Mar / Apr, 2014 by jo-ann kalaka-Adams

March/April 2014 • Volume 12 • Issue 2 EDITORIAL The Sign of Leser-Trélat: Is It Really So? —For Your Eyes Only Lavery, Parish, Lambert, Lee, and Lambert

Perianal Giant Condyloma Acuminatum (Buschke-Löwenstein Tumor) Shenoy

Aplastic Anemia and Hoyeraal-Hreidarsson Syndrome Malbora, Avci, and Ozbek

COMMENTARY Xerosis Cutis: A Common Predicament of Raynaud’s Disease Chacon, Franca, Ledon, Savas, and Nouri

ORIGINAL CONTRIBUTION Dermatologic Manifestation of Hyperandrogenism: A Retrospective Chart Review Clark, Rudolph, Gerber, Glick, Shalita, and Lowenstein

DEPARTMENTS NEW therapy update LUZU (Luliconazole) 1% Cream

Gupta, Cvetković, Abramovits, and Vincent

NEW to the clinic EpiCeram

Merkel Cell Carcinoma

Minokadeh, Wulkan, Beer, and Waibel

Bilateral Zosteriform Extragenital Lichen Sclerosus Kumar, Jha, Mallik, Raihan

CORRESPONDENCE Traumatic Panniculitis in a Chinese Woman Oh, Tan, Thirumoorthy, Pang, and Lee

Rosacea: Could Topical Azelaic Acid and Oral Tetracyclines Modify Videocapillaroscopic Pattern? Ganzetti, Giuliodori, Campanati, and Offidani

BOOK REVIEW Lasers and Energy Devices for the Skin Wang

Scheinfeld

THE HEYMANN FILE Addressing the Role of Human Herpesviruses 6 and 7 in DRESS Heymann

photo capsule Lucio’s Phenomenon and/or Relapsing Erythema Necroticans Sehgal, Prasad, Kaviarasan, and Malhotra

case studies Palmoplantar Papules and Hyperkeratosis in a Deaf Man Taylor, Kwatra, and McMichael Lebanese Dermatological Society

Proliferative Fasciitis in the Abdominal Region

Zaraa, Zaouak, El Euch, Chelly, Haouet, Mokni, and Ben Osman

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

Rosacea is with her wherever she goes . So is Finacea . ®

It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. You have made Finacea® the #1 Dermatologist-prescribed topical rosacea brand.1

INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated. IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®. Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings. In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less. Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy. Please see Brief Summary of full Prescribing Information on adjacent page. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

1. According to IMS NPATM (National Prescription Audit) July 2010-October 2013 © 2014 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross, Finacea and the Finacea logo are registered trademarks of Bayer. All rights reserved. FIN-10-0001-14 | February 2014

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TABLE OF CONTENTS March/April 2014 • Volume 12 • Issue 2

EDITORIAL

The Sign of Leser-Trélat: Is It Really So?—For Your Eyes Only ..................................................................... 76

Michael Joseph Lavery, MB BCh BAO; Lawrence Charles Parish, MD, MD (Hon); Peter C. Lambert, MA; Robert E. Lee, MD; W. Clark Lambert, MD, PhD

COMMENTARY

Xerosis Cutis: A Common Predicament of Raynaud’s Disease...................................................................... 80

Anna H. Chacon, MD; Katlein Franca, MD, MS; Jennifer Ledon, BS; Jessica Savas, BS; Keyvan Nouri, MD

ORIGINAL CONTRIBUTION

Dermatologic Manifestation of Hyperandrogenism: A Retrospective Chart Review ...................................... 84

Charlotte M. Clark, MD, MS; Jennifer Rudolph, MD; Donald A. Gerber, MD; Sharon Glick, MD; Alan R. Shalita, MD; Eve J. Lowenstein, MD, PhD

Departments New Therapy Update

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

LUZU (Luliconazole) 1% Cream ................................................................................................................... 90

Aditya K. Gupta, MD, PhD, FRCPC; Donna Cvetković, MSc; William Abramovits, MD; Kimberly Dawn Vincent, MD

New to the clinic

Noah Scheinfeld, MD, JD, Section Editor

EpiCeram .................................................................................................................................................... 96

Noah Scheinfeld, MD, JD

The Heymann File

Warren R. Heymann, MD, Section Editor

Addressing the Role of Human Herpesviruses 6 and 7 in DRESS ............................................................. 100

Warren R. Heymann, MD

Photo Capsule

Lucio’s Phenomenon and/or Relapsing Erythema Necroticans ................................................................. 103

Virendra N. Sehgal, MD; Pullabatla V. S. Prasad, MD; Pichai K. Kaviarasan, MD; Shalini Malhotra, DNB

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Palmoplantar Papules and Hyperkeratosis in a Deaf Man ......................................................................... 107

Sarah L. Taylor, MD; Shawn G. Kwatra, BS; Amy J. McMichael, MD

Proliferative Fasciitis in the Abdominal Region ......................................................................................... 111

Ines Zaraa, MD; Anissa Zaouak, MD; Dalenda El Euch, MD; Ines Chelly, MD; Slim Haouet, MD; Mourad Mokni, MD; Amel Ben Osman, MD

Perianal Giant Condyloma Acuminatum (Buschke-Löwenstein Tumor) ....................................................... 114

Santosh Shenoy, MD

Aplastic Anemia and Hoyeraal-Hreidarsson Syndrome .............................................................................. 117

Baris Malbora, MD; Zekai Avci, MD; Namik Ozbek, MD

TABLE OF CONTENTS July/August 2013 March/April 2014 •• Volume Volume 11 12 •• Issue Issue 42

Merkel Cell Carcinoma .............................................................................................................................. 120

Ardalan Minokadeh, PhD; Adam J. Wulkan, MD; Kenneth Beer, MD; Jill S. Waibel, MD

Bilateral Zosteriform Extragenital Lichen Sclerosus .................................................................................. 123

Piyush Kumar, MD; Abhijeet Kumar Jha, MD; Sambeet Kumar Mallik, MD; Mohammed Raihan, MD

CORRESPONDENCE

Traumatic Panniculitis in a Chinese Woman .............................................................................................. 127

Choon Chiat Oh, MBBS, MRCP; Kong Bing Tan, MBBS, FRCPA, FRCPath; Thamotharampillai Thirumoorthy, MBBS, FRCP; Shiu Ming Pang, MBBS, FRCP; Haur Yueh Lee, MRCP

Rosacea: Could Topical Azelaic Acid and Oral Tetracyclines Modify Videocapillaroscopic Pattern? ........... 128

Giulia Ganzetti, MD; Katia Giuliodori, MD; Anna Campanati, MD; Annamaria Offidani, MD

Book Review

Jennifer L. Parish, MD, Section Editor

Lasers and Energy Devices for the Skin .................................................................................................... 132

Krystle Wang, MD

ABOUT OUR JOURNAL

Editorial

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.

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

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

FOR INTERDIGITAL TINEA PEDIS DUE TO TRICHOPHYTON RUBRUM AND EPIDERMOPHYTON FLOCCOSUM IN ADULT PATIENTS

INTRODUCING LUZU L U ZU FA S T: 2 W E EK S, 14 DOS E S Efficacy demonstrated at 4 weeks post-treatment The only topical azole antifungal approved to treat interdigital tinea pedis with once-daily dosing over a 2-week period

Indications and Usage LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum in patients 18 years of age and older. Important Safety Information • LUZU is indicated for topical use only and is not indicated for ophthalmic, oral or intravaginal use. • LUZU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when LUZU is prescribed for nursing mothers. Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies. © 2014 Valeant Pharmaceuticals North America LLC.

DM/LUZ/13/0004

• The most common adverse reactions in clinical

trials were application site reactions, which occurred in less than 1% of subjects in both LUZU and vehicle arms. Most adverse reactions were mild in severity.

Please see full Brief Summary of Prescribing Information on adjacent page. Reference: LUZU [prescribing information]. Bridgewater, NJ: Medicis, a division of Valeant Pharmaceuticals; 2013.

S:7â&#x20AC;?

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION FOR LUZU (luliconazole) This Brief Summary does not include all the information needed to use LUZU safely and effectively. See full Prescribing Information for LUZU. LUZU (luliconazole) Cream, 1% for topical use Initial U.S. Approval: 2013 Rx Only INDICATIONS LUZU (luliconazole) Cream, 1% is an azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older. DOSAGE AND ADMINISTRATION For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or intravaginal use. When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for two (2) weeks. When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for one (1) week. CONTRAINDICATIONS None ADVERSE REACTIONS

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with LUZU Cream, 1% the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity. Post-Marketing Experience The following adverse reactions have been identified during post-marketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. DRUG INTERACTIONS The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4. Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro assessment. The induction potential of luliconazole on CYP enzymes has not been evaluated. USE IN SPECIFIC POPULATIONS

Pregnancy: Pregnancy Category C.

to pregnant female rats. No treatment related effects on maternal toxicity or malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Increased incidences of skeletal variation (14th rib) were noted at 25 mg/kg/day. No treatment related effects on skeletal variation were noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. No treatment related effects on maternal toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day (24 times the MRHD based on BSA comparisons). In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered from the beginning of organogenesis (gestation day 7) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No treatment effects on postnatal development were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Nursing Mothers It is not known whether luliconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LUZU Cream, 1% is administered to women who are breastfeeding. Pediatric Use The safety and effectiveness of LUZU Cream, 1% in pediatric patients have not been established. The number of pediatric patients â&#x2030;Ľ12 years of age were too small to adequately assess safety and efficacy. Geriatric Use Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent were 65 and over, while 1.4 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted. Luliconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosomal aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus test). In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1X MRHD based on BSA comparisons). PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Inform patients that LUZU Cream, 1% is for topical use only. LUZU Cream, 1% is not intended for intravaginal or ophthalmic use. Manufactured for: Medicis, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807

There are no adequate and well-controlled studies of LUZU Cream, 1% in pregnant women. LUZU Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The animal multiples of human exposure calculations were based on daily dose body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 1% cream per day (1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day). Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 7-17)

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215 Product of Japan Issued: 11/2013 140127 DM/LUZ/13/0005(1)

March/April 2014

Volume 12 • Issue 2

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

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

Virendra N. Sehgal, MD Delhi, India

Anthony A. Gaspari, MD Baltimore, MD

Jasna Lipozencic, MD, PhD Zagreb, Croatia Eve J. Lowenstein, MD, PhD New York, NY

Robert L. Baran, MD Cannes, France Anthony V. Benedetto, DO Philadelphia, PA

Michael Geiges, MD Zurich, Switzerland

George M. Martin, MD Kihei, HI

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael H. Gold, MD Nashville, TN

Marc S. Micozzi, MD, PhD Rockport, MA

Orin M. Goldblum, MD Indianapolis, IN

Alexander J. Stratigos, MD Athens, Greece

George F. Murphy, MD Boston, MA

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China 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 Boni E. Elewski, MD Birmingham, AL Charles N. Ellis, MD Ann Arbor, MI Howard A. Epstein, PhD Philadelphia, PA

Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK María Daniela Hermida, MD Buenos Aires, Argentina Warren R. Heymann, MD Camden, NJ Tanya R. Humphreys, MD Bala-Cynwyd, PA

Joseph L. Pace, MD, FRCP Naxxar, Malta Art Papier, MD Rochester, NY Johannes Ring, MD, DPhil Munich, Germany Roy S. Rogers III, MD Rochester, MN Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Vincenzo Ruocco, MD Naples, Italy

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

Riccarda Serri, MD Milan, Italy

Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel

Because atopic dermatitis is a disease of both chronic inflammation and skin barrier dysfunction1...

ZE I M I X E R A E M TH OW P G N I L A E H

Adding EpiCeram® to current treatment can help optimize results by replenishing lipids, repairing skin barrier function The only complete Rx formulation containing ceramides, cholesterol, and conjugated linoleic acid (CLA), a fatty acid with anti-inflammatory properties2 Mimics natural concentrations of lipids in the skin with a unique 3:1:1 ratio3 Controlled release for sustained delivery and enhanced absorption4 Steroid-free, fragrance-free, noncomedogenic,4 paraben-free, and propylene glycol-free Provides important pH benefits to the skin5 EpiCeram® is a Prescription Product.

See brief Prescribing Information below.

References:

1.Elias PM, Sun R, Eder AR, et al. Treating atopic dermatitis at the source: corrective barrier repair therapy based upon new pathogenic insights. Expert Rev Dermatol. 2013;8(1):27-36. 2. Kippenberger S, Loitsch SM, Grundmann-Kollmann M, et al. Activators of peroxisome prolilferator-activated receptors protect human skin from ultraviolet-B-light-induced inflammation. J of Investigative Dermatology. 2001;117(6):1430-1436. 3. Bikowski J. Understanding the structure, function, and strategies for repair of the epidermal barrier. Practical Dermatology. 2009; May:17-18. 4. Data on File. South Plainfield, NJ: PuraCap Pharmaceutical, LLC; 2013. 5. Kircik L, Hougeir F, Bikowski J. Barrier dysregulation, atopic dermatitis, and the role for a ceramide-dominant, physiologic lipid-based barrier repair emulsion. J Drugs Dermatol. 2013;12(9):611-614. EpiCeram® is a registered trademark of PuraCap Pharmaceutical LLC South Plainfield, NJ 07080 © 2014 PuraCap™ Pharmaceutical LLC All Rights Reserved.

Epi-FMM-43-01

Controlled Release Skin Barrier Emulsion ®

The ultimate complement to treatment

Visit www.epiceram-us.com for full PI, samples, and money saving coupons. Rx Only For Topical Dermatological Use Only Product Description EpiCeram® Controlled Release Skin Barrier Emulsion is a steroid free, fragrance free ceramide dominant emulsion containing ceramides, conjugated linoleic acid (CLA), and cholesterol in an emollient base. Indications for Use EpiCeram® Controlled Release Skin Barrier Emulsion is to be used to treat dry skin conditions and to manage and relieve the burning and itching associated with various types of dermatoses, including atopic dermatitis, irritant contact dermatitis, and radiation dermatitis. EpiCeram® helps to relieve dry, waxy skin by maintaining a moist wound and skin environment, which is beneficial to the healing process. Contraindications EpiCeram® Controlled Release Skin Barrier Emulsion is contraindicated in persons with known hypersensitivity to any of the components of the formulation.

Warnings EpiCeram® Controlled Release Skin Barrier Emulsion does not contain a sunscreen and should always be used in conjunction with a sunscreen in sun exposed areas. In radiation dermatitis and/or in conjunction with ongoing radiation therapy, apply following radiation therapy. Do not apply within 4 hours prior to radiation therapy. Apply twice daily or as indicated by the radiation therapist. After application, a temporary tingling sensation may occur (10 to 15 minutes). Keep this and similar products out of the reach of children. Follow directions for use. If condition does not improve within 10 to 14 days, consult a physician. Instructions for Use Apply in a thin layer to the affected skin areas two times per day (or as needed) and massage gently into the skin. If the skin is broken, cover EpiCeram® Controlled Release Skin Barrier Emulsion with a dressing of choice. How Supplied EpiCeram® Controlled Release Skin Barrier Emulsion is supplied as follows: NDC 51013-800-90: 90 gram tube Store at 15°C to 30°C (59°F to 86°F). Do not freeze. Rx only — Prescription Medical Device; Federal Law restricts this device to sale by or on the order of a physician.

March/April 2014

Volume 12 • Issue 2

Editorial

The Sign of Leser-Trélat: Is It Really So?—For Your Eyes Only Michael Joseph Lavery, MB BCh BAO;1 Lawrence Charles Parish, MD, MD (Hon);2 Peter C. Lambert, MA;3 Robert E. Lee, MD;3 W. Clark Lambert, MD, PhD4,5

he Leser-Trélat sign, as a marker for internal malignancy, has been the subject of controversy since its inception. Even its very definition has been called into question.

The sign has been attributed to two professors of surgery: Edmund Leser (1853–1916), a German, and Ulysse Trélat (1795– 1879), a Frenchman, but they were describing angiomas in association with cancer.1 Eugen Hollander was actually the first to describe the association of seborrheic keratoses and cancer.2 The situation is even more muddled, however. Not until 1926 did Walter Freudenthal (1894–1952) clearly delineate seborrheic keratosis from actinic keratosis.3

eruption of these keratoses should be on unaffected skin—not on eczematous or erythrodermic skin.4 Making an Association Helen Olandorf Curth (1899–1982), in 1976, set forth 5 specific criteria for a causal relationship between dermatoses and internal malignancy.5 These are: 1. Similar time of onset. 2. A corresponding clinical course, with remission after treatment and recurrence with tumor growth. (One report revealed a reduction in the seborrheic keratoses after chemoradiotherapy for lung carcinoma and the recurrence of the seborrheic keratoses 1 year later, which coincided with an increase in size of the lung carcinoma.6)

Clinical Findings The definition of the sign of Leser-Trélat involves the sudden eruption of multiple seborrheic keratoses or the sudden increase in size or number of existing seborrheic keratoses (Figure), in association with an underlying malignancy. This paraneoplastic disease should be differentiated in patients who have gradual development of such widespread keratoses. Even the definition provokes debate, including the number of seborrheic keratoses needed to constitute this sign and the time frame required for a “sudden eruption.” Both seborrheic keratoses and malignancies, needless to say, are common in the elderly population and the mere presence of both during a workup could be a coincidence. The problem can be compounded further when a detailed history is attempted. The exact time frame of the development of these keratoses may be vague, as this patient subgroup often has difficulty in visualizing such lesions. Adding to the confusion is the observation that a sudden eruption of multiple seborrheic keratoses can occur in inflammatory dermatoses. At least one author notes that the

3. An association of the paraneoplastic sign with a specific tumor—seborrheic keratosis does not have this, although adenocarcinomas have the most common association. 4. The association between the dermatosis and malignancy should be high. 5. The paraneoplastic dermatoses are usually rare—seborrheic keratoses are common (but their rapid onset is not). Several authors have reported patients who have a sudden eruption of seborrheic keratosis and on investigation an underlying malignancy is identified. The most prevalent disease is adenocarcinoma, mainly of the stomach or colon (around 33%)7; however, other associations have been documented, including lymphoproliferative disorders (20%).7 Although it is generally accepted that members of the older population have keratoses, which has led some to feel that the legitimacy of the sign is spurious, the

From the Department of Dermatology, Antrim Area Hospital, Antrim, Northern Ireland;1 the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA;2 St. George’s University School of Medicine, St. Georges, Grenada, WI;3 and the Departments of Dermatology4 and Pathology,5 Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: Michael Lavery, MB BCh BAO, Antrim Area Hospital, Bush Road, Antrim, BT41 2RL, Northern Ireland • E-mail: mlavery88@yahoo.ie

SKINmed. 2014;12:76–78

March/April 2014

EDITORIAL the malignancy. Recently, a healthy 66-year-old woman with the Leser-Trélat sign (a significant number of new seborrheic keratoses) was observed with no evidence of internal malignancy on investigation, even after 2 years of follow-up.12 This suggests that the correlation between the sign and internal cancer, although high, is not absolute. It has also been the experience of one of us (WCL) that the sign of Leser-Trélat is not subtle. The appearance of multiple new seborrheic keratoses and/or the enlargement of existing one(s) occurs explosively. If you question whether you are seeing this sign you probably are not. It is this sudden onset that is the hallmark of the sign. Molecular Changes

Figure. Sign of Leser-Trélat: Seborrheic keratosis on the back of a 79-year-old man who underwent rapid expansion (in a period of less than 6 weeks). He was found to have colon cancer on an investigation prompted by recognition of this sign.

cardinal feature is the sudden onset of new keratoses or the rapid increase in size and number of existing keratoses. There are case reports of the Leser-Trélat sign of patients in their third decade of life to support this theory.8–9 Although acanthosis nigricans may be present secondary to benign conditions, it is malignant acanthosis nigricans that is associated with the sign of Leser-Trélat in approximately 20% of cases.10 The presence of both the sign of Leser-Trélat and malignant acanthosis nigricans, in tandem, is further evidence of the necessity for prompt investigations. Most documented cases of seborrheic keratoses and malignancy involve patients diagnosed with seborrheic keratoses initially and an underlying malignancy is subsequently identified. This has been the experience of one of us (WCL), who observed the sign in an 84-year-old Caucasian woman who developed more than 100 new seborrheic keratoses on her back in a 3-month period and was later found to have gastric cancer. This was also the experience of the histopathologist who received a biopsy of a rapidly expanding lesion (histologically confirmed as a seborrhoeic keratosis) on the back of a 79 year old man, who was found to have colon cancer (Figure). In both cases, the cancer investigations were initiated, because the Leser-Trélat sign was recognized. There are reports, however, of patients having undergone treatment for internal cancer, only to develop the Leser-Trélat sign months to years later.6,11 One might conclude that eruptive seborrheic keratoses may occur as a sign of re-emergence of SKINmed. 2014;12:76–78

Studies of molecular changes in a patient with the Leser-Trélat sign were reported in 1987. Epidermal growth factor (EGF) receptors are usually found on basal keratinocytes, decreasing as they differentiate in the upper portion of the epidermis. In this study of seborrheic keratoses, staining for these receptors was shown in all epidermal layers except the stratum corneum. Urinary tissue growth factor α (present preoperatively), which binds to EGF receptors, also decreased along with the EGF receptors,13 after surgical excision of the underlying malignancy.13 Immunohistochemical analysis performed to further evaluate the EGF receptor protein has led to speculation that the sudden eruption of seborrheic keratoses may be caused by overexpression of the EGF receptor.14 New molecular studies have demonstrated mutations in fibroblast growth factor receptor 3 and phosphatidylinositol 3-kinase catalytic subunit α; however, they have left further questions regarding how these precisely operate in seborrheic keratosis.12 Conclusions Since its inception, controversy has raged over the very existence of the Leser-Trélat sign. Despite this, it is still listed as a paraneoplastic sign. Recent immunohistochemical analysis could provide fascinating insight into this condition. Further studies are needed to determine whether immunohistochemical analysis would be beneficial as a diagnostic aid for the sign of Leser-Trelat to detect an underlying malignancy before detailed investigations are performed. It can be difficult in the clinic to distinguish between numerous seborrheic keratoses and the Leser-Trélat sign, as to the time frame, especially if the seborrheic keratoses are present on difficult to visualize areas (eg, the back). Good detective work is required, as patients may not volunteer, or be able to volunteer, a sudden change in existing, or the sudden onset of, seborrheic keratoses. It is this sudden onset that is the hallmark of the Leser-Trélat sign. The Sign of Leser-Trélat: Is it Really So?

March/April 2014

EDITORIAL

References 1 Leser E. Ueber ein die Krebskrankheit beim Menschen haugig begleitendes, noch wenig gekanntes Symptom. Munchen Med Wochenschr. 1901;48:2035–2036. 2 Hollander EV. Beitrage zur Fruhdiagnose des Darmcarcinomas Hereditatsverhaltnisse und Hautveranderungen. Deutsche Medicinische Wochenschrift. 1900;26:483–485. 3 Freudenthal W. Verruca senilis und Keratoma senile. Arch f Dermat u Syph (Berlin). 1926;152:505–528. 4 Rampen F, Schwengle L. The sign of Leser-Trélat: does it exist? J Am Acad Dermatol. 1989;21:50–55. 5 Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, et al. Cancer of the Skin. Vol 2. Philadelphia, PA: WB Saunders; 1976:1308– 1341.

8 Ellis DL, Yates RA. Sign of Leser-Trélat. Clin Dermatol. 1993;11:141–148. 9 Barron LA, Prendiville JS. The sign of Leser-Trélat in a young woman with osteogenic sarcoma. J Am Acad Dermatol. 1992;26:344–347. 10 Chung VQ, Moschella SL, Zembowicz A, et al. Clinical and pathologic findings of paraneoplastic dermatoses. J Am Acad Dermatol. 2006;54:745–762. 11 Yaniv R, Servadio Y, Feinstein A, et al. The sign of LeserTrélat associated with transitional cell carcinoma of the urinary-bladder—a case report and short review. Clin Exp Dermatol. 1994;19:142–145. 12 Safa G, Darrieux L. Leser-Trélat sign without internal malignancy. Case Rep Oncol. 2011;4:175–177.

6 Heaphy MR, Millns JL, Schroeter AL. The sign of LeserTrélat in a case of adenocarcinoma of the lung. J Am Acad Dermatol. 2000;43:386–390.

13 Ellis DL, Kafka SP, Chow JC, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trélat, and multiple acrochordons: a possible role for alphatransforming growth factor in cutaneous paraneoplastic syndrome. N Engl J Med. 1987;317:1582–1587.

7 Shah KR, Boland CR, Patel M, et al. Cutaneous manifestations of gastrointestinal diseases: part 1. J Am Acad Dermatol. 2013;68:189.e12–189.e13.

14 Ponti G, Luppi G, Losi L, et al. Leser-Trélat syndrome in patients affected by six multiple metachronous primitive cancers. J Hematol Oncol. 2010;3:2–7.

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March/April 2014

Volume 12 • Issue 2

COMMENTARY

Xerosis Cutis: A Common Predicament of Raynaud’s Disease Anna H. Chacon, MD;1 Katlein Franca, MD, MS;2 Jennifer Ledon, BS;3 Jessica Savas, BS;4 Keyvan Nouri, MD5

aynaud’s phenomenon is characterized by episodic vasospasm of medium-sized arteries of the digits leading to white, blue, and red distal discoloration that occurs upon exposure to cold stimuli or as a result of emotional stress (Figure 1). It typically falls into one of two settings: (1) primary Raynaud’s phenomenon (Raynaud’s disease), or (2) secondary Raynaud’s phenomenon. Raynaud’s disease usually occurs in adolescent and young women and is not related to an underlying medical etiology.1 It is estimated to affect 3% to 5% of the population.2 In contradistinction, the secondary subtype is associated with an underlying medical disease and occurs less frequently than primary Raynaud’s phenomenon.3 Notably, the leading causes of secondary Raynaud’s phenomenon include various rheumatic disorders, diseases with abnormal blood proteins, drugs, and arterial diseases.4

The distal portion of the fingers and toes are the most frequently affected site in patients, and the disease is usually bilateral; however, the nose, earlobes, and nipples may also be involved. Symptoms of xerosis resulting from ischemia can last for years, occasionally leading to digital ulceration, necrosis, and eventually gangrene requiring amputation.5 Although gangrene occurs in less than 1% of cases, xerosis is presumably much more common and is often an underreported sign, although the incidence is unknown.6 While management of xerosis is difficult, spontaneous resolution is exceedingly rare. It is a common predicament of Raynaud’s phenomenon that has not been clearly addressed considering the spectrum of available therapies. Etiology Skin dryness frequently parallels the severity of Raynaud’s. The presence of xerosis of the digits can also serve as a predictor of connective tissue disease. The etiology of vasospasm and its relationship to xerosis is complex, and its pathophysiology is only

partially understood. The sympathetic nervous system regulates vasomotor tone. Because vasodilatation occurs only on withdrawal of the sympathetic activity, hyperreactivity of the sympathetic nervous system may be a contributing factor.7 The skin is often dry as a result of decreased sweating and sympathetic dysregulation. Additional features of Raynaud’s likely involve an imbalance of local vasoconstrictors, or vasodilators as well as abnormal local defects of vessels and hematogenous effects that compromise perfusion to the distal digits leading to xerosis.8 Raynaud’s can cause dry skin, which precedes other findings, such as discoloration, ulceration, and gangrene. Clinical Findings A thorough history and careful physical examination are imperative in the comprehensive evaluation of patients with Raynaud’s disease. The digits should be meticulously examined for xerosis and trophic changes, which may serve as important clues for prolonged or severe attacks (Figure 2). The skin may become atrophic, dry, and chaffed on the palmar surfaces. The nails may also become dry, brittle, lytic, and deformed. Since ulcerations tend to develop on the finger pads or around the nail bed, xerosis of the respective areas should be addressed early. Disruption of the skin barrier caused by dryness may heal slowly, leaving scars and occasionally becoming infected. Management Because most therapies have only been investigated in patients with Raynaud’s phenomenon and ulceration, not all treatments have been proven to be effective in patients with primary or secondary Raynaud’s disease. If an underlying cause is found, treatment of that associated condition will often lead to improvement of the xerotic symptoms of Raynaud’s.4 In both diseases, exposure to cold stimuli should be avoided as this can worsen the

From the Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL Address for Correspondence: Anna H. Chacon, MD, 1475 N.W. 12th Avenue, Suite #2175, Miami, FL 33136 • E-mail: annachaconmd@gmail.com

SKINmed. 2014;12:80–82

March/April 2014

COMMENTARY jelly and hydrating ointments within the gloves has helped to maintain moisture and prevent chafing. Residence in a warm, humid climate may be helpful, and the use of a humidifier in dry climates may also be considered.10 Trauma and pressure to the fingertips should be avoided, as this tends to disrupt the skin barrier and may provide a nidus for infection and a source for the development of ulceration. Alternative therapies such as ginkgo biloba and other herbal remedies are of limited efficacy and are not recommended for patients with severe symptoms.11 Calcium channel blockers should be employed throughout treatment, particularly in patients with severe and progressive disease.12 In refractory cases, surgical modalities may be worth a try. For single-digit involvement, local digital sympathectomies can be effective at reducing xerotic symptoms, particularly because compensatory hyperhidrosis is a common complication.13 Cervical and endoscopic thoracic sympathectomies may initially relieve patients of their symptoms; however, the symptoms often recur after a period of 12 to 18 months.14

Figure 1. A violaceous hue of the index and middle fingers, as well as areas of hyperemia (red) in the fourth and fifth fingers, in a patient with Raynaud’s disease.

Conclusions Xerosis from Raynaud’s phenomenon can be extremely bothersome and may take weeks or months to completely resolve. Patients should be taught to recognize and manage symptoms of xerosis early on in the course of treatment by returning to warm, humid environments and hydrating the affected areas with moisturizing ointments. Prevention is an important aspect of therapy, because xerosis can predispose to additional sequelae such as ulceration, infection, and additional ischemia. Stress modification and social support are valuable aspects of treatment and counseling and relaxation training may be helpful. Affected digits can be soaked in an antiseptic solution twice daily to soften the skin.15 After drying, patients can apply an antibiotic or hydrating ointment to the areas of broken skin and use an occlusive dressing. Infections are commonly characterized by pain, redness, swelling, and purulent discharge. Treatment with anti-staphylococcal antibiotics or cephalosporins is usually effective for infectious complications.15

Figure 2. Persistent vasospasm of medium arterioles can sometimes lead to xerosis of the terminal digits as illustrated in the index and middle fingers of the right hand of this patient with xerosis cutis associated with Raynaud’s disease.

References 1 Wigley FM. Clinical practice. Raynaud’s phenomenon. N Engl J Med. 2002;347:1001–1008.

dryness.9 This includes measures to avoid cold exposure not only to the digits but also for the rest of the body, because generalized vasospasm may be induced by a reduction in core body temperature.9 Warm, insulated gloves accompanied by hand or leg warmers may be worn when possible, and occasionally several of our patients have reported that the application of petroleum SKINmed. 2014;12:80–82

2 Brand FN, Larson MG, Kannel WB, McGuirk JM. The occurrence of Raynaud’s phenomenon in a general population: the Framingham Study. Vasc Med. 1997;2:296–301. 3 Hirschl M, Kundi M. Initial prevalence and incidence of secondary Raynaud’s phenomenon in patients with Raynaud’s symptomatology. J Rheumatol. 1996;23:302– 309.

Xerosis Cutis: A Common Predicament of Raynaud’s Disease

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COMMENTARY

4 Hirschl M, Hirschl K, Lenz M, et al. Transition from primary Raynaud’s phenomenon to secondary Raynaud’s phenomenon identified by diagnosis of an associated disease: results of ten years of prospective surveillance. Arthritis Rheum. 2006;54:1974–1981.

women are exaggerated in women with primary Raynaud’s phenomenon. Br J Clin Pharmacol. 2001;52:17–23. 10 Fraenkel L, Zhang Y, Chaisson CE, et al. Different factors influencing the expression of Raynaud’s phenomenon in men and women. Arthritis Rheum. 1999;42:306–310.

5 Gelber AC, Wigley FM, Stallings RY, et al. Symptoms of Raynaud’s phenomenon in an inner-city African-American community: prevalence and self-reported cardiovascular comorbidity. J Clin Epidemiol. 1999;52:441–446.

11 Malenfant D, Catton M, Pope JE. The efficacy of complementary and alternative medicine in the treatment of Raynaud’s phenomenon: a literature review and metaanalysis. Rheumatology (Oxford). 2009;48:791–795.

6 Zeni S, Ingegnoli F. [Raynaud’s phenomenon]. Reumatismo. 2004;56:77–81.

12 Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis. Rheumatology (Oxford). 2005;44:145–150.

7 Herrick A, el-Hadidy K, Marsh D, Jayson M. Abnormal thermoregulatory responses in patients with reflex sympathetic dystrophy syndrome. J Reumatol. 1994;21:1319–1324.

13 Kotsis SV, Chung KC. A systematic review of the outcomes of digital sympathectomy for treatment of chronic digital ischemia. J Rheumatol. 2003;30:1788–1792.

8 Maricq HR, Weinrich MC, Valter I, Palesch YY, Maricq JG. Digital vascular responses to cooling in subjects with cold sensitivity, primary Raynaud’s phenomenon, or scleroderma spectrum disorders. J Rheumatol. 1996;23:2068–2078.

14 Tomaino MM, Goitz RJ, Medsger TA. Surgery for ischemic pain and Raynaud’s’ phenomenon in scleroderma: a description of treatment protocol and evaluation of results. Microsurgery. 2001;21:75–79. 15 Hummers LK, Wigley FM. Management of Raynaud’s phenomenon and digital ischemic lesions in scleroderma. Rheum Dis Clin North Am. 2003;29:293–313.

9 Gardner-Medwin JM, Macdonald IA, Taylor JY, Riley PH, Powell RJ. Seasonal differences in finger skin temperature and microvascular blood flow in healthy men and

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Xerosis Cutis: A Common Predicament of Raynaud’s Disease

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March/April 2014

Volume 12 • Issue 2

Original contribution

Dermatologic Manifestation of Hyperandrogenism: A Retrospective Chart Review Charlotte M. Clark, MD, MS;1 Jennifer Rudolph, MD;2 Donald A. Gerber, MD;3 Sharon Glick, MD;4 Alan R. Shalita, MD;* Eve J. Lowenstein, MD, PhD4 Abstract Several studies have described a wide spectrum of hyperandrogenism diseases, many of which are difficult to distinguish from each other. In order to better understand diseases of hyperandrogenism, the authors performed a retrospective study of the cutaneous features and metabolic findings in women with hyperandrogenism. A retrospective chart analysis compiled by three dermatologists in both academic and private settings was performed, including patients presenting with ≥2 manifestations of hyperandrogenism. Relevant dermatologic and associated manifestations and laboratory and imaging study findings were reviewed. Moderate to severe acne was the most common manifestation. Other common manifestations that patients first presented with include hirsutism, acanthosis nigricans, androgenic alopecia, and skin tags. Oligomenorrhea was the most common systemic presenting sign. Statistical analysis of various clinical markers revealed correlations with hyperandrogenemia. Acanthosis nigricans and hirsutism were found to be useful clinical markers for hyperandrogenism, whereas androgenic alopecia was not. This study provides some insights into the presentation and diverse manifestations seen in hyperandrogenism. (SKINmed. 2014;12:000–000)

yperandrogenism is a manifestation of a heterogeneous group of disorders that can be first detected dermatologically. Cutaneous signs of hyperandrogenism include acne, hirsutism, androgenic alopecia, acanthosis nigricans (AN), seborrheic dermatitis, and skin tags (acrochordons). Polycystic ovary syndrome (PCOS) is the most common cause of hyperandrogenism in women, associated with gynecological, endocrine, and metabolic abnormalities. Other causes of hyperandrogenism include Cushing’s syndrome, prolactinoma, primary hypothyroidism, acromegaly, nonclassical late-onset congenital adrenal hyperplasia, hypogonadotropic hypogonadism, premature ovarian failure, obesity-related insulin resistance, virilizing adrenal or ovarian androgen-secreting tumors, and drugs.1–7 The PCOS diagnostic criteria were developed during a National Institutes of Health conference in 1990, and revised in 2003 by the Rotterdam Consensus Group. Diagnosis is based on the presence of 2 of the 3 criteria: (1) menstrual dysfunction; (2) hyperandrogenism (as manifested primarily by hirsutism, acne, and alopecia) or hyperandrogenemia; and (3) the presence of ovarian cysts on ultrasound (US) meeting radiologic criteria of size and number.2,3,13,15 In 2006, the Androgen Excess Society task force

reviewed the current evidence-based definitions of PCOS.2 By utilizing features of menstrual dysfunction, hirsutism, polycystic ovaries, and hyperandrogenemia, the task force identified 9 potential phenotypes of PCOS.2 Certain phenotypes were linked to increased risk for metabolic dysfunctions, including the following: (1) hirsutism and/or hyperandrogenemia, and oligomenorrhea with or without polycystic ovaries, and (2) hirsutism and/or hyperandrogenism, and normal menses with polycystic ovaries.2,3,13 Despite these efforts to define hyperandrogenism, areas of controversy still exist when considering the diagnosis of PCOS. PCOS is commonly associated with menstrual abnormalities, infertility, insulin resistance, obesity, sleep apnea, and even endometrial cancer. Abnormal menses, specifically infrequent menstruation associated with anovulation, is the most frequent finding of hyperandrogenism. Other important clinical markers for hyperandrogenism include obesity, hirsutism, androgenic alopecia, AN, acne, and skin tags. Long-term sequelae associated with PCOS include reproductive, metabolic, and cardiovascular abnormalities. Women with PCOS have an increased risk of infertility and miscarriages.10 Hyperandrogenism is correlated with increased risk for endometrial carcinoma in part by the hyperse-

From St. Luke’s-Roosevelt Hospital Center, New York, NY;1 Yale New Haven Health System, New Haven, CT;2 and the Departments of Rheumatology3 and Dermatology,4 State University of New York Downstate Medical Center, Brooklyn, NY *Deceased. Address for Correspondence: Charlotte M. Clark, MD, 1090 Amsterdam Avenue, Suite 11B, New York, NY 10025 • E-mail: McCarlotta@gmail.com

SKINmed. 2014;12:84–88

March/April 2014 cretion of luteininzing hormone (LH).10 Up to 40% of patients with PCOS have impaired glucose tolerance, and another 10% of patients with PCOS will develop diabetes by the fourth decade.10 Increased abdominal adiposity is a common finding in hyperandrogenic women and is believed to impart an increased risk for myocardial infarction by 7-fold.12 Recently, studies have indicated a higher prevalence of obstructive sleep apnea in PCOS patients that cannot be explained by obesity alone.10 PCOS is a constellation of signs and symptoms that are not indicative of this syndrome when found alone. Thus, the approach of evaluating patients remains controversial. This study examines hyperandrogenism in women to further advance our understanding of this complex group of disorders. Patients and Methods The institutional review board exempted our study from review (FWA 00003624, study number: 08-077, under the guideline 45CFR46,101(b) use of existing data). A retrospective chart review was performed on data during the study period January 1, 2005, until December 31, 2009. Data were identified by computer search for key criteria by dermatologists SG, EJL, and ARS, from hospital clinics and private practice of patients seen within the past 5-year period. All patient-protected health information was de-identified. A sole written key corresponding each patient to a study number was kept in a locked drawer by the principal investigator, without the storage of an electronic key. Of charts reviewed, 98 patients met study the inclusion criteria, documenting ≥2 signs and symptoms of androgen excess. Twenty patients were excluded from the study for lack of sufficient data (n=78). Criteria of clinical hyperandrogenism included chart documentation of ≥2 signs and symptoms of androgen excess including any combination of at least 2 signs from 2 separate categories of the following: (1) family or personal history of diabetes, infertility, and/or PCOS; (2) dermatologic: hirsutism, acne, androgenic alopecia, skin tags, seborrhea, and/or AN; (3) biochemical: elevated LH:follicle-stimulating hormone (FSH) ratio, testosterone, dehydroepiandrosterone sulfate (DHEAS), insulin, HbA1c, glucose, prolactin, abnormally low sex hormone–binding globule (SHBG) and/or a positive US finding for polycystic ovaries; and (4) clinical: irregular menses, obesity, abnormal central fat distribution, and/or early menarche and/or pubarche. Prepubescent, perimenopausal or postmenopausal, and pregnant women were excluded from this study, in addition to the exclusion of patients without at least 2 of the aforementioned clinical criteria for hyperandrogenism. SKINmed. 2014;12:84–88

ORIGINAL CONTRIBUTION The presence of acne was evaluated using a scale of mild, moderate, or severe, and was converted to a numerical value. The free androgen index (FAI) was calculated as the quantity of 100 multiplied by the fraction of total testosterone (TT) divided by SHBG or 100×TT/SHBG. Weight was assessed using body mass index (BMI), calculated by dividing the weight in kilograms by height in meters squared, or BMI as weight in kilograms divided by height in meters squared. We used the World Health Organization classification of obesity, which grades a normal BMI as 18.5 to 24.9, overweight as 25 to 29.9, obese as 30 to 39.9, and morbidly obese as ≥40. Pretreatment laboratory test results were recorded in select patients and pretreatment and post-treatment laboratory values were available for comparative purposes. Laboratory Guidelines

LH and FSH The literature suggests that an LH:FSH ratio >2 signifies hyperandrogenism.5 An elevation of LH concentration >10 IU/L has been linked with infertility.14 The ratio of LH to FSH has been reported to be as high as 95% of patients with PCOS.14 We utilized the LH:FSH ratio of ≥2 as a marker of hyperandrogenism in our analysis.

US Testing US testing is recommended in patients with results of elevated testosterone, mostly to exclude adrenal or ovarian neoplasms.15 Ovarian US testing must meet specific and complex criteria to establish PCOS characteristics.15 The key US features consistent with PCOS is the combination of the ovarian size (ovarian volume >10 cm3) and the number of pre-antral follicles within the ovary (typically >12 per ovary).3 In adolescents, the presence of excessive ovarian stroma and ovarian enlargement is the most specific finding for polycystic ovaries.3 Polycystic ovaries on US testing can be found in approximately 22% of the general population, and so the finding of polycystic ovaries on US in the absence of other hyperandrogenism features should not be considered to be PCOS.12,15

Quantifying Degree of Hirsutism Hirsutism is defined as the excessive growth of terminal hair in a masculine distribution in women. The areas of excessive hair growth are androgen-dependent and include the chin, upper lip, chest, back, breasts, abdomen, and anterior part of the thigh. There are many cultural differences in what is considered normal body hair, and hirsutism is objectively classified by the modified Ferriman-Gallway (FG) scale. The FG scale defines hirsutism as a score of ≥8.19

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ORIGINAL CONTRIBUTION

Table. Significant Associations in Hyperandrogenic Women With AN, Hirsutism, Overweight, Obese, and Morbidly Obese BMI, and Elevated FAIa AN (n=29)

No AN (n=26)

P Value

34.34±3.41

28.11±4.02

.018

Insulin, IU/mL

54.71±24.36

16.58±11.18

.029

HbA1c

5.72±0.29

5.3±0.17

.043

Hirsutism (n=40)

No Hirsutism (n=29)

P Value

29.4±12.37

72.27±51.59

.05

Normal BMI (n=18)

Overweight BMI (n=13)

P Value

%FT

1.06±0.28

1.81±0.88

.022

HbA1c

5.2±0.49

5.66±0.29

.049

Normal BMI (n=18)

Obese BMI (n=21)

P Value

TT, ng/dL

50.82±12.59

72.44±12.73

.016

%FT

1.06±0.28

1.72±0.81

.029

DHEAS, µg/dL

262.85±82.5

153.99±43.19

.020

Normal BMI (n=18)

Morbidly Obese BMI (n=8)

P Value

TT, ng/dL

50.82±12.59

79.78±37.9

.042

Insulin, IU/mL

15.31±14.04

50.8±45.52

.054

BMI, kg/m

SHBG, nmol/L

Elevated FAI (n=13)

Normal FAI (n=14)

P Value

DHEAS, µg/dL

325.42±97.34

194.48±61.66

.018

HbA1c

5.66±0.32

5.29±0.24

.045

SHBG, nmol/L

18.31±5.42

74.14±37.88

.006

Abbreviations: AN, acanthosis nigricans; BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; FAI, free androgen index; %FT, percentage free testosterone; HbA1c, hemoglobin A1c; SHBG, sex hormone–binding globule; TT, total testosterone. a Values according to Student t test.

[Table]). Hirsutism was correlated with the need for facial hair removal (chi-square, P=.001) and skin tags (P=.013), as well as inversely correlated with presence of mild acne (P=.001).

Results In the Table, various significant hyperandrogenic markers and their associations are indicated.

Acne

Acanthosis Nigricans The occurrence of AN was significantly associated with obesity and insulin resistance markers (elevated HbA1c and insulin levels) compared with women without AN (Table). Chi-square analysis demonstrated findings of AN to correspond with diabetes (personal history, family history, or both; P=.0139) and an elevated FAI (≥5, P=.02). AN was inversely correlated with findings of androgenic alopecia (P=.0258).

Using chi-square analysis, we found an association between certain hyperandrogenic markers and moderate to severe acne. Compared with women with mild acne, women with moderate to severe acne were more likely to have hirsutism (chi-square, P=.0008), skin tags (P=.0402), a need for facial hair removal (P=.0020), and US findings positive for ovarian cysts (P=.0434).

Hirsutism

The presence of androgenic alopecia was inversely correlated with the incidence of AN (chi-square, P=.0258). No other significant associations were noted in patients with androgenic alopecia in our analysis.

Androgenic Alopecia

Manifestation of hirsutism was associated with notably lower SHBG blood levels compared with hyperandrogenic women without hirsutism (29.4 nmol/L and 72.27 nmol/L, respectively SKINmed. 2014;12:84–88

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ORIGINAL CONTRIBUTION

Body Mass Index An overweight BMI was in accordance with elevated insulin resistance markers (HbA1c) and an elevated percentage of free testosterone (Table). Overweight women were more likely to have an incidence of overall (chi-square, P=.05) and personal history of diabetes (P=.0158), hirsutism (P=.05), and AN (P=.0004). When compared with patients with a normal BMI, obese patients had greater serum total testosterone and percentage of free testosterone and lower DHEAS levels (Table). Obese patients were more likely to have a personal history of diabetes (chi-square, P=.0006), hirsutism (P=.0489), and AN (P=.0005), compared with patients with normal BMI. Morbid obesity was correlated with higher serum total testosterone (79.78 ng/dL) and insulin levels (50.8 IU/mL), compared with patients with normal BMI (50.82 ng/dL and 15.31 IU/mL, respectively) (Table). A greater incidence of personal history of diabetes (chi-square, P=.0008) and AN (P=.0009) was associated with morbid obesity.

Free Androgen Index Women with elevated FAI levels (â&#x2030;Ľ5) had more frequent clinical manifestations of AN (chi-square, P=.0212). Elevated FAI levels were associated with higher serum DHEAS, HbA1c, and SHBG levels, compared with patients with a normal FAI level (Table). Discussion This study provides additional insights into the clinical and biochemical manifestations of hyperandrogenism. The presence of AN was associated with more health risks than other categories. It was significantly correlated with obesity, insulin resistance markers (serum HbA1c and insulin levels), and overall occurrence of diabetes (personal history, family history, or both). Overweight, obese, and morbidly obese patients were all associated with an increased incidence of AN, compared with the normal BMI group. From this, we propose that AN is an excellent marker for hyperandrogenism and can be a reliable indicator of metabolic and endocrinology disturbances. An elevated BMI (overweight, obese, and morbidly obese) corresponded with hyperandrogenemia (elevated total and/or percentage free testosterone levels), AN, and a personal or family history of diabetes. Obesity was associated with AN, hirsutism, personal history of diabetes, and hyperandrogenemia (increased total and percentage free testosterone levels), when compared with patients with a normal BMI. Also of note, obese patients had decreased DHEAS serum levels when compared with paSKINmed. 2014;12:84â&#x20AC;&#x201C;88

tients with a normal BMI. Published literature has suggested the possibility of different degrees of androgen sensitivity in the sebaceous glands and hair follicles with respect to obesity.6 This is proposed because of the lack of clinical hyperandrogenism findings, such as acne or hirsutism, in some obese women.6 Despite an inverse association with serum DHEAS, we found obesity to be significantly associated with findings of hirsutism and AN. The lower DHEAS serum levels in our obese patients might simply demonstrate that obesity itself may play a more significant role in insulin sensitivity and androgen production. Overweight patients shared a similar profile, with findings of increased percentage free testosterone levels, increased HbA1c, hirsutism, AN, and overall and personal history of diabetes. Morbidly obese women had increased incidence of total testosterone and insulin levels, AN, and personal history of diabetes. We also noted the relevance in classifying acne severity when acne was present, which has not been previously published. Moderate to severe acne was related to positive US findings for ovarian cysts. Presence of moderate to severe acne was the sole clinical symptom associated with US findings for cysts. More severe acne (moderate to severe acne) was associated with skin tags and hirsutism. Despite the lack of data to calculate FAI in the majority of our patients, an elevated FAI was statistically correlated with increased DHEAS, HbA1c, and AN. Although an elevated FAI was not associated with hirsutism, hirsutism was related with lower SHBG levels, implying that hirsutism is associated with an elevated FAI when one considers the calculation for FAI (100Ă&#x2014;TT/ SHBG). Of note, hirsutism was correlated with a higher incidence of skin tags. Seborrhea (data not shown) and moderate to severe acne were also correlated with the presence of skin tags. This is significant, in that, the presence of many skin tags implies a hyperandrogenism state. There are multiple metabolic and endocrine profiles under the classification of hyperandrogenism. Moderate to severe acne, skin tags, seborrhea, and hirsutism appear to be more frequent with each other and can denote one possible phenotype of hyperandrogenism. Another possible phenotype detected in this study included AN, an elevated BMI (including overweight, obese, and morbidly obese), diabetes (overall history and/or a personal history), elevated insulin resistance markers (HbA1c and insulin), and hyperandrogenemia (elevated total and/or percentage free testosterone levels). The calculated FAI was another important diagnostic tool, and based on these results we would recommend clinicians to implement the FAI calculation when trying to determine hyperanDermatologic Manifestation of Hyperandrogenism

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ORIGINAL CONTRIBUTION

drogenism. An elevated FAI level could be included with a third hyperandrogenism phenotype, including an elevated HbA1c, elevated DHEAS levels, AN, and possibly hirsutism. Conclusions From this study it appears that AN is the most sensitive cutaneous marker for hyperandrogenism and is associated with more health risks. Hirsutism is another useful clinical marker of hyperandrogenism, whereas androgenic alopecia was not. The calculated FAI was a useful diagnostic tool in determining hyperandrogenism, and the authors believe physicians should implement FAI calculation during clinical practice. This study provides some insight into the presentation and diverse manifestations seen in hyperandrogenism. References 1 Amato P, Simpson JL. The genetics of polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18:707–718. 2 Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an androgen excess society guideline. J Clin Endocrinol Metab. 2006;91:4237–4245. 3 Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update. 2003;9:505–514. 4 Balen A, Michelmore K. What is polycystic ovary syndrome? Are national views important? Hum Reprod. 2002;17:2219–2227. 5 Banaszewska B, Spaczynski RZ, Pelesz M, Pawelczyk L. Incidence of elevated LH/FSH ratio in polycystic ovary syndrome women with normo- and hyperinsulinemia. Rocz Akad Med Bialymst. 2003;48:131–134. 6 Carmina E, Rosato F, Janni A, Rizzo M, Longo RA. Extensive clinical experience: Relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab. 2006;91:2–6. 7 Cordain L, Eades MR, Eades MD. Hyperinsulinemic diseases of civilization: more than just syndrome X. Comp Biochem Physiol A Mol Integr Physiol. 2003;136:95–112. 8 Cupisti S, Kajaia N, Dittrich R, et al. Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome. Eur J Endocrinol. 2008;158:711–719. 9 Diamanti-Kandarakis E, Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Nestler JE. A modern medical quandary: Polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endorinol Metab. 2003;88:1927–1932. 10 Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223–1236.

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11 Franks S. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J Clin Endocrinol Metab. 2006;91:786– 789. 12 Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18:671–683. 13 Lee AT, Zane LT. Dermatologic manifestations of polycystic ovary syndrome. Am J Clin Dermatol. 2007;8:201– 219. 14 Legro RS. A 27-year-old woman with a diagnosis of polycystic ovary syndrome. JAMA. 2007;297:509–519. 15 Lowenstein EJ. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatol Ther. 2006;19:210–223. 16 Randall VA. Androgens and hair growth. Dermatol Ther. 2008;21:314–328. 17 Rosenfield RL. What every physician should know about polycystic ovary syndrome. Dermatol Ther. 2008;21:354– 361. 18 Schmidt JB. Other antiandrogens. Dermatology (Basel, Switzerland). 1998;196:153–157. 19 Somani N, Harrison S, Bergfeld WF. The clinical evaluation of hirsutism. Dermatol Ther. 2008;21:376–391. 20 Stein I, Leventhal M. Amenorrhoea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29:181–185. 20 Talbott E, Clerici A, Berga SL, et al. Adverse lipid and coronary heart disease risk profiles in young women with polycystic ovary syndrome: results of a case-control study. J Clin Epidemiol. 1998;51:415–422. 21 Yildiz BO, Yarali H, Oguz H, Bayraktar M. Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:2031– 2036. 22 Williamson K, Gunn AJ, Johnson N, Milsom SR. The impact of ethnicity on the presentation of polycystic ovarian syndrome. Aust NZ J Obstet Gynaecol. 2001;41:202– 206. 23 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84:3666– 3672. 24 Wijeyaratne CN, Balen AH, Barth JH, Belchetz PE. Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? Clin Endocrinol (Oxf). 2002;57:343–350. 25 Van Santbrink EJ, Hop WC, Fauser BC. Classification of normogonadotropic infertility: polycystic ovaries diagnosed by ultrasound versus endocrine characteristics of polycystic ovary syndrome. Fertil Steril. 1997;67:452– 458.

Dermatologic Manifestation of Hyperandrogenism

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March/April 2014

Volume 12 • Issue 2

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

LUZU (Luliconazole) 1% Cream Aditya K. Gupta, MD, PhD, FRCPC;1,2 Donna Cvetković, MSc;2 William Abramovits, MD;3,4 Kimberly Dawn Vincent, MD5

inea pedis (commonly referred to as athlete’s foot) is a dermatophytic infection of the feet that presents as pruritic, inflamed regions located on the sole (vesicular type), sides of the foot (moccasin type), or between the toes (interdigital type).1–10 Tinea pedis may be a chronic or recurring condition and is the most common form of dermatophytosis in the postpubescent period.1–10 Tinea pedis is a public health problem because of its contagious and recurrent pathology.5–10 The most common etiologic agents include Trichophyton rubrum (which is the most often found), followed by Trichophyton interdigitale and Epidermophyton floccosum.1–10 Topical antifungals are the current gold standard treatment for tinea pedis, and systemic therapy is generally reserved for patients with refractory infections, those involving a large diseased area (moccasin-type tinea pedis), and immunocompromised or immunedeficient individuals.5–10

cream 1% for only 2 days resulted in an efficacy equivalent to that achieved after 4 days of treatment with lanocanozole 1% cream, terbinafine 1% cream, or bifonazole 1% cream.5,21,22 A clinical study comparing the efficacy of 2 weeks of treatment with luliconazole cream 1% with 4 weeks of treatment with bifonazole cream 1% showed that the efficacy and safety of 2 weeks of treatment with luliconazole was comparable to 4 weeks of treatment with bifonazole 1%, when evaluations were performed at week 4.23

A variety of topical antifungals are currently available for the treatment of dermatomycoses, including tinea pedis; nevertheless, most of these require long-term application, and in many cases recurrence is a challenge.5–18 New antifungal agents with greater potency and pathogen-eradicating activity, short-term application, and long-lasting retention in the skin are thus preferred for successful treatment of tinea pedis.5–18

The first study examined the efficacy and safety of luliconazole cream of varying concentrations (1% [group A, 74 patients], 0.5% [group B, 67 patients], 0.1% [group C, 72 patients]) when used once daily for 2 weeks for both plantar and interdigital tinea pedis.24 A total of 241 patients were enrolled; however, 213 participants were evaluated for efficacy.24 For clinical assessments, severity of infection was rated along a 5-point scale ranging from 0 (no symptoms) to 4 (severe, aggravated symptoms).24 These, along with mycologic assessments (KOH) were performed at baseline and again at weeks 2, 4, and 6 to detect the presence of fungal disease and document clinical progression.24 The overall improvement rating was obtained by comparing the clinical score at baseline with that of subsequent biweekly visits.15 Adverse effects were also recorded at each visit.24

Luliconazole {(−)-(E)-[(4R)-4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene](1H-imidazol-1-yl) acetonitrile} is a novel, optically active antifungal imidazole.5,19,20 Although luliconazole’s exact mechanism of action against dermatophytes is presently unknown, it has been shown to exhibit antifungal activity by disrupting ergosterol synthesis via inhibition of the enzyme lanosterol demethylase.5,19,20 A preclinical study comparing the efficacy of several topical antifungals (including luliconazole) in a guinea pig model of tinea pedis showed that the application of luliconazole

Clinical Studies The safety and efficacy of luliconazole cream 1% was evaluated in 2 randomized, double-blind, multicenter trials with participants who had a clinical and potassium hydroxide (KOH)–confirmed diagnosis of interdigital tinea pedis.14,24,25

Results of this study are presented in Table I.24 A dose-dependent relationship in the negative conversion rate of fungi at 2 weeks

From the Division of Dermatology, 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;3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School; Dermatology Treatment and Research Center, Dallas, TX;4 Belle Meade Dermatology, Nashville, TN5 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. Mycologic and Clinical Results Evaluated at 2, 4, and 6 Weeks in Patients With Tinea Pedis Treated With a 2-Week Regimen of Luliconazole Cream 1%, 0.5%, or 0.1% 2 Weeks

4 Weeks

6 Weeks

0.5%

0.1%

0.5%

0.1%

0.5%

0.1%

Mycologic response1 (plantar and interdigital)

RVU

79.9% (59 of 74)

76.1% (51 of 67)

72.2% (52 of 72)

87.7% (65 of 74)

94.0% (63 of 67)

88.9% (64 of 72)

Mycologic responsea (interdigital only)

81.1% (30 of 37)

62.9% (22 of 35)

58.3% (21 of 36)

RVU

Clinical responseb

52.7% (39 of 74)

44.8% (30 of 67)

45.1% (32 of 71)

79.9% (59 of 74)

74.6% (50 of 67)

72.2% (52 of 72)

87.8% (65 of 74)

94.0% (63 of 72)

88.9% (64 of 72)

Abbreviation: RVU, raw values unreported. Negative conversion rate of fungi; number of patients showing disappearance of fungi/patients eligible for evaluation. b Global improvement (moderately to significantly improved) as assigned by the investigator. Adapted by Watanabe et al.24 a

Table II. Complete Clearancea at 2 and 4 Weeks Post-Treatment 2 Weeks

4 Weeks

Luliconazole Cream, 1%

Vehicle

Luliconazole Cream, 1%

Vehicle

2 weeksa

26.8% (11 of 41)

9.1% (2 of 22)

45.7% (16 of 35)

10% (2 of 20)

4 weeks

53.7% (22 of 41)

4.5% (1 of 22)

62.9% (22 of 35)

25.0% (5 of 20)

Proportion of patients who cleared both clinical cure and mycologic cure. Adapted from Jarratt et al.25 a

and a significant difference in conversion rates between groups was found for interdigital tinea pedis only.24 Indeed, negative conversion rates were 81.1% for group A, 62.9% for group B, and 58.3% for group C (P=.079) and there was a trend between the 3 groups by Cochran-Mantel-Haenszel method (P=.038) at 2 weeks.24 No significant differences were observed in the rates of global improvements between the 3 treatment groups including both types of tinea pedis.24 As a result of the significant trend observed between concentrations, the 1% formulation of luliconazole cream was selected as the optimal concentration for future investigations for interdigital tinea pedis.24 Another group subsequently evaluated luliconazole cream 1% for both 2- and 4-week treatment periods.25 Patient eligibility was based on clinical assessments of interdigital tinea pedis and positive mycologic test results (KOH) for Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum.25 SKINmed. 2014;12:90â&#x20AC;&#x201C;93

Participants (n=147) were randomized in a 2:2:1:1 ratio to receive either luliconazole cream 1% for either 2 or 4 weeks or vehicle for either 2 or 4 weeks.20 Participants applied either luliconazole cream 1% or vehicle to the entire area of the forefeet including all interdigital web spaces and approximately 2.5 cm (1 in) of the surrounding area of the foot once daily for the duration of the treatment period.25 The primary endpoint of this study was complete clearance defined as negative mycology (KOH and culture) and a score of 0 on the Physicianâ&#x20AC;&#x2122;s Global Assessment.25 All participants were mycologically and clinically assessed at the end of treatment, and at 2 and 4 weeks post-treatment.25 The post-treatment results of this study are presented in Table II. In the 2-week treatment cohort, complete clearance was attained by 26.8% (11 of 41) vs 9.1% (2 of 22) of the treatment and vehicle groups, respectively.25 In the 4-week treatment cohort, 45.7% (16 of 35) of participants receiving luliconazole cream 1% achieved complete clearance vs 10.0% (2 of 20) of the

LUZU (Luliconazole) 1% Cream

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vehicle group.25 Participants in both cohorts showed continuous mycologic and clinical improvement at 4 weeks post-treatment (Table 2).25 Safety In a 2006 study, all of the adverse events were mild in severity and occurred at the site of application and were clinically insignificant.24 These included eczema and contact dermatitis in 1 patient each in group A (2.6%), pruritus in 1 patient in group B (1.4%), and dyshidrotic eczema, erythema, and pain in 1 patient each in group C (2.6%). In the 2013 study, none of the participants withdrew from the study because of an adverse event.25 Twenty-three adverse events were reported across all treatment groups; most were mild to moderate in severity and included headache (3%), injury (2%), and cough (2%) for the luliconazole groups; however, they were determined to be unrelated or unlikely to be related to luliconazole cream 1%.25

similar to the 4-week treatment group.25 The antifungal effects of luliconazole cream 1% persisted for several weeks post-treatment.25 The efficacy, short treatment interval, and low rate of treatment-emergent adverse events make luliconazole cream 1% an ideal candidate for the treatment of tinea pedis. Disclosure Dr Aditya K. Gupta was an advisor to and has performed clinical trials for Valeant Pharmaceuticals International Inc.

Although the use of luliconazole cream 1% has yet to be studied in pregnant women, it is advised that the drug be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.19 In addition, caution should be exercised when the drug is administered to women who are breastfeeding, because it is unknown whether the drug is excreted in human breast milk.19 The safety and effectiveness of the drug in pediatric patients have not been established.19 No overall differences in safety and effectiveness were observed between geriatric patients and younger patients.19 Indications and Administration LUZU (luliconazole) cream 1% manufactured by Medicis, a division of Valeant Pharmaceuticals (West Laval, Quebec, Canada), is a Food and Drug Administration–approved azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by Trichophyton rubrum and Epidermophyton floccosum in patients 18 years and older.5,19,20 As per the manufacturer’s instructions, this drug is for topical use solely; not for ophthalmic, oral, or intravaginal use.19 When treating interdigital tinea pedis, a thin layer of LUZU Cream 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for 2 weeks.19 Conclusions Luliconazole cream 1% demonstrates exceptional potency in clearing interdigital tinea pedis infection when applied once daily for either 2 or 4 weeks.14,24,25 Notably, at week 6, participants in the 2-week treatment group exhibited complete clearance SKINmed. 2014;12:90–93

References 1 Weinstein A, Berman B. Topical treatment of common superficial tinea infections. Am Fam Physician. 2002;65:2095–2102. 2 Al Hasan M, Fitzgeral SM, Saoudaian M, et al. Dermatology for the practicing allergist: tinea pedis and its complications. Clin Mol Allergy. 2004;2:5. 3 Panackal AA, Halpern EF, Watson AJ. Cutaneous fungal infections in the United States: analysis of the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS), 1995-2004. Int J Dermatol. 2009;48:704–712. 4 Merlin K, Kilkenny M, Plunkett A, Marks A. The prevalence of common skin conditions in Australian school children: 4 Tinea pedis. Br J Dermatol. 1999;140:897– 901. 5 Niwano Y, Kuzuhara N, Kodama H, et al. In vitro and in vivo antidermatophyte activities of NND-502, a novel optically active imidazole antimycotic agent. Antimicrob Agents Chemother. 1998;42:967–970. 6 Gupta AK, Chow M, Daniel CR, Aly R. Treatments of tinea pedis. Dermatol Clin. 2003;21:431–462. 7 Gupta AK, Chaudry M, Elewski B. Tinea corporis, tinea cruris, tinea nigra, and piedra. Dermatol Clin. 2003;21:395–400. 8 Gupta AK, Brintnell WC. Sanitation of contaminated footwear from onychomycosis patients: using ozone gas: a novel adjunct therapy for treating onychomycosis and tinea pedis. J Cutan Med Surg. 2014;17:243–249. 9 Gupta AK, Skinner AR, Cooper EA. Evaluation of the efficacy of ciclopirox 0.77% gel in the treatment of tinea pedis interdigitalis (dermatophytosis complex) in randomized, double-blind, placebo-controlled trial. Int J Dermatol. 2005;44:590–593. 10 Gupta AK, Skinner AR. Cooper EA. Interdigital tinea pedis (dermatophytosis simples and complex) and treatment with ciclopirox 0.77% gel. Int J Dermatol. 2003;42:23–27. 11 Fredriksson T. Treatment of dermatomycoses with topical tioconazole and miconazole. Dermatologica. 1983;66:20–33. 12 Hirsch HA. Clinical evaluation of terconazole. European experience. J Reprod Med. 1989;34:593–596. 13 Kokoschka EM, Niebauer G, Mounari M, Monici Preti P. Treatment of dermatomycoses with topical fenticonazole and econazole. Mykosen. 1986;29:45–50.

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14 Kuokkanen K. Topical tioconazole in dermatomycosis. Mykosen. 1982;25:274–280.

20 Rubin AI, Bagheri B, Scher RK. Six novel antimycotics. Am J Clin Dermatol. 2002;3:71–81.

15 McVie DH, Littlewood S, Allen BR, et al. Sulconazole versus clotrimazole in the treatment of dermatophytosis. Clin Exp Dermatol. 1986;11:613–618.

21 Koga H, Tsuji Y, Inoue K, et al. In vitro antifungal activity of luliconazole against clinical isolates from patients with dermatomycoses. J Infect Chemother. 2006;12:163–165.

16 Stettendorf S. Tolerability and efficacy of bifonazole in dermatomycoses. Arzneim-Forsch/Drug Res. 1983;33:750–754. 17 Takahashi H. New topical imidazoles under development in Japan. TJN-318 (NND-318): evaluation of antifungal activities and the results of clinical open study on dermatomycoses. In: Yamaguchi H, Kobayashi GS, Takahashi H, eds. Recent Progress in Antifungal Chemotherapy. New York, NY: Mercel Dekker Inc; 1991:103– 112. 18 Wagner W, Reckers-Czaschka R. Oxiconazole in dermatomycosis—a double-blind, randomized therapy compared with bifonazole. Mykosen. 1987;30:484–492. 19 Medicis, a division of Valeant Pharmaceuticals. LUZU (luliconazole) cream, 1% label information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204153s000lbl. pdf. Accessed February 10, 2014.

22 Uchida K, Nishiyama Y, Yamaguchi H. In vitro antifungal activity of luliconazole (NND-502), a novel imidazole antifungal agent. J Infect Chemother. 2004;10:216–219. 23 Watanabe S, Takahashi H, Nishikawa T, et al. A comparative clinical study between 2 weeks of luliconazole 1% cream treatment and 4 weeks of bifonazole 1% cream treatment for tinea pedis. Mycoses. 2006;49:236–241. 24 Watanabe S, Takahashi H, Nishikawa T, et al. Dose-finding comparative study of 2 weeks of luliconazole cream treatment for tinea pedis – comparison between three groups (1%, 0.5%, 0.1%) by a multi-center randomised double-blind study. Mycoses. 2006;50:35–40. 25 Jarratt M, Jones T, Kempers S, et al. Luliconazole for the treatment of interdigital tinea pedis: a double-blind, vehicle-controlled study. Cutis. 2013;91:203–2010.

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Michael H. Gold, Md • Lawrence Charles Parish, Md • Wm. Phillip Werschler, Md Joel Cohen, Md • dr. Erin Gilbert, Md, Phd • dr. Miles Graivier, Md • Michael Kane, Md Mukta Sachdev, Md • dr. Julie Woodward, Md, Phd TRIALS INCLUDED:

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Editors: Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD Joel Cohen, MD Dr. Erin Gilbert, MD, PhD Dr. Miles Graivier, MD Michael Kane, MD Mukta Sachdev, MD Dr. Julie Woodward, MD, PhD Danny Vleggaar, MD

TOXINS

IntroductIon and HIstory of BotulInum toxIns BotulInum toxIns – suBtypes BotulInum toxIns In use In aestHetIc medIcIne Botox Cosmetic Dysport Xeomin PurTox Neuronox ChinaTox Other Toxins InjectIon tecHnIques for cosmetIc IndIcatIons Glabella Crow’s Feet and Lower Eyelid Forehead Brow Lift Bunny Lines Nose Nasolabial Folds Gummy Smile Upper and Lower Lip Lines Marionette Lines Cobblestone Chin Neck and Platysmal Bands BotulInum toxIn for HyperHIdrosIs BotulInum toxIn–otHer IndIcatIons used for aestHetIc medIcIne BotulInum toxIn–comBInatIon tHerapy wItH otHer modalItIes With Fillers With Lasers and Light Sources With Chemical Peels With Surgical Procedures adverse events of BotulInum toxIn topIcal BotulInum toxIns future devIces and tHeIr role In muscle relaxtIon Index

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AN INdISPENSABLE REFERENCE: Convenient, pocket-sized reference of Clinical trials performed with Toxins. The design of each review is not merely to provide an abstract of the study but to give its purpose, pertinent methods, results and conclusions along with opinion of the importance of the study. The editors have sought to provide a balanced overview of the most recent studies, abstracts and meeting presentations having an impact on the treatment of therapeutic and aesthetic cutaneous medicine.

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March/April 2014

Volume 12 • Issue 2

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

EpiCeram Noah Scheinfeld, MD, JD

topic dermatitis (AD) is primarily a disease of the barrier integrity of the skin. The skin’s inability to retain moisture generates an immune response, creating inflammatory mediators; hence, the itch associated with AD. As a result of genetic defects (eg, a defective filaggrin gene, among others, that decreases ceramides in the skin), the skin cannot maintain its moisture. It is estimated that 10% to 20% of the American pediatric population experiences AD during their first decade. Topical preparations that allow the skin to maintain its moisture are essential parts of AD treatment. Such moisturizers may take many forms, with 6 types of preparations that can help the skin to maintain its moisture (Table). There are many defects in the skin associated with AD, which include a lack of ceremides and lipids.3,4 For example, ceramides are a combination of fatty acids and a sphingoid base joined by an amide bond between the carboxyl group of the fatty acid and the amino acid group of the base. These moisturizers can be taken up by keratinocytes, processed in lamellar bodies, and resecreted back into the stratum corneum to become a part of the dermal matrix.3 There is undoubtedly an important role for lipids in the stratum corneum concerning the cutaneous barrier function. Ceramides account for ≥50% of total intercellular lipids and are pivotal for lipid packing and permeability. Altered sphingoid base profiles could contribute to the barrier abnormality in AD.4 Skin Barrier Emulsion EpiCeram (PuraCap Pharmaceutical LLC, South Plainfield, NJ) is a promising agent for providing both a barrier to moisture loss and retention of moisture in the skin. EpiCeram is a prescriptiononly, 510k-cleared moisturizer, first approved by the Food and Drug Administration in 2006. It functions as a topical skin-barrier repair product for the treatment of AD, where it seems to be helpful in preventing the development of AD. It has a high compliance rate, and data suggest that it decreases transepidermal water loss.5

EpiCeram Controlled-Release Skin Barrier Emulsion is a steroid-free, fragrance-free, ceramide-dominant emulsion containing ceramide, conjugated linoleic acid (CLA), and cholesterol in an emollient base. EpiCeram is formulated at an acidic pH (5.0), as lamellar body production and secretion of ceramides are impaired at the high pH of eczematous skin; moreover, EpiCeram contains 2% petrolatum, which provides similar benefits of pure petrolatum but without the greasiness, which is an important consideration for an eczema prevention strategy.4 These physiologic lipids are delivered via a patented time-release system to ensure a physiological level over time.5 EpiCeram is a 3:1:1 ratio of ceramide, cholesterol, and free fatty acid contained in submicron-sized spheres. These ingredients mirror the lipid concentration in normal non-atopic skin. Clinical Support In a 50-center, open-label, interventional study, 207 patients used EpiCeram for 3 weeks either as monotherapy or in combination with another AD treatment.6 Outcome measures included investigator and patient satisfaction, Investigator Global Assessment (IGA) scale, patient-perceived improvement in atopic dermatitis, pruritus severity, and two quality-of-life questions. A total of 50% of the patients had success with IGA (clear or almost clear IGA scores) after 3 weeks of treatment with EpiCeram as monotherapy or in combination with another treatment, and 75% of the patients reported satisfaction after 3 weeks of treatment. Pruritus diminished, and quality of life improved. Of significance, 71% used EpiCeram alone and only 29% elected to use it combined with a corticosteroid or calcineurin inhibitor. Another 5-center, investigator-blinded, randomized trial study compared Epicerum with Cutivate (fluticasone; PharmaDerm, Melville, NY) in patients with moderate to severe AD.7 Primary outcome measures were: (1) reduction in disease severity, assessed by Severity Scoring for Atopic Dermatitis (SCORAD) scores; (2) improvement in pruritus; and (3) improvements in sleep habits. EpiCeram reduced clinical disease severity, decreased pruritus,

From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Weil Cornell Medical College, Assistant Clinical Professor of Dermatology, 150 West 55th Street, New York, NY 10019 • E-mail: nss1scheinfeld@gmail.com

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new to the clinic

Table. Six Types of Preparations That Help Skin Maintain Its Moisture Type of Moisturizer

Example

Effect

Natural moisturizing factors

Lactic acid, urea

Adds moisturizing factors back to the skin

Occlusives

Vasoline and Aquaphor

Once the skin is soaked with water, eg, after a bath, keeps the water in the skin

Humectants

Glycerol or glycerin

Hygroscopic substances used to keep things moist

Emollients (lipids)

Linoleic acid, ceremides

Add lipids back to the skin

Rejuvenators

Collagen, elastin (these are more for cosmetic use than treatment for atopic dermatitis)

Parts of the dermis (difficulty is delivering them to the dermis)

Hydrocolloids

Oatmeal bath preparations

Help water adhere to the skin

Sun-protective agents

Sunscreen, sunblocks

Every time a photon hits the skin, it releases water from the skin

and improved sleep habits both 14 and 28 days after initiation of therapy. Although the fluticasone-treated group showed significantly greater improvement at 14 days, SCORAD, pruritus, and sleep habit scores for EpiCeram did not differ significantly from the fluticasone-treated group by 4 weeks. Despite these studies, controversy remains as to the ideal and most cost-effective agent to moisturize AD skin.8,9 A small study of 39 patients with mild to moderate AD claimed that glycyrrhetinic acid–containing barrier repair cream (Atopiclair; Sinclair Pharma, London, England), a ceramide barrier repair cream (EpiCeram), and an over-the-counter petroleum-based skin protectant moisturizer (Aquaphor Healing Ointment; Beiersdorf AG, Hamburg, Germany) as monotherapy for mild to moderate AD in children found that Aquaphor Healing Ointment was as effective as prescription Atopiclair and EpiCeram.8,9 The studies that compare EpiCeram with common moisturizers can not be equated with EpiCeram’s studies, because the former studies that lump all moisturizers together are smaller and involve mild to moderate dermatitis, while the latter are larger, well-powered, and abated moderate to severe AD. The care of atopics needs to be individualized, based on severity and individual characteristics, as explored in a 2013 paper10 that discussed controversies involving the use of 501k moisturizers. Conclusions EpiCeram is contained in a soothing vehicle that is highly cosmetically acceptable. It offers an alternative to corticosteroids and other moisturizers. Its composition gives atopic skin the lipids and ceremides that it lacks in higher concentration than any other 501k moisturizer on the market. EpiCeram is worthy of further clinical and experimental investigation. SKINmed. 2014;12:96–97

References 1 Fowler JF, Nebus J, Wallo W, et al. Colloidal oatmeal formulations as adjunct treatments in atopic dermatitis. J Drugs Dermatol. 2011;11:804–807. 2 Hon KL, Leung AK, Barankin B. Barrier repair therapy in atopic dermatitis: an overview. Am J Clin Dermatol. 2013;14:389–399. 3 Loiseau N, Obata Y, Moradian S, et al. Altered sphingoid base profiles predict compromised membrane structure and permeability in atopic dermatitis. J Dermatol Sci. 2013;72:296–303. 4 Lowe AJ, Tang ML, Dharmage SC, et al. A phase I study of daily treatment with a ceramide-dominant triple lipid mixture commencing in neonates. BMC Dermatol. 2012;12:3. 5 EpiCeram [package insert]. South Plainfield, NJ: PuraCap Pharmaceuticals; 2011. 6 Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol. 2009;8:1106– 1111. 7 Kircik L, Hougeir F, Bikowski J. Atopic dermatitis, and the role for a ceramide-dominant, physiologic lipid-based barrier repair emulsion. J Drugs Dermatol. 2013;12:1024–1027. 8 Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as clinically effective as, and more cost-effective than, prescription barrier creams in the treatment of children with mild-to-moderate atopic dermatitis: a randomized, controlled trial. J Drugs Dermatol. 2011;10:531–537. 9 Nolan K, Marmur E. Moisturizers: reality and the skin benefits. Dermatol Ther. 2012;25:229–233. 10 Wolf R, Parish LC. Barrier-repair prescription moisturizers: do we really need them? Facts and controversies. Clin Dermatol. 2013;31:787–791.

EpiCeram

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Soft Tissue Augmentation – Volume Enhancement Soft Tissue Augmentation – Other Indications Injectable Fillers in Skin of Color Complications of Fillers

FILLERS Poly-L-Lactic Acid – Present and Future Calcium Hydroxyapatite

Editors: Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD Joel Cohen, MD Dr. Miles Graivier, MD Derek Jones, MD Bruce Katz, MD Mukta Sachdev, MD Ava Shamban, MD Danny Vleggaar, MD

Permanent Fillers for Soft Tissue Augmentation Injectable Fat for Soft Tissue Augmentation Soft Tissue Augmentation – NL Folds Soft Tissue Augmentation – Oral Commisures Soft Tissue Augmentation – Lips Soft Tissue Augmentation – Volume Enhancement Soft Tissue Augmentation – Other Indications Injectable Fillers in Skin of Color Complications of Fillers Index

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COMING SOON: TAAG TOXINS EdITOrS: Michael H. Gold, Md • Lawrence Charles Parish, Md • Wm. Phillip Werschler, Md

Joel Cohen, Md • dr. Erin Gilbert, Md, Phd • Miles Gravier, Md • Michael Kane, Md • Mukta Sachdev, Md dr. Julie Woodward, Md, Phd • danny Vleggaar, Md

March/April 2014

Volume 12 • Issue 2

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

Addressing the Role of Human Herpesviruses 6 and 7 in DRESS Warren R. Heymann, MD

rug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced hypersensitivity syndrome that may affect adults and children. There have been a number of cases that have been associated with reactivation of infection with human herpesviruses 6 (HHV6) and 7 (HHV7). The cases have been increasingly reported in the literature, the most recent describing a 15-year-old Caucasian boy treated with sulfasalazine for inflammatory bowel disease.1 What is the role of HHV6 and HHV7 in the pathogenesis of DRESS? The Viruses HHV6 and HHV7 are known as the roseolaviruses. They are beta herpesviruses characterized by slow growth and elective tropism for T lymphocytes. HHV6A is more common in immunocompromised hosts and may be a possible cofactor in acquired immunodeficiency syndrome progression. HHV6B is the primary agent of roseola. Both HHV6 and HHV7 are prevalent worldwide, with more than 90% of the population infected. The peak age of infection for HHV6 is 6 to 9 months, and 1 to 2 years for HHV7. Oral secretions predominantly transmit both viruses, although vertical transmission during gestation or by breast-feeding may occur. Latency of these viruses is noted in macrophages and CD4+ T cells; reactivation occurs with immunosuppression. Chronic infection exists mostly in the salivary glands, which allows for oral transmission of the viruses.2

Aside from DRESS syndrome and roseola, both viruses have been implicated as potential etiologic agents in pityriasis rosea, lichen planus, and graft-versus-host disease. HHV6 has also been linked to so-called HHV-6 encephalopathy, scleroderma, Gianotti-Crosti syndrome, Stevens-Johnson syndrome, the purpuric gloves-and-socks syndrome, and purpura fulminans.3

Clinical Manifestations DRESS is estimated to occur in every 1000 to 10,000 drug exposures. The most frequently reported medications include the aromatic anticonvulsants, antidepressants, sulfonamides and sulfones, nonsteroidal antiinflammatory drugs, anti-infective agents (antibiotics, antiviral, and antifungal), angiotensin-converting enzyme inhibitors, β-blockers, and allopurinol.4 Vemurafenib, the BRAF inhibitor utilized in the treatment of metastatic melanoma, was recently reported to cause DRESS.5 The eruption of DRESS usually appears 3 weeks to 2 months after introduction of the drug. The eruption is primarily morbilliform, although with infiltrative papules demonstrating follicular accentuation and occasional targetoid lesions. Facial edema is noted in approximately 25% of patients, and the process may progress to an exfoliative erythroderma. Histologically, vacuolar alteration at the epidermal/dermal junction, and a lichenoid/ perivascular infiltrate with eosinophils and occasional atypical lymphocytes is observed.6 Visceral involvement is part of the syndrome, and the most commonly affected organ is the liver.7 Nephritis, carditis, neurologic, gastrointestinal, and endocrinologic (diabetes, autoimmune thyroid disease) may all be appreciated.6 The mortality rate is approximately 10% to 20%.4 There is no international consensus for diagnosing DRESS syndromes, although a cutaneous eruption, hematologic abnormalities (eosinophils >1500 mm3, the presence of atypical lymphocytes), and systemic involvement (lymphadenopathy >2 cm in diameter, hepatitis with transaminases more than twice normal, interstitial nephritis, interstitial pneumonia, or carditis) are necessary to confirm the diagnosis. The Japanese Research Commit-

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

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tee on Severe Cutaneous Adverse Reaction (J-SCAR) includes HHV6 reactivation as a criterion in diagnosing DRESS.6 Pathogenesis What is the pathogenesis of DRESS? Just like Grandma’s apple pie, it takes the perfect blend of ingredients for the reaction to occur: genetic predisposition, drug detoxification enzymatic abnormalities, and the sequential reactivation of the herpes viruses. Certain HLA patterns may predispose populations to develop the syndrome. Most recently, for example, HLAB*13:01 has been associated with dapsone hypersensitivity.8 Using aromatic anticonvulsants (such as phenytoin), defective enzymes, such as epoxide hydrolase or glutathione transferase, allow for the formation of toxic metabolites that contribute to the pathogenesis of DRESS. But what is the role of the roseolaviruses?

Conclusions DRESS is a potentially life-threatening syndrome that must be recognized and treated. While HHV6 and HHV7 potentially play a major role in the pathogenesis of the disorder, their precise role in the pathomechanism of DRESS awaits elucidation. While most patients will improve with steroid therapy, ganciclovir may be an adjunctive agent in severe cases in which HHV6 reactivation has been documented. It is hoped that future research will accurately define the relationship of the roseolaviruses to DRESS so that the condition may be treated more expeditiously or avoided altogether. References

The answer awaits further study. The reasons why herpes viruses are implicated in DRESS are: (1) the late onset of the syndrome following drug exposure; (2) clinical features resembling a viral infection; and (3) episodic exacerbation following drug withdrawal. Polymerase chain reaction analysis demonstrates a sequential appearance of HHV6 (or Epstein-Barr virus), followed by HHV7 and finally cytomegalovirus. Increased levels of IgG to HHV6 are noted approximately 2 to 3 weeks after the onset of the eruption, whereas this is not observed with Stevens-Johnson syndrome/toxic epidermal necrolysis.9 Ultimately, pro-inflammatory cytokines are responsible for the clinical presentation. What needs to be determined is the intricate interplay between drug exposure, immune status, and viral reactivation as to how this leads the inflammatory response. Management and Therapy Management of DRESS involves the following: (1) discontinuation of the offending drug; (2) supportive care and consultation with appropriate specialists; (3) steroids administered systemically or topically for symptomatic relief (Note that Lee and colleagues7 question the role of systemic steroids for hepatic dysfunction as they did not reduce mortality in their study); (4) consideration of other immunosuppressive agents (cyclosporine, mycophenolate mofetil, rituximab); and (5) gangciclovir, which may be of adjunctive benefit when HHV6 reactivation has been clearly documented.10

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1 Ferrero NA, Pearson KC, Zedek DC, Morrell DS. Case report of drug rash with eosinophilia and systemic symptoms demonstrating human herpesvirus-6 reactivation. Pediatr Dermatol. 2013;30:608–613. 2 Caselli E, DiLuca D. Molecular biology and clinical associations of Roseolaviruses human herpes virus 6 and human herpes virus 7. New Microbilogica. 2007;30:173– 187. 3 Wolz M, Sciallis GF, Pittelkow MR. Human herpesviruses 6, 7, and 8 from a dermatologic perspective. Mayo Clin Proc. 2012;87:1004–1014. 4 Criado PR, Avanci J, Santi CG, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. Isr Med Assoc J. 2012;14:577–582. 5 Wenk KS, Pichard DC, Nasabzadeh T, Jang S, Venna SS. Vemurafenib-induced DRESS. JAMA Dermatol. 2013;149:1242–1243. 6 Husain Z, Reddy BY, Schwartz RA. DRESS syndrome (parts I and II). J Am Acad Dermatol. 2013;68:693, e1– 14; 709, e1–9. 7 Lee T, Lee YS, Yoon SY, et al. Characteristics of liver injury in drug-induced systemic hypersensitivity reactions. J Am Acad Dermatol. 2013;69:407–415. 8 Zhang FR, Liu H, Irwanto A, et al. HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med. 2013;369:1620–1628. 9 Criado PR, Crialdo RFJ, Avancini J, Santi CG. Drug reaction with eosinophilia and systemic symptoms (DRESS)/ drug-induced hypersensitivity syndrome (DISH): a review of current concepts. An Bras Dermatol. 2012;87:435– 449. 10 Moling O, Tappeiner L, Piccin A, et al. Treatment of DIHS/DRESS syndrome with combined N-acetylcysteine, prednisone, and valganciclovir—a hypothesis. Med Sci Monit. 2012;18:CS57–CS62.

Human Herpesviruses 6 and 7 in DRESS

Please forward your completed application for processing to: Larry Millikan, MD, Secretary-Treasurer General Ms Anna Gjeci, Executive Secretary 1508 Creswood Road Philadelphia, PA 19115, USA Tel: 215-677-3060 Cell: 267-438-2543 Fax: 215-695-2254 E-mail: IACDworld@yahoo.com Web: www.IACDworld.org SMCOMP_v10_i2_ADS.indd 396 121 SMCOMP_v10_i1_ADS.indd SMCOMP_v9_i5_ADS.indd 60

OFFICIAL PUBLICATION

28/03/12 12:1 9:5 24/12/11 19/01/12 2:0

March/April 2014

Volume 12 • Issue 2

PHOTO CAPSULE

Lucio’s Phenomenon and/or Relapsing Erythema Necroticans Virendra N. Sehgal, MD; Pullabatla V. S. Prasad, MD; Pichai K. Kaviarasan, MD; Shalini Malhotra, DNB

ucio’s phenomenon1 is an entity of critical dimension. It was initially described as pure and primitive (prehistoric) diffuse leprosy/diffuse lepromatous leprosy/lazarineleprosy/lucio–latapí leprosy,2 a systemic and peculiar form of leprosy. Relapsing erythema necroticans3 is a rare manifestation triggered by inadequate and irregular multidrug therapy (MDT) in multibacillary leprosy. Its clinical3 and histological4 features are exclusive and are discussed below A 22-year-old woman presented for consultation for extensive, painful skin ulcerations, loss of hair over the eyebrows and eyelashes, and recurrent epistaxis of 2 years’ duration. She was taking MDT for treatment of multibacillary leprosy intermittently. Examination of the skin surface revealed multiple, well-circumscribed, ulcerated nodules suggestive of erythema nodosum leprosum (type 2). Varying pattern of the ulcers was apparent. The margins of the ulcer were irregular and jagged. The floor was necrotic and chalky white in color (Figure 1). The background of the ulcers was erythematous, shiny, scaly, and indurated. The lesions were distributed over the face, front and back of the trunk, and extremities. The superficial cutaneous nerves were thickened and/or tender. Elicit “glove and stocking” type of anesthesia with loss of temperature, touch, and pain was present. Bacterial index of 3+ and morphological index of 20% was demonstrated on slit-skin smear5 examination. Hematoxylin-eosin–stained sections prepared from the adjoining erythematous skin revealed a subepidermal, hemorrhagic blister, containing a few red and inflammatory cells. The overlying crust was cellular, as was the underlying dermis (Figure 2).

Figure 1. Multiple ulcers are depicted, with irregular and jagged margins; the floor was necrotic and chalky white.

From the DermatoVenereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, Department of Dermatology, Venereology and Leprosy, RMMCH, Annamalai University, Chidambaram, and the Departments of Dermatology and Venereology, Safdarjung Hospital, Vardhman Mahavir Medical College, New Delhi, India Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond), DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033 (India) • E-mail: drsehgal@ndf.vsnl.net.in

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Figure 2. A subepidermal, hemorrhagic blister, containing a few red and inflammatory cells; the overlying crust was cellular.

References 1 Lucio R, Alvarado I. Opusculo Sobre el Mal. de San Lazaro O, Elefan ciasis de los Griegos. Mexico: M. Murguia y Cia; 1852:53. 2 Latapi F, Zamora AC. The spotted leprosy of Lucio (la lepra “manchada” deLuchio), an introduction to its clinical and histological study. Int J Lepr. 1948;16:421–430.

3 Sehgal VN. Lucio’s phenomenon/erythema necroticans. Int J Dermatol. 2005;44:602–605. 4 Sehgal VN, Joginder. Slit-skin smear in leprosy. Int J Dermatol. 1990;29:9–16. 5 Sehgal VN, Prasad PV, Kaviarasan PK, et al. Relapsing painful multiple ulcerative skin eruptions: challenge. Am J Dermatopathol. 2013 (In Press).

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Lucio’s Phenomenon and/or Relapsing Erythema Necroticans

Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

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16/05/2014 08:13

March/April 2014

Volume 12 • Issue 2

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

Palmoplantar Papules and Hyperkeratosis in a Deaf Man Sarah L. Taylor, MD; Shawn G. Kwatra, BS; Amy J. McMichael, MD

A 31-year-old man presented with a history of extensive thickened skin of the palms and soles since the age of 7. The patient reported difficulty in ambulating and in using his hands secondary to his skin condition and associated pain. He also reported being seen by numerous specialists in the past for his hands, feet, and fingernails. He tried various topical medications, none of which were successful in minimizing the lesions on the hands and feet. Pertinent review of systems was positive for complete deafness diagnosed at 9 months of age. The patient did not speak and used sign language to communicate. His family history was significant for two brothers, both of whom are deaf and who have a similar skin condition of their hands and feet, but with lesser severity than the patient. The patient had no other medical issues. (SKINmed. 2014;12:107–109)

xamination revealed a young, deaf, African American man with numerous verrucous hyperpigmented papules of the bilateral palmar creases (Figure 1). All 10 fingernails showed leukonychia, koilonychia, and onycholysis and were brittle with peeling of the distal nail plates. The plantar surfaces of the feet showed extensive, thick yellow hyperkeratosis, with cracks and fissuring of the heels. The toenails were extremely thick, onychogryphotic, and yellow, with significant hyperkeratosis and thick subungual debris. The interdigital spaces of the toes showed hyperkeratosis and multiple brown verrucousappearing papules. The dorsal aspects of the hands and feet and the rest of his skin were not involved. Laboratory findings on the clinic visit day included normal values for a complete blood cell count and complete metabolic panel. A lipid panel was also performed, which was normal except for elevated triglycerides (163 mg/dL). No skin biopsy was obtained. Systemic therapy with oral isotretinoin 40 mg twice a day was started. Topical therapy was also initiated with urea 50% cream twice daily to the hands and feet. Within the first month of treatment, his feet and hands improved significantly with a decrease in the hyperkeratosis of the skin and nails and improved function of all digits (Figure 2). The patient reported a much

higher quality of life with the improvement of his hands and feet with combination isotretinoin and urea cream treatment. The patient’s palmoplantar keratoderma (PPK) continued to be well controlled for 2 years on maintenance therapy of isotretinoin 40 mg along with urea 40% cream. Discussion PPK constitutes a heterogeneous group of disorders characterized by thickening of the palms and soles.1,2 The PPKs can initially be divided into inherited or acquired. The keratodermas can then be further subdivided based on whether only an isolated keratoderma is present or whether other skin findings are present and/or other organs are involved.1,2 Clinical features of PPK with sensorineural deafness include diffuse palmoplantar hyperkeratosis in association with slowly progressive, bilateral, high-frequency hearing loss (onset in early childhood).1 Deafness precedes the skin changes (onset in mid childhood).1 This has an autosomal-dominant pattern of inheritance.3,4 Molecular biology features include a connexin 26 mutation (different domains than those mutated in Vohwinkel syndrome). In addition, a mitochondrial point mutation has been demonstrated as the cause of this phenotype, making this the

From the Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC Address for Correspondence: Shawn G. Kwatra, MD, Department of Dermatology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071 • E-mail: skwatra@wfubmc.edu

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Figure 1. Hyperkeratosis of the soles.

Figure 2. Improved hyperkeratosis during treatment.

only type of keratoderma associated with a mutation in mitochondrial DNA (serine tRNA).4 Inherited disorders of keratinization are associated with deafness in a few rare syndromes, often in association with other clinical features. Syndromal nonepidermolytic PPKs with hearing loss comprise PPