any other medicine for acne. Using EPIDUO gel with topical medicines that contain sulfur, resorcinol or salicylic acid may cause skin irritation. • Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. WHAT SHOULD I AVOID WHILE USING EPIDUO GEL? • You should avoid spending time in sunlight or artificial sunlight, such as tanning beds or sunlamps. EPIDUO gel can make your skin sensitive to sun and the light from tanning beds and sunlamps. You should wear sunscreen and wear a hat and clothes that cover the areas treated with EPIDUO gel if you have to be in the sunlight. • You should avoid weather extremes such as wind and cold as this may cause irritation to your skin. • You should avoid applying EPIDUO gel to cuts, abrasions and sunburned skin. • You should avoid skin products that may dry or irritate your skin such as harsh soaps, astringents, cosmetics that have strong skin drying effects and products containing high levels of alcohol. • You should avoid the use of “waxing” as a hair removal method on skin treated with EPIDUO gel. • EPIDUO gel may bleach your clothes or hair. Allow EPIDUO gel to dry completely before dressing to prevent bleaching of your clothes.

APPLYING EPIDUO GEL: • Wash the area where the gel will be applied with a mild cleanser and pat dry. • EPIDUO gel comes in a tube and a pump. If you have been prescribed the: ο Tube: Squeeze a small amount (about the size of a pea) of EPIDUO gel onto your fingertips and spread a thin layer over the affected area. ο Pump: Depress the pump to dispense a small amount (about the size of a pea) of EPIDUO gel and spread a thin layer over the affected area. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT EPIDUO GEL? • Talk to your doctor or pharmacist • Go to www.epiduo.com or call 1-866-735-4137

GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Revised: February 2013

References: 1. Gollnick HPM, Draelos Z, Glenn MJ, et al; Adapalene–BPO Study Group. Adapalene–benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol. 2009;161(5):1180-1189. 2. Czernielewski J, Michel S, Bouclier M, Baker M, Hensby C. Adapalene biochemistry and the evolution of a new topical retinoid for treatment of acne. J Eur Acad Dermatol Venereol. 2001;15(suppl 3):5-12. 3. Phase 3 (CSR 18088). Data on file. Galderma Laboratories, L.P. 4. Pariser DM, Westmoreland P, Morris A, Gold MH, Liu Y, Graeber M. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol. 2007;6(9):899-905. 5. According to data from Symphony Health Solutions, Pharmaceutical Audit Suite, Retail Audit, December 2013-November 2014.

www.epiduo.com/hcp

May/June 2015

Volume 13 • Issue 3

Editorial

Cutaneous Adaptations and Subcutaneous Soft Tissue Alterations Following Mechanical Stress: The Coxsackie A6 Virus May Offer a Solution W. Clark Lambert, MD, PhD;1 Michael A. De Marco, BA;1 Lawrence Charles Parish, MD, MD (Hon)2

kin alterations, such as “weightlifter’s nodule” presented in this issue of SKINmed1 may arise secondary to trauma or chronic stress in seemingly predictable patterns. Closer examination often reveals a higher order of complexity; however, the concept is complicated by the fact that some patients may experience these alterations, whereas many others may not.

the deep lesion may not be responsive. The two processes, ie, epidermal and dermal lesion, can reinforce each other, eventually causing the patient considerable distress, along with even more secondary conditions usually observed by physical therapists and personal trainers. We suspect that these disorders are vastly underreported in the medical literature.

In some cases, the reason for this discrepancy appears to be readily understood, such as in patients with a mild form of epidermolysis bullosa simplex who might develop foot and ankle bullae secondary to mild trauma from exercise. Even here, however, the underlying diagnosis may be elusive. Instead, some of these patients may actually have the acral peeling skin syndrome.2 Often, the underlying diagnosis is even less straightforward. A related lesion, the dermatofibroma,3 is sometimes clearly related to trauma, but in other cases there is no clear explanation, even when an association is well-known. For example, multiple dermatofibromas may arise in association with a systemic collagen vascular disorder4; however, the reason for this association is not known.

Case in Point

Mechanical Stress Many alterations in the dermis may be caused by mechanical insults and are associated with epidermal callus formation. Whereas the dermal lesion is amenable to the treatments advocated for weightlifter’s nodule,1 such as injection with steroid medication, the epidermal alteration requires a different approach. Treatment of these simple lesions may be challenging, and, without this,

A patient who consulted one of us (WCL), a 72-year-old Caucasian man, had a callus for decades on his left hallux, aggravated by participation in a running club. The lesion persisted despite discontinuing this activity and was retractile to numerous mechanical treatments. Following a long weekend spent with his grandson, who had a case of hand, foot, and mouth disease acquired at school, the patient also developed this disorder, with lesions on his hands, feet, and mouth. One of the lesions consisted of a totally asymptomatic bulla underlying the callus on the left hallux (Figure 1). The lesion unroofed spontaneously, approximately 1 week following formation (Figure 2). Following this event, the callus could no longer be seen and has not recurred during the ensuing 4 months. Conclusions Hand, foot, and mouth disease is caused by the Coxsackie A6 virus, which produces a bullous lesion in the stratum malpighii (“prickle cell layer”) underlying the stratum corneum. The mech-

See also Case Study, page 246. From the Departments of Dermatology and of Pathology and Laboratory Medicine, Rutgers University – New Jersey Medical School, Newark, NJ;1 and the Department of Dermatology and Cutaneous Biology and Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA3 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers University – New Jersey Medical School, Departments of Dermatology and of Pathology and Laboratory Medicine, Room C576 Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

SKINmed. 2015;13:167–168

167

May/June 2015

Editorial

Figure 1. Bulla underlying callus on the left hallux.

Figure 2. Bulla, unroofed, underlying callus on the left hallux. Note the structural detail on the underside of the bulla roof.

anisms have been studied and are fairly well-known.5 We suggest that a modified Coxsackie virus or viral product may form the basis for a superior treatment modality for callus, an otherwise common, vexing problem that often complicates care of underlying dermal reactive lesions. References 1 Goldberg J, Campanelli C, Lee JB. Weightlifter’s nodule: a new variant of athlete’s nodule. Skinmed. 2015;13:246– 249. 2 Szczecinska W, Nesteruk D, Wertheim-Tysarowska K, et al. Under-recognition of acral peeling skin syndrome:59

new cases with 15 novel mutations. Br J Dermatol. 2014;17:1206–1210. 3 Parish LC, Yazdanian S, Lambert WC, Lambert PC. Dermatofibroma: a curious tumor. Skinmed. 2012;10:268–270. 4 Lin R, Landsman L, Krey P, Lambert WC. Multiple dermatofibromas occurring in systemic lupus erythematosus: a report of three cases and review of the literature. Cutis. 1986;37:46–51. 5 Downing C, Ramirez-Fort MK, Doan HQ, et al. Coxsackievirus A6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60:381–386.

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May/June 2015

Volume 13 • Issue 3

COMMENTARY

Patch: A Skin Lesion in Need of Definition Vikram K. Mahajan, MD; Nitin Ranjan, MD

ermatologists have traditionally used specific terms to describe skin lesions, and the importance of descriptive terminology is most evident in this specialty; yet, there is no agreement among dermatologists on standard definitions of basic skin lesions despite the dermatology lexicon being rich in descriptive terms. The problem was noted by Watt and Jilson during the 1960s while proposing simplified definitions for 10 basic cutaneous lesions. Later, the glossary of basic dermatology lesions was published by the International League of Dermatological Societies Committee on Nomenclature, and most definitions currently in use are broadly in agreement with these. The common descriptive terms for primary cutaneous lesions—macule, papule, nodule, and plaque—have been well-defined, with minor variations in most dermatology textbooks and reference books; however, some of these definitions for basic skin lesions have not received universal acceptance for being ambiguous and unclear.1–4 Lewis and colleagues1 even suggested the adoption of, with some modifications, the definitions for basic skin lesions proposed by Watt and Jilson. Their suggested modifications regarding size or whether solid, hollow, superficial, or deep were not agreed upon by others.2–4 For instance, a nodule larger than 1.0 cm is currently described as a “large nodule” rather than a “tumor” or a “mass,” as has been suggested by Watt and Jilson or Lewis and colleagues.1 It has also been noted that the definitions of the International League of Dermatological Societies Committee on Nomenclature are inconsistent and vary among terms and across countries, eg, English, American, and German versions of the league’s glossary list the size of a papule as 0.5 cm, while in the French and Spanish versions it is 1.0 cm.4 Another particular problem that has never been agreed upon by dermatologists is the definition of a “patch” despite its usage by many journals and in most standard textbooks for describing early lesions of mycosis fungoides, digitate dermatosis, leprosy, or other dermatoses that have a fine scale, minimal atrophy, or altered skin texture.5,6 Some authors even consider the term patch as obsolete, while others advocate avoiding its use altogether.7,8 Ashton4 favored the suggestion by Lewis and colleagues1 to use 1 cm

as the cutoff between macule and patch, a papule and a nodule, a vesicle and a bulla, and so on. Accordingly, a patch has been described as a nonpalpable, flat skin lesion measuring >1 cm in diameter, and with a color (hypopigmented or hyperpigmented) different from the surrounding skin.1 Such a definition of patch clearly lacks clarity and is confusing since it differs from a macule only in size. The different definitions of patch are also obfuscated by differences in its definition in French vs English. Currently preferred terms “large macule” or “area” for describing a macule that is 1 cm to 2 cm or >2 cm in diameter, respectively, are perhaps more useful and convenient;7,8 furthermore, there is no consensus on the issue of scaling or other textural changes within the definition of a macule.5 In view of this difficulty in defining “patch,” we put forth to the International League of Dermatologic Societies or other international dermatologic organizations our proposed definition of patch to stimulate a debate and build international consensus on this rarely discussed term. The “patch” and other relevant and related basic dermatologic lesions are thus defined below. Patch As proposed by us, a patch is “a circumscribed flat skin lesion with nonelevated borders, and having obvious altered skin texture or fine scaling with or without changes in skin color.” A patch can be erythematous and hypopigmented or hyperpigmented, and its borders may be well-defined, ill-defined, regular, or irregular.” Altered skin texture, atrophy, or fine scaling must form the hallmark feature of a patch. Macule A macule is a circumscribed change in skin color of any size or shape that is nonpalpable and without depression. It can be circular, oval, or irregular in shape and may have distinct margins (well-defined) or merge with the surrounding skin (ill-defined). It may be hypopigmented, hyperpigmented, or depigmented, but has no alteration in the skin texture or scaling within the

From the Department of Dermatology, Venereology & Leprosy, Dr. R. P. Govt. Medical College, Kangra (Tanda)-176001 (Himachal Pradesh), India Address for Correspondence: Vikram K. Mahajan, MD, Dr. R. P. Govt. Medical College, Department of Dermatology, Venereology & Leprosy, Kangra (Tanda)-176001, Himachal Pradesh, India • E-mail: vkm1@rediffmail.com

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lesion. A macule measuring >1 cm or more in diameter is best defined as a “large macule” (1–2 cm) or an “area” (>2 cm).

A nodule is a solid, round, elevated, and palpable lesion of >5 mm to 10 mm in size. A nodule measuring >10 mm is better described as a “large nodule,” avoiding the term “tumor” as it usually connotes neoplasm. It can be ellipsoid or globular in shape and pedunculated or sessile. Depending on its depth it can be epidermal, epidermal-dermal, dermal, dermal-subdermal, or subcutaneous. In addition, features such as being warm, hard, soft, fluctuant, tender, movable, or fixed can vary according to the underlying pathology.

any skin lesion. It is also highly desirable to make size-based cutoffs as uniform as possible for all types of skin lesions. We believe that the proposed definition is clinically concise, morphologically accurate, and unambiguous. The term patch will then be helpful in the clinical description of dry, atrophic, and rough textured lesions of tuberculoid leprosy; mildly scaly and with altered texture/color lesions of early- (patch) stage cutaneous Tcell lymphoma; perifollicular hypopigmented lesions of pityriasis versicolor having fine and branny scales; dry, hypopigmented, sometimes with fine scales, and rough surfaced lesions of pityriasis alba, and so on. Because there are no textural changes, the widely accepted nomenclature “café au lait macules” or “ash leaf macules” must be preferred to occasionally used terminology “café au lait spot” or “Fitzpatrick patch,” respectively.9 Similarly, in the classification of toxic epidermal necrolysis with or without spots10 the term “spot” can be replaced with “atypical erythema multiforme–like” lesions, as they often progress to blister formation. Viewpoints are open to debate and any modifications, as revision in the proposed definition(s) will be essential with the evolving dermatology lexicon.

Plaque

References

Papule A papule is a solid, elevated, and palpable lesion up to 5 mm in size. Depending on common shapes and other features, it can be sessile, pedunculated, dome-shaped, flat-topped, filiform, acuminate, umblicated, rough, or smooth. Nodule

A plaque is a solid, elevated, and palpable skin lesion >1 cm in diameter. It generally has a flat plateau-like surface and may involve the epidermis, dermis, or both. It may have a round, oval, discoid/uniformly thickened shape or an annular shape when centrally depressed. Its borders may be regular or irregular. It may be formed by the extension of coalescence of papules or nodules. Plaques >2 cm in diameter are preferably described as “large plaques.” Additional features such as scaling, necrosis, erosion, ulceration, crusting, and an eschar formation are indicative of underlying pathology.

1 Lewis EJ, Dahl MV, Lewis CA. On standard definitions: 33 years hence. Arch Dermatol. 1997;133:1169. 2 Reisfeld PL. On standard dermatologic definitions. Arch Dermatol. 1998;134:636–637. 3 Resnik KS, Ackermann AB. On standard definitions of individual skin lesions. Arch Dermatol. 1998;134:636–637. 4 Ashton RE. Standard definitions in dermatology: the need for further discussion. Arch Dermatol. 1998;134:637. 5 Cox NH, Coulson IH. Diagnosis of skin disease. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Textbook of Dermatology. 8th ed. Oxford, England: Wiley-Blackwell; 2010:5.7. 6 Yu MI, Lee HR, Han TY, et al. A Solitary erosive patch on the left nipple. Int J Dermatol. 2012;51:27–28.

Comments A patch (a lesion of altered skin texture) can clearly be delineated with these morphologic features from a “macule” (a lesion having only altered skin color) and a “plaque” (an elevated and palpable plateau-like flat surfaced lesion of >1 cm in diameter). This will also solve the problem of a tie-in with the definition of erythema nodosum and plaque/nodule noted by Ashton.4 A nodule of erythema nodosum with its ill-defined border and erythematous surface can be differentiated from a patch as being subcutaneous in depth. This will also exclude any ambiguity in as-yet evolving skin lesions. It will be prudent to record other adjective features of these primary lesions and their actual size, or the range of sizes, in view of varied opinions on size for defining

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7 Thappa DM. Principles of diagnosis in dermatology. In: Thappa DM, ed. Essentials in Dermatology. 2nd ed. New Delhi, India: Jaypee Brothers Medical Publishers (P) Ltd; 2009:16–23. 8 Bedi BMS. Principles of clinical diagnosis: physical examination. In: Valia RG, Valia AR, eds. IADVL Textbook of Dermatology. 3rd ed. Mumbai, India: Bhalani Publishing House; 2008:95–109. 9 Schwartz RA, Fernandez G, Kotulska K, et al. Tuberous sclerosis complex: advances in diagnosis, genetics, and management. J Am Acad Dermatol. 2007;57:189–202. 10 Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, StevensJohnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92–96.

Patch: A Skin Lesion in Need of Definition

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Marnie nussbaum, MD Dr. Nussbaum specializes in general and cosmetic dermatology. She is also Clinical Instructor of Dermatology at Weill Cornell Medical Center. Among her numerous awards are the Outstanding House Staff Award and the Women in Science Award. Dr. Nussbaum is a member of the American Academy of Dermatology, the American Society of Dermatologic Surgery and the Women’s Dermatologic Society.

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Fig. 1 The fabric washed in Tide Free & Gentle is clean down to the fiber level, demonstrating superior clean ability; not only removing or lifting stains, dirt and odor particles, but preventing them from reattaching or redepositing to the fabrics, wash after wash. Original image in B&W. Soil has been colorized to show contrast.

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Fig. 2 Soil residues left on fibers attract dirt from the wash water.

Step 2: Block

• Anti-Redeposition Technology: Concentrated polymers sweep in to trap the dirt in the wash water, to prevent it from reattaching to the fabric fibers. Our bodies produce up to 50 grams of body soil per day, including mucus, dead skin, sweat, sebum and bacteria. Clothing may look clean, but in a given laundry load, all that soil combines in the water to create a very dirty environment. This is important because even if a stain appears to have been removed from clothing the first trip through the washing machine, dirt attracts dirt, so any soil residues left on clothing fibers will cause dirt in the wash water to redeposit on clothes over time. See Fig. 2. Dirt redeposition is a primary reason why whites tend to appear dingy after numerous washings – not just dye transfer as is commonly believed. As larger high eﬃciency washers continue to become the norm in American households, this issue becomes more pronounced. High eﬃciency washers use three times less water so soil is more concentrated in the wash water, increasing the likelihood of redeposition of dirt on clothing. However, Tide Free & Gentle’s unique “Lift and Block” technology provides a superior clean from wash to wash. Patients benefit from the gentleness of a dye- and perfume-free detergent without having to sacrifice superior cleaning power.

The Importance of Patient Compliance in a Laundry Regimen

“I recommend Tide Free & Gentle to my patients because it drives compliance since it is not only gentle, but provides a better clean,” says Dr. Nussbaum.

Fig. 3 Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets. But it’s also very important to remind patients with sensitive skin issues that the entire laundry regimen needs to be free of dyes and perfumes. Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets. See Fig. 3. For this reason, it is critical to remind patients that caring for sensitive skin doesn’t stop with detergent; the entire laundry regimen needs to be dye-free and perfumefree. In fact, fabric softeners that do not contain dyes or fragrance, such as Downy Free & Gentle, may have sensitive skin benefits, such as reducing friction between clothes and skin and, therefore, skin irritation.

Dermatologists Play an Important Role

Dermatologists can help patients ensure they are achieving the best results for their laundry and their skin. Talk with your patients, particularly those with sensitive skin, about their current laundry detergent choices and help them understand the benefits of following a Free & Gentle regimen. Be sure to recommend products that complement your patient’s skin health needs while also helping them achieve the optimal result of clean laundry.

References

1 Misery, L., Sibaud, V., Merial-Kieny, C., & Taieb, C. Sensitive skin in the American population: Prevalence, clinical data, and role of the dermatologist. Int J Dermatol. 2011;50:961–967. 2 2010 Habits, Practices and Attitudes conducted by P&G.

CMY

May/June 2015

Volume 13 • Issue 3

Original contribution

Topical Nitroglycerine in Perniosis/Chilblains Prashant Verma, MD Abstract The treatment of perniosis is largely inadequate. The success rate of 0.2% nitroglycerine ointment is demonstrated in the present series. Twenty-two patients clinically diagnosed with severe perniosis were prescribed the topical vasodilator nitroglycerine. Digital photography and patient self-report of the clinical appearance, degree of irritation, and pain and soreness of the lesions were assessed on a 3-point scale to assess therapeutic response. A total of 18 of the 22 patients had regression of the lesions within the first week of treatment and complete regression in 2 weeks. Of these patients, 2 who experienced a relapse were successfully treated with another course of topical nitroglycerine. Two of 22 patients had regression of the lesions during the second week and complete regression in another week. Response was delayed in patients with a longer duration of disease. Topical 0.2 % nitroglycerine ointment may be a promising alternative treatment option in perniosis. (SKINmed. 2015;13:176–177)

erniosis (also pernio or chilblains) is an inflammatory skin condition presenting as pruritic and/or painful erythematous to violaceous acral lesions after exposure to cold. It is common in young and middle-aged women.1 The direct cause of pernio is cold exposure; specifically, exposure to both mild nonfreezing cold and humidity.2 Perniosis is usually idiopathic; however, chronic perniosis may be secondary to various systemic diseases.3 Treatment involves rewarming of the whole body and avoidance of further exposure to cold.4 Several treatment modalities have been used; however, the treatment of chilblains remains largely unsatisfactory.1 Nifedipine in high doses remains the mainstay of treatment.5 Pentoxyfilline,6 hydroxychloroquine sulphate,7 phenoxybenzamine,8 and corticosteroids9 have also been shown to be effective. Topical nitroglycerine, a vasodilator, has been used successfully in infants with peripheral arterial ischemia.10,11 Case Report The series involved 22 patients with severe perniosis who presented to our dermatology clinic. A detailed history and physical examination were undertaken in each patient. Complete blood cell count and urine analysis were conducted. Antinuclear antibody levels (by indirect immunofluorescence) could be assayed in only 4 patients due to limited resources. Antinuclear antibody results were negative in all 4 patients. All patients were prescribed warm

water soaks and cold protection measures. Written informed consent was obtained from each patient before prescribing nitroglycerine. The patients were treated with topical nitroglycerine ointment 0.2% applied twice a day. Patients were asked to apply a thick layer without occlusion. After complete regression of the lesions, patients were maintained on warm water soaks and cold protection measures (woollen gloves and socks and cold exposure avoidance). In addition, all patients were prescribed oral cetirizine dihydrochloride 10 mg once daily. Patients were followed up weekly while on topical nitrogesic and thereafter once in 2 weeks until the end of the winter season. Digital photographs were taken at each visit until remission of the lesions. In addition, patients kept a daily diary of any change in the clinical appearance, degree of irritation, and pain and soreness of the lesions assessed on a 3-point scale: better, same, or worse. The duration of established lesions and the appearance of new lesions were also recorded. Patients were also asked to report headache and palpitations. The age of patients ranged from 13 to 24 years, and 19 were women and 3 were men. The duration of lesions ranged from 10 days to 30 days. Two of the 22 patients gave a history of perniosis in first-degree relatives. Results from physical examination were normal in all patients. Complete blood cell counts and urine analysis were also within normal limits in all patients. A total of 20 of 22 patients completed the study while 2 were lost to follow-up. Eighteen of the 22 patients had regres-

From North Delhi Municipal Corporation Medical College & Hindu Rao Hospital, Delhi, India Address for Correspondence: North Delhi Municipal Corporation Medical College & Hindu Rao Hospital, 9 State Bank Colony, G.T Karnal Road, Delhi-110009, India • E-mail: drprashant_derma@yahoo.co.in

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sion of the lesions within the first week and complete regression in 2 weeks. They were then maintained on warm water soaks and cold protection measures until the end of the winter season. Two patients experienced relapse during the follow-up period and were again successfully treated with 2 weeks of topical nitroglycerine. Two of the 22 patients had regression of lesions during the second week and complete regression in another week. In all other cases, symptoms improved earlier. Irritation and pain improved within 2 days in all patients and resolved in 5 to 7 days in 16 patients. Four patients continued to have slight itching in the absence of lesions. Patients with a longer duration of disease took somewhat longer time to respond. No side effects were noted in all but one patient who experienced transient headache.

vascular changes and hence may take longer to respond, as was observed in the present study. Topical nitroglycerine may prove to be a safer alternative to oral nifedipine. Conclusions Perniosis is an under-researched subject, the treatment options for which are limited. Topical nitroglycerine, an innocuous and effective treatment for perniosis, requires further exploration in perniosis through randomized double-blind studies. References 1 Prakash S, Weisman MH. Idiopathic chilblains. Am J Med. 2009;122:1152–1155.

Discussion

2 Goette DK. Chilblains (perniosis). J Am Acad Dermatol. 1990;23(2 pt 1):257–262.

Chilblains are the result of an abnormal reaction to cold and are usually localized to acral sites. The lesions are often itchy and usually tender, erythematous, and inflammatory, and may blister or ulcerate.12 Many factors may be implicated in the etiology of the condition, varying from genetic to hormonal to increase in nerve bundles.1 Histopathologically, chilblains are characterized by edema of the papillary dermis, a perivascular lymphocytic infiltrate, and thickening of the blood vessel walls with intimal proliferation leading to obliteration of vascular lumen.12 Chilblains are more commonly seen in women,1,12 as observed in the present study. Perniosis is usually self-limited, yet it may cause considerable morbidity and sequelae such as ulceration, blistering, and scarring.1,12 In the present report, ulceration and crusting were seen in 2 patients, which healed with some scarring. Unlike an earlier study,13 only 2 of the 22 patients had a history of perniosis in one of their first-degree relatives in the present series. Treatment of perniosis continues to be largely unsatisfactory. Topical nitroglycerine is commonly used in the treatment of anal fissures and is well tolerated except for causing mild transient headaches in some patients.14

3 Viguier M, Pinquier L, Cavelier-Balloy B, et al. Clinical and histopathologic features and immunologic variables in patients with severe chilblains. A study of the relationship to lupus erythematosus. Medicine (Baltimore). 2001;80:180–188.

Nitroglycrine, an organic nitrate generates nitric oxide, which activates guanylate cyclase, producing cyclic guanosine monophosphate. This signalling ultimately results in vasodilatation through relaxation of the smooth muscles. Nitroglycerin is well absorbed across intact skin, delivering the highest dose to the area directly beneath.10 It has been used effectively to treat peripheral arterial ischemia in infants without significant side effects.10,11 In a personal observation, perniosis in an infant was effectively treated with topical 0.2% nitroglycerine ointment. Therefore, it was thought prudent to extend the use of topical nitroglycerine ointment to perniosis. The present series demonstrates the efficacy and safety of nitroglycerine in perniosis. Lesions of longer duration may have more prominent underlying

10 Baserga MC, Puri A, Sola A. The use of topical nitroglycerin ointment to treat peripheral tissue ischemia secondary to arterial line complications in neonates. J Perinatol. 2002;22:416–419.

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4 Almahameed A, Pinto DS. Pernio (chilblains). Curr Treat Options Cardiovasc Med. 2008;10:128–135. 5 Patra AK, Das AL, Ramadasan P. Diltiazem vs. nifedipine in chilblains: a clinical trial. Indian J Dermatol Venereol Leprol. 2003;69:209–211. 6 Noaimi AA, Fadheel BM. Treatment of perniosis with oral pentoxyfylline in comparison with oral prednisolone plus topical clobetasol ointment in Iraqi patients. Saudi Med J. 2008;29:1762–1764. 7 Yang X, Perez OA, English JC 3rd.Successful treatment of perniosis with hydroxychloroquine. J Drugs Dermatol. 2010;9:1242–1246. 8 TREATMENT of chilblains by phenoxybenzamine; a clinical trial in general practice by the South-East Scotland Faculty of the College of General Practitioners. Br Med J. 1957;2:1521–1522. 9 Ganor S. The treatment of chilblains with fluocinolone cream under ecclusive dressing. Harefuah. 1973;84:163.

11 Wong AF, McCulloch LM, Sola A. Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates. J Pediatr. 1992;121:980–983. 12 Crowson AN, Magro CM. Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases. Hum Pathol. 1997;28:478–484. 13 Raza N, Habib A, Razvi SK, Dar NR. Constitutional and behavioral risk factors for chilblains: a case-control study from Pakistan. Wilderness Environ Med. 2010;21:17–21.e1. 14 Gorfine SR. Topical nitroglycerin therapy for anal fissures and ulcers. N Engl J Med. 1995;333:1156–1157.

Topical Nitroglycerine in Perniosis/Chilblains

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May/June 2015

Volume 13 • Issue 3

Original contribution

Oral Finasteride Presents With Sexual-Unrelated Withdrawal in Long-Term Treated Androgenic Alopecia in Men Nicolas Perez-Mora, MD, PhD; Carlos Velasco, MD; Fernando Bermúdez, MBA Abstract Side effects associated with oral finasteride (FT) (1 mg/d) and topical 5% minoxidil (M5) have been previously described. The authors have evaluated long-term adverse effects and causes of long-term therapy withdrawal in patients with androgenic alopecia (AGA) treated with M5+FT vs M5 without FT. A total of 130 AGA patients with a minimum 2-year follow-up volunteered to complete a questionnaire on side effects. Patients’ responses were classified as “never,” “rarely,” “sometimes,” “often,” and “all the time.” An adverse effect was considered in the presence of an “often” or “all the time” response. A total of 100 patients received combined M5+FT and were compared with 30 patients receiving single-therapy M5 according to the physician’s clinical criteria. Erectile dysfunction (3%), diminished libido (4%), and reduced ejaculation (7%) were present in patients taking M5+FT but were absent in patients taking M5. Only 1 of 100 patients taking M5+FT quit long-term therapy due to sexual adverse effects (diminished libido). The main causes for therapy withdrawal in the FT group were lack of positive results in 11% and in the M5 group side effects in 4% (P<.02). Increased body hair was different between groups: with 6.6% in the M5 group and 4% in the M5+FT group (P<.03). FT demonstrates sexual-unrelated reasons as the main cause of therapy withdrawal in long-term treated AGA patients. (SKINmed. 2015;13:179–183)

ndrogenic alopecia (AGA) in men is an emotionally distressing and frustrating dermatologic problem characterized by the progressive miniaturization and loss of terminal hairs on the scalp in a defined distribution.1,2 Advances in genetics and hair follicle biology have improved the understanding of the pathogenesis of AGA. The role of androgens and follicular androgen receptors, in genetically predisposed individuals, has been established as the key factors of follicular injury.3–6 In addition, immunoregulatory,7 microinflammatory,8 and apoptotic mechanisms9 acting synergistically with hormonal factors are also implicated. AGA is the most common type of hair loss in men. It is estimated that prevalence rates in Caucasian populations is around 30% for men in their 30s, 40% for men in their 40s, and 50% for men in their 50s.10,11 The primary recommended therapies for AGA in evidence-based clinical guidelines are topical 5% minoxidil and oral finasteride (1 mg/d).12–14

Many clinical studies have independently targeted topical minoxidil (2%–5%)15–19 and oral finasteride (1 mg/d)20–25 to evaluate their safety and efficacy. Few studies have directly compared the efficacy and safety of topical minoxidil vs oral finasteride.26,27 In addition, there is a paucity of literature comparing the safety and efficacy of both drugs alone, or in combination, for treating patients with AGA.28 As a direct consequence, there is a lack of studies evaluating the incidence of adverse effects of combined topical minoxidil with oral finasteride (M5+FT) compared with topical single-therapy minoxidil (M5). Causes of discontinuation of therapy in longterm AGA treated patients may also differ depending on each therapeutic regimen. The aims of our study were to: (1) evaluate adverse effects in long-term AGA patients treated with M5+FT vs patients treated with M5, and (2) evaluate causes of FT and/or M5 therapy discontinuation in long-term treated AGA patients.

From Svenson Medical, Madrid, Spain Address for Correspondence: Nicolas Perez-Mora, MD, PhD, Svenson Medical, Paseo de la Castellana 155, 28046 Madrid, Spain • E-mail: nperezmora@svenson.es

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Methods

Study population A letter and written questionnaire were submitted by postal mail to 358 patients. All patients had been diagnosed with AGA by 25 different physicians at 33 different hair care centers. Therapy profile and clinical outcome of patients were retrospectively assessed by using patient records and clinical information from a single centralized intranet database. This tool allowed us to verify that the diagnostic protocol is similar regardless of where or by whom the patient was located. All patients receiving the questionnaire had had a minimum 2-year follow-up (range: 2–5 years). A total of 159 of 358 patients (44.4%) volunteered to complete and reply to the questionnaire. A total of 29 patients receiving follicular unit transplantation were excluded from the study. A total of 130 patients with AGA were included into the study. The mean age of the studied population was 35.1±11.2 years.

Treatment assessment methods Topical minoxidil was used at 5% concentration one to two times per day and was indicated according to the physician’s clinical criteria. As a general rule, patients were started on singletherapy M5, and oral FT was added to the patients’ regimen, if satisfactory results were not achieved after 6 months of singletherapy M5. Thirty patients received single-therapy topical minoxidil (M5 group) and 100 patients received topical minoxidil together with oral finasteride 1 mg/d (M5+FT group). The questionnaire included the following 15 clinical manifestations: (1) side effects attributed to minoxidil: scalp pruritus, hair color change, scalp pain, body hair increase, hypotension associated with antihyper-

tensive therapy, and palpitations; and (2) side effects attributed to finasteride: erectile dysfunction, diminished libido, reduced ejaculation, urinary urgency, gynecomastia, decreased body hair, depression, weakness, and insomnia. All clinical manifestations were classified according to the following scale score: “never,” “rarely,” “sometimes,” “often,” and “all the time.” Adverse effects were considered in the presence of an “often” or “all the time” response. Patients were also questioned about causes of self-discontinuation of therapy according to the three following response categories: side effects, lack of positive results, or presence of positive results.

Statistical Methods Statistical analyses were performed using SPSS version 20.0.0 (IBM, Armonk, NY) with P<.05 being statistically significant for all results. Results The mean age of the patients was 39.7±14.3 years in the M5 group and 33.6±9.7 years in the M5+FT group. The incidence of adverse events between groups is summarized in Table I and Table II. Increased body hair was different between groups, with 6.6% in the M5 group and 4% in the M5+FT group (P<.03). The incidence of scalp-related clinical manifestations such as pruritus, scalp pain, or hair color change was also higher in patients in the single-therapy M5 group, although the differences did not reach statistical significance (Table I). Erectile dysfunction (3%), diminished libido (4%), and reduced ejaculation (7%) were present in the M5+FT group but were absent in the single-therapy M5 group (Table II).

Table I. Long-Term Adverse Effects Attributed to Minoxidil in 130 Patients With Androgenic Alopecia Adverse Effect

M5+FT

P Valuea

P Valueb

Scalp pruritus

6.6 (2/30)

3 (3/100)

Hair color change

3.3 (1/30)

1 (1/100)

Scalp pain

3.3 (1/30)

1 (1/100)

Body hair increase

6.6 (2/30)

4 (4/100)

<.03

Hypotension

3.3 (1/30)

0 (0/100)

Palpitations

0 (0/30)

0 (0/100)

Abbreviations: M5, minoxidil single-therapy (n=30 patients); NS, not significant; M5+FT, combined minoxidil and finasteride therapy (n=100 patients). Values are expressed as percentage (number). a Fisher exact test: adverse effect included “often” or “all the time” responses. b U Mann-Whitney test: included all scale-score responses. SKINmed. 2015;13:179–183

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Table II. Long-Term Adverse Effects Attributed to Finasteride in 130 Patients With Androgenic Alopecia Adverse Effect

M5+FT

P Valuea

P Valueb

Erectile dysfunction

0 (0/30)

3 (3/100)

Diminished libido

0 (0/30)

4 (4/100)

Reduced ejaculation

0 (0/30)

7 (7/100)

Urinary urgency

0 (0/30)

2 (2/100)

Gynecomastia

0 (0/30)

0 (0/100)

Decreased body hair

0 (0/30)

1 (1/100)

Depression

6.6 (2/30)

2 (2/100)

Weakness

0 (0/30)

1 (1/100)

Insomnia

3.3 (1/30)

5 (5/100)

ized trials have directly compared the efficacy of topical M5 vs oral FT.26,27 A randomized open trial of 100 AGA patients suggests that combined therapy with FT and M5 may be superior to monotherapy with either agent.28 Thus, the safety and efficacy of M5 vs M5+FT therapy in long-term treated AGA deserves further investigation.12 We have declined to assess and compare efficacy results in the present study, because our patients were assigned to each therapeutic regimen in an uncontrolled manner and according to the best clinical criteria of the patient’s physician. Some authors have reported better hair growth results when FT therapy is maintained over 5 years.29,30 Due to that, we found it of clinical interest to analyze causes of long-term therapy withdrawal in AGA patients treated with single-therapy M5 vs patients treated with combined M5+FT. To the best of our knowledge this specific comparative analysis has not been previously performed.

Figure 1. Causes of long-term therapy self-discontinuation in 130 patients with androgenic alopecia. Topical minoxidil 5%: 130 patients; minoxidil single-therapy (M5): 30 patients; combined minoxidil and finasteride therapy (M5+FT): 100 patients; oral finasteride 1 mg/d: 100 patients. Chi-square test: P<.02.

Causes of therapy discontinuation in these 130 long-term treated AGA patients are summarized in the Figure. Only 1 of 100 M5+FT patients quit long-term therapy due to sexual adverse effects (diminished libido). The main causes for therapy withdrawal in the FT group were lack of positive results in 11% and in the M5 group were side effects in 4.6% (P<.02). Discussion Available data suggest that FT may be more effective than M5 for the induction of hair growth, but few prospective randomSKINmed. 2015;13:179–183

Adverse effects associated with topical M5 are infrequent and have been previously described. The most common side effects are scalp-related events31 and increased body hair.32 Our study confirmed that side effects are the main cause of M5 therapy withdrawal. Six of 130 patients (4.6%) discontinued long-term therapy due to M5-attributed side effects (Figure). Interestingly, the incidence of increased body hair was lower in M5+FT patients and reached statistical significant difference (P<.03) (Table I). The underlying mechanism of this beneficial effect might be a specific action of FT on the androgen paradox response of body follicular androgen receptors.4

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Recent clinical reviews have focused on the side effects of oral FT21,33 and on the varied degree of FT-induced sexual dysfunction,34,35 which include erectile dysfunction (0.75%–3.8%), reduced ejaculation (1%–7.7%), and diminished libido (1.9%– 4.9%). Our M5+FT-treated patients showed a similar percentage of sexual-related side effects (Table II); therefore, causes of FT long-term withdrawal were expected to be associated with sexual dysfunction. Surprisingly, the main cause of self-discontinuation of FT was the lack of positive results (11%), and only one patient (1%) quit therapy due to diminished libido (Figure). A limitation of our study is that we focused only on long-term treated AGA patients. Previous authors have described FT-induced depression in a subset of AGA patients,36–38 but we did not find a higher incidence of depression in the M5+FT group (2%) as compared with the M5 group (6%). None of our FT patients presented with gynecomastia, as reported in previous studies.39,40 Conclusions Our study demonstrates that the main cause of self-discontinuation of therapy has been different for each drug in long-term treated AGA, with lack of positive results in 11% of patients in the FT group and side effects in 4.6% of patients in the M5 group (P<.03; Figure). FT withdrawal caused by sexual side effects is infrequent in long-term treated patients with AGA. M5 and FT present with a different pattern of therapy discontinuation in long-term treated patients with AGA. References 1 Norwood OT. Male pattern baldness: classification and incidence. South Med J. 1975;68:1359–1365. 2 Hamilton JB. Patterned loss of hair in man: types and incidence. Ann N Y Acad Sci. 1951;53:708–728. 3 Kaufman KD. Androgen metabolism as it affects hair growth in androgenetic alopecia. Dermatol Clin. 1996;14:697–711. 4 Randall VA. Androgens and hair: a biological paradox. In: Nieschlag E, Behre HM, eds. Testosterone: Action, Deficiency and Substitution. 3rd ed. New York, NY: Cambridge University Press; 2004: 207–229. 5 Inui S, Itami S. Androgen actions on the human hair follicle: perspectives. Exp Dermatol. 2013;22:168–171.

8 Mahé YF, Michelet JF, Billoni N, et al. Alopecia and micro-inflammation. Int J Dermatol. 2000;39:576–584. 9 El-Domyati M, Attia S, Saleh F, et al. Evaluation of apoptosis regulatory markers in androgenetic alopecia. J Cosmet Dermatol. 2010;9:267–275. 10 Hoffmann R, Happle R. Current understanding of androgenetic alopecia. Part II: clinical aspects and treatment. Eur J Dermatol. 2000;10:410–417. 11 Otberg N, Finner AM, Shapiro J. Androgenetic alopecia. Endocrinol Metab Clin North Am. 2007;36:379–398. 12 Blumeyer A, Tosti A, Messenger A, et al. Evidence-based (S3) guideline for the treatment of androgenetic alopecia in women and in men. J Dtsch Dermatol Ges. 2011;9 suppl 6:S1–S57. 13 Tsuboi R, Itami S, Inui S. Guidelines for the management of androgenetic alopecia. J Dermatol. 2012;39:113–120. 14 Lee WS, Lee HJ, Choi GS. Guidelines for management of androgenetic alopecia based on BASP classification: The Asian Consensus Committee guideline. J Eur Acad Dermatol Venereol. 2013;27:1026–1034. 15 De Villez RL. Topical minoxidil therapy in hereditary androgenetic alopecia. Arch Dermatol. 1985;121:197–202. 16 Rietschel RL, Duncan SH. Safety and efficacy of topical minoxidil in the management of androgenetic alopecia. J Am Acad Dermatol. 1987;16:677–685. 17 Price VH, Menefee E, Strauss PC. Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and 2% topical minoxidil, placebo, or no treatment. J Am Acad Dermatol. 1999;41:717–721. 18 Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002;47:377–385. 19 Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007;57:767–774. 20 Leyden J, Dunlap F, Miller B et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999;40:930–937. 21 Mella JM, Perret MC, Manzotti M, et al. Efficacy and safety of finasteride therapy for androgenetic alopecia: a systematic review. Arch Dermatol. 2010;146:1141– 1150. 22 Price VH, Menefee E, Sanchez M, et al. Changes in hair weight in men with androgenetic alopecia after treatment with finasteride (1 mg daily): 3- and 4-year results. J Am Acad Dermatol. 2006;55:71–74.

6 Heilmann S, Kiefer AK, Fricker N. Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology. J Invest Dermatol. 2013;133:1489–1496.

23 Kaufman KD. The Finasteride Male Pattern Hair Loss Study Group: long-term (5-year) multinational experience with finasteride 1 mg in the treatment of men with androgenetic alopecia. Eur J Dermatol. 2002;12:38–49.

7 Jaworsky C, Kligman AM, Murphy GF. Characterization of inflammatory infiltrates in male pattern alopecia: Implications for pathogenesis. Br J Dermatol. 1992;127:239–246.

24 Sato A, Takeda A. Evaluation of efficacy and safety of finasteride 1 mg in 3177 Japanese men with androgenetic alopecia. J Dermatol. 2012;39:27–32.

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25 Olsen EA, Whiting DA, Savin R, et al. Global photographic assessment of men aged 18 to 60 years with male pattern hair loss receiving finasteride 1 mg or placebo. J Am Acad Dermatol. 2012;67:379–386. 26 Saraswat A, Kumar B. Minoxidil vs finasteride in the treatment of men with androgenetic alopecia. Arch Dermatol. 2003;139:1219–1221. 27 Arca E, Acikgoz G, Tastan HB, et al. An open randomized, comparative study of oral finasteride and 5% topical minoxidil in male androgenetic alopecia. Dermatology. 2004;209:117–125. 28 Khandpur S, Suman M, Reddy BS. Comparative efficacy of various treatment regimens for androgenetic alopecia in men. J Dermatol. 2002;29:489–498. 29 Kaufman KD, Rotonda J, Shah AK, et al. Long-term treatment with finasteride 1 mg decreases the likelihood of developing further visible hair loss in men with androgenetic alopecia. Eur J Dermatol. 2008;18:400–406.

33 Trost L, Saitz TR, Hellstrom WJ. Side effects of 5-alpha reductase inhibitors: a comprehensive review. Sex Med Rev. 2013;1:24–41. 34 Anitha B, Inamadar AC, Ragunatha S. Finasteride: its impact on sexual function and prostate cancer. J Cutan Aesth Surg. 2009;2:12–16. 35 Gur S, Kadowitz PJ, Hellstrom WJ. Effects of 5-alpha reductase inhibitors on erectile function, sexual desire and ejaculation. Expert Opin Drug Saf. 2013;12:81–90. 36 Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, et al. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7–12. 37 Traish AM, Hassani J, Guay AT, et al. Adverse side effects of 5a-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients. J Sex Med. 2011;8:872–884.

30 Rossi A, Cantisani C, Scarnò M, et al. Finasteride 1 mg daily administration on male androgenetic alopecia in different age groups: 10-year follow-up. Dermatol Ther. 2011;24:455–461.

38 Irwig MS. Depressive symptoms and suicidal thoughts among former users of finasteride with persistent sexual side effects. J Clin Psychiatry. 2012;73:1220– 1223.

31 Ebner H, Müller E. Allergic contact dermatitis from minoxidil. Contact Dermatitis. 1995;32:316–317.

39 Green L, Wysowski DK, Fourcroy JL. Gynecomastia and breast cancer during finasteride therapy. N Engl J Med. 1996;335:823.

32 Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004;50:541–553.

40 Mansouri P, Farshi S, Safar F. Finasteride-induced gynecomastia. Indian J Dermatol Venereol Leprol. 2009;75:309– 310.

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May/June 2015

Volume 13 • Issue 3

Original contribution

Topical Minoxidil: Systematic Review and Meta-Analysis of Its Efficacy in Androgenetic Alopecia Aditya K. Gupta, MD, PhD, FRCPC;1,2 Andrew Charrette, MSc2 Abstract Topical minoxidil has become a mainstay in the treatment of androgenetic alopecia (AGA). Despite being a longstanding treatment for AGA, relatively few reviews of its efficacy have been published. The current study sought to synthesize the available efficacy data by performing a systematic review of the literature and conducting random-effects pairwise meta-analyses for the outcomes percent increase in hair count from baseline, investigator assessment, and patient self-assessment. Results showed that minoxidil is more effective than placebo in promoting total and nonvellus hair growth (mean difference [MD], 16.68; 95% confidence interval [CI], 9.34–24.03 and MD, 20.90; 95% CI, 9.07–32.74). A significantly higher proportion of participants in the minoxidil group had greater hair growth than participants in the placebo group as judged by both investigators and self-reports (relative risk [RR], 2.28; 95% CI, 1.58–3.31 and RR, 1.56; 95% CI, 1.34–1.80). Despite significant clinical efficacy, cosmetically acceptable results are present in only a subset of patients. Compliance is thought to be a major limiting factor and is being addressed by novel formulations and combinations. (SKINmed. 2015;13:185–189)

inoxidil, a topical treatment for androgenetic alopecia (AGA), is currently available in 2% and 5% formulations in the United States.1 Despite being a longstanding overthe-counter treatment for AGA, relatively few reviews of the efficacy of minoxidil for the treatment of AGA in men have been published. This review summarizes the clinical efficacy of minoxidil by performing meta-analyses of the outcomes vellus, nonvellus, and total hair counts; investigator assessment; and patient self-assessment and reviews the latest efforts to improve patient safety and compliance. Methods A systematic review of the literature was performed using the keywords “minoxidil,” “androgenetic alopecia,” “trial,” and “randomized controlled trial.” Only double-blind, placebo-controlled, randomized controlled trials (RCTs) of men with androgenetic alopecia were included for analyses. Contributions must also have been written in English in order to be included. Data were extracted from the selected papers and entered into review software.2

Inverse variance, random-effects pairwise meta-analyses were performed for the outcomes vellus, nonvellus, and total hair count. All hair count data were recorded as a percent mean increase from baseline±standard deviation. For studies in which sample variance data were not reported, the significance value reported was used to estimate the variance.3 The results of metaanalyses of hair count outcomes were expressed as the mean difference (MD) with 95% confidence intervals (CIs). The outcomes investigator assessment and patient self-assessment were analyzed using Mantel-Haenszel random-effects pairwise meta-analyses. These outcomes were expressed as the proportion of participants with increased hair growth as noted by the investigators or the patients themselves. Results of the meta-analyses of these outcomes were summarized by the relative risk (RR) of increased hair growth between the minoxidil and placebo groups. Intention-to-treat rates were used wherever possible. Between-study heterogeneity was assessed both qualitatively by comparing trial and participant baseline characteristics and quantitatively using the I2 statistic.

From the Division of Dermatology, Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 and Mediprobe Research Inc, London, Ontario, Canada2 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Results Our search strategy yielded 310 reports, 11 of which were included for analyses after full text review (Figure 1).4–14 The number of papers included in the meta-analyses differed for each outcome: vellus hair count (n=5), nonvellus hair count (n=6), total hair count (n=5), investigator assessment (n=8), and patient self-assessment (n=11). Results showed that compared with the placebo group, participants in the minoxidil group had a significantly greater increase in total hair count from baseline (MD, 20.90; 95% CI,

310 contributions from various sources

259 contributions excluded based on title and abstract review 51 contributions for full-text review

9.07–32.74; Figure 2). Patients in the minoxidil group also had a significantly greater increase in nonvellus mean hair count from baseline (MD, 16.68; 95% CI, 9.34–24.03, respectively); however, the mean increase in vellus hair count from baseline did not differ significantly between participants in the minoxidil and placebo groups (MD, 3.74; 95% CI, 1.39–8.86). There was high between-trial heterogeneity for the outcomes mean increase in total and nonvellus hair count from baseline (I2=93% and I2=83%) but no between-trial heterogeneity for the outcome mean increase in vellus hair count from baseline. A significantly higher proportion of participants in the minoxidil group compared with the placebo group had increased hair growth as reported by investigators (RR, 2.28; 95% CI, 1.58–3.31); however, the heterogeneity between trials for this outcome was high (I2=84%). Similarly, a significantly higher proportion of participants in the minoxidil group reported increased hair growth compared with the placebo group (RR, 1.56; 95% CI, 1.34–1.80), with moderate between-trial heterogeneity (I2=48%) (Figure 3). Patient Safety and Compliance

40 contributions excluded: Duplicate publications = 2 Not RCT = 9 Did not meet inclusion criteria = 28 Full-text not available = 1

11 contributions included for meta-analysis

Figure 1. Study selection process. RCT indicates randomized controlled trial.

Patient compliance is an important issue associated with minoxidil use. Compliance issues stem from unsatisfactory results, unwanted side effects, and burdensome dosage frequency. As demonstrated in the meta-analyses, studies have demonstrated that minoxidil is significantly better than placebo at promoting nonvellus and total hair regrowth both objectively and as reported by clinicians and the patients themselves. These results may vary, with some patients reporting only “peach fuzz”–like regrowth. It is important that patients are informed about the variability in results observed with minoxidil use, as individual results may not meet patient expectations. It is equally important that patient history, physical examination, and laboratory tests are conducted in order

Figure 2. Forest plot of comparison minoxidil vs placebo, outcome: total hair count. SD indicates standard deviation; CI indicates confidence interval. SKINmed. 2015;13:185–189

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Figure 3. Forest plot of comparison minoxidil vs. placebo, outcome: patient self-assessment. SD indicates standard deviation; CI indicates confidence interval.

to identify the cause of alopecia and ensure that minoxidil is indeed an appropriate treatment choice. Minoxidil is associated with only minor side effects such as pruritus and contact dermatitis, which resolve upon the cessation of treatment.5,8,11 These side effects are attributed to patient sensitivity to propylene glycol, a dissolving agent in the solution formulation of topical minoxidil.11 A recently marketed 5% foam formulation of minoxidil utilizes a hydroalcoholic vehicle without propylene glycol.11 The foam formulation is also easier to apply because it reduces unwanted spread of the product.11 The development of a more cosmetically appealing application procedure may decrease unwanted side effects while promoting regular use.11 Hair shedding is another unwanted side effect of minoxidil use. Once-daily minoxidil high extra combination (MHEC), comprised of 12.5% minoxidil, 5% azelaic acid, and 0.25% betamethasone 17-valerate, was recently evaluated against minoxidil 5% in a 24-week trial in Iran.15 MHEC was shown to significantly decrease hair shedding compared with minoxidil 5% alone twice daily (P<.05).15 Both azelaic acid and betamethasone 17-valerate have been suggested to promote hair growth on their own and, when used in combination with topical minoxidil, provide another promising topical agent that may increase patient compliance. The inconvenience of twice-daily application is another factor affecting patient compliance. Concomitant administration of retinoids has been shown to enhance the permeability of the SKINmed. 2015;13:185â&#x20AC;&#x201C;189

stratus corneum, allowing for optimal drug penetration.16 Both in vitro and in vivo evidence indicates a synergistic effect of combined use.17â&#x20AC;&#x201C;19 Application of 0.025% tretinoin in combination with a 0.5% minoxidil solution induced terminal hair growth in 66% of the 36 patients assessed in preliminary studies.17 No significant difference in efficacy or incidence of adverse events between the twice-daily application of 5% minoxidil solution and the once-daily application of the 5% minoxidil and 0.05% tretinoin combination solution was found.19 The combination of minoxidil and tretinoin may aid patient compliance since only one application per day is required. In further efforts to increase patient compliance and consistent drug delivery, novel delivery systems are actively being researched. An array of microparticle and nanoparticle formulations of minoxidil are being tested and refined in order to improve the penetrance and sustained release of the drug into the skin.20â&#x20AC;&#x201C;24 The pilosebaceous pathway has been identified as a promising avenue for the administration of topical drugs as the hair follicle can act as a depot for sustained release of drugs and is surrounded by a dense network of capillaries.23,25 Vesicle-based delivery systems also improve minoxidil administration parameters to improve patient compliance and enhance cosmetic outcomes. Conclusions Results from the meta-analyses indicate that minoxidil is significantly more effective than placebo in stimulating total and nonvellus hair regrowth and that a higher proportion of participants in the minoxidil treatment group experienced visible

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Table. Characteristics of Included Studies Outcomes No.

Total Hair Count

Nonvellus Hair Count

Vellus Hair Count

Investigator Assessment

Patient SelfAssessment

2% Minoxidil Placebo

77 77

2% Minoxidil Placebo

214 214

IIIv–V

2% Minoxidil Placebo

86 83

IIIv–V

2% Minoxidil Placebo

76 75

Katz et al8

IIIv–Va

2% Minoxidil Placebo

46 45

Kreindler 19879

“Discernable vertex balding”

2% Minoxidil Placebo

49 50

IIIv–IV

2% Minoxidil Placebo

19 19

Olsen et al11

IIIv–V

2% Minoxidil Placebo

158 78

Petzoldt et al12

III–V

2% Minoxidil Placebo

101 100

Piepkorn and Weidne13

–

III–IV

2% Minoxidil Placebo

21 11

Shupack et al14

IIIv–IV

2% Minoxidil Placebo

11 11

Mean Age, y

HamiltonNorwood Severity

Treatment Length, mo

Groups

Anderson et al4

IIIv–IV

Civatte et al5

IIIv–V

Connors et al6

–

DutréeMuelenberg et al7

Source

Olsen et al1

hair regrowth compared with the placebo group as assessed by investigators and the patients themselves. Minoxidil may only elicit a cosmetically acceptable level of regrowth in a subset of patents. One of the major impediments to effective treatment has been patient compliance. Foam delivery has significantly improved the practicality of using topical minoxidil and may improve compliance. Combination solutions and novel delivery systems are being actively researched and tested in the aim of increasing patient compliance and ultimately improving overall product efficacy. Despite its current limitations, minoxidil remains a popular treatment for AGA because it is readily available, safe, and effective.

3 3

3 Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions [internet]. 5.1.0 ed. The Cochrane Collaboration; 2011. www.cochrane-handbook. org. 4 Anderson C. Topical minoxidil in androgenetic aopecia Scandinavian and Middle East experience. Int J Dermatol. 1988;27:447–451. 5 Civatte J, Laux B, Simpson NB, Vickers CF. 2% topical minoxidil solution in male-pattern baldness: preliminary European results. Dermatologica. 1987;175 suppl 2:42– 49. 6 Connors TJ, Cooke DE, De Launey WE, et al. Australian trial of topical minoxidil and placebo in early male pattern baldness. Australas J Dermatol. 1990;31:17– 25.

1 Rogaine (minoxidil) [product monograph]. New Brunswick, NJ: Johnson and Johnson Inc; 2011.

7 Dutrée-Meulenberg R, Nieboer C, Koedijk F, Stoltz E. Treatment of male pattern alopecia using topical minoxidil in The Netherlands. Int J Dermatol. 1988;27:435– 440.

2 The Nordic Cochrane Centre TCC. RevMan [internet]; 2011. http://ims.cochrane.org/revman/download. Accessed June 15, 2014.

8 Katz HI, Hien NT, Prawer SE, Goldman SJ. Long-term efficacy of topical minoxidil in male pattern baldness. J Am Acad Dermatol. 1987;16:711–718.

References

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9 Kreindler TG. Topical minoxidil in early androgenetic alopecia. J Am Acad Dermatol. 1987;16:718–724. 10 Olsen EA, DeLong ER, Weiner MS. Dose-response study of topical minoxidil in male pattern baldness. J Am Acad Dermatol. 1986;15:30–37. 11 Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002;47:377–385.

18 Bazzano GS, Terezakis N, Galen W. Topical tretinoin for hair growth promotion. J Am Acad Dermatol. 1986;15:880–3, 890–893. 19 Shin HS, Won CH, Lee SH, et al. Efficacy of 5% minoxidil versus combined 5% minoxidil and 0.01% tretinoin for male pattern hair loss: a randomized, doubleblind, comparative clinical trial. Am J Clin Dermatol. 2007;8:285–290.

12 Petzoldt D; German topical Minoxidil Study Group. The German double-blind placebo-controlled evaluation of topical minoxidil solution in the treatment of early male pattern baldness. Int J Dermatol. 1988;27:430–434.

20 Mura S, Manconi M, Fadda AM, et al. Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil: in vitro evaluation of drug permeation by infrared spectroscopy. Pharm Dev Technol. 2013;18:1339–1345.

13 Piepkorn MW, Weidner M. Comparable efficacy of 2% minoxidil gel and solution formulations in the treatment of male pattern alopecia. J Am Acad Dermatol. 1988;18:1059–1062.

21 Gelfuso GM, Gratieri T, Simão PS, de Freitas LAP, Lopez RFV. Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate. J Microencapsul. 2011;28:650–658.

14 Shupack JL, Kassimir JJ, Thirumoorthy T, Reed ML, Jondreau L. Dose-response study of topical minoxidil in male pattern alopecia. J Am Acad Dermatol. 1987;16:673–676. 15 Pazoki-Toroudi H, Babakoohi S, Nilforoushzadeh MA, et al. Therapeutic effects of minoxidil high extra combination therapy in patients with androgenetic alopecia. Skinmed. 2012;10:276–282.

22 Padois K, Cantiéni C, Bertholle V, et al. Solid lipid nanoparticles suspension versus commercial solutions for dermal delivery of minoxidil. Int J Pharm. 2011;416:300–304. 23 Jain B, Singh B, Katare OP, Vyas SP. Development and characterization of minoxidil-loaded liposomal system for delivery to pilosebaceous units. J Liposome Res. 2010;20:105–114.

16 Ferry JJ, Forbes KK, VanderLugt JT, Szpunar GJ. Influence of tretinoin on the percutaneous absorption of minoxidil from an aqueous topical solution. Clin Pharmacol Ther. 1990;47:439–446.

24 Jun-Bo T, Zhuang-Qun Y, Xi-Jing H, et al. Effect of ethosomal minoxidil on dermal delivery and hair cycle of C57BL/6 mice. J Dermatol Sci. 2007;45:135–137.

17 Kwon OS, Pyo HK, Oh YJ, et al. Promotive effect of minoxidil combined with all-trans retinoic acid (tretinoin) on human hair growth in vitro. J Korean Med Sci. 2007;22:283–289.

25 Blume-Peytavi U, Massoudy L, Patzelt A, et al. Follicular and percutaneous penetration pathways of topically applied minoxidil foam. Eur J Pharm Biopharm. 2010;76:450–453.

“Ca baso, before treatment”, Moulage No. 543, made by Lotte Volger in 1927 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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May/June 2015

Volume 13 • Issue 3

Original contribution

Cosmetic Regulations: A Comparative Study Jyoti Suhag, MPharm; Harish Dureja, PhD Abstract The regulatory framework, compliance requirement, efficacy, safety, and marketing of cosmetic products are considered the most important factors for growth of the cosmetic industry. There are different regulatory bodies across the globe that have their own insights for regulation; moreover, governments such as the United States, European Union, and Japan follow a stringent regulatory framework, whereas cosmetics are not so much strictly regulated in countries such as India, Brazil, and China. The alignment of a regulatory framework will play a significant role in the removal of barriers to trade, growth of market at an international level, innovation in the development and presentation of new products, and most importantly safety and efficacy of the marketed products. The present contribution gives insight into the important cosmetic regulations in areas of premarket approval, ingredient control, and labeling and warnings, with a special focus on the cosmetic regulatory environments in the United States, European Union, Japan, and India. Most importantly, the authors highlight the dark side of cosmetics associated with allergic reactions and even skin cancer. The importance of cosmetic regulations has been highlighted by dint of which the society can be healthier, accomplished by more stringent and harmonized regulations. (SKINmed. 2015;13:191–194)

he earliest documented use of cosmetics occurred around 4000 BCE in ancient Egypt.1 The marketing of a cosmetic product is responsible for dramatic change in the cosmetic sector.2 The current market demands, development in advertisement technology, efficacy, safety, and availability of a wide range of cosmetics and a better regulatory framework are the key factors for the successful marketing of cosmetics.3 The alignment of a better regulatory framework can enhance trade and leads to further innovation with the safety of products. The regulations that ensure safety and efficacy of cosmetic products and avoid adverse impacts on the health of users vary from one country to another.4 The present contribution compares the regulation of cosmetics in the United States, European Union (EU), Japan, and India.

The Office of Cosmetics and Colors under the Center for Food Safety and Applied Nutrition (CFSAN) within the Food and Drug Administration (FDA) regulates cosmetic products.5,6 The European Cosmetic Toiletry and Perfumery Association, now Cosmetics Europe—The Personal Care Association (COLIPA), and the European Commission have the overall responsibility for cosmetics legislation within the EU.7 The EU Cosmetics Directive 76/768/EEC (safety of cosmetic products for human use) will be replaced with the Regulation European Commission (EC) No 1223/2009 with effect from July 2013.8 In Japan, the Pharmaceutical Affairs Law (1943) regulates the quality, efficacy, and safety of cosmetics.9,10 In

India, the Central Drugs Standard Control Organization (CDSCO) is the main regulatory body for the regulation of cosmetics.11 Premarket Approval In the United States, cosmetic products and ingredients are not subjected to FDA premarket approval, except for color additives.5 The FDA neither reviews nor has the authority to regulate cosmetics before marketing.12 The FDA has no authority to require premarket safety assessment, as it does with drugs; therefore, cosmetics are among the least-regulated products on the market.13 Currently, there is no law under the EU Cosmetics Directive 76/768/EEC for registration of cosmetic manufacturers or importers, as well as no premarket approval requirements provided for cosmetic products manufactured or imported within the EU.14 Premarket approval was necessary for each cosmetic product to be marketed in Japan; however, after the deregulation strategy in 2001, cosmetic products do not undergo the process of premarket approval.15,16 In reference to the Drugs and Cosmetics Act (D&C Act), a license is necessary for the manufacture of cosmetics for sale and distribution in India. No cosmetics shall be imported into India unless the product is registered under the rules by the licensing authority appointed by the central government under Rule 21 or by a person to whom such powers may be delegated under Rule 22.17,18,19

From the Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India 124001 Address for Correspondence: Harish Dureja, PhD, Maharshi Dayanand University, Department of Pharmaceutical Sciences, Rohtak, India 124001 • E-mail: harishdureja@gmail.com

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Ingredients Control As per the FDA, no approval is required for the use of any new ingredient in a cosmetic formulation. All color additives must be tested for safety and approved by the FDA for their proposed use in marketing cosmetic formulation.20,21 Various ingredients are listed as restricted and prohibited under the EU Cosmetics Directive 76/768/EEC. Testing of cosmetic ingredient(s) and safety evaluation is done by the Scientific Committee on Consumer Safety (SCCS) and when a new substance is added.22 The final decision on inclusion or exclusion of substances is taken by the commission and the member states.22,23 A positive list system was applicable in Japan under which each ingredient used in a cosmetic formulation had to be pre-approved by the Ministry of Health, Labour and Welfare (MHLW) before the deregulation strategy.16 Presently, new regulations provide lists of prohibited and restricted ingredients. Labeling and Warnings The label statements required under the authority of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Fair Packaging and Labeling Act (FP&L Act) must appear on the inside of as well as any outside container or wrapper.24,25 The ingredients must be written by their International Nomenclature Cosmetic Ingredient (INCI) names and declaration of ingredients must be in descending order of predominance.25,26,27 All label statements must be in English language and be placed with such prominence and conspicuousness that they are readily noticed and understood by consumers during purchase (21 CFR 701.2).24,25 In the EU, Article 6 of the Cosmetic Directive 76/768/EEC identifies labeling requirements for cosmetic products. Ingredient listing is provided only on the outer packages with the use of INCI names in descending order.28 The information must be provided in national or official language or languages of the respective member state.4,7 Labeling of cosmetics in Japan is done as per the Pharmaceutical Affairs Law. Full ingredient labeling must be provided for cosmetics as per the INCI terms in Japanese language only.15,16 In India, labeling is done as per the Bureau of Indian Standards, the Product Commodity Regulatory Ordinance, and Schedule S of the D&C Act.29 A distinctive batch number is given in figures preceded by the letter “B.” Where a package of a cosmetic has only one label, such labels shall contain all information required to be shown on both the inner and outer labels.30 All information is required to be written in English language.31 Testing and Safety The FDA advises manufacturers (responsible for the safety of cosmetics) to conduct toxicological or other tests that are appropriate to prove the safety of their cosmetics.24 If the safety of a cosmetic is not confirmed, then the label should bear the warnSKINmed. 2015;13:191–194

ing “The safety of this product has not been determined” (Sec. 21 CFR 740.10).5,24 There are no mandatory good manufacturing practice (GMP) requirements for cosmetics. The companies follow GMP guidelines issued by the FDA as well as quality assurance guidelines published by the Cosmetic Good Manufacturing Practices.32 Guidelines for safety testing of cosmetic ingredients in the EU have been prepared by the SCCS and COLIPA.22 The safety of a cosmetic product is based on the safety of its ingredients. The manufacturer or his agent or the person placing an imported cosmetic product into the market is responsible for safety of cosmetic products through in-market surveillance.22,33 Information on the qualitative as well as the quantitative composition of a cosmetic product and on adverse effects should be easily available to the public.34 Cosmetic manufacturers should adhere to GMPs as per the Cosmetics Directive 76/768/EEC. Voluntary GMP guidelines have been given up by COLIPA and the European Commission on GMP.35,36 In Japan, the manufacturer or importer is required to check the safety of their products before marketing and also to maintain records. The Japanese Cosmetic Industry Association (JCIA) has published voluntary technical guidelines for manufacturing and quality control.15 As per the D&C Act, testing of a cosmetic product is performed by a Central Drugs Laboratory or in the laboratories approved by the central government. Licensed manufacturers should manufacture cosmetics as per GMP conditions, specified in schedule M-II of the D&C Act.28,37 The Table lists the comparison of the various features of cosmetic regulation in different countries. As highlighted previously, there is no regulation of most regulatory agencies and almost all ingredients are not independently tested for safety, efficacy, and known toxins. This has led to some cosmetics being linked to allergic reactions and even skin cancer. Conclusions A considerable difference has been found in the cosmetic regulations of different countries such as the United States, EU, Japan, and India. Regulatory authorities in the United States and EU have a strong control in their countries, while, in India, regulations are less strict. As per new Indian standards, premarket approval is required for import and sale of cosmetics; however, no premarket regulations are applicable in the United States, EU, and Japan. The safety of the final formulation is the main concern of strict regulation applicable in these countries. The present contribution highlights the major differences in these cosmetic regulations. Harmonization of cosmetic regulation must be considered a high priority. Nonetheless, harmonization of cosmetics regulation is going to be beneficial for cosmetic manufacturers. This can be possible by coordinated cosmetic regulation and by dint, where cosmetic manufacturers can address business chal-

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Table. Comparison of Various Features of Cosmetic Regulations in Different Countries Contents

United States

Japan

India

Law applicable

Food, Drug & Cosmetic Cosmetics Directive Act [Sec. 201 (i)] 76/768/EEC [Article 1]

European Union

Pharmaceutical Affairs Law [Article 2–3]

Drugs and Cosmetics Act [Sec. 2]

Soap in definition

Excluded

Included

Excluded

Governmental body

Food and Drug Administration (FDA)

Cosmetics Europe

Ministry of Health, Labour and Welfare (MHLW)

Central Drugs Standard and Control Organization (CDSCO)

Cosmetic regulation

US FDA CFR Title 21

Cosmetics Directive 76/768/EEC

Pharmaceutical Affairs Law (PAL)

Drugs and Cosmetics Act

Manufacturer premises

Voluntary

Compulsory but not harmonized

Compulsory

Premarket requirements

Not applicable

Applicable

INCI names in labeling

Yes (with small variations) Yes

Color additive safety requirement

21 CFR 73, 74, 81, 82

Annex IV of Cosmetics Directive 76/768/EEC

Ordinance 30 of 1966

Labeling standards

Federal Food, Drug, and Cosmetic Act Fair Packaging and Labeling Act

Cosmetics Directive 76/768/EEC

PAL

Drugs and Cosmetics Act (Schedule S)

Labeling declarations

FDA 21 CFR 701 & 740

Article 6 of Cosmetics Directive 76/768/EEC

Article 61 of PAL

BIS and PCRO

Safety warning

On principal display panel

On outer and inner packages

On inner label only

Ingredient listing

Full ingredient listing

Name and quantity of hazardous ingredients

Label language

English

National/member state

Japanese

English

Expiration date

No date required

Date of minimum durability

Expiration date if shelf-life <3 y

Indicated as “Use before date”

Safety and efficacy

Responsibility of manufacturer

Manufacturer maintains Product Information File

Manufacturer must able to prove safety and efficacy

Manufacturer must maintain records

Testing guidelines

Cosmetic Ingredient Review guidelines (voluntary)

SCCP and COLIPA

Japanese Cosmetic Industry Association (JCIA) (voluntary)

Central Drug Laboratory (CDL)

Animal testing

Yes

Ban after 7th amendment in Cosmetics Directive 76/768/EEC

Yes

Good manufacturing practice guidelines

FDA

COLIPA

JCIA

Schedule M-II

Yes (in Japanese language) -

lenges globally in order to enhance profit and reduce the risk of noncompliance. Furthermore, if the cosmetic product were to be controlled under the same umbrella of regulation, the cost of cosmetics would decrease, which is beneficial to the general public and across the globe, and the general public would have access to superior quality of cosmetic product. The call on harmonization of cosmetic regulations regarding premarket approval, conSKINmed. 2015;13:191–194

trol over the ingredients used in cosmetic formulations, GMP, labeling, safety, and efficacy of these cosmetic products should be required to address this alarming issue. Cosmetic regulations need to be harmonized and stringent so that society can be protected from exposure to carcinogens, hormone disruptors, and other toxins.

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References 1 Dureja H, Kaushik D, Gupta M, et al. Cosmeceuticals: an emerging concept. Indian J Pharmacol. 2004;37:155–159. 2 Srikanth T, Hussen SS, Abha A, et al. A comparative view on cosmetic regulations: USA, EU and India. Der Pharmacia Lett. 2011;3:334–341. 3 Prance L. Marketing boosts cosmetic sales. http://www. cosmeticsdesign.com/Market-Trends/Marketing-boostscosmetic-sales. Accessed February 13, 2012. 4 Comparative study on cosmetics legislation in the EU and other principal markets with special attention to so-called borderline products. http://ec.europa.eu/enterprise/newsroom/cf/_getdocument.cfm?doc_id=4557. Accessed February 14, 2012. 5 FDA authority over Cosmetics. http://www.fda.gov/Cosmetics/GuidanceComplianceRegulatoryInformation/ ucm074162.htm. Accessed February 20, 2012. 6 About the centre for food safety and applied nutrition. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/ default.htm. Accessed April 15, 2012. 7 About cosmetics Europe. http://www.cosmeticseurope.eu/ about-cosmetics-europe.html. Accessed March 6, 2012. 8 EU cosmetics (Regulation EC) No 1223/2009). http://www. reach24h.com/en/eu-cosmetics.html. Accessed March 5, 2012. 9 Pharmaceutical administration and regulations in Japan. http://www.nihs.go.jp/mhlw/yakuji/yakuji-e_20110502-02. pdf. Accessed March 14, 2012. 10 The pharmaceutical affairs law. http://www8.cao.go.jp/ kisei-kaikaku/oto/otodb/english/houseido/hou/lh_02070. html. Accessed March 16, 2012. 11 Central drugs standard control organization. http://cdsco.nic. in/html/Drugs_ContAd.html. Accessed February 29, 2012. 12 Vogel L. US legislators propose crackdown on toxic cosmetics. Canadian Med Ass J. 2011;183:1169–1170. 13 Regulations. http://safecosmetics.org/section.id=30. Accessed March 14, 2012. 14 Notification. http://www.imb.ie/images/uploaded/docments /230910_FAQs_Cosmetics.pdf. Accessed February 24, 2012. 15 Import and Marketing of Spa products-Chapter 2. www. asean.or.jp/en/trade/lookfor/top/market/pdf/e4.pdf. Accessed February 22, 2012. 16 Salvador A, Chisvert A, eds. Analysis of cosmetic products. Amsterdam: Elsevier; 2007:1–40. 17 Notification. http://cdsco.nic.in/IMP&REG_Eng.pdf. cessed March 29, 2012.

Ac-

18 The new cosmetics import regulation of India. http://taxandregulatoryaffairs.wordpress.com/2011/04/07/the-new-cosmetics-import-regulation-of-india/. Accessed April 5, 2012. 19 Cosmetics Q&A: prohibited ingredients. http://www.fda. gov/Cosmetics/ResourcesForYou/Consumers/CosmeticsQA/ucm167234.htm?utm_campaign=Google2&utm_ source=fdaSearch&utm_medium=website&utm_ term=RESTRICTED%20COSMETICS&utm_co. Accessed April 28, 2012. 20 Cosmetic: cosmetic colors. http://www.fdaimports.com/

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industries/cosmetics/cosmetic_colors.php. Accessed April 14, 2012. 21 Colors in cosmetics: regulation and nomenclature in the United States. http://www.ctfa.org/colors-cosmetics-regulation-and-nomenclature-united-states. Accessed March 25, 2012. 22 The SCCS’s notes of guidance for the testing of cosmetic ingredients and their safety evaluation. http://ec.europa. eu/health/scientific_committees/consumer_safety/docs/ sccs_s_004.pdf. Accessed March 30, 2012. 23 Scientific Committee on Consumer Safety (SCCS). http:// ec.europa.eu/health/scientific_committees/consumer_ safety/index_en.htm. Accessed April 14, 2012. 24 FDA cosmetics handbook. http://www.mlmlaw.com/library/guides/fda/Coshdbok.htm. Accessed April 11, 2012. 25 Cosmetic labeling guide. http://www.fda.gov/cosmetics/ cosmeticlabelinglabelclaims/cosmeticlabelingmanual/ ucm126444.htm. Accessed March 14, 2012. 26 Ahmed FK. Focus on U.S. cosmetic regulation. http://www. bluestoneformulations.com/pdfs/getfile(2).pdf. Accessed April 22, 2012. 27 International cosmetic legal and regulatory database. http://eservices.ctfa.org/site/IRDB_Promo.pdf. Accessed April 20, 2012. 28 INCI. http://www.essentialwholesale.com/Learning-Library/Bulk-Cosmetics-Natural-Organic_10.3. Accessed April 22, 2012. 29 Sankholkar DS. Current Indian cosmetic regulations and suggested way forward. Pharma Times. 2009;41:30–31. 30 The drugs and cosmetics act and rules. http://cdsco.nic. in/html/copy%20of%201.%20d&cact121.pdf. Accessed February 27, 2012. 31 Part XV-Labelling, packing and standards of cosmetics. http://202.54.104.237/intranet/eip/legislation/uploads/15%20D&C%20Rules.pdf. Accessed April 22, 2012. 32 Guidelines for cosmetic good manufacturing practices. http://www.lotioncrafter.com/pdf/CTFA.cGMPs.pdf. Accessed April 24, 2012. 33 Notes of guidance for testing of cosmetic ingredients for their safety evaluation. http://ec.europa.eu/health/archive/ ph_risk/committees/sccp/documents/out12_en.pdf. Accessed April 28, 2012. 34 Cosmetic product information requirements in the European Union. https://www.google.co.in/url?sa=t&rct=j&q=& esrc=s&source=web&cd=1&ved=0CCQQFjAA&url=http%3 A%2F%2Fwww.cosmeticseurope.eu%2Fdownloads%2F61. html&ei=yPWUT_rTJ4rzrQe1mbGJBQ&usg=AFQjCNGkG 14VT2i4ZJ1MVykBOryz7-HAIQ&sig2=ZWRmSJKzhzX. Accessed April 4, 2012. 35 A guide to the cosmetic products (safety) regulations 2008. http://www.bis.gov.uk/assets/biscore/consumer-issues/ docs/guide-to-cpsr.pdf. Accessed April 26, 2012. 36 EudraLex-Volume 4 good manufacturing practice (GMP) guidelines. http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm. Accessed April 29, 2012. 37 Schedule M. http://cdsco.nic.in/html/GMP/ScheduleM s(GMP).pdf. Accessed April 27, 2012.

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The Use of Traditional Chinese Medicine in Some Dermatologic Diseases: Part II—Autoimmune Bullous Disorders and Lichen Planus Adone Baroni, MD,PhD;1 Eleonora Ruocco, MD, PhD;1 Teresa Russo, MD;1 Vincenzo Piccolo, MD;1 Long Geng, MD, PhD;2 Hongbo Zhou, MD, PhD;3 Hong-Duo Chen, MD;2 Xing-Hua Gao, MD, PhD2 Abstract Over the centuries, traditional Chinese medicine (TCM) and Western medicine have traveled along parallel lines with no opportunity for collaboration. In recent decades, while an interest in TCM has been growing among Western clinicians, progress has been made in the comprehension of pathogenic mechanisms of skin disorders, and the communication between Western and Eastern medicines has become more and more intensive. In this paper, the authors discuss TCM remedies used in the treatment of autoimmune bullous disorders (pemphigus and bullous pemphigoid) and lichen planus. Future studies on the active components of the TCM will certainly shed new light on the still obscure aspects of some dermatologic diseases. (SKINmed. 2015;12:195–203)

utoimmune bullous disorders, the prototypes of which are represented by pemphigus and bullous pemphigoid, are diseases associated with blisters and vesicles as their primary skin lesions. Pemphigus is characterized histologically by acantholysis and blister formation owing to the loss of cellcell adhesion among keratinocytes. Blisters develop at the junction between the epidermis and dermis in bullous pemphigoid.

result in better therapeutic efficacy and fewer side effects, thus reducing the rates of recurrence and complications. TCM for bullous diseases was used in single extracted form, or ready-made herbal mixtures, or being prescribed according to syndromic spectrum, as reviewed below.

The most common treatment for bullous diseases are corticosteroids, often used in relatively moderate or high doses. Longterm use of corticosteroids can produce several side effects. A rebound or aggravation of the bullous disease often occurs after withdrawal of corticosteroids. Other immunosuppressants, such as cyclosporine, cyclophosphamide, azathioprine, or methotrexate, are also frequently required as steroid-sparing or adjuvant drugs. In recent years, high-dosage intravenous gamma globulin and plasma exchange have been tried in severe cases.

Licorice Preparations

In the mid-1980s many reports were published on TCM for the treatment of autoimmune bullous disorders. These reports mostly claimed that combining TCM and Western medicine would

Some clinical studies have concluded that the combination of corticosteroids and compound glycyrrhizin can shorten healing time and allow reduction in the dosage of corticosteroids.1,2

Single Herb or Herbal Extracts

Glycyrrhizin is a compound obtained from the roots of licorice. Licorice has been widely used in TCM for its claimed effects of different types, ie, anti-inflammation (including antiallergic effects and hindering arachidonic acid metabolizing enzymes), anti-virus, anti-tumor, and immunomodulating (inducing interferon-γ and some other cytokines) effects. Licorice has been the most common composition of herbal mixtures for chronic liver disease, eczema, dermatitis, and urticaria.

See also Part I–Acne, Psoriasis, and Atopic Dermatitis. SKINmed. 2015;13(1):32–38. From the Department of Dermatology and Venereology, Second University of Naples, Naples, Italy;1 The First Hospital of China Medical University, Shenyang, China;2 and Liaoning College of Health Vocational Technology, Shenyang, China3 Address for Correspondence: Adone Baroni, MD, PhD, c/o II Policlinico, Edificio 3, Quarto Piano, Via Pansini 5 - 80131 Napoli, Italy • E-mail: adone.baroni@gmail.com

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Tripterygium wilfordii Hook F Preparations Tripterygium wilfordii Hook F (TwHf ) has been used in TCM for hundreds of years. Glycosides of Tripterygium wilfordii (GTW) extracted from the root of TwHf have been made in the form of 10-mg tablets. GTW have been prescribed to treat many autoimmune diseases, such as rheumatoid arthritis, chronic hepatitis, chronic nephritis, and several skin disorders such as systemic lupus erythematosus (SLE), allergic angiitis, anaphylactoid purpura nephritis, eczema, and Bechet’s disease. In recent years, many clinical trials showed that combined TwHf preparations and corticosteroid therapy had definite effects on pemphigus and bullous pemphigoid. The combination therapy reduced the duration to control the symptoms. TwHf would allow for a reduction in the dosage of corticosteroids in these autoimmune disorders3,4 and could reduce the side effects caused by corticosteroids.5 TwHf has both immunosuppressive and antiinflammatory activities, including inhibition of cytokine gene expression in T cells.6 The anti-inflammatory actions have been attributed to the inhibition of cyclooxygenase-2 and prostaglandin E2 in rheumatoid arthritis fibroblasts and other cell types.7 Various components of TwHf are toxic and can cause liver injury, genetic damage, and birth defects.8–11 All forms of this herb should not be used by pregnant or nursing women, young children, and those with kidney or liver disease. There are many other side effects, such as skin eruptions, skin pigmentation, stomatitis, softening of finger nails, and infertility. In addition, frequent upper abdominal pain, nausea, and reduced appetite have been reported.12 These side effects are correlated with dosage as well as duration of intake.

Other Preparations Total glucosides of paeony (TGP) have been used for a long time in the history of medicine, particularly for the treatment of rheumatoid arthritis, SLE, and hepatitis.13–15 Some clinical reports suggested that TGP oral administration is effective for treating pemphigus vulgaris and pemphigus erythematosus.16,17 TGP extracted from the root of Paeonia lactiflora, a Chinese traditional herbal

medicine, contains paeoniflorin and other components such as hydroxyl-paeoniflorin, paeonin, albiflorin, and benzoylpaeoniflorin.18 TGP has anti-inflammatory, antioxidative, hepatoprotective, and immunoregulatory activities, without evident toxicity or side effects.19–21 Ready-Made Prescriptions of TCM Clinical and laboratory research has demonstrated that the total effective rate was significantly higher in the JinGui ShenQi pill (JSP) (Table I) combined with prednisone group than that in the prednisone alone group, for the treatment of bullous pemphigoid patients (P<.05). It could upregulate the expression of glucocorticoid receptor (GR) α and downregulate GR-β in skin lesions, which might improve body sensitivity to glucocorticoids.22 The Chinese herbal TianPaoChuang granules (Table II) combined with corticosteroids or immunosuppressants proved to be more effective in pemphigus. One of the mechanisms of action may be that the combination could be able to decrease serum levels of IgG4 in patients.23 In addition, another ready-made Chinese herbal medicine, TianPaoChuang I (meaning pemphigus 1) (Table III), combined with corticosteroids in pemphigus shortens the duration of treatment and reduces the dosage of corticosteroids. At the same time, it decreases the serum level of IFN-γ. A study on in vitro skin cultures showed that acantholysis was completely inhibited by 0.5×10–3 mol/L hydrocortisone (HC) plus TianPaoChuang I (concentration of 1/100), while HC alone did not have this inhibitory effect at the same concentration.24 There are many other ready-made prescriptions of Chinese medicine for pemphigus or bullous pemphigoid. For instance, the ShiDuQing capsule (Table IV) combined with corticosteroid therapy showed obvious clinical effects on bullous pemphigoid.25 BaSheng Tang JiaJian (Table V), with addition or subtraction of herbs according to the patients’ requirements, has a similar therapeutic effect.26

Table I. Composition of JinGui ShenQi Pill ShuDi (Radix Rehmanniae Praeparata), ShanYao (Rhizoma Dioscoreae), ShanZhuYu (Fructus Corni), FuLing (Poria), MuDanPi (Cortex moutan Radicis), ZeXie (Rhizoma Alismatis), RouGui (Cortex Cinnamomi), and FuZi (Radix Aconiti Praeparata). Table II. Composition of TianPaoChuang Granules DiFuZi (Fructus Kochiae), BaiXianPi (Cortex Dictamni), FangFeng (Radix Ledebouriellae), JinYinHua (Flos Lonicerae), LianQiao (Fructus Forsythia), PuGongYing (Herba Taraxaci), DiDing (Herba Violae), HuangQin (Radix Scutellariae), ZhiZi (Fructus Gardeniae), DanPi (Cortex moutan Radicis), DangGui (Radix Angelicae Sinensis), ShengDi (Radix Rehmanniae), ChiShao (Radix Paeoniae Rubra), JieGeng (Radix Platycodi), and GanCao (Radix Glycyrrhizae). SKINmed. 2015;13:195–203

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Table III. Composition of TianPaoChuang I HuangLian (Rhizoma Coptidis), HuangQin (Radix Scutellariae), ZhiZi (Fructus Gardeniae), JinYinHua (Flos Lonicerae), TuFuLing (Rhizoma Smilacis Glabrae), ShengDi (Radix Rehmanniae), YiYiRen (Semen Coicis), and CangZhu (Rhizoma Atractylodis). Table IV. Composition of ShiDuQing Capsule DiHuang (Radix Rehmanniae), DangGui (Radix Angelicae Sinensis), DanShen (Radix Salviae Miltiorrhiae), ChanTui (Perisstracum Cicadae), HuangQin (Radix Scutellariae), BaiXianPi (Cortex Dictamni), TuFuLing (Rhizoma Smilacis Glabrae), GanCao (Radix Glycyrrhizae), and KuShen (Radix Sophorae Flavescentis). Table V. Composition of BaSheng Tang JiaJian ShengBaiZhu (uncooked Rhizoma Atractylodis Macroceph), ShengZhiQiao (uncooked Fructus Aurantii Immaturus), ShengYiRen (uncooked Semen Coicis), ShengQianShi (uncooked Semen Euryales), ShengDiHuang (uncooked Radix Rehmanniae), ShengZhiZi (uncooked Fructus Gardeniae), HuangBai (Cortex Phellodendri), KuShen (Radix Sophorae Flavescentis), ChuanBiXie (Rhizoma Dioscoreae Hypoglaucae), DangShen (Radix Salviae Miltiorrhiae), BaiXianPi (Cortex Dictamni), DiGuPi (Cortex Lycci Radicis), DanPi (Cortex moutan Radicis), SangBaiPi (Cortex Mori Radicis), CheQianZi (Semen Plantaginis), and ZeXie (Rhizoma Alismatis). Table VIA. Composition of Modified HuangLian JieDu Decoction HuangLian (Rhizoma Coptidis), ZhiZi (Fructus Gardeniae), HuangQin (Radix Scutellariae), HuangBai (Cortex Phellodendri), YiYiRen (Semen Coicis), ChanYi (Perisstracum Cicadae), HongTeng (Caulis Sargentodoxae), TuFuLing (Rhizoma Smilacis Glabrae), ShengDiHuang (uncooked Radix Rehmanniae), HuaShi (Talcum), DiFuZi (Fructus Kochiae), KuShen (Radix Sophorae Flavescentis), and CangZhu (Rhizoma Atractylodis). Table VIB. Composition of modified QingYing Decoction LingYangJiao (Cornu Saigae Tataricae) or ShuiNiuJiao (Cornu Bubali), ShengDiTan (carbonized Radix Rehmanniae), ErHuaTan (carbonized Flos Lonicerae), BaiMaoGen (Rhizoma Imperatae), ShengShiGao (Gypsum Pibrosum), LianZiXin (Plumula Nelumbinis), HuangLian (Rhizoma Coptidis), ShengZhiZi (uncooked Fructus Gardeniae), TianHuaFen (Radix Trichosanthis), and DiDing (Herba Violae).

TCM Based on Syndromic Differentiation According to the principles of TCM, pemphigus and bullous pemphigoid are caused by heart fire and spleen dampness and are affected by evil of wind, heat toxin, summer heat, and dampness, fumigating the skin and muscle. So these diseases can be generally divided into 4 types and treated based on syndromic differentiation. The first one is the exuberant toxin and heat type.27–29 It is characterized by an acute onset of rapidly increasing and enlarging vesicles, turning into ulcerated lesions with yellow exudate and leaving an erosive and reddened surface. The patient with this type, whose tongue is red or crimson, experiences fever with thirst, dry stool, and dark and burning urine. Modified HuangLian JieDu decoction27 (Table VIA), modified QingYing decoction28 (Table VIB), and some self-made Chinese herbal medicines based on the therapeutic method of clearing heat toxicity in Yingfen have been successfully used in this form. The second type is dampness and heat accumulation type.27,28 The vesico-bullous lesions arise from normal or erythematous SKINmed. 2015;13:195–203

skin followed by erosion and exudation. The patient typically feels dysphoria with symptoms of dry mouth, dry stool, brownish urine, reddish tongue, and whitish greasy hair. It has been reported that this form could be treated with various prescriptions, such as modified QingJie ChuShi drink (QCD)29 (Table VIIA), modified YinChen ChiXiaoDou decoction (YCD)27 (Table VIIB), and BiXie ShenShi decoction (BSD)30 (Table VIIC) for clearing heat dampness and cooling blood and detoxification. The third type is spleen deficiency with phlegm dampness accumulation.28 The vesicle surface ulcerates, leading to patchy erosions and then to thick crusts not easy to peel, with clear or yellow exudate. The patient feels fatigue and asthenia with a thirsty sensation but has no will to drink water. At the same time, the symptoms of abdominal distension with loose stool, light-red tongue, and whitish greasy hair occur. The formula for invigorating the spleen and removing dampness should be chosen for patients with this type. Prescriptions commonly include a modified ChuShiWeiLing decoction (Table VIII).29

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Table VIIA. Composition of Modified QingJie ChuShi Drink FuLing (Poria), CheQianCao (Plantago asiatica), HuaShi (Talcum), BaiZhu (Rhizoma Atractylodis Macroceph), MaiDong (Radix Ophiopogonis), YinChen (Herba Artemisiae Capillaris), HuangQin (Radix Scutellariae), ShengDi (Radix Rehmanniae), DaQingYe (Folium Isatidis), ShengYiRen (uncooked Semen Coicis), BaiMaoGen (Rhizoma Imperatae), and ShengGanCao (uncooked Radix Glycyrrhizae). Table VIIB. Composition of Modified YinChen ChiXiaoDou Decoction YinChen (Herba Artemisiae Capillari), ChiXiaoDou (Semen Phaseoli), TuFuLing (Rhizoma Smilacis Glabrae), FangJi (Radix Stephaniae Tetrandrae), HuangBai (Cortex Phellodendri), ZhiZi (Fructus Gardeniae), CangZhu (Rhizoma Atractylodis), FangFeng (Radix Ledebouriellae), ZeXie (Rhizoma Alismatis), ChiShao (Radix Paeoniae Rubra), KuShen (Radix Sophorae Flavescentis), and XiaoHuMa (Fructus Leonuri). Table VIIC. Composition of BiXie ShenShi Decoction BiXie (Rhizoma Dioscoreae Hypoglaucae), YiYiRen (Semen Coicis), HuangBai (Cortex Phellodendri), MuDanPi (Cortex moutan Radicis), ZeXie (Rhizoma Alismatis), HuaShi (Talcum), TongCao (Medulla Tetrapanacis), TuFuLing (Rhizoma Smilacis Glabrae), CheQianCao (Plantago asiatica L.), and HuangLian (Rhizoma Coptidis). Table VIII. Composition of Modified ChuShiWeiLing Decoction CangZhu (Rhizoma Atractylodis), HuaShi (Talcum), GanCao (Radix Glycyrrhizae), ChaoBaiZhu (Rhizoma Atractylodis Macroceph Praeparata), ShengBianDou (uncooked Semen Lablab Album), FuLing (Poria), ShanYao (Rhizoma Dioscoreae), HuangBai (Cortex Phellodendri), ShengYiRen (uncooked Semen Coicis), ZhuLing (Polyporus Umbellatus), and ZhuYe (Lophatherum gracile Brongn). Table IX. Composition of Modified JieDu YangYin Decoction NanBeiShaShen (Radix Adenophorae, Radix Glehniae), Ejiao (Colla Corii Asini), ShengHuangQi (uncooked Radix Astragali seu Hedysari), TianDong (Radix Asparagi), MaiDong (Radix Ophiopogonis), JinYinHua (Flos Lonicerae), PuGongYing (Herba Taraxaci), CheQianCao (Plantago asiatica L.), XuanShen (Radix Scrophulariae), HuangJing (Rhizoma Polygonati), DanShen (Radix Salviae Miltiorrhiae), ShiHu (Herba Dendrobii), and ShengGanCao (uncooked Radix Glycyrrhizae). Table X. Composition of MeiBao ShiRun ShaoShang Gao HuangQin (Radix Scutellariae), HuangBai (Cortex Phellodendri), HuangLian (Rhizoma Coptidis), DiLong (Lumbricus), and YingShuQiao (Pericarpium Papaveris).

The fourth type is deficiency of both qi and Yin type.28 Persistent heat consuming Yin causes perspiration, polydipsia, dysphoria, lassitude, and asthenia accompanied by light reddish tongue fissured and thin whitish hair. This type always appears in the long-term duration of disease or after prolonged treatment with corticosteroids. It should be treated by the formula for benefiting qi and nourishing Yin, combined with clearing toxicity and eliminating dampness, such as with modified JieDu YangYin decoction (Table IX).29,30 In addition, based on the principle of treatment according to syndrome differentiation in TCM, herbs are used for clearing heat toxicity and removing fire, such as HuangLian (Rhizoma Coptidis), ZhiZi (Fructus Gardeniae), and HuangQin (Radix Scutellariae). YinChen (Herba Artemisiae Capillaris) and CangZhu (Rhizoma Atractylodis) are used for promoting diuresis and excreting toxin. DangGui (Radix Angelicae Sinensis), FangFeng (Radix Ledebouriellae), ChanTui (Perisstracum Cicadae), NiuBangZi (Fructus Arctii), and others are used for nourishing blood and calming wind heat evil. SKINmed. 2015;13:195â&#x20AC;&#x201C;203

Topical Therapy in TCM Medicated baths are a traditional means of external TCM. A self-made Chinese herbal medicine JieDu QuShi decoction including KuShen (Radix Sophorae Flavescentis), BaiXianPi (Cortex Dictamni), and YeJuHua (Flos Chrysanthemi Indici), is formulated as a bath lotion. It is used for 30 minutes once daily, consecutively for 10 days. After bathing, a self-made XiaoYan JieDu powder comprised of HuaShi (Talcum) and HuangBai (Cortex Phellodendri) is applied topically.31 In addition, MeiBao ShiRun ShaoShang Gao (Table X), an ointment for burns and scalds, has been proved by one clinical study to be an eutherapeutic treatment for bullous pemphigoid.32 Glucocorticoids are the first choice of therapy for autoimmune bullous disorders. TCM has been used as adjuvant therapy for shortening the duration of disease, improving efficacy, and reducing complications and side effects caused by corticosteroids

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Table XIA. Composition of BuYang HuanWu Decoction HuangQi (Radix Astragali seu Hedysari), ChiShao (Radix Paeoniae Rubra), BaiShao (Radix Paeoniae Alba), DiLong (Lumbricus), BaiHuaSheSheCao (Herba Hedyoti Diffusae), TuFuLing (Rhizoma Smilacis Glabrae). Table XIB. Composition of TaoHong SiWu Decoction TaoRen (Semen Persicae), HongHua (Flos Carthami), DangGui (Radix Angelicae Sinensis), ChiShao (Radix Paeoniae Rubra), ChuanXiong (Rhizoma Ligustici Chuanxiong), XiangFu (Rhizoma Cyperi), ZhiQiao (Fructus Aurantii Immaturus). Table XIIA. Composition of DanZhi XiaoYao Powders ChaiHu (Radix Bupleuri), DanPi (Cortex moutan Radicis), ChiShao (Radix Paeoniae Rubra), BaiShao (Radix Paeoniae Alba), HuangQin (Radix Scutellariae), ZhiZi (Fructus Gardeniae), DanShen(Radix Salviae Miltiorrhiae), YuJin (Radix Curcumae), ShengDi (Radix Rehmanniae), and FuLing (Poria). Table XIIB. Composition of ChaiHu ShuGan Powders DanShen (Radix Salviae Miltiorrhiae), ChiShao (Radix Paeoniae Rubra), ChuanXiong (Rhizoma Ligustici Chuanxiong), ShengDi (Radix Rehmanniae), HuangQi (Radix Astragali seu Hedysari), HongHua (Flos Carthami), TaoRen (Semen Persicae), QingHao (Herba Artemisiae), ChenPi (Pericarpium Citri Reticulatae), XiangFu (Rhizoma Cyperi), FuLing (Poria), and GanCao (Radix Glycyrrhizae).

treatment. It should be kept in mind that the choice of herbal remedies are diversified and information on their mechanisms of actions is insufficient, which has hindered the application of TCM in treating bullous diseases thus far. Lichen Planus Lichen planus (LP) is a chronic, pruritic, papular eruption characterized by violaceous, polygonal lesions that affect the skin and/or mucosa and skin appendages such as nails and hair. Oral ulcerations associated with LP have the potential to become malignant. The first-line treatment of cutaneous LP is topical steroids of strong potency. Topical calcineurin inhibitors have been successfully used for the treatment of LP, especially lesions involving mucous membranes. Systemic steroids can also be given for symptom control and possibly more rapid resolution. Oral acitretin has been shown to be effective in published studies. Even with these effective treatments, relapses are common. Patients with widespread LP may respond to narrow-band or broadband UV-B therapy or psoralen with UV-A therapy. There have been a large number of reports illustrating the therapeutic effects of TCM combined with Western medicine on LP, especially oral lichen planus (OLP). Prescription Based on Syndrome Differentiation Theoretically, the pathogenesis of LP is recognized in Chinese medicine as resulting from stagnation of liver qi and blood stasis, SKINmed. 2015;13:195–203

qi depression transforming into fire, Yin deficiency of liver and kidney, hyperactivity of fire caused by Yin deficiency, dampness, or dampness heat caused by spleen deficiency. The Chinese herbal medicines of BuYang HuanWu decoction (Table XIA)33 and TaoHong SiWu decoction (Table XIB)34 are prescribed for the syndrome of blood stasis caused by qi deficiency. This syndrome is marked by palpitation and shortness of breath, anorexia and fatigue, chest stuffiness, abdominal distension, plump purplish tongue, and sometimes petechiae and thready hesitant pulse.33 The prescriptions of DanZhi XiaoYao (Table XIIA) and ChaiHu ShuGan powders (Table XIIB)35–39 are given for syndromes of qi depression transforming into fire and qi stagnation and blood stasis caused by stagnation of liver qi. Their actions are aimed at dispersing stagnated liver qi, clearing heat, and promoting blood circulation. The syndrome presents with oral mucosa lesions, congestive erosions, red tongue, yellow hair, and stringy rapid pulse. Modified ZhiBai DiHuang pill (Table XIIIA), modified ZengYe decoction (Table XIIIB), LiuWei DiHuang decoction (Table XIIIC), and modified SiWu decoction (Table XIIID) are all useful for hyperactivity of fire caused by Yin deficiency as well as the syndrome of wind dryness caused by blood deficiency, which are the result of Yin deficiency of the liver and kidney. These syndromes are characterized by oral pain, dry mouth and eyes, soreness of limbs, weakness, night sweating, dizziness and tinnitus, fissured deep red tongue with thin hair, and weak or thready rapid pulse.33–36

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Table XIIIA. Composition of Modified ZhiBai DiHuang Pill ZhiMu (Rhizoma Anemarrhenae), HuangBai (Cortex Phellodendri), ShuDi (Radix Rehmanniae Praeparata), ShanZhuYu (Fructus Corni), MuDanPi (Cortex moutan), FuLing (Poria), ZeXie (Rhizoma Alismatis), and ShanYao (Rhizoma Dioscoreae). Table XIIIB. Composition of Modified ZengYe Decoction ShengHuangQi (uncooked Radix Astragali seu Hedysari), BaiHuaSheSheCao (Herba Hedyoti Diffusae), TuFuLing (Rhizoma Smilacis Glabrae), QingDai (Indigo Naturalis), HuangLian (Rhizoma Coptidis), ShengMa (Rhizoma Cimicifugae), HuangQin (Radix Scutellariae), and YinHuaTeng (Caulis Lonicerae Japonicae). Table XIIIC. Composition of LiuWei DiHuang Decoction ShengDi (Radix Rehmanniae), FuLing (Poria), MuDanPi (Cortex moutan), ChiShao (Radix Paeoniae Rubra), ZeXie (Rhizoma Alismatis), ShanYao (Rhizoma Dioscoreae), NvZhenZi (Fructus Ligustri Lucidi), and HanLianCao (Herba Ecliptae). Table XIIID. Composition of Modified SiWu Decoction ShuDi (Radix Rehmanniae Praeparata), BaiShao (Radix Paeoniae Alba), DangGui (Radix Angelicae Sinensis), ChuanXiong (Rhizoma Ligustici Chuanxiong), DiFuZi (Fructus Kochiae), LongDanCao (Radix Gardeniae), HuangQin (Radix Scutellariae), and HuangBai (Cortex Phellodendri). Table XIVA. Composition of PingWei Powders HuoXiang (Herba Agastachis), PeiLan (Herba Eupatorii), ShanYao (Rhizoma Dioscoreae), FuLing (Poria), ShaRen (Fructus Amomi), BaiHuaSheSheCao (Herba Hedyoti Diffusae), and TuFuLing (Rhizoma Smilacis Glabrae). Table XIVB. Composition of WuLing Powders BaiZhu (Rhizoma Atractylodis Macroceph), FuLing (Poria), ZeXie (Rhizoma Alismatis), GuiZhi (Ramulus Cinnamomi), DangShen (Radix Codonopsis Pilosulae), ZhiGanCao (Radix Glycyrrhizae preparata), YinChen (Herba Artemisiae Capillaris), and ShaRen (Fructus Amomi). Table XIVC. Composition of HuangLian WenDan Decoction HuangLian (Rhizoma Coptidis), BanXia (Rhizoma Pinelliae), ChenPi (Pericarpium Citri Reticulatae), FuLing (Poria), HuaShi (Talcum), CangZhu (Rhizoma Atractylodis), ZhiShi (Fructus Aurantii Immaturus), HuoXiang (Herba Agastachis), and PeiLan (Herba Eupatorii).

In addition, there are other TCM syndromes, including the syndrome of dampness stagnancy or dampness heat caused by spleen deficiency33–35 that are treated by PingWei powders (Table XIVA) (the former) and WuLing powders (Table XIVB) and HuangLian WenDan decoction (Table XIVC) (the latter). The former syndrome presents with thirst without desire to drink, fullness in the head with binding sensation, anorexia and nausea, soreness of limbs, loose stool, plump pale tongue, greasy white hair, and soft slippery pulse. The latter presents with thirst, gastric upset, constipation, sallow face, red tongue with greasy yellow hair, and slippery rapid pulse. Moreover, the syndrome of wind dampness with toxin heat characterized by aversion to wind, fever, sweating, headache with binding sensation, swelling and pain in throat, and soft rapid pulse can be treated by XiaoFeng powders (Table XV).

It was reported that the herbs of ChiShao (Radix Paeoniae Rubra) and DangGui (Radix Angelicae Sinensis) depress capillary permeability, reduce inflammatory exudation, and promote its absorption; and DanShen (Radix Salviae Miltiorrhiae) and ChuanXiong (Rhizoma Ligustici Chuanxiong) ameliorate microcirculation and accelerate repair of the epithelial tissue.40 Clinical observation of 47 patients with OLP41 taking treatment with TianWang BuXin decoction plus a WuWei XiaoDu drink (Table XVII) showed no statistical difference of curative effect between the TCM-treated group and the control group of Western medicine treated with prednisone and thalidomide.

Special Prescriptions of TCM

The clinical trials demonstrated that the total effective rate of cure of OLP with many formulas of TCM were all greater than 80%.42–46 These prescriptions include modified QingWei powders (Table XVIIIa), LianLi decoction (Table XVIIIB), TongYou decoction (Table XVIIIC), FengSui mini-pills (Table XVIIID), and WuMei pills (Table XVIIIE).

Modified LiangGe powders (Table XVI) combined with biological lysozyme spray often heal and definitively cure OLP lesions.

Some ready-made Chinese herbal medicines have also been used for therapy in LP with positive outcomes.47,48 One example is

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Table XV. Composition of XiaoFeng Powders JingJie (Herba Schizonepetae), FangFeng (Radix Ledebouriellae), QiangHuo (Rhizoma seu Radix Notopterygii), HuangQin (Radix Scutellariae), JinYinHua (Flos Lonicerae), LianQiao (Fructus Forsythiae), ChanYi (Periostracum Cicadae), HuangLian (Rhizoma Coptidis), WuXiaoShe (Zaocys Dhumnades), and ShengGanCao (uncooked Radix Glycyrrhizae). Table XVI. Composition of Modified LiangGe Powders LianQiao (Fructus Forsythia), HuangQin (Radix Scutellariae), ZhiZi (Fructus Gardeniae), BoHe (Herba Menthae), DaHuang (Radix et Rhizoma Rhei), ZhuYe (Lophatherum gracile Brongn), ShengGanCao (uncooked Radix Glycyrrhizae), XuanShen (Radix Scrophulariae), ShengDi (Radix Rehmanniae), MaiDong (Radix Ophiopogonis), DanShen (Radix Salviae Miltiorrhiae), ChuanXiong (Rhizoma Ligustici Chuanxiong), DangGui (Radix Angelicae Sinensis), and ChiShao (Radix Paeoniae Rubra). Table XVII. Composition of TianWang BuXin Decoction Plus WuWei XiaoDu Drink RenShen (Radix Ginseng), XuanShen (Radix Scrophulariae), DanShen (Radix Salviae Miltiorrhiae), FuLing (Poria), TianDong (Radix Asparagi), MaiDong (Radix Ophiopogonis), ShengDi (Radix Rehmanniae), JinYinHua (Flos Lonicerae), YeJuHua (Flos Chrysanthemi Indici), PuGongYing (Herba Taraxaci), TuFuLing (Rhizoma Smilacis Glabrae), and YinChen (Herba Artemisiae Capillaris).

Table XVIIIA. Composition of Modified QingWei Powders ShengShiGao (Gypsum Pibrosum), ShengDi (Radix Rehmanniae), HuangLian (Rhizoma Coptidis), ShengMa (Rhizoma Cimicifugae), DanPi (Cortex moutan Radicis), DangGui (Radix Angelicae Sinensis), JinYinHua (Flos Lonicerae), TaoRen (Semen Persicae), PuGongYing (Herba Taraxaci), BaiZhu (Rhizoma Atractylodis Macroceph), and DanShen (Radix Salviae Miltiorrhiae). Table XVIIIB. Composition of LianLi Decoction DangShen (Radix Codonopsis Pilosulae), HuangQi (Radix Astragali seu Hedysari), GanJiang (Rhizoma Zingiberis), BaiZhu (Rhizoma Atractylodis Macroceph), FuLing (Poria), DanShen (Radix Salviae Miltiorrhiae), TaoRen (Semen Persicae), and GanCao(Radix Glycyrrhizae). Table XVIIIC. Composition of TongYou Decoction ShengDi (Radix Rehmanniae), ShuDi (Radix Rehmanniae Praeparata), ShiHu (Herba Dendrobii), DanPi(Cortex moutan Radicis), DangGui (Radix Angelicae Sinensis), ChiShao (Radix Paeoniae Rubra), TaoRen (Semen Persicae), HongHua (Flos Carthami), NiuXi (Radix Achyranthis Bidentatae), and GanCao (Radix Glycyrrhizae). Table XVIIID. Composition of FengSui Mini-pills HuangBai (Cortex Phellodendri), ShaRen (Fructus Amomi), and ZhiGanCao (Radix Glycyrrhizae preparata). Table XVIIIE. Composition of WuMei Pills WuMei (Fructus Schisandrae), XiXin (Herba Asari), RouGui (Cortex Cinnamomi), DangShen (Radix Codonopsis Pilosulae), FuZi (Radix Aconiti Praeparata), ChuanJiao (Pericarpium Zanthoxyli), GanJiang (Rhizoma Zingiberis), HuangLian (Rhizoma Coptidis), HuangBai (Cortex Phellodendri), and DangGui (Radix Angelicae Sinensis).

YangYin YiQi LiShi decoction (Table XIXA) and another is JianPi YiShen HuaShi decoction (Table XIXB). Research on Chinese traditional drugs used for antipyretic detoxification in treating OLP revealed that the herbs could regulate peripheral blood T-lymphocyte subpopulations, which can partly explain their curative effect.49 Prescriptions aimed at dispersing stagnated liver qi for relieving qi stagnation and nourishing blood, include ChuanXiong (RhiSKINmed. 2015;13:195â&#x20AC;&#x201C;203

zoma Ligustici Chuanxiong), GouQi (Fructus Lycci), XiaKuCao (Herba Elscholtziae seu Moslae), BaiXianPi (Cortex Dictamni), BaiShao (Radix Paeoniae Alba), and ChiShao (Radix Paeoniae Rubra). Topical Therapy in TCM Recently, some Chinese herbal medicine films, powders, or gargles have been used as topical therapies in patients with mucosal lesions. These drugs are generally capable of clearing heat

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Table XIXA. Composition of YangYin YiQi LiShi Decoction HanLianCao (Herba Ecliptae), NvZhenZi (Fructus Ligustri Lucidi), GanCao (Radix Glycyrrhizae), HuangJing (Rhizoma Polygonati), YiYiRen (Semen Coicis), FuLing (Poria), ZeXie (Rhizoma Alismatis), ShengMa (Rhizoma Cimicifugae), DangGui (Radix Angelicae Sinensis), etc. Table XIXB. Composition of JianPi YiShen HuaShi Decoction ShuDi (Radix Rehmanniae Praeparata), ShanYao (Rhizoma Dioscoreae), ShanYu (Fructus Corni), RouGui (Cortex Cinnamomi), DanNanXing (Rhizoma Arisarmatis prparata), and FuLing (Poria).

toxin, eliminating bood stasis dampness, promoting tissue regeneration, and arresting pain. They include DaHuang (Radix et Rhizoma Rhei), DangGui (Radix Angelicae Sinensis), YanHuSuo (Rhizoma Corydalis), BingPian (Borneolum), and BaiJi (Rhizoma Bletillae).50–54 Conclusions Over the centuries, TCM and Western medicine have traveled along parallel lines with no opportunity to collaborate. In recent decades, an interest in TCM has been growing among Western clinicians, progress has been made in the comprehension of pathogenic mechanisms of skin disorders, and the communication between Western and Eastern medicines has become more and more intensive. In the future, controlled studies aimed at evaluating the usefulness of TCM in dermatologic disorders and the foundations of its pharmacokinetics should be carried out. With guidance from clinicians, it is likely that important discoveries will result from these studies. References 1 Wang XZ. Clinical observation of curative effect of pemphigus treated by compound glycyrrhizin tablet. China Prescrip Drug. 2006;8:61–62. 2 Qin ZF, Zhao XC, Liu JC, et al. The clinical research for compound glycyrrhizin injection in the treatment of pemphigus and pemphigoid. China J Lepr Skin Dis. 2007;23:262–263. 3 Wang YH, Ye H, Yu L, et al. The effect of Tripterygium Wilfordii combined with corticosteroid in the treatment of pemphigus and pemphigoid. Cen China Med J. 2001;25:65–66. 4 Yu LP, Qin H, Tan DF. Clinical observation of Corticosteroids therapy combined with glycosides of T. wilfordii in pemphigus. Mod J Integ Trad Chin West Med. 2009;18:268. 5 Qu Z. The clinical observation for Glucosides of Tripterygium wilfordii treatment combined with prednisone in pemphigus vulgaris. China Foreign Med Treat. 2009;17:93. 6 Tao XL, Davis L, Hashimoto K, et al. The Chinese herbal remedy T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. J Pharmacol Exp Ther. 1996;276:316–325.

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7 Tao XL, Schulze-Koops H, Ma L, et al. Effects of Tripterygium wilfordii hook F extracts on induction of cyclooxygenase 2 activity and prostaglandin E2 production. Arthritis Rheum. 1998;41:130–138. 8 Peng B, Miao MS, Wang YL, et al. Initial discussion of mice acute hepatic injury caused by tripterygium glycosides [in Chinese]. Zhongguo Zhong Yao Za Zhi. 2004;28:1067–1070. 9 Takei A, Nagashima G, Suzuki R, et al. Meningoencephalocele associated with Tripterygium wilfordii treatment. Pediatr Neurosurg. 1997;27:45–48. 10 Chan WY, Ng TB. Adverse effect of Tripterygium wilfordii extract on mouse embryonic development. Contraception. 1995;51:65–71. 11 Xu W, Ziqing L, Yinrun D, et al. Tripterygium hypoglaucum (level) Hutch induces aneuploidy of chromosome 8 in mouse bone marrow cells and sperm. Mutagenesis. 2004;19:379–382. 12 Jiang M. Pharmacological and clinical study on polyglycoside of Tripterygium wilfordii Hook f. Chin Med J (Taipei). 1996;57:S35. 13 Wang B, Yao YY, Zhou AW, et al. Protective effect of total glucosides of paeony on joint damage in adjuvant arthritis rats. Chin J Pharmacol Toxicol. 1996;10:211–214. 14 Wang B, Yao YY, Zhou AW, et al. Study on immunomodulatory effect of total glucosides of paeony and its relationship with nitric oxide in adjuvant arthritis rats. Chin J Immunol. 1996;12:104–106. 15 Zhou LL, Wei W, Shen YX, et al. The effects of TGP on CJS131-induced systemic lupus erythematosus-like model in mice. Chin Pharmacol Bull. 2002;18:175– 177. 16 Wang JF, Xia JX, Li FQ. TGP combined with QuMiXin cure one case with pemphigus erythematosus. 2011 academic conference papers assembly. Dermatovenereol Chin West Integ Med. 2011;153. 17 Song Yu. TGP combined with TCM cure one patient with pemphigus vulgaris. 2009 academic conference papers assembly. Dermatovenereol Chin West Integ Med. 2009:251. 18 Wang H, Wei W, Wang NP, et al. Effects of total glucosides of peony on immunological hepatic fibrosis in rats. World J Gastroenterol. 2005;11:2124–2129. 19 Zheng YQ, Wei W, Zhu L, et al. Effects and mechanisms of Paeoniflorin, a bioactive glucoside from paeony root, on adjuvant arthritis in rats. Inflamm Res. 2007;56:182– 188.

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20 Zhang LL, Wei W, Wang NP, et al. Paeoniflorin suppresses inflammatory mediator production and regulates G protein-coupled signaling in fibroblast-like synoviocytes of collagen induced arthritic rats. Inflamm Res. 2008;57:388–395. 21 Liu DF, Wei W, Song LH. Protective effect of paeoniflorin on immunological liver injury induced by bacillus Calmette-Guerin plus lipopolysaccharide: modulation of tumour necrosis factoralpha and interleukin-6 MRNA. Clin Exp Pharmacol Physiol. 2006;33:332–339. 22 Liu BG, Li ZY, Du M. Effects of jingui shenqi pill combined prednisone on expression of glucocorticoid receptor and its clinical effect in treating bullous pemphigoid patients. Chin J Integ Trad West Med. 2006;26:881–884. 23 Chen H, Xu L, Wu LL, et al. Researching of the regulation of antibody subtypes with the chinese herbal- pemphigus granules. Tianjin Pharmacy. 2010;22:40–42. 24 Luo XQ, Zhu LC, Tao LD, et al. The clinical and laboratory research for Chinese traditional medicine in the treatment of pemphigus. J Clin Dermatol. 2003;32:38–41. 25 Hao CY, Lu YY. Shiduqing capsule combined with hormone therapy efficacy of bullous pemphigoid. China J Mod Med. 2010;20:1565–1566. 26 Shi SZ. Effects of integrated traditional chinese and western medicine therapy on 30 cases pemphigus. Beijing J Trad Chin Med. 2001;20:33–34. 27 Han LM, Zhao YZ. Integrated traditional and Western Medicine in Treating Pemphigus and Pemphigoid. Chin J Integ Med. 1999;5:216–217. 28 Wang H, Wang P, Deng BX. Analysis of integrated traditional chinese and western medicine therapy on 120 cases pemphigus and pemphigoid. Chin J Dermato Venerol Integ Trad W Med. 2007;16:154–156. 29 Meng L. Integrated traditional chinese and western medicine therapy on 45 cases pemphigus. J SiChuan TCM. 2003;21:70–71. 30 Gou JF, Chen ML, Yu QY, et al. Application of regulating dampness method in the treatment of pemphigus. Guang Ming J Chin Med. 2010;25:1990–1991. 31 Tan CY. Nursing of pemphigus by bath of traditional chinese medicine combined with glucocorticoid. Mod J Integrat Trad Chin West Med. 2007;16:4224–4225. 32 Du XF, Liang JX, Kuang YY, et al. Effect observation of external therapy in pemphigoids by ShiRunShaoShangGao. World Health Digest Med Per. 2011;8:273–274. 33 Zhang ZR, Huang QQ. Clinical observation of therapy based on different symptoms in treating 25 patients with oral lichen planus. Hunan Journal of Traditional Chinese Medicine. 2001;17:26-27.

treating 106 patients with oral lichen planus. Chinese Journal of New Clinical Medicine. 2011;4:1065-1067. 37 Huang ZQ, Tang YH. Treatment based on syndrome differentiation of 75 patients with oral lichen planus. Jiangsu J Trad Chin Med. 2000;21:26–27. 38 Zeng XQ. Observation on treatment of oral lichen planus by western medicine combined with traditional Chinese medicine. Lishizhen Med and Medica Res. 2009;20:2359. 39 Li XR, Wu F. Study on the effect of TCM in treatment for lichen planus. Chin J Nat Med. 2006;8:264–265. 40 Ma H, Li Y. 68 cases of oral lichen planus treated by combination of TCM and Western Medicine. Mod J Integrat Trad Chin West Med. 2005;14:1330. 41 Jiang LY, Jiang ZX. 47 cases of oral lichen planus treated by modified TianWang BuXin decoction and WuWei XiaoDu drink. Jiangxi J Trad Chin Med. 2011;42:27–28. 42 Xu SF. 30 patients of oral lichen planus treated by Chinese herbal Medicine. Sichuan J Trad Chin Med. 2001;19:66. 43 Chen JL. Clinical observation on treatment of oral lichen planus with JiaWei LianLi decoction. Hubei J Trad Chin Med. 2000;22:27. 44 Zhang XP, Chen SM. 32 patients of oral lichen planus treated by JiaWei TongYou decoction. Sichuan J Trad Chin Med. 1995;6:47. 45 Zhao LX, Li LT, Wei KJ. Observation on therapeutic effects of FengSui mini-pill in treating patients of oral lichen planus. J North China Coal Med Univ. 2004;6:779–780. 46 Li SB. Treating oral lichen planus by WuMei pill in 5 cases. Chin J Prac Chin Mod Med. 2003;14:2183. 47 Xia QZ, Han Y, Zhou LN. 18 cases of oral lichen planus treated by YangYin YiQi decoction. Chin J Integ Trad Western Med. 2002;22:187. 48 Jiang YQ, Xin YJ. Clinical observation of oral lichen planus treated by spleen-kidney-nourishing and dampness-eliminating therapy. Shanghai J Trad Chin Med. 2000;7:35–36. 49 Yang LH, Zheng J, Zhang J, et al. Clinical curative effect on antipyretic detoxification Chinese traditional drug to oral lichen planus and observation of effect on peripheral blood T lymphocytes. Prog Mod Biomed. 2009;9:2694–2696. 50 Tan SF. Clinical observation on curative effect of western medicine combined with traditional Chinese medicines treatment in oral lichen planus. Chin Mod Med. 2011;18:106–107. 51 Zhang H, Gu Y, Zhu YH, et al. Clinical research in treatment of oral lichen planus with XiaoBan film. Chin J Pract Chin Mod Med. 2003;9:1317–1318.

34 Wu GR, Jiang P. 63 patients with oral lichen planus treated by traditional Chinese medicine base on syndrome differentiation. Jilin J Trad Chin Med. 2004;24:33.

52 Gao YJ, Ling TY, Xia SL, et al. A clinical study of therapeutic efficacy of JieZhiShuang gargle as a treatment of oral mucositis. J Clin Stomatol. 2001;17:10–11.

35 Li YW. Treatment based on syndrome differentiation of 39 patients with oral lichen planus. J Hubei Col Trad Chin Med. 2000;2:40.

53 Wang YH, Li XN. Clinical observation on treatment of oral lichen planus with Chinese herbal medicine film. Guangming J Chin Med. 2009;24:1721–1722.

36 Jiang JS. Observation on therapeutic effects of western medicine combined with traditional Chinese medicines treatment based on different symptoms and signs in

54 Luo KL, Yu H, Zhang JM. Treatment of lichen planus with KouQiangKuiYang powder. Chin J Info Trad Chin Med. 1998;5:45.

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SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD For each of the following numbered questions, chose the single most appropriate lettered response. 1. The first line choice of treatment for autoimmune bullous diseases is: a. Azathioprine. b. Cyclophosphamide. c. Cyclosporine. d. Glucocorticoids. e. Methotrexate.

f. TrianPao Chuang I g. The ShiDuQing capsule. h. All of these.

5. The first-line treatment of cutaneous lichen planus is: a. Broadband ultraviolet-B (UV-B) treatment. b. Narrowband ultraviolet-B (UV-B) treatment. c. Psoralen plus ultraviolet-A (UV-A) radiation. d. Systemic corticosteroids. e. Topical steroids of strong potency. f. Topical steroids of low potency.

ANSWERS TO EXAMINATION: 5. e

3. Which of the following has (have) been administered as a corticosteroid-sparing or adjuvant therapy for autoimmune bullous diseases? a. Glycyrrhizin. b. Tripterygium wilfordii Hook F. c. Total glucosides of paeony. d. The JinGui ShenQi pill. e. TianPao Chuang granules.

Licorice has been said to (have): Anti-inflammatory effects. Anti-tumor effects. Anti-viral effects. Immunomodulatory effects. Inhibit arachadonic acid activating enzymes. All of these.

1. d 2. e 3. h 4. f

2. Which of the following has (have) been administered as a corticosteroid-sparing or adjuvant therapy for autoimmune bullous diseases? a. Azathioprine. b. Cyclophosphamide. c. Cyclosporine. d. Methotrexate. e. All of these.

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

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

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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Basal Cell Carcinoma Part I: Basal Cell Carcinoma Has Come of Age Min Deng, MD;1 Amanda F. Marsch, MD;2 Vesna Petronic-Rosic, MD, MSc1 Abstract Almost 2 centuries after its recognition, basal cell carcinoma (BCC) remains the most common cancer worldwide, with a 30% overall lifetime risk in the United States and an incidence that continues to increase annually. The increasing incidence of BCC is multifactorial and likely correlates to multiple risk factors, including exposure to both ionizing and UV radiation. Despite its relatively indolent growth, what was once referred to as a rodent ulcer or basal cell epithelioma is now identified as a full-fledged malignancy. The authors describe the societal burden of this disease and characterize its malignant potential, emphasizing associated clinical and histopathologic prognostic features. (SKINmed. 2015;12:206–213)

asal cell carcinoma (BCC) is no new addition to the list of dermatologic diagnoses. First characterized in 1827 by Arthur Jacob (1790–1874), BCC was described as an anomalous condition with two remarkably different biologic behaviors. The first, a fixed stage with elevated, smooth, glossy edges and a vascular center, could remain unchanged for years. The second, an ulcerative stage (Figure 1), demonstrated slow progression, but potent destructive ability, which could obliterate soft tissue, eye, and bone indiscriminately. Despite his insightful characterization of the damaging capability of these lesions, Jacob distinguished them from “genuine” carcinoma based on the lack of pain, rapid growth, malodor, hemorrhage, and invasion into the lymphatics.1 Almost 2 centuries after its recognition, BCC remains the most common cancer worldwide, with an incidence that continues to increase annually. Despite its relatively indolent growth, what was once referred to as a rodent ulcer, or basal cell epithelioma, is now identified as a full-fledged malignancy. How extensive is the burden of this tumor on society? What led to this change in terminology? With the recent identification of the hedgehog pathway in the pathogenesis of BCCs, there is increased interest in using targeted molecular therapies. How has the advent of these agents changed our perception of this disease? What is in the future for BCC? Epidemiology BCC is the most common skin cancer worldwide and represents an epidemic among Caucasian populations. While melanoma is

far more lethal, the prevalence of BCCs combined with its locally invasive and occasional metastatic behavior are responsible for its significant morbidity, mortality, and associated healthcare related costs. Due to of the limitations in nationwide registries, the true incidence of BCC is based on smaller subpopulation studies from multiple countries. Such reports around the world all point to increasing incidence, with the exception of Australia where the incidence has slightly decreased. In the United States alone, the age-adjusted incidence rate for BCC in men is estimated to have increased by as much as 2.5-fold between 1986–1988 and 2004–2006 (606 cases per 100,000 person-years vs 1488 cases per 100,000 person-years), while the age-adjusted incidence rate for women increased by as much as almost two-fold (519 cases per 100,000 person-years vs 1019 cases per 100,000 person-years).2 There is a 30% overall lifetime risk for developing BCC.3 For patients with a history of BCC, the risk of developing a subsequent BCC is 44%, or 10 times greater, within the following 3 years.4 In Europe, the incidence of BCC is similarly increasing, at an estimated rate of 5.5% per year. The latest data from Ireland indicate that this increase has been partly driven by younger age groups engaging in riskier leisure activities.5 The greatest increase in incidence of BCCs has been in urban-dwelling young adults (<34 years) with a positive correlation with increasing socioeconomic status.

From the Section on Dermatology, The University of Chicago Pritzker School of Medicine,1 and the Department of Dermatology, University of Illinois at Chicago College of Medicine,2 Chicago, IL Address for Correspondence: Vesna Petronic-Rosic, MD, MSc, The University of Chicago, Section of Dermatology, 5841 S Maryland Ave MC 5067 L503, Chicago, IL 60637 • E-mail: vrosic@medicine.bsd.uchicago.edu

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Figure 1. Over time, basal cell carcinoma tends to ulcerate and become locally destructive, hence the name “rodent ulcer.”

Figure 2. Intravascular islands of basaloid cells indicate hematologic spread of the tumor.

Although less common in Asia, the overall trends in this region are similar to those in other parts of the world. Data from Singapore suggest a 3% annual increase in the incidence of BCCs between 1968 and 1972 and 1993 and 1997.6 Studies from Hong Kong noted an almost three-fold increase between 1990 and 1999.7 In contrast, the incidence of BCC in Australia is decreasing, with nearly a 20% decline; hence from 1985 to 1992 and from 1997 tp 2006.8 This is likely the result of aggressive public education campaigns, which began in the 1980s. The overall increasing incidence of BCC is multifactorial and likely correlates with multiple risk factors, including exposure to both ionizing and UV radiation. Other risk factors include immunosuppression, arsenic exposure, psoralen and UV-A radiation, and genodermatoses.9 Burden of Disease The true cost of BCC and its effect on the US economy is difficult to determine given the multiple variables, such as treatment modality, treatment setting, and lack of differentiation from other nonmelanoma skin cancers within the International Classification of Diseases, 9th Revision coding system. Based on extrapolated data, the estimated cost of treatment for all nonmelanoma skin cancers (NMSCs) within the United States in 2004 was $2.4 billion––this includes $1.45 billion in direct and $961 million in indirect costs.10 This value is possibly still underestimated, as it only accounts for the treatment of NMSC and does not include the cost of screening or diagnosis. Given that the number of skin cancer procedures in the MediSKINmed. 2015;13:206–213

care database alone increased by 77% between 1992 and 2006, it is certain that the current cost is significantly higher.11 Malignant Potential The majority of BCCs are slow-growing and thus curable when diagnosed and treated in a timely manner; however, a small subset of BCCs with more aggressive biologic behavior, including recurrence and metastasis, is now recognized and accounts for the majority of disease-related mortality. It is this small subset, estimated to account for only 0.0028% to 0.55% of all BCCs, that has influenced the terminology of this disease to reflect that of a malignancy.12 While the locally destructive capability of BCCs has been wellknown since it was first described, recognition of its metastatic potential in the English literature did not occur until 1894 when Cecil Beadles described a lymph node enlarged by characteristic pathologic cells obtained postmortem from the jaw of a man with an extensive rodent ulcer on the ipsilateral cheek.13 It is now known that BCCs can metastasize via the lymphatic or hematologic route (Figure 2).3,12 In contrast to the majority of BCCs, metastatic BCCs (mBCCs) in patients with regional lymph node involvement result in a shortened median survival time of 87 months from time of metastasis, and this further diminishes to 24 months in patients with distant metastasis tumors. BCCs most commonly metastasize to the lymph nodes (54%) followed by the lungs (28%) and bone (24%).12 Of these sites, bony metastasis in particular appears to be a poor prognostic feature, with an estimated mean survival of only 12 months from time of diagnosis. For unclear reasons, patients with lung metastases have a relatively longer median survival time of 66 months.12

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Figure 3. The micronodular variant of basal cell carcinoma is characterized by a worm-like growth in the dermis and is considered an aggressive histologic subtype with high recurrence rates. (Hematoxylin and eosin stain, original magnification ×20.)

Figure 5. Infiltrative and sclerosing/morpheaform basal cell carcinomas are characterized by small irregularly shaped basaloid strands and islands with jagged borders. The fibrotic stroma is associated with the sclerosing/morpheaform subtype. (Hematoxylin and eosin stain, original magnification ×20.)

Figure 4. Metatypical or basosquamous basal cell carcinoma contains foci of squamous differentiation and is typically associated with an infiltrative growth pattern. (Hematoxylin and eosin stain, original magnification ×70.)

Figure 6. Sclerosing/morpheaform basal cell carcinoma, typically presents as a flat, whitish pink indurated plaque reminiscent of a scar.

The biologic behavior of these aggressive BCCs is so distinct that it has led many authors to search for both clinical and histologic prognostic factors to help differentiate these tumors. Clinical Prognostic Features Clinical features of mBCC include large primary tumor size, location on the head and neck, history of prior treatments, and radiation exposure. Although there are reports of cases arising from small primary tumors <1 cm in diameter, most mBCCs SKINmed. 2015;13:206–213

originate from larger primary tumors (average diameter of 7.5 cm) that have been neglected for years.14,15 More than half of mBCCs originate from giant BCCs (tumors >5 cm in diameter) and the overall incidence of metastasis for primary BCCs >3 cm in diameter is estimated to be 1.9%.16 This is the result of several factors. Increasing preoperative tumor size is directly correlated with increased subclinical spread, hindering their complete removal.17 In addition, larger tumors are associated with a more aggressive histologic subtype. In a cohort of 50 patients with giant BCCs, 72% were associated with an aggressive histologic

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subtype (micronodular [Figure 3], metatypical [Figure 4], morpheaform [Figures 5 and 6]) vs only 18% in small tumors. Giant BCCs were also more likely to be recurrent, making treatment more difficult compared with their smaller counterparts (68% vs 4%).18

ers for immunosuppression.25 While one study showed the overall 5-year tumor recurrence rate to be higher in HIV-positive individuals (13.8% vs 2.9%), these patients were also more likely to be treated with nonsurgical therapies than their counterparts, further complicating interpretation of the data.24

Location of the primary tumor for metastatic BCCs is similar to the general trend for all BCCs, with predominance in the head and neck regions.14,16,19 Primary BCCs on the ear, however, are the most common origin for metastatic BCCs and have a more aggressive phenotype.16 In a retrospective chart review of all BCCs treated at an academic center, 40% to 57% of BCCs on the ear were classified as an aggressive histologic subtype compared with 33% to 38% on other facial areas. In addition, primary tumors occurring on the ear were more likely to require three or more stages during Mohs surgery.20 Other regional prognostic factors include tumors located on the eyes and nose, which significantly correlate with increased subclinical spread and incomplete excision.17,21

Histologic Prognostic Features

Additional clinical features associated with a more aggressive phenotype and higher recurrence rate include a history of radiation or prior treatment.22 Many individuals with metastatic BCCs have a documented history of radiation, whether for treatment of acne or of skin cancer. In one review of mBCC, more than 50% of patients had a history of radiation therapy.16 Another author reported that 16% of patients with giant BCCs had a history of ionizing radiation, significantly more than those with smaller tumors.18 Compared with primary tumors, recurrent BCCs have significantly higher subclinical spread and are 3.2 times more likely to require three or more stages during Mohs micrographic surgery for complete clearance.17 In contrast to previously treated BCCs, immunosuppression does not appear to be a significant risk factor for aggressive biologic behavior. A review of solid organ transplant recipients from multiple collaborating institutions revealed 68 patients with 73 distinct metastatic skin cancers, none of which were BCCs.23 In studies assessing the number of Mohs surgery stages during treatment of BCCs, there was no difference between immunocompromised and control patients.17 Retrospective studies of BCCs in HIV-infected patients showed the overall incidence in patients with HIV to be twice that of controls and with a younger age at diagnosis (50.5 years vs 70 years); however, tumors were predominantly of the superficial subtype and other potentially confounding risk factors, such as UV exposure, were not assessed.24,25 There was also no correlation between overall incidence of BCCs and CD4 T-helper cell count or prior antiretroviral treatment, both of which are markSKINmed. 2015;13:206–213

A multivariate analysis of 20 histologic features of BCCs yielded only three that are independent predictors of tumor recurrence––growth pattern (histologic subtype), shape of cell groups (round, spiky, mixed), and narrow resection margin distance.26 Of all the histologic features of BCCs that have been examined in relation to their clinical behavior, histologic subtype has been the most extensively studied. More than 26 subtypes of BCCs have been described.27–30 Sloane and colleagues first classified BCCs into three main subtypes, including nodular (Figures 7–10), superficial (Figures 11–13), and infiltrating.31,32 Later, the micronodular (Figure 3) and sclerosing (Figures 5 and 6) subtypes were introduced by Sexton and Rippey, respectively.33,34 It wasn’t until 2002, however, that the classification scheme was greatly broadened by Weedon and colleagues to include variants such as pigmented (Figures 14–16), fibroepithelial tumor of Pinkus (Figure 17), basosquamous (Figure 4), and adenoid subtypes.35 In a survey of an Australian community, the overall incidence of nodular BCCs (Figures 7–10) was the highest (up to 50%), followed by the superficial subtype (13.3%) (Figures 11–13). Morpheaform/sclerosing (Figures 5 and 6), infiltrative (Figure 5), and micronodular (Figure 3) subtypes together comprised only 8.9% of the total BCCs.36 Of these subtypes, morpheaform (Figures 5 and 6), micronodular (Figure 3), and infiltrative (Figure 5) BCCs have traditionally been considered more aggressive variants of BCC based on their overrepresentation in large, recurrent, and metastatic BCCs. A review of mBCCs showed that basosquamous/metatypical, infiltrative, and morpheaform were the most common subtypes, accounting for 34% of all reported mBCCs.12 In one author’s experience, infiltrative BCCs were also overrepresented in recurrent BCCs, accounting for 65% of the recurrent tumors as opposed to 20% in nonrecurrent tumors.37 Similarly, various case series of giant BCCs reported that approximately 30% to 72% of giant BCCs had a histologic pattern associated with more aggressive phenotypes (micronodular, morpheaform, basosquamous/ metatypical) compared with only 18% of small BCCs.18,38,39 Do BCCs evolve and take on more aggressive phenotypes or do these histologic patterns remain stable? Evidence from multiple

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Figure 7. Nodular basal cell carcinoma is characterized by the presence of predominately rounded collections of basaloid keratinocytes with conspicuous peripheral palisading embedded in a myxoid stroma. (Hematoxylin and eosin stain, original magnification Ă&#x2014;4.)

Figure 10. Biopsy of this ulcerated plaque with rolled borders revealed a nodular and infiltrative growth pattern.

Figure 8. Nodular basal cell carcinoma presents as a smooth, pearly papule, typically with overlying telangiectatic vessels.

Figure 11. Superficial basal cell carcinoma: collections of basaloid keratinocytes arranged in a peripheral palisade within a myxoid stroma bud from the epidermis into the superficial dermis, often in a multifocal pattern. (Hematoxylin and eosin stain, original magnification Ă&#x2014;4.)

Figure 9. Biopsy of this lesion revealed a nodular basal cell carcinoma with an infiltrative growth pattern. Both the infiltrative growth pattern and the facial location place it at a higher risk of recurrence. SKINmed. 2015;13:206â&#x20AC;&#x201C;213

Figure 12. Superficial basal cell carcinoma presents as a slowly enlarging scaly red patch.

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Figure 15. This irregular pearly plaque shows patchy pigmentation. Biopsy revealed a nodular growth pattern in addition to conspicuous pigment-laden stromal macrophages. Figure 13. A more advanced superficial basal cell carcinoma has a thin, translucent rolled border and multiple surface erosions. (Photo courtesy of Dr Aleksandar Krunic.)

Figure 16. A more advanced and ulcerated pigmented basal cell carcinoma that had a nodular growth pattern on histopathologic evaluation. (Photo courtesy of Dr Milena Lyon.)

Figure 14. Pigment is irregularly distributed within this nodular basal cell carcinoma, mostly within stromal melanophages. (Hematoxylin and eosin stain, original magnification Ă&#x2014;80.)

authors suggests that aggressive subtypes of BCCs are histologically stable from inception through their clinical course. A comparison of 21 recurrent BCCs with their primary counterparts showed no differences in the histologic pattern of tumor cells.40 Histologic analysis of two patients with particularly aggressive BCCs demonstrated no changes in the pattern of their tumors throughout their clinical course, from primary lesion to multiple recurrences and subsequent metastasis.41 In both of the preceding reports, the histologic pattern of recurrent and metastatic BCCs was compared with that of the original excision specimen SKINmed. 2015;13:206â&#x20AC;&#x201C;213

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Figure 17. The fibroepithelial tumor of the Pinkus variant of basal cell carcinoma is characterized by long, thin, branching and anastomosing basaloid epithelial strands, two-to three-cells thick, arising from many foci along the epidermis and anastomosing to compartmentalize the loose fibrovascular stroma. (Hematoxylin and eosin stain, original magnification Ă&#x2014;1.) Basal Cell Carcinoma Has Come of Age

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rather than the biopsy specimens, since small biopsy specimens are incomplete and can often miss additional patterns.42 There is substantial evidence to suggest that undertreatment and lack of margin control are more common with histologically aggressive subtypes of BCCs and contribute to the development of recurrent and metastatic tumors. In one series of recurrent BCCs, seven of 29 tumors (24%) recurred a second time, which is significantly higher than the overall recurrence rate for primary tumors. Histologic examination of the preceding excision in those seven cases demonstrated that six of the tumors had a positive resection margin and one had only a 0.12-mm resection margin.40 Data from a plastic surgery department encompassing 2358 patients and 3957 BCC removals demonstrated that a standard excision with 3-mm to 5-mm clinically healthy margin was associated with an overall incomplete excision rate of 13.9%, with 65.3% involving the lateral margin, 18.1% the deep margin, and 7.6% involving both.21 Nodular and superficial subtypes were most often associated with complete excisions. In contrast, nodular BCCs with sclerosing aspects, sclerosing BCC, and basosquamous BCCs were significantly associated with incomplete excisions. Location on the face, specifically the nose, eyes, and ears, as well as tumor penetration into and beyond the subcutaneous fat, also demonstrated higher rates of incomplete excision (Figure 9).21 The recurrence rate for incompletely excised BCCs was 26.8%, which was significantly higher than the 5.9% for those reported as completely excised primary BCCs. Re-excision of recurrent tumors with subsequently negative margins resulted in only a 6.0% repeat recurrence rate, which was no different than that for completely excised primary tumors.21 Together, these data suggest that recurrence is strongly correlated with incomplete tumor removal.

clearance rates. An analysis of surgical margins in consecutive BCCs at an academic center showed that only 6.4% and 3.6% of nodular and superficial BCCs, respectively, involved the standard surgical margins. In contrast, 18.6% of micronodular BCCs, 26.5% of infiltrative BCCs, and 33.3% of morpheaform BCCs involved the surgical margins.33 Regarding Mohs surgery, the morpheaform and basosquamous BCC subtypes were most likely to require three or more stages for complete clearance; this is a reflection of their larger size and propensity for subclinical spread.17 Conclusions The incidence and associated healthcare costs of BCC continue to rise annually in the United States. A small subset of BCCs accounts for the majority of its disease-related mortality. This subset displays more aggressive behavior and includes BCCs located on the head and neck region, large primary tumor size, tumors with a history of prior treatment or radiation, and tumors with more aggressive histopathology, such as the morpheaform, micronodular, and infiltrative patterns. References

Of the many subtypes of BCCs, the morpheaform, infiltrative, and micronodular BCCs are more histologically extensive and more likely to be undertreated, which may account for their more “aggressive” behavior. In a community survey of all BCCs diagnosed in the Hunter Region of New South Wales, Australia, morpheaform and micronodular BCCs had a mean diameter of 11 mm, which was significantly greater (125%) compared with nodular BCCs.36 In a smaller study concentrated on morpheaform BCC, this size differential was even more pronounced, with an estimated lateral subclinical spread of 7.8 mm compared with 2.1 mm seen in nodular BCCs.43 Tumor depth also appears to be significantly different. Compared with nodular and superficial tumors, micronodular and infiltrative BCCs demonstrated greater average tumor depth.42 The overall greater average size seen with micronodular and infiltrative subtypes probably accounts for their decreased SKINmed. 2015;13:206–213

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1 Jacob A. Observations respecting an ulcer of peculiar character, which attacks the eyelids and other parts of the face. Med Recorder Orig Papers Intell Med Surg. 1827;12:320–323. 2 Wu S, Han J, Li WQ, Li T, Qureshi AA. Basal-cell carcinoma incidence and associated risk factors in U.S. women and men. Am J Epidemiol. 2013;178:890–897. 3 Gupta AK, Daigle D, Martin G. Basal cell carcinoma. Skinmed. 2014;12:33–38; quiz 38. 4 Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch Dermatol. 2000;136:1524– 1530. 5 Deady S, Sharp L, Comber H. Increasing skin cancer incidence in young, affluent, urban populations: a challenge for prevention. Br J Dermatol. 2014;171:324–331. 6 Koh D, Wang H, Lee J, et al. Basal cell carcinoma, squamous cell carcinoma and melanoma of the skin: analysis of the Singapore Cancer Registry data 1968-97. Br J Dermatol. 2003;148:1161–1166. 7 Cheng SY, Luk NM, Chong LY. Special features of non-melanoma skin cancer in Hong Kong Chinese patients: 10-year retrospective study. Hong Kong Med J. 2001;7:22–28. 8 Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 2012;166:1069–1080. 9 Sehgal VN, Chatterjee K, Pandhi D, Khurana A. Basal cell carcinoma: pathophysiology. Skinmed. 2014;12:176– 181.

Basal Cell Carcinoma Has Come of Age

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REVIEW

10 Bickers DR, Lim HW, Margolis D, et al. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55:490–500. 11 Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283–287. 12 McCusker M, Basset-Seguin N, Dummer R, et al. Metastatic basal cell carcinoma: prognosis dependent on anatomic site and spread of disease. Eur J Cancer. 2014;50:774–783. 13 Beadles C. Rodent Ulcer. Trans Pathol Soc Lond. 1894;45:176–181. 14 Menz J, Sterrett G, Wall L. Metastatic basal cell carcinoma associated with a small primary tumour. Australas J Dermatol. 1985;26:121–124. 15 Wysong A, Aasi SZ, Tang JY. Update on metastatic basal cell carcinoma: a summary of published cases from 1981 through 2011. JAMA Dermatol. 2013;149:615–616. 16 Snow SN, Sahl W, Lo JS, et al. Metastatic basal cell carcinoma. Report of five cases. Cancer. 1994;73:328–335. 17 Batra RS, Kelley LC. Predictors of extensive subclinical spread in nonmelanoma skin cancer treated with Mohs micrographic surgery. Arch Dermatol. 2002;138:1043– 1051. 18 Randle HW, Roenigk RK, Brodland DG. Giant basal cell carcinoma (T3). Who is at risk? Cancer. 1993;72:1624– 1630. 19 Lo JS, Snow SN, Reizner GT, et al. Metastatic basal cell carcinoma: report of twelve cases with a review of the literature. J Am Acad Dermatol. 1991;24:715–719. 20 Mulvaney PM, Higgins HW, Dufresne RG, Cruz AP, Lee KC. Basal cell carcinomas of the ear are more aggressive than on other head and neck locations. J Am Acad Dermatol. 2014;70:924–926. 21 Codazzi D, Van Der Velden J, Carminati M, et al. Positive compared with negative margins in a single-centre retrospective study on 3957 consecutive excisions of basal cell carcinomas. Associated risk factors and preferred surgical management. J Plast Surg Hand Surg. 2014;48:38–43. 22 Rowe DE, Carroll RJ, Day CL. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol. 1989;15:424– 431. 23 Martinez JC, Otley CC, Stasko T, et al. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol. 2003;139:301–306. 24 Hausauer AK, Maurer T, Leslie KS, et al. Recurrence after treatment of cutaneous basal cell and squamous cell carcinomas in patients infected with human immunodeficiency virus. JAMA Dermatol. 2013;149:239–241. 25 Silverberg MJ, Leyden W, Warton EM, et al. HIV infection status, immunodeficiency, and the incidence of non-melanoma skin cancer. J Natl Cancer Inst. 2013;105:350– 360.

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26 Dixon AY, Lee SH, McGregor DH. Histologic features predictive of basal cell carcinoma recurrence: results of a multivariate analysis. J Cutan Pathol. 1993;20:137– 142. 27 Wade TR, Ackerman AB. The many faces of basal-cell carcinoma. J Dermatol Surg Oncol. 1978;4:23–28. 28 Claassen SL, Royer MC, Rush WL. Granular cell basal cell carcinoma: report of a case and review of the literature. Am J Dermatopathol. 2014;36:e121–e124. 29 Elwood H, Gardner J, Galloway W, Shalin SC. A case of a giant sarcomatoid basal cell carcinoma with heterologous osteosarcomatous elements. J Cutan Pathol. 2014;41:550–551. 30 Tse JY, Pawlak AC, Boussahmain C, et al. Basal cell carcinoma with osteosarcomatous component. Am J Dermatopathol. 2013;35:261–265. 31 Dominguez-Prado I, Rodriguez-Fraile M, Alcalde JM, et al. Identification of the lymph node drainage and selective sentinel lymph node biopsy in a patient with amelanotic melanoma of the uvula. Rev Esp Med Nucl. 2011;30:325–326. 32 Vantuchova Y, Curik R. Histological types of basal cell carcinoma. Scripta Medica (BRNO). 2006;79: 261–270. 33 Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol. 1990;23:1118–1126. 34 Rippey JJ. Why classify basal cell carcinomas? Histopathology. 1998;32:393–398. 35 Weedon D, Strutton G. Skin Pathology. 2nd ed. London, England: Churchill Livingstone; 2002. 36 Kricker A, Armstrong B, Hansen V, et al. Basal cell carcinoma and squamous cell carcinoma growth rates and determinants of size in community patients. J Am Acad Dermatol. 2014;70:456–464. 37 Rippey JJ. Why classify basal cell carcinomas? Histopathology. 1998;32:393–398. 38 Arslan H, Güzel MZ, Cnar C. Treatment of giant basal cell carcinomas of the head and neck with aggressive resection and complex reconstruction. J Craniofac Surg. 2012;23:1634–1637. 39 Archontaki M, Stavrianos SD, Korkolis DP, et al. Giant basal cell carcinoma: clinicopathological analysis of 51 cases and review of the literature. Anticancer Res. 2009;29:2655–2663. 40 Dixon AY, Lee SH, McGregor DH. Histologic evolution of basal cell carcinoma recurrence. Am J Dermatopathol. 1991;13:241–247. 41 Lattes R, Kessler RW. Metastasizing basal-cell epithelioma of the skin: report of two cases. Cancer. 1951;4:866–878. 42 Welsch MJ, Troiani BM, Hale L, et al. Basal cell carcinoma characteristics as predictors of depth of invasion. J Am Acad Dermatol. 2012;67:47–53. 43 Salasche SJ, Amonette RA. Morpheaform basal-cell epitheliomas. A study of subclinical extensions in a series of 51 cases. J Dermatol Surg Oncol. 1981;7:387–394.

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Volume 13 • Issue 3

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD For each of the following numbered questions, chose the single most appropriate lettered response.

2. a. b. c. d.

Worldwide, the incidence of basal cell carcinoma: Continues to decrease annually. Continues to increase annually. Has remained unchanged since 1979. Decreased during the late 20th century and then leveled off. e. Increased during the 20th century and then leveled off. 3. A basal cell carcinoma arising in which of the following cutaneous sites is most likely to metastasize? a. Back. b. Brow. c. Ear. d. Eyelid. e. Nose.

4. Which of the following does not appear to be a significant risk factor for aggressive biologic behavior of a patient’s basal cell carcinoma? a. Histologic subtype of the tumor. b. Immunosuppression of the patient. c. Prior treatment of the tumor with radiation. d. Prior treatment with radiation for another malady (eg, acne). e. Size of the basal cell carcinoma. 5. Of the following, which histologic subtype of basal carcinoma is least likely to show involvement of the standard surgical margins upon surgical excision? a. Infiltrative. b. Micronodular. c. Morpheaform. d. Nodular. e. These histologic subtypes are equally likely to show involvement of the standard surgical margins following surgical excision.

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

1. Worldwide, the most common form of cancer is: a. Adenocarcinoma of the breast (female mammary gland). b. Adenocarcinoma of the colon. c. Adenocarcinoma of the prostrate. d. Basal cell carcinoma of the skin. e. Squamous cell carcinoma of the skin.

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May/June 2015

Volume 13 • Issue 3

Perils of Dermatopathology W. Clark Lambert, MD, PhD, Section Editor

Attack of the Living Dead: Why You Need a GMS Stain With a PAS Stain to Detect Fungi in Dermatopathology Specimens Divya Sharma, BA;1,2 Amy Weiss, BA;1,2 Stephen Peters, MD;2 W. Clark Lambert, MD, PhD1,2 “All generalizations are false, including this one.”––Mark Twain

ungal histopathologic stains, although not 100% sensitive or specific, are useful for providing efficient presumptive diagnoses of infection while waiting for fungal culture results, when no cultures are obtained, or when they might give a false-negative result. If a fungal infection is suspected from a routine dermatopathologic read, using a standard (usually hematoxylin and eosin [H&E]) stain, a dermatopathologist may request a fungal stain. Alternatively, a dermatologist presented with a case that could possibly represent a dermatophytosis or candidosi may request a fungal stain when submitting a biopsy specimen. Although dermatomycoses or superficial fungal infections are not imminently dangerous, a systemic mycotic infection might result in a fatality, particularly among immunocompromised patients. In immunosuppressed individuals, a superficial fungal infection may not cause inflammation during the acute phases, and so clinical history may indicate the need for special stains. Alternatively, the patient may have undergone, or is about to undergo, an open reduction of a fracture. Some dermatophytes, in addition to readily growing in skin, grow well in bone marrow, where they are likely to cause a much more serious infection; thus, an accurate dermatopathologic diagnosis may be critical for the patient.

dosis is a significant issue. Other lesions are often treated with topical agents, such as fluorinated corticosteroids, which may temporarily cause the eruption to improve, only to return after the agent is discontinued and perhaps more severe than before. This may result in a confusing clinical picture that, even if eventually resolved, may cause the patient unnecessary distress. Diagnosing the cause as a dermatomycosis is important and necessary, and needs to be done promptly. The most common fungal stain requested by clinicians and dermatopathologists alike is a periodic acid–Schiff (PAS) stain. This is a mistake, because the PAS stain is not completely reliable in diagnosing cutaneous dermatomycoses. It tends to stain primarily, or exclusively, live fungi, whereas only dead fungi may be visible on the dermatopathologic section. Whenever a PAS stain is requested to diagnose a potential dermatomycosis, a Gomorri methenamine silver (GMS) stain should be requested as well. Similar to PAS, the GMS stains fungal structures but, unlike it, stains preferentially dead fungi. Although only dead fungi may be seen on histopathologic specimens, the live fungi are almost certainly present as well, causing a live infection. An “attack of the living dead” is in progress, readily identifiable only with a GMS stain.1–5

Diagnosing an Eruption

Illustrative Cases

Even when the clinical issue consists of simply diagnosing an eruption, which is the case in the overwhelming majority of instances, establishing the cause as a dermatophytosis or as candi-

These points are illustrated by the cases shown in Figures 1–6. Figures 1–3 show sections of a patient with tinea versacolor. Although special staining may be unnecessary to make the diag-

From the Departments of Pathology and Laboratory Medicine,1 and of Dermatology,2 Rutgers-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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Figure 1.Tinea corporis (Tinea versicolor) with hematoxylin and eosin stain (original magnification ×480). Although abundant in this section, fungal hyphal forms and spores are not easily visualized.

Figure 3. Same case as Figure 1, but with Gomorri methenamine silver stain (original magnification ×480). Abundant fungal hyphal forms and spores are again easily visualized.

Figure 2. Same case as Figure 1, but with periodic acid– Schiff stain (original magnification ×480). Abundant fungal hyphal forms and spores are easily visualized. The curved hyphae confirm this as tinea versacolor.

Figure 4. Tinea corporis with hematoxylin and eosin stain (original magnification ×947). Although present in this section, fungal hyphal forms and spores are not easily visualized.

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nosis, because the fungi are usually abundant, it is important to distinguish between the organism of tinea versacolor and other fungi, since the management may differ. Tinea versacolor is more

likely to both recur and lead to pigmentary changes, which are likely to persist after the organism has been eliminated. Stains to be Considered The walls of fungi contain polysaccharides (1,2-glycol groups), which can be identified with Schiff’s reagent in the PAS stain or hexamine (methenamine) silver solutions in the GMS stain, as the oxidizer (periodic acid or chromic acid) forms aldehydebinding sites for the Schiff or silver ions.

Figure 5. Same case as Figure 4, but with periodic acid–Schiff (PAS) stain (original magnification ×937). Although present in this section, fungal hyphal forms and spores are not easily visualized.

Figure 6. Same case as Figure 4, but with, Gomorri methenamine silver stain (original magnification ×937). Fungal hyphal forms and spores are easily visualized. SKINmed. 2015;13:217–220

The GMS stain highlights the wall of the fungus; however, the unpredictable nature of silver precipitation makes its use challenging. The difficulty in finding stained organisms may arise from insufficient silver impregnation, high background staining, overstaining, and/or an undesirable precipitate. The fungi appear brown-black on a pale green background produced with Light Green counterstaining. A disadvantage of this stain is that normal tissue structures, such as neurosecretory granules, melanin, basement membranes, and collagen fibers, may be confused with yeast. To help differentiate normal structures vs fungi, it is possible to co-localize the GMS-stained structures in tissue sections with those stained with H&E or PAS. Another method is to combine GMS with an H&E counterstain, instead of Light Green, to observe co-localization; however, these specialized methods are time-consuming and require special expertise to carry out. PAS stain is considered more reliable in comparison to GMS stain, because it is relatively simple to conduct even for inexperienced technologists. It detects glycogen in tissues, and fungal walls contain substantial amounts of glycogen. Periodic acid oxidizes substances with nearby glycol groups or their amino/ alkylamino derivatives forming dialdehydes that combine with Schiff’s reagent to create an insoluble red-purple compound that causes the fungal cell wall to appear pink to red to purple. The PAS stain discerns the polysaccharide-laden wall of most fungal organisms, except Histoplasma capsulatum, and a PAS+ granule in mature spores is characteristic of microsporidia. A major disadvantage of this stain, however, is that it can stain many components of normal cells from a variety of animal species, such as glycogen, basement membranes, and neuronal glycolipids. Other intracellular components that may be stained are neutral mucosubstances, epithelial sulfomucins and sialomucins, colloid of thyroid, reticular fibers, paneth cell granules, adrenal chromaffin cells, intranuclear inclusions in vas deferens, afibrillar cells of arterioles of kidney, granules within reticuloendothelial cells, salivary glands, gastric and Brunner’s glands, mucin from the respiratory tract, and acinar and endocrine glands. Thus, a PAS stain may stain diverse structures

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within a single field, obscuring live fungi even when they are present. Such a case is shown in Figures 4–6, in which only the GMS stain clearly shows fungi. To minimize the interference of these extraneous stained structures, the stain may be performed with diastase digestion. For example, granules with glycogen are found within keratinocytes and may mimic fungal spores, but glycogen is diastase-sensitive. In addition, the strength of the oxidizer, the duration of exposure, and the density of sugars in the specimen of interest can influence the location where the Schiff molecule will bind. Finally, the PAS stain performed with diastase digestion is labor-intensive and time-consuming for technologists, making it expensive and cumbersome to carry out.

with topical steroids, which tends to make a dermatophyte infection improve clinically even as fungi/yeast grow and become more apparent, followed by flaring after the steroid is discontinued, at which time biopsy/scraping may be repeated with a better chance of identifying the organism. Above all, the physician should remember that fungal infections may present in diverse ways, and that “all generalizations are false, including this one.” References 1 Bancroft JD, Gamble M. Theory and Practice of Histological Techniques. 5th ed. New York, NY: Churchill Livingstone; 2002:335–338. 2 Carson FL. Histotechnology: A Self-Instuctional Text. 2nd ed. Chicago,IL: American Society of Clinical Pathology; 1997. 3 Della Speranza V, Fail R. A common mistake when staining for fungi. HistoLogic. 2005;38:1–3.

Conclusions In the end, no stain is ideal for the identification of fungi, and the diagnosis may be missed. This situation is made more difficult by the fact that, due to host response and other factors, the organisms may be sparse or appear nontypical. Clinicopathologic correlation may be necessary, such as empirical treatment

4 Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clin Microbiology Rev. 2011;24:247–280. 5 Thompson SW. Selected Histochemical and Histopathological Methods. Springfield, IL: Charles C Thomas; 1966: 480–481,496–499.

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.

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May/June 2015

Volume 13 • Issue 3

New to the Clinic Noah Scheinfeld, JD, MD, Section Editor

1% Ivermectin Cream (Soolantra) for the Treatment of Rosacea Noah Scheinfeld, JD, MD

osacea is a multifactorial disease whose causes include the Demodex folliculorum mite found in the pilosebaceous unit, which is the most common ectoparasite in humans.1 One aspect of the pathophysiology of rosacea skin is the inflammatory reaction to D folliculorum, which acts against a background of oily skin and elicits pathologic immune responses. Rosacea skin shows a higher expression of genes encoding proinflammatory cytokines (interleukin [IL] 8, IL-1b, and tumor necrosis factor α [TNF-α]) and inflammasome-related genes (NALP-3 and CASP-1), LL-37, and VEGF, as well as CD45RO, MPO, and CD163. The presence of these cytokines indicates that rosacea engenders broad immune system activation. Ivermectin has been shown to exert anti-inflammatory effects by inhibiting lipopolysaccharide-induced production of inflammatory cytokines, including TNF-α and IL-1b, while increasing the anti-inflammatory cytokine IL-10. While the D folliculorum mite cannot be confirmed as the most important or even the most common causative agent of rosacea, it is found on most adult noses. When D folliculorum, and perhaps other parasites are killed, rosacea abates. Soolantra (ivermectin 1%, the active ingredient) cream in a soothing cream base has both anti-inflammatory and antiparasitic activity and has been proven effective in treating rosacea in three phase III clinical trials. In December 2014, the Food and Drug Administration (FDA) approved the 1% ivermectin cream as a once-daily cream to treat rosacea based on these trials. Comparison of Antiparasitic Treatment vs Metronidazole and Azelaic Acid in Rosacea

proved individual cases of rosacea. For example, an immunocompetent patient with recalcitrant papulopustular rosacea responded to combination therapy of oral ivermectin and topical permethrin.2 Similarly, rosacea-like demodicidosis, recalcitrant to other treatments, also improved with combination therapy with oral ivermectin and topical permethrin cream.3 The use of topical metronidazole 0.75% gel compared with permethrin 5% in a study found that permethrin 5% cream is a safe alternative for the topical treatment of papulopustular rosacea. Another study noted that permethrin 5% cream is superior to metronidazole 0.75% gel and placebo in decreasing D folliculorum infection and is as effective as metronidazole 0.75% gel in treating the erythema and papules associated with rosacea.4 In a split-face study of 23 women and 1 man, azelaic acid 20% cream was equally as effective as metronidazole 0.75% cream or permethrin 5% cream after 15 weeks.5 Rosacea abated in all three arms, but azelaic acid cream was significantly more effective against inflammatory lesions but not erythema when compared with metronidazole or permethrin creams. Patients using azelaic acid cream had the greatest degree of satisfaction. In a study of 63 patients, researchers found that the effect of permethrin 5% cream on D folliculorum infection was superior to that of metronidazole 0.75% gel or placebo. The effect of permethrin 5% cream on erythema and papules was found to be more effective than placebo and as effective as metronidazole 0.75% gel; however, permethrin had no effect on telangiectasia, rhinophyma, and pustules.6,7 1% Ivermection Cream for the Treatment of Rosacea

Before the approval of 1% ivermectin cream to treat rosacea, a number of reports found that antiparasitic medications im-

Based on the promise held by the antiparasitic treatment of rosacea, Galderma Laboratories (Fort Worth, TX) developed

From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Weill Cornell Medical College, 150 West 55th Street, New York, NY 10019 • E-mail: scheinfeld@earthlink.net

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Soolantra.8 Soolantra’s base is Cetaphil® moisturizing cream, a dermatologist-recommended formula that is fragrance-free, lanolin-free, mild, and nonirritating. Three 12-week studies have been published on the treatment of rosacea with 1% ivermectin cream, which compared ivermectin 1% cream with metronidazole 0.75% cream9 and ivermectin cream with placebo.10 The first report9 included 962 patients who participated in comparing the response of moderate papulopustular rosacea oncedaily ivermectin 1% cream vs twice-daily metronidazole 0.75% cream. Participants with rosacea were randomized to receive ivermectin 1% cream (n=478) or metronidazole 0.75% cream (n=484). At week 16, ivermectin 1% cream achieved significant superiority to metronidazole 0.75% cream in terms of reduction in inflammatory lesions from baseline (83.0% vs 73.7%). A total of 84.9% of the patients in the ivermectin 1% cream treatment group were “clear” or “almost clear” vs 75.4% of patients in the metronidazole 0.75% cream group who were “clear” or “almost clear,” respectively. Side effects (topical only) were rare with the use of ivermectin 1% cream and most patients demonstrated excellent improvement with treatment. The most common related adverse effect was skin irritation (3 patients [0.6%] vs 4 patients [0.8%]) for ivermectin 1% cream and metronidazole 0.75% cream, respectively. Thirteen patients reported serious but unrelated adverse events. A total of three patients (0.6%) in the ivermectin 1% cream group experienced related adverse events leading to discontinuation (caused by skin irritation and hypersensitivity), compared with 10 (2.1%) patients in the metronidazole 0.75% cream group (caused by skin irritation, allergic dermatitis, aggravation of rosacea, erythema, pruritus, and general disorders [feeling hot]).9 In the second report,10 a total of 683 patients with moderate to severe papulopustular rosacea were included in study 1 (ivermectin 1% cream: 451, vehicle: 232) and 688 patients in study 2 (ivermectin 1% cream: 459, vehicle: 229). In studies 1 and 2, the majority of patients with rosacea completed the study (91.4% and 92.6%, respectively). The patients in the treatment groups were similar at baseline in terms of demographics and baseline disease characteristics, with about 31 to 33 inflammatory lesions on average and the majority having moderate rosacea. The demographics were a preponderance of women (68.2% and 66.7% in studies 1 and 2, respectively) and, as would be expected in a rosacea study, mostly Caucasian/white (96.2% and 95.3%), with a mean age of 50.4 and 50.2 years, respectively. The second trial of ivermectin cream 1% vs placebo presented compelling data that the medication was effective.10 The proportion of patients with rosacea who achieved clear or almost clear SKINmed. 2015;13:222–224

status at week 12 for studies 1 and 2 were 38.4% and 40.1% for ivermectin cream 1% compared with 11.6% and 18.8% for vehicle, respectively. A significant difference between treatment arms in both studies was observed by week 4 (10.9% and 11.8% vs 5.6% and 5.7%, respectively). For inflammatory lesion counts, the mean difference between ivermectin 1% cream and vehicle from baseline to week 12 was –8.13 lesions for study 1 and –8.22 for study 2, with a hefty 95% confidence interval. The investigators found that the median reduction from baseline in inflammatory lesion counts for both studies was 76.0% and 75.0%, respectively, vs 50.0% for both vehicle groups, with significant differences apparent by week 2. The incidence of adverse effects was comparable between studies 1 and 2 (40.5% and 36.5% for ivermectin 1% cream vs 39.4% and 36.5% for vehicle, respectively). Fewer patients in the ivermectin 1% groups tended to report related adverse effects than in the vehicle groups (4.2% and 2.6% vs 7.8% and 6.5%, respectively), as well as for related dermatologic adverse effects (3.5% and 1.5% vs 6.9% and 5.7%) and related adverse effects leading to discontinuation (1.3% and 0.2%, vs 1.7% for both vehicle groups). A similarly low proportion of patients reported serious adverse effects for ivermectin 1% cream and vehicle groups (0.7% and 1.5% vs 0.4% and 1.7%). There were no related serious side effects. The most common related adverse effect in study 1 was sensation of skin burning: eight (1.8%) in the ivermectin 1% cream group vs 6 (2.6%) in the vehicle group. For study 2, the most common related adverse effects for ivermectin 1% were pruritus and dry skin (3 patients each [0.7%]) compared with 0 and 2 patients (0.9%) for vehicle, respectively. Conclusions Ivermectin 1% cream, shown to be safe and effective in 12 weeks of trials, was safe and well-tolerated for an additional 40 weeks (up to 52 weeks in total), although some patients reported skin burning and skin irritation.8 It is clear now that D folliculorum is among the many causes of rosacea and that drugs that target D folliculorum as monotherpy can ameliorate the disease. Ivermectin 1% cream is an added total in the armamentarium of dermatologists, and its smoothing base, study data, and effectiveness will become part of my armamentarium as a first-line agent. Ivermectin 1% cream only infrequently causes burning and irritation, and these effects are within the range of existing branded agents that can be prescribed to any rosacea patient. Few good randomized study data exist on how 1% ivermectin cream compares in terms of tolerance or effectiveness with metronidazole 0.75% gel or metronidazole 1% gel or cream or lotion, brimonidine, azelic acid 15% gel, time-release 40-mg doxycycline, and, most important, with other anti-demodex

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preparations such as oral ivermectin pills or topical permethrin 5% cream. That being said, the new 1% cream is in line with the Cetaphil® vehicle and likely will be well tolerated. As an effective product, it may likely be expensive, similar to Sklice® (ivermectin 0.5%) lotion approved by the FDA in 2012 to treat head lice, which has not been a major commercial success and has superseded other agents and shifted the treatment for head lice. I am happy that 1% ivermectin cream is on the market and eagerly await coupons that will facilitate patients using the medications, likely in combination with existing agents. References 1 Karincaoglu Y, Bayram N, Aycan O, Esrefoglu M. The clinical importance of demodex folliculorum presenting with nonspecific facial signs and symptoms. J Dermatol. 2004;31:618–626. 2 Allen KJ, Davis CL, Billings SD, Mousdicas N. Recalcitrant papulopustular rosacea in an immunocompetent patient responding to combination therapy with oral ivermectin and topical permethrin. Cutis. 2007;80:149– 151. 3 Forstinger C, Kittler H, Binder M. Treatment of rosacealike demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999;41:775–777. 4 Swenor ME. Is permethrin 5% cream effective for rosacea? J Fam Pract. 2003;52:183–184.

5 Mostafa FF, El Harras MA, Gomaa SM, et al. Comparative study of some treatment modalities of rosacea. J Eur Acad Dermatol Venereol. 2009;23:22–28. 6 Koçak M, Yagli S, Vahapoglu G, Eksioglu M. Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. A randomized double-blind placebo-controlled study. Dermatology. 2002;205:265–270. 7 Signore RJ. A pilot study of 5 percent permethrin cream versus 0.75 percent metronidazole gel in acne rosacea. Cutis. 1995;56:177–179. 8 Ivermectin cream will contribute much to the treatment of patients with rosacea: interview with Dr Zoe Draelos Payer Perspectives in Dermatology (/payer-perspectives-in-dermatology) – Rosacea (/payer-perspectivesin-dermatology/121-cat-121). http://www.ahdbonline. com/payer-perspectives-in-dermatology/1804-ivermectin-cream-will-contribute-much-to-the-treatment-ofpatients-with-rosacea-interview-with-dr-zoe-draelos. Accessed January 17, 2015. 9 Taieb A, Ortonne JP, Ruzicka T, et al. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2014 Sep 16 [Epub ahead of print]. 10 Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13:316–323.

Pellagra: Courtesy of Museo delle Cere Anatomiche L. Cattaneo, University of Bologna, Italy. Photo by Cristian Mancini. Submitted by Diana Garrisi, London, UK.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 10th World Congress of the International Academy of Cosmetic Dermatology Rio de Janeiro, Brazil, November 14–16, 2015 Abstract deadline: August 16, 2015 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 10th World Congress of the International Academy of Cosmetic Dermatology in Rio de Janeiro, Brazil, November 14–16, 2015. 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, 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 10th World Congress of the International Academy of Cosmetic Dermatology in Rio de Janeiro, Brazil, November 14–16, 2015. 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, August 16, 2015 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. The winner(s) will publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. All applicants will receive e-mail notice of the Resident Case Report Review Committee’s decision by September 15, 2015. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor The University of Chicago Pritzker School of Medicine, Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

Official publication of IACD

(8 8

44 ll ur tio 4sp n t 44 h

l g ad ift for

May/June 2015

Volume 13 • Issue 3

NEW THERAPY UPDATE William Abramovits, MD; Aditya K Gupta, MD, PhD, FRCPC, Section Editors

XELJANZ (Tofacitinib) for Chronic Plaque Psoriasis Aditya K. Gupta, MD, PhD, FRCPC;1,2 Deanne Daigle, MSc;2 William Abramovits, MD;3–5 Kimberly Dawn Vincent, MD6

everal targeted, more effective therapies have recently emerged onto the psoriasis treatment landscape. Tofacitinib is one such novel agent. Its mechanism of action involves the inhibition of the Janus kinase signaling pathway implicated in several immune-mediated diseases including psoriasis. Oral tofacitinib was previously approved for rheumatoid arthritis but has also demonstrated encouraging results in the treatment of chronic plaque psoriasis in phase I to III clinical trials.

Physician Global Assessment (PGA) of psoriasis grade of “clear” or “almost clear” for tofacitinib 5 mg and 15 mg twice a day were also significantly greater than placebo, with a significant difference between 15 mg twice a day and placebo evidenced as early as week 2.

Many patients with psoriasis demonstrate rapid clinical improvement when treated with biologic agents; however, high cost and potential for adverse effects continue to prompt the search for targeted therapies that lend a balance of efficacy, safety, and feasibility to the patient. Although the exact pathogenesis of psoriasis has yet to be elucidated, immunologic events are understood to partially result from increased tyrosine kinase activity. The Janus family of kinases is a subset of the tyrosine kinases used by several cytokines involved in psoriasis. The oral formulation of tofacitinib, a novel Janus kinase inhibitor, has recently undergone phase I to III clinical trials to investigate its efficacy and safety in the treatment of chronic plaque psoriasis. Phase II

The efficacy and safety of oral tofacitinib 5 mg and 10 mg were evaluated in two identically designed multicenter, randomized, double-blind, placebo-controlled, phase III trials.3,4 Participants who had plaque psoriasis covering ≥10% BSA and a PASI score ≥12 received oral tofacitinib 5 mg or 10 mg twice a day for 52 weeks or matching placebo twice a day for 16 weeks. Participants in the placebo group were then re-randomized to oral tofacitinib 5 mg or 10 mg twice a day for the remaining 36 weeks. Trial 1 and trial 2 enrolled 900 and 959 participants, respectively. Efficacy rates for the pivotal phase III trials are presented in Table II. In trials 1 and 2, the rates of PASI 75 and PGA of “clear” or “almost clear” were significantly greater than placebo for both dosages of tofacitinib (Ps<.0001).

Various doses of oral tofacitinib were investigated in a phase IIb multicenter, randomized, double-blind, parallel-group, placebocontrolled trial.1,2 A total of 197 participants with chronic plaque psoriasis for ≥6 months, ≥15% body surface area (BSA) involvement, and a Psoriasis Area Severity Index (PASI) ≥13 received 2 mg, 5 mg, or 15 mg of oral tofacitinib or placebo twice daily for 12 weeks. Efficacy rates are presented in Table I. PASI 75 response rates were significantly higher in patients in all tofacitinib groups vs those in the placebo group, with significant increases in PASI 75 response rates observed at week 4. Week 12 rates of

The rates of all adverse events (AEs) in Trials 1 and 2 were 54.19%, 66.94%, and 53.33% and 58.90%, 60.89%, and 40.90% in the tofacitinib 5 mg, 10 mg, and placebo groups, respectively. In Trial 1, the most common AEs with tofacitinib 5 mg were upper respiratory tract infection (9.09%), headache (7.71%), and blood creatine phosphokinase increase (7.16%), while the most common AEs with tofacitinib 10 mg were nasopharyngitis (15.28%), blood creatine phosphokinase increase (10.56%), and upper respiratory tract infection (9.72%). In Trial 2, the most common AEs with tofacitinib 5 mg were naso-

Phase III

Pivotal Phase III Trials (NCT01276639 and NCT01309737)

From the Department of Medicine, University of Toronto School 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, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Phase IIb Efficacy Rates Tofacitinib 2 mg

Tofacitinib 5 mg

Tofacitinib 15 mg

Placebo

25.00a

40.82b

66.67b

2.00

Participants with PASI 90

14.58c

18.37b

33.33b

0.00

Participants with PASI 50

39.58

65.31

87.50

20.00

40.82a

72.92b

10.00

Primary endpoint, % Participants with PASI 75 Secondary endpoints, % c

Participants with PGA score 24.49 of “clear or “almost clear”

Abbreviations: PASI, Psoriasis Area Severity Index; PGA, Physician Global Assessment. aP<.001 vs placebo. bP<.0001 vs placebo. cP<.05 vs placebo.

Table II. Efficacy Rates From Pivotal Phase III Trials Trial 1 (NCT01276639)

Trial 2 (NCT01309737)

Tofacitinib 5 mg (n=363)

Tofacitinib Placebo 10 mg (n=360) (n=177)

Tofacitinib 5 mg (n=376)

Tofacitinib Placebo 10 mg (n=374) (n=193)

Participants with PGA grade of “clear” or “almost clear”

41.87a

59.17a

9.04

46.01a

59.09a

10.88

Participants with PASI 75

39.94a

59.17a

6.21

46.01a

59.63a

11.40

19.83a

39.44a

0.56

24.47a

38.77a

5.18

Primary endpoints, %

Secondary endpoints, % Participants with PASI 90

Abbreviations: PASI, Psoriasis Area Severity Index; PGA, Physician Global Assessment. P<.0001 vs placebo. a

pharyngitis (12.57%), upper respiratory tract infection (7.59%), hypercholesterolemia (6.28%), while the most common AEs with tofacitinib 10 mg were nasopharyngitis (13.91%), upper respiratory tract infection (7.87%), and blood creatine phosphokinase increased (6.82%). The rates of serious AEs in Trial 1 were 6.61%, 5.28%, and 4.44%, and in Trial 2, 4.71%, 4.99%, and 4.55% in the tofacitinib 5 mg, 10 mg, and placebo groups, respectively. Rates of discontinuation as a result of an AE in Trials 1 and 2 were 3.03% and 2.88%, 2.22% and 2.63%, and 6.21% and 2.55%, in the tofacitinib 5 mg, 10 mg, and placebo groups, respectively. It is unclear whether AEs were related to study drug.

Withdrawal and Retreatment Study (NCT01186744) A phase III, randomized, double-blind, parallel-group, withdrawal and retreatment trial was conducted to investigate the efficacy of continuous vs intermittent therapy with oral tofacitinib.5 A total of 666 adult participants with chronic plaque psoriasis covering ≥10% BSA, a PASI ≥12, and a PGA score of 3 “moderate” or 4 “severe” initially received tofacitinib 5 mg or 10 mg twice a day (initial treatment phase). Participants were withSKINmed. 2015;13:227–229

drawn from treatment after 24 weeks and responders, classified as participants who achieved both a PASI 75 and PGA rating of “clear” or “almost clear,” were then re-randomized 3:1 to placebo twice a day or their previous dose of tofacitinib and monitored for relapse (treatment withdrawal phase). Patients who relapsed during the treatment withdrawal phase then received the same dose of tofacitinib to which they were initially randomized for 16 weeks (retreatment). After 24 weeks of initial treatment, 43.8% and 67.6% of participants achieved PASI 75 response and 41.6% and 62.8% achieved a PGA grade of “clear” or “almost clear” in the tofacitinib 5-mg and 10-mg groups, respectively. A total of 111 (33.5%) participants in the 5-mg group and 185 (55.2%) participants in the 10-mg group attained both outcomes and were eligible to enter the treatment withdrawal phase. By the end of the treatment withdrawal phase, a significantly greater percentage of participants in the tofacitinib 5-mg and 10-mg groups maintained a PASI 75 response compared with those switched to placebo (5 mg vs 5 mg to placebo, P=.008; 10 mg vs 10 mg

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to placebo, P<.0001), with similar proportions of participants achieving PGA responses (5 mg vs 5 mg to placebo, P=.0027; 10 mg vs 10 mg to placebo, P<.0001). Approximately 92.3% and 93.0% of participants who continued to receive tofacitinib 5 mg or 10 mg during the treatment withdrawal phase did not relapse at 16 weeks compared with 32.8% and 42.9% of those switched from 5 mg and 10 mg to placebo, respectively. Among those switched to placebo, median time to loss of PASI 75 response was 8 weeks and median time to relapse was 16 weeks, regardless of their initial dose of tofacitinib. Of those who relapsed while taking placebo during treatment withdrawal, 36.8% retreated with 5 mg and 61.0% retreated with 10 mg regained PASI 75 response, while 44.8% and 57.1% who lost a PGA response achieved “clear” or “almost clear” status after 16 weeks of retreatment with tofacitinib 5 mg and 10 mg, respectively.

outcomes than intermittent treatment. Twice-daily tofacitinib (10 mg) was shown to be noninferior to a single subcutaneous 50-mg dose of etanercept. The phase II to III trials also demonstrated significant improvements across a variety of measures of health-related quality of life not reported herein. Intended for oral use, if and when approved, tofacitinib will compete against apremilast and the traditional systemic therapies, which include methotrexate, sulfasalazine, mycophenolate mofetil, cyclosporine, and acitretin (some used off-label). Head-to-head studies are unlikely. Comparisons of PASI reductions and PGA in clinical studies, AEs, and cost coverage issues will help dermatologists to decide between these drugs and between them and biologics. Tofacitinib’s effects on psoriatic arthritis may add to the decision-making process. References

Noninferiority Trial (NCT01241591) The noninferiority of tofacitinib was compared with one subcutaneous dose of etanercept or placebo in a phase III, randomized, double-blind, parallel group study.6 The trial enrolled 1101 participants with plaque psoriasis covering ≥10% BSA. Participants received oral tofacitinib 5 mg or 10 mg twice a day and placebo subcutaneous injections at 3- to 4-day intervals for 12 weeks, or matching placebo tablets twice a day and subcutaneous injections of etanercept 50 mg every 3 to 4 days for 12 weeks. Mean differences in the proportion of participants who attained a PGA score of “clear” or “almost clear” were 47.11%, 68.18%, and 66.27% in the tofacitinib 5-mg, tofacitinib 10-mg, and etanercept 50-mg groups, respectively, while the proportion who achieved PASI 75 response were 39.51%, 63.64%, and 58.81% in the tofacitinib 5-mg, tofacitinib 10-mg and etanercept 50-mg groups, respectively. The mean differences in PGA (1.91; 95% confidence interval, –5.22 to 9.05) and PASI 75 responses (4.83; 95% confidence interval, –2.57 to 12.23) between the tofacitinib 10-mg and etanercept 50-mg groups demonstrated that oral tofacitinib 10 mg twice a day for 12 weeks was noninferior to a single injection of etanercept 50 mg; however, noninferiority of tofacitinib 5 mg to etanercept 50 mg could not be established. Conclusions Tofacitinib was approved by the US Food and Drug Administration in 2012 for treatment of rheumatoid arthritis. Phase I to III clinical trials have shown that tofacitinib is also effective in the treatment of chronic plaque psoriasis. Participants treated with various doses of tofacitinib demonstrated significant clinical improvement compared with those given placebo in phase II and phase III trials, with continuous treatment maintaining better SKINmed. 2015;13:227–229

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1 CinicalTrials.gov Web site. Pfizer, Inc. A phase 2B, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial evaluating the efficacy and safety of dose regimens with oral CP-690,550 in the treatment of subjects with moderate to severe chronic plaque psoriasis [Internet]. 2012 [cited 2015 Mar 9]. https://clinicaltrials.gov/ct2/show/NCT00678210. Accessed May 10, 2015. 2 Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167:668– 677. 3 CinicalTrials.gov Web site. Pfizer, Inc. A phase 3, multisite, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy and safety of 2 oral doses of CP-690,550 in subjects with moderate to severe chronic plaque psoriasis [Internet]. 2014 [cited 2015 Mar 11]. https://clinicaltrials.gov/ct2/show/study/ NCT01309737. Accessed May 10, 2015. 4 CinicalTrials.gov Web site. Pfizer, Inc. Phase 3 randomized, double-blind, placebo-controlled, parallelgroup study of the efficacy and safety of 2 oral doses of CP-690,550 in subjects with moderate to severe chronic plaque psoriasis [Internet]. 2014 [cited 2015 Mar 11]. https://clinicaltrials.gov/ct2/show/study/ NCT01276639. Accessed May 10, 2015. 5 Bissonnette R, Iversen L, Sofen H, et al. Tofacitinib withdrawal and re-treatment in moderate-to-severe chronic plaque psoriasis: a randomised controlled trial. Br J Dermatol. 2014 Nov 21 [Epub ahead of print]. 6 CinicalTrials.gov Web site. A phase 3, multi site, randomized, double blind, placebo controlled, parallel group study of the efficacy and safety of 2 oral doses of CP690,550 and 1 subcutaneous dose of etanercept in subjects with moderate to severe chronic plaque psoriasis [Internet]. 2014 [cited 2015 Mar 18]. https://clinicaltrials.gov/ct2/show/study/NCT01241591. Accessed May 10, 2015.

XELJANZ (Tofacitinib) for Chronic Plaque Psoriasis

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May/June 2015

Volume 13 • Issue 3

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

Necrotic Carpal Tunnel Syndrome: A Standard Deviation From the Median Nerve Warren R. Heymann, MD

arpal tunnel syndrome (CTS) is the most frequent entrapment neuropathy, affecting 3.8% of the general population. The peak ages for incidence are 40 to 60 years, and the disorder is more common in women.1 Necrotic CTS (NCTS) is rare and patients may present to dermatologists, even pediatric dermatologists, as was seen in a recently reported case of a 10-year-old boy.2 During the past several weeks, I have considered the diagnosis of NCTS in two patients. Recognition of NCTS is essential because it may easily be misdiagnosed. Clinical Details An 86-year-old man noted a blister on the radial side of his distal right index finger. He had recently fractured his right wrist and underwent orthopedic surgery, where a stabilizing plate was placed; cephalexin was prescribed for the blister itself. On examination, a sharply defined ulcer was noted at the site of the prior blister. He demonstrated an absent pinprick sensation with diminished strength in the distribution of the median nerve. The second patient was a 67-year-old woman who presented with ulcerations and intact bullae of the distal left second and third digits with a background of edema and questionable sclerodactyly. I initially suspected blistering dactylitis, although I was concerned about other entities, such as Raynaud disease, scleroderma, or pernio. A bacterial culture of the blister fluid grew only “normal skin flora.” Results from antinuclear antibody and anti-Scl-70 were negative. At her subsequent visit, it was apparent that her lesions were in the distribution of the median nerve. Both patients were referred to assess for NCTS, with the presumption that they would likely require surgical decompression.

Salient Points Risk factors that affect the volume or contour of the carpal tunnel which lead to median nerve compression with the development of CTS may be intrinsic (eg, tumors or tumor-like lesions) or extrinsic (eg, pregnancy, oral contraceptive agents, menopause, obesity, renal failure, obesity, hypothyroidism, congestive heart failure, or a wrist fracture). In addition, disorders that affect the median nerve itself result in a higher incidence of CTS (eg, diabetes, alcoholism, vitamin toxicity or deficiency, neurotoxin exposure).1 In children, genetic or metabolic disorders may be responsible (eg, familial thickening of the transverse ligament or mucopolysaccharidosis).2 Occupations that require the use of vibratory tools or repeated, forceful movements of the hands and wrist (such as assembly work or food packaging) are associated with CTS. To date, evidence does not support a definitive link to computer keyboard or mouse use.3 The key to considering the diagnosis of CTS is based on understanding the anatomy of the carpal tunnel and its relation to the medial nerve. The carpal tunnel is found at the base of the palm and is bounded by the carpal bones and by the transverse carpal ligament. Within the tunnel run digital tendons and their synovial sheaths, plus the median nerve. Any increase in volume in this region, or change in contour, has the potential to cause ischemia of the median nerve, thereby leading to CTS. The median nerve provides sensory branches to the lateral three fingers (thumb, index, and middle) and the radial half of the ring finger. When the nerve is compressed, symptoms are manifested in the distribution of the nerve. The sensory cutaneous branch of the median nerve (which innervates the palm) arises 6 cm proxi-

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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mal to the transverse carpal ligament and then passes superficial to the ligament––this explains why the palm is not affected in CTS.4 The thumb may be spared of CTS due to overlapping innervation by the superficial radial nerve.2

manifesting as acroosteolysis, accompanied by severe Raynaud phenomenon, nail dystrophy, and cuticular hyperkeratosis.6 Other nail findings may include Beau’s lines, subungual hyperkeratosis, transverse melanoncyhia, and onychomadesis.2

CTS may be classified in three stages: stage I often presents with nocturnal awakenings with the sensation of a swollen, numb hand. Pain may radiate from the wrist to the shoulder, and patients experience a tingling in their hand and fingers. Hand shaking (the “flick” sign) relieves the symptoms. Stage II is diurnal with the symptoms being noted when the patient remains in the same position for a protracted time or when performing repeated wrist movements. Patients report objects falling from their hands when motor involvement ensues. Stage III is characterized by atrophy of the thenar eminence and a poor response to surgical decompression.1

Therapeutic Approach

When the diagnosis of CTS is considered, three classical clinical maneuvers may assist in diagnosis: (1) the Tinel sign––repeatedly tapping the wrist over the transverse carpal ligament causing pain and paresthesia over the distribution of the median nerve; (2) the Phalen sign––the patient holds the elbow in full extension while flexing the wrist 90 degrees for at least 60 seconds; a positive test result causes pain or paresthesias; and (3) the median nerve (Durkan’s) compression test––applying pressure over the transverse carpal ligament. The test is positive if pain or paresthesias develop within 30 seconds. If CTS is considered severe enough so that surgery is a likely option, electrodiagnostic studies (including nerve conduction studies and electromyography) are warranted 3

Treatment for CTS may be conservative, especially in patients in whom the aggravating factors may resolve in time (such as pregnancy) or with treatment (such as hypothyroidism). Splints, intralesional, or systemic steroids may be of value.3 For NCTS, however, the treatment of choice is surgical decompression by sectioning the transverse ligament, with most patients improving, although bone resorption is irreversible.2 Conclusions Having seen two such patients, I can appreciate why the diagnosis of NCTS can be missed. A clinician could easily diagnose scleroderma, lupus, dermatomyositis, Raynaud disease, vasculitis, endocarditis, or blistering dactylitis, and not give NCTS a second thought. The diagnostic clue is recognizing the median nerve distribution of the lesions. Establishing this diagnosis will have a profound impact on patients––get them the evaluation and surgery they need and they will consider you outstanding beyond a standard deviation from the median! References

From a practical perspective, dermatologists see patients on a daily basis with CTS; however, routine diagnosis and management rests with primary care physicians, rheumatologists, orthopedic, and/or hand surgeons. Rarely, however, dermatologists may be the physicians who recognize the disorder, which is especially true for NCTS. The presumed pathogenesis for NCTS is altered autonomic innervation resulting in ischemia. The attendant sensory neuropathy may result in a diminished pain threshold, allowing for increased traumatic or thermal injury. These neurovascular abnormalities explain the clinical correlates of erythema, bullae, erosions, and ulcerations.5 Severe cases of NCTS may easily be mistaken for scleroderma (or other connective tissue diseases),

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1 Ibrihim I, Khan WS, Goddard N, Smitham P. Carpal tunnel syndrome: a review of the recent literature. Open Orthop J. 2012;6:69–76. 2 Maldonado Garciá C, Valente Duarte de Sousa IC, López Cepeda L. Necrotic carpal tunnel syndrome in a child. Pediatr Dermatol. 2014;31:500–503. 3 Wipperman J, Potter L. Carpal tunnel syndrome––try these diagnostic maneuvers. J Fam Pract. 2012;61:726– 732. 4 Ghasemi-Rad M, Nosair E, Vegh A, et al. A handy review of carpal tunnel syndrome: from anatomy to diagnosis and treatment. World J Radiol. 2014;6:284–300. 5 Scarfi F, Arunachalam M, Galeone M, Bassi A, Difonzo E. Fingertip necrosis as a sign of carpal tunnel syndrome. J Am Acad Dermatol. 2013;68;e51–e52. 6 Tosti A, Morelli R, D’Alessandro R, Bassi F. Carpal tunnel syndrome presenting with ischemic lesions, acroosteolysis and nail changes. J Am Acad Dermatol. 1993;29:287– 290.

Necrotic Carpal Tunnel Syndrome

The 11th Annual

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May/June 2015

Volume 13 • Issue 3

CONTACT DERMATITIS CAPSULE Matthew J. Zirwas, MD, Section Editor

Patch Testing Pearls: Solutions to Common Clinical Dilemmas Jonathan G. Bonchak, MD; Matthew J. Zirwas, MD

atch testing can be challenging. Providers frequently run into obstacles such as excited skin syndrome and confounding concomitant medications, which may raise questions as to the practicality of patch testing in certain patients. We aim to answer some of the more commonly asked questions here. 1. A patient with suspected contact dermatitis arrives to the office for patch testing. She has a diffuse eczematous eruption involving most of her back. The nurse asks you where the patches should be placed. It is not uncommon for patients to present with widespread dermatitis involving the entire back; however, patches MUST be placed on nondermatitic skin, as placement of allergens on eczematous skin may produce excited skin syndrome, which decreases the dermatologist’s ability to accurately interpret patch test results. In addition, areas of preexisting dermatitis may be impossible to distinguish from positive patch test reactions. Although there is regional variation in the skin response to allergens,1 the arm, thigh, and chest are generally considered adequate sites for patches in patients with widespread back dermatitis (Figures 1 and 2). If the dermatitis is so widespread that there is not enough clear skin on which to place the patches, short-term treatment with oral corticosteroids, stopped 3 days prior to patch testing, may be considered with the aim of temporary clearing of the skin so that testing can be completed. 2. A patient with suspected allergic contact dermatitis (ACD) is interested in patch testing; however, she has near-complete resolution of her signs while taking oral corticosteroids and she is hesitant to stop treatment for a week during testing.

Most patients with suspected ACD experience significant diminution of dermatitis with oral corticosteroids. Concern for exacerbation of the dermatitis during the week of testing is common. Although cessation of oral corticosteroid 3 to 5 days prior to testing is optimal, satisfactory results are usually obtained on a daily prednisone dose of 10 mg.2 Additionally, topical steroids may be used at any sites that do not contain patches without affecting the final read. 3. A patient being treated with methotrexate for her rheumatoid arthritis calls the office to inquire about the drug’s effect on patch testing. She is worried that she will have to skip doses in order to get accurate results. It is common for patients to present to the office while taking methotrexate or other immunosuppressant medications. The consensus put forth by the North American Contact Dermatitis Group states that little or no impact is made on patch test results by concurrent therapy with methotrexate, tumor necrosis factor α inhibitors, and ustekinumab.2 Patients should be reassured and dosing continued while undergoing patch testing. 4. Twenty-four–hours after patch placement, the patient calls the office to complain of severe pruritus at the site of testing. She asks what medication she can take without affecting the results. Patients experience varying degrees of pruritus during the course of patch testing. Allergic or irritant reactions to the applied allergens or even adhesive on the patches can cause significant discomfort. Diphenhydramine and H1 histamine antagonists, such as loratadine, can be taken to ameliorate these events without interfering with results. Hydroxyzine may also be used, but patients need to be warned of its strong sedative effects. Anecdotally, patients have reported significant relief by applying peppermint oil mixed into moisturizer or coconut oil around (but not on) the site of patch testing.

From the Division of Dermatology, Ohio State University College of Medicine, Columbus, OH Address for Correspondence: Matthew J. Zirwas, MD, OSU Dermatology East, 540 Officenter Place, Suite 240, Gahanna, OH 43230 • E-mail: matt.zirwas@osumc.edu

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Figure 1. Patches placed on a patient’s upper and outer aspect of the arm.

Figure 2. Positive patch test results on the thighs.

5. A patient is concerned an occupational exposure is responsible for her dermatitis. She brings unlabeled chemicals from work to be patch tested. Industrial compounds are important sources of exposure in ACD. Material safety data sheets may identify irritants or allergens in industrial substances, but these sheets may not be available for a variety of reasons. In general, chemicals that come into contact with the skin for prolonged periods during a workday will not be severe irritants or toxins and thus can be safely patch tested. If the patient is unsure of whether he or she comes into direct contact with the materials, suggest that the patient bring the material to the office, erring on the side of caution until there is more information on the substance. 6. The patient is unable to return to the office for patch removal after 48 hours. An office visit is not necessary for patch removal; they may be removed at home after 48 hours. The patient should have someone remove the patches, trace each boundary with a dark marker, and renumber the columns as they were done at the patch placement appointment. A photo of the back immediately after removal and 1 hour after removal should be taken in case they are needed as references on the day of the final reading. As always, showers and excessive sweating should be avoided until after the final observation is complete.

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Conclusions The patch test is an established and important tool for dermatologists.3 Patients can benefit greatly from the results, but getting through to the final read can be a challenge in some cases. Providers want to ensure patient comfort and safety while doing everything possible to obtain accurate results. The key is to be adaptive. These tips should encourage patch testers that despite the hurdles that commonly arise in the patch testing clinic, the majority of patients are good candidates for testing. Conflicts of interest Dr Zirwas reports relationships with Valeant, SmartPractice, Stiefel, Medimetriks, FitBit, and Sun Laundry. References

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1 Memon AA, Friedmann PS. Studies on the reproducibility of allergic contact dermatitis. Br J Dermatol. 1996;134:208–214. 2 Fowler JF, Maibach HI, Zirwas M, et al. Effects of immunomodulatory agents on patch testing: expert opinion 2012. Dermatitis. 2012;23:301–303. 3 Adams RM. Patch testing––a recapitulation. J Am Acad Dermatol. 1981;5:629–646.

Patch Testing Pearls: Solutions to Common Clinical Dilemmas

May/June 2015

Volume 13 • Issue 3

Common Diseases: Treatment Options Noah Scheinfeld, MD, JD, Section Editor

Dissecting Cellulitis Noah Scheinfeld, MD, JD

erifolliculitis capitis abscedens et suffodiens, or dissecting cellulitis (DC), predominantly occurs in 20- to 40-yearold African American men.1 Less frequently, DC occurs in women, the young, and other racial groups. Familial cases occur; however, DC’s genetics and pathophysiology remain unknown. Clinical Presentation

DC usually starts on the scalp vertex or occiput as a folliculitis. It expands into patches of perifollicular pustules, nodules, abscesses, and sinuses (Figure). Nodules may be firm or fluctuant, and pus and serous fluid can be expressed. The course is typically chronic and relapsing.3 Different lesions can be present simultaneously, and healing often occurs with scarring alopecia that may be patchy or confluent. Not infrequently, keloidal scars form in areas of inflammation. Histologically, DC has a variety of hair pathology, including pigmented casts and black dots (resembling those of alopecia areata). There are “3-dimensional” yellow dots imposed over dystrophic hairs, and large, yellow amorphous areas and pinpoint white dots with a whitish halo.2 A deep, superficial, and granulomatous and suppurative perifolliculitis may be present. Lymphocytes and plasma cells surround cystically dilated, disrupted hair follicles, which may contain Gram-positive cocci. Periodic acid-Schiff with diastase stain reveals no fungi. The initial perifolliculitis evolves toward forming profound abscesses, fistulas, and the destruction of pilosebaceous follicles with granuloma formation, often accompanied by lymphoplasmacytic and gigantic cell histology that mimics that of hidradenitis suppurativa (HS).3 DC can also occur in parallel with acne conglobata (AC), HS, and pilonidal cysts (PNCs), a syndrome referred to as the follicular occlusion triad, or tetrad.4 DC has been reported to occur with pyoderma vegetans; marginal keratitis; pityriasis rubra pilaris; keratitis-ichthyosis-deafness syndrome; synovitis, acne, palmoplantar pustulosis, hyperostosis, osteitis (SAPHO) syndrome; Crohn’s disease; pyoderma gangrenosum; and a variety of arthri-

tis types (eg, osteomyelitis, sternocostoclavicular hyperostosis, and spondyloarthritis).4 One patient developed squamous cell carcinoma associated with chronic DC.5 DC should be distinguished from several other scalp conditions including acne keloidalis nuchae, pseudopelade of Brocq, tinea capitis, alopecic and aseptic nodules of the scalp (pseudocyst of the scalp), folliculitis decalvans, and folliculotropic mycosis fungoides with large-cell transformation. Treatment Although no consensus exists for the treatment of DC, I offer the following recommendations, taking into account that DC can be treated as a chronic and relapsing condition. Initially, I tell patients to stop applying occlusive scalp preparations. I explain that DC is an inflammatory follicular disease, not primarily an infection. I prefer to start with injections of intralesional triamcinolone acetate 5 to 10 mg/mL, up to 3 mL. In addition, I offer to incise nodules that are filled with pus, which usually provides rapid relief by decreasing the pressure of the pus-filled lesions.1 Because bacteria seem to aggravate the condition, some clinicians prefer also to initiate treatment with double-strength trimethoprim/sulfamethoxazole twice a day (BID)6 or a quinolone, such as ciprofloxacin 250 to 500 mg BID8 or levofloxacin 500 to 750 mg daily. Therapy may range from 10 to 30 days or may last longer, depending on the severity of the case. My preferred regimen includes rifampin 300 mg BID and clindamycin 300 mg BID (the standard starting regimen for HS, which is a disease that parallels DC), although many clinicians select minocycline 100 mg BID9 or doxycycline 100 mg BID for their greater anti-inflammatory effect instead of clindamycin. In women, antiandrogens combined with antimicrobials can have a role in therapy.9 The use of antimicrobials raises questions, just as in AC and HS. Are they acting as antimicrobials or as anti-inflammatory agents?

From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Department of Dermatology, Weill Cornell Medical College, 150 West 55th Street, New York, NY 10019 • E-mail: scheinfeld@earthlink.net

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They likely act as both. To add to the confusion, one report noted that a culture from a lesion grew a heavy load of Prevotella intermedia and Peptostreptococcus asaccharolyticus. Treatment with oral clindamycin 600 mg every 8 hours was given for 6 weeks along with topical isotretinoin, and the patient’s condition improved significantly over the next 12 months.10 Most topical antimicrobials and retinoids are weak arrows in abating DC and usually not recommended. Having stated this, there may be a role for topical clindamycin, dapsone (which sometimes helps HS), tretinoin, or tazorotene, if there is not too much inflammation or scar tissue. Immunosuppression in the form of prednisone 40 to 60 mg daily for 2 to 3 weeks also has a place in the armamentarium.6 In case reports, isotretinoin has succeeded in abating, lessening, and sometimes eliminating new flares of DC in cases where antimicrobials did not abate the DC,11,12 although there have been mixed results with oral isotretinoin.13 In a bygone era, radiation was used to destroy hair follicles, just as in the treatment of tinea capitis. With the advent of lasers, this therapy is rarely used. Epilation of the hair follicles are the goal for using the 800 nm laser,14 long-pulse non–Q-switched ruby laser,15 and the 1064 nm long-pulsed Nd:YAG laser.16 It is proposed that the 1064 nm laser, which penetrates most deeply and whose reports note that patients hair grew back, is the optimal choice. Carbon Dioxide laser ablation, a destructive therapy, should be reserved for patients in whom nonablative lasers have failed.17 A case report showed that photodynamic therapy was successful in one woman.18 Modern external beam radiation therapy for refractory dissecting cellulitis of the scalp can be used when all other means fail.19

Figure. Dissecting cellulitis of the scalp with nodules and pustules.

References 1 Scheinfeld NS. A case of dissecting cellulitis and a review of the literature. Dermatol Online J. 2003;9:8. 2 Rakowska A, Slowinska M, Kowalska-Oledzka E, et al. Trichoscopy of cicatricial alopecia. J Drugs Dermatol. 2012;11:753–758. 3 Benvenuto ME, Rebora A. Fluctuant nodules and alopecia of the scalp. Perifolliculitis capitis abscedens et suffodiens. Arch Dermatol. 1992;128:1115–1119. 4 Salim A, David J, Holder J. Dissecting cellulitis of the scalp with associated spondylarthropathy: case report and review. J Eur Acad Dermatol Venereol. 2003;17:689– 691.

On the horizon, recalcitrant DC has been successfully treated in several cases with tumor necrosis factor α blockers, eg, adalimumab13 and infliximab,20 mirroring results for the treatment of HS and AC. Oral alitretinoin, already approved in many European Union countries for chronic hand dermatitis and eventually to be approved in the United States, has been reported to be highly effective for DC.21

5 Curry SS, Gaither DH, King LE Jr. Squamous cell carcinoma arising in dissecting perifolliculitis of the scalp, A case report and review of secondary squamous cell carcinomas. J Am Acad Dermatol. 1981;6:673–678.

Conclusions

8 Onderdijk AJ, Boer J. Successful treatment of dissecting cellulitis with ciprofloxacin. Clin Exp Dermatol. 2010;35:440.

DC remains a source of significant morbidly, pain, and even shame for patients. Its etiology remains unknown, which is why clinicians have deployed so many treatments against it. The treatments outlined above should be helpful, taking into account that oral medications alone are not curative and longterm use of combination therapy is often required. SKINmed. 2015;13:236–238

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6 Quarles FN, Brody H, Badreshia S, et al. Acne keloidalis nuchae. Dermatol Ther. 2007;20:128–132. 7 Greenblatt DT, Sheth N, Teixeira F. Dissecting cellulitis of the scalp responding to oral quinolones. Clin Exp Dermatol. 2008;33:99–100.

9 Goldsmith PC, Dowd PM. Successful therapy of the follicular occlusion triad in a young woman with high dose oral antiandrogens and minocycline. J R Soc Med. 1993;86:729–730. 10 Brook I. Recovery of anaerobic bacteria from a case of dissecting cellulitis. Int J Dermatol. 2006;45:168–169.

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11 Khaled A, Zeglaoui F, Zoghlami A, Fazaa B, Kamoun MR. Dissecting cellulitis of the scalp: response to isotretinoin. J Eur Acad Dermatol Venereol. 2007;21:1430–1431. 12 Georgala S, Korfitis C, Ioannidou D, et al. Dissecting cellulitis of the scalp treated with rifampicin and isotretinoin: case reports. Cutis. 2008;82:195–198. 13 Navarini AA, Trüeb RM. 3 cases of dissecting cellulitis of the scalp treated with adalimumab: control of inflammation within residual structural disease. Arch Dermatol. 2010;146:517–520. 14 Boyd AS, Binhlam JQ. Use of an 800-nm pulsed-diode Laser in the treatment of recalcitrant dissecting cellulitis of the scalp. Arch Dermatol. 2002;138:1291–1293. 15 Chui CT, Berger TG, Price VH, Zachary CB. Recalcitrant scarring follicular disorders treated by laser-assisted hair removal: a preliminary report. Dermatol Surg. 1999;25:34–37. 16 Krasner BD, Hamzavi FH, Murakawa GJ, Hamzavi IH. Dissecting cellulitis treated with the long-pulsed Nd:YAG laser. Dermatol Surg. 2006;32:1039–1044.

17 Liu Y, Ma Y, Xiang LH. Successful treatment of recalcitrant dissecting cellulitis of the scalp with ALA-PDT: case report and literature review. Photodiagnosis Photodyn Ther. 2013;10:410–413. 18 Glass LF, Berman B, Laub D. Treatment of perifolliculitis capitis abscedens et suffodiens with the carbon dioxide laser. J Dermatol Surg Oncol. 1989;15:673–676. 19 Chinnaiyan P, Tena LB, Brenner MJ, Welsh JS. Modern external beam radiation therapy for refractory dissecting cellulitis of the scalp. Br J Dermatol. 2005;152:777– 779. 20 Wollina U, Gemmeke A, Koch A. Dissecting cellulitis of the scalp responding to intravenous tumor necrosis factor-alpha antagonist. J Clin Aesthet Dermatol. 2012;5:36– 39. 21 Prasad SC, Bygum A. Successful treatment with alitretinoin of dissecting cellulitis of the scalp in keratitis-ichthyosis-deafness syndrome. Acta Derm Venereol. 2013;93:473–474.

Historical Diagnosis and treatment: epithelioma

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May/June 2015

Volume 13 • Issue 3

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Eve Lowenstein, MD, PhD, Section Editor

Onychomycosis Mark Bernhardt, MD Dr Elliot was not prepared to say that it was onychomycosis, as he did not think a positive diagnosis could be made without the microscope, but that he would like to make a suggestion as to treatment. Every one knew that cases of onychomycosis were almost hopeless, and at best, most tedious; but he had employed a method of treatment which had proved excellent…. (T)he man’s fingers were baked in a machine such as was used for rheumatic joints. The nails grew back after only a few exposures, and became normal. In view of this result, it might be worthwhile to try similar treatment in such cases-dry heat at 350° to 400° Fahr. ––Presented by Dr MacKee for Dr Fordyce. J Cutan Dis. 1915;33:211. Call me Ishmael.––Moby Dick, Herman Melville

remember griseo. With all due respect to the late Dr Blank, it wasn’t much, but it was all we had. I remember itraconazole. I remember terbinafine. There was something that came between the two, but I don’t remember it. I remember pulse therapy. I remember topical ciclopirox. I remember them all. Laser Therapy I remember seeing the first billboard advertising laser treatment for toenail fungus. That’s odd, I thought, I don’t remember reading anything in my journals about this. And then I started seeing more and more ads for laser treatment of toenail fungus. The ads were sprouting, well, like mushrooms. My pa-

tients would ask whether it was legitimate, and I had to admit my ignorance. I didn’t even know anyone who was doing this. The couple of patients who told me they’d had it done were unimpressed, but then I read this 1915 paper. If heat therapy had originally been advocated a century ago, it was about time I brought myself up to date about this latest weapon against the scourge of onychomycosis. Confirmed Treatment But it wasn’t that simple. The companies making lasers to treat onychomycosis insisted that their technology did not actually fry the fungus. Some claimed that there was selective thermolysis of fungal chromophores such as xanthomegnin or melanin, but to me that’s still targeted heating. Others claimed their laser worked by altering intracellular enzymatic reactions. Some researchers confessed that the mode of action for their machines was as yet unknown. But they worked, that they all agreed upon. Well, actually, every laser manufacturer claimed that its particular product worked, but they weren’t so sure about their competitors. And––no––I could not find a comparative study, say, of a pulsed 1064 Nd-Yag laser vs a bimodal 870- and 930-nm laser. But I did find a lot of ads. A lot of ads. Maybe I’ve just seen too many hyped-up miracle cures turn out to be less than expected. Maybe I’ve grown disillusioned by the gap between marketing and medicine. Call me skeptical.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA Address for Correspondence: Mark Bernhardt, MD, Private practice, 1601 East Broward Blvd, Fort Lauderdale, FL 33301 • E-mail: cheesedb@aol.com

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Cosmetic Surgery Capsule

6th Annual Cosmetic Surgery Forum 2014 Top Resident Presentations December 3–6, 2014, Las Vegas, NV topical corticosteroids. The patient’s condition improved with a combination of topical tacrolimus, topical urea, systemic antipruritics, and systemic neuropathic pain modulators.

A Chronic Pruritic Plaque on the Left Shoulder

Jessica K. Crabbe, BS; Kerry K. Shaughnessy, MD; Loretta S. Davis, MD; Division of Dermatology, Medical College of Georgia at Georgia Regents University, Augusta, GA

he objective of this report is to raise awareness of postherpetic neuralgia with pruritus as a possible trigger for lichen simplex chronicus (LSC) while stressing the potential for severe disease in the absence of proper diagnosis and treatment. This case demonstrates an unusually striking dermatomal distribution of LSC on the shoulder of a 54-year-old HIV-positive woman felt to be triggered by postherpetic neuralgia and associated pruritus. Adjacent skin demonstrated striae consistent with overuse of

HIV predisposes patients to herpes zoster and postherpetic neuralgia at a younger age than in the general population. The pruritus accompanying postherpetic neuralgia can trigger the development of LSC in a segmental distribution. The mainstays of LSC therapy are potent or superpotent topical corticosteroids with their inherent risks for steroid atrophy and adrenal suppression. Adjunctive or alternative therapies include topical calcineurin inhibitors, keratolytics and emollients, topical capsaicin, and doxepin cream. Sedating antihistamines, low dose tricyclic antidepressants, and neuropathic pain modulators may be necessary to control the associated pruritus.

Figure. Possible distributions. SKINmed. 2015;13:241–244

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Monitoring for Rhabdomyolysis in Patients on Isotretinoin Therapy

Divya Shokeen, MD; Eric Rudnick MD; Christina L. Mitchell, MD

Department of Dermatology, University of Florida College of Medicine, Gainesville, FL

cne vulgaris is due to an inflammatory disease process of the pilosebaceous unit. Though treatment can be arduous and vary based on disease severity, in the severe nodulocystic variant of acne vulgaris, isotretinoin is still the most effective therapy. During the initial introduction of the medication in 1982, multiple side effects were noted. With the advent of the iPledge program, continued monitoring of LFTs, TG and appropriate dosing, patients can be fairly safely monitored while on the medication; however, several case reports have shown that possibly monitoring of creatinine phosphokinase levels and avoidance of excessive strenuous exercise while on treatment with isotretinoin should be considered. This case of an 18-year-old man on 30 mg of isotretinoin shows a significantly elevated creatinine phosphokinase level of greater than 30,000, as well as elevated AST and ALT a week after an hour long arm workout. Throughout the lab evaluation of the patient, there was no elevation in his creatinine level, though the patient complained of both pain and swelling in bilateral upper extremities and darkening urine. This possible side effect should be discussed prior to start of treatment. Patients should not be deterred from maintaining their usual exercise regimen; however, they should monitor themselves for severe muscular swelling pain and inform their dermatologist prior to continuing isotretinoin.

Bilateral Peri-Ocular Primary Mucinous Carcinoma Treated with Mohs Micrographic Surgery

Figure. H&E staining at 100x displays an epithelial component widely dispersed in lakes of pale-staining basophilic mucin in the dermis. Tumor cells display eosinophilic cytoplasm and small vesicular nuclei focally arranged in a cribriform pattern.

the left lateral canthus and a 3 × 3 mm firm dome shaped papule at the right lateral canthus. An excisional biopsy of the left lateral canthus and a punch biopsy of the right lateral canthus were performed; both revealed mucinous carcinoma. Bilateral mammography and colonoscopy were negative for malignancy. Immunohistochemistry stains of tumor cells in both lesions were positive for CAM 5.2, CK7, HMW, EMA, CEA, ER, PR, BRST-2 and were negative for CK20 and organ specific markers of CDX2 and TTF-1. Ki-67 stain showed a low proliferation index of 1–5%. The diagnosis of bilateral primary mucinous carcinoma was made. Both lesions were successfully removed via Mohs micrographic surgery. Primary complex closure was performed because it yielded an aesthetically pleasing result while facilitating the ability to more easily monitor for recurrence.

Squamous Cell Carcinoma Arising in Hidradenitis Suppurativa

David Rayhan, MD; Peter Abasolo, MD; Jeremy Kampp, MD; Shi-Kaung Peng, MD, PhD Division of Dermatology, Los Angeles County Harbor-UCLA Medical Center, Torrance, CA

ucinous carcinoma is a rare malignancy that can either be of primary cutaneous etiology or metastasize to the skin from the breast or intestine. A 64-year-old woman presented to dermatology clinic for evaluation of a 1 × 1.5 cm firm, mobile, dermal nodule with an irregular surface at SKINmed. 2015;13:241–244

Bonita Kozma, MD; Holly Kerr, MD Department of Dermatology, Henry Ford Hospital, Detroit, MI

idradenitis suppurativa (HS) is a chronic inflammatory condition characterized by nodules and scarring sinus tracts, with terminal hair follicles and apocrine glands. A rare complication is the development of squamous cell carcinoma (SCC) in chronic HS. We describe a case of a 44-year-old woman with over a 30-year history of HS in the axillae, groin, and

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buttocks. She reported many prior surgeries for treatment. The excisions cured her axillary HS, but her condition persisted in the groin and buttocks. Physical exam revealed scarred nodules and sinus tracts over the bilateral buttocks and groin. A large exophytic nodule was present over the anterior peri-vulvar area extending to the perineum. Biopsies revealed moderately differentiated invasive SCC. The patient was found to have malignant hypercalcemia and stage 4 vulvar SCC with metastasis to the liver upon further workup. The patient unfortunately passed away three months later. To date, there have been 67 cases reported of SCC arising in HS. Most cases occur in HS that has been present for over 20 years. HPV may play a role in malignant degeneration. Given the high mortality, it may be prudent for patients with severe longstanding disease to undergo excision earlier.

Ulcerations of Striae Distensae with Chronic Corticosteroids and Bevacizumab

Cerrene N. Giordano, MD; Karen L. Connolly, MD; Holly Kerr MD

We report a case of a 38-year-old Caucasian woman with a 4-year history of a right frontal anaplastic astrocytoma who developed ulcerations within striae distensae. The patient had been treated with 3 years of chronic oral dexamethasone, external beam radiation, and systemic temozolomide. After failing initial therapy, the patient began treatment with bevacizumab. Following initiation of bevacizumab, she noticed abrupt onset of painful ulcerations on the trunk and extremities, all localized to the striae distensae. Two lesional biopsies performed revealed ulceration without evidence of infection, microthrombotic event, inflammation, or vasculitis. Upon discontinuation of bevacizumab, the ulcerations resolved. Bevacizumab has been associated with various dermatologic side effects, including delayed wound healing, hand foot syndrome, xerosis, and nonspecific papuloerythematous eruptions. Ulceration of striae distensae in association with combination chronic corticosteroid use and bevacizumab therapy is an important newly reported complication. Implications for the patient can be serious, as this can be a treatment-limiting side effect.

Department of Dermatology, Henry Ford Hospital, Detroit, MI

triae distensae due to chronic corticosteroid use are commonly seen in patients with brain malignancies. Ulceration of striae distensae is an uncommonly reported adverse effect seen in association with high-dose corticosteroid use along with administration of bevacizumab, a humanized antibody against vascular endothelial growth factor (VEGF).

An Adolescent with Solid Facial Edema (Morbihan Disease)

Conor P. Dolehide, MD; Bhavnit K. Bhatia, MD; James O. Ertle, MD Department of Dermatology, Rush University Medical Center, Chicago, IL

15-year-old man presented with a 2-year history of acne and facial swelling. Physical examination revealed acneiform papules and cysts, as well as edema of the glabella, eyelids, and cheeks. There was a dramatic transformation of the patientâ&#x20AC;&#x2122;s face when compared to a photograph from his eighth grade graduation. Histopathology demonstrated periadnexal and perivascular lymphocytic inflammation as well as dermal fibrosis. Ectatic lymphatic endothelium stained with D2-40. His disease initially improved with isotretinoin and oral glucocorticoids, but he continues to have significant edema of the central face.

Figure. Ulcerations occurring in striae distensae. SKINmed. 2015;13:241â&#x20AC;&#x201C;244

In 1957, French dermatologist Robert Degos described chronic edema in the upper part of the face of a French farmer who came from Morbihan (a region of Northwestern France). In 1991, Gorin et al. designated this syndrome as Morbihan disease. It is also known as lymphedematous rosacea or solid facial edema. It is characterized by slowly accumulating edema of the forehead, glabella, eyelids, and cheeks. The pathogenesis of the condition remains unclear. The edema will not resolve without interven-

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May/June 2015

COSMETIC SURGERY CAPSULE Retained Dermal Filler Masquerading as Periorbital Edema

Tanya T. Khan, MD; Julie A. Woodward, MD Duke University Eye Center, Department of Oculoplastic and Reconstructive Surgery, Durham, NC

Figure. Acneiform papules and edema of the glabella, eyelids, and cheeks.

tion and may be refractory to treatment. The most effective treatment seems to be isotretinoin, although mixed results have been reported. Other treatment options may include systemic glucocorticoids, oral antimicrobials, and steroid sparing agents.

42-year-old Caucasian woman presented with a 1–2 year history of left upper eyelid drooping that was causing headache from brow hiking to be able to see. On examination, the eyelid was found to have dermatochalasis, trace edema, and subtle left globe dystopia (Figure A). Options of biopsy versus imaging were discussed for a variety of causes before the patient mentioned that hyaluronic acid (HA) filler was injected into her left superior sulcus 6 years prior to presentation. Hyaluronidase injection into the patient’s left upper eyelid led to prompt resolution of the edema within one hour and subsequent volume loss in the upper sulcus (Figure B). One week later, a different HA filler was carefully injected into the left upper eyelid with improved volume restoration (Figure C). Dermal fillers typically last in the skin from six months up to 1–2 years. While edema is a well-known adverse outcome related to dermal filler injections, prolonged periorbital edema has rarely been reported beyond five months from time of injection. We present a case of an unusually extended course of HA fillerassociated edema that lasted for 6 years in an otherwise highly mobile facial muscle area that was diagnostically dissolved with hyaluronidase.

Figure. A case of retained dermal filler.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2015;13:241–244

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6th Annual Cosmetic Surgery Forum 2014

MEDIA PARTNER

May/June 2015

Volume 13 • Issue 3

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

Weightlifter’s Nodule: A New Variant of Athlete’s Nodule Jamie Goldberg, MD; Carmen Campanelli, MD; Jason B. Lee, MD

A 17-year-old high school football player presented to our dermatology clinic complaining of two asymptomatic lumps on the upper part of his back. The first lump was noticed on the right side of the upper aspect of his back following a weightlifting session. The second lump appeared on the left side of the upper part of his back several weeks later. The patient’s personal and family medical history was unremarkable. Physical examination revealed an ill-defined, firm, mobile subcutaneous nodule measuring approximately 3 cm on the right upper part of the back and a similar but smaller nodule on the left upper portion of the back (Figure 1). The location of the lesions corresponded to the areas of maximal pressure produced by a squat bar that he uses frequently during weightlifting (Figure 2). Histologic analysis of the right lesion revealed a markedly expanded dermis caused by a striking increase in the number of collagen bundles that were relatively normal in thickness, accompanied by a subtle increase in the number of fibroblasts (Figure 3). In some foci, fibroplasia along with increased deposition of mucin further contributed to the expansion of the dermis (Figure 3). Although the process spanned the entire dermis, it was more pronounced in the deep reticular dermis, particularly near the subcutis as collagen bundles were arranged in a more haphazard array in this region. Verhoeff-Van Gieson stain revealed diminished and fragmented elastic fibers within some of the involved areas. This reactive fibrosis can be seen in athlete’s nodules as a result of repetitive blunt pressure. We proposed a diagnosis of weightlifter’s nodule to further classify these lesions and the patient was instructed to discontinue associated weightlifting activities. (SKINmed. 2014;12:246–249)

ports-related dermatoses have been described in a wide variety of athletes including surfers, boxers, runners, equestrians, football players, martial art participants, and weightlifters.1–7 Many of the conditions are a result of recurrent local friction and pressure at the involved sites. The types of lesions encountered depend on the acuteness, chronicity, and frequency of exposure as well as the predominant type of mechanical stress. Recurrent frictional stress may result in alteration of the epidermis with or without fibrosis of the superficial dermis, whereas recurrent blunt pressure may result in significant alteration of the dermal matrix. For example, runner’s foot blister represents intraepidermal blister from acute frictional stress, whereas callus and knuckle pads represent local lichenification of the skin ac-

companied by some degree of subepidermal fibrosis from repetitive friction and blunt pressure. In 1991, the term athlete’s nodule was proposed by researchers to encompass sports-related dermatoses in which recurrent friction and pressure resulted in formation of collagenomatous cutaneous nodules at the involved sites.8 They are typically asymptomatic, symmetric, and believed to develop in response to firm pressure. Because the nodules consisted of an increased number of normal-appearing collagen bundles without a concomitant increase in the number of fibroblasts, the authors proposed that the lesions were best categorized as acquired connective tissue nevi of collagen type, ie, collagenomas.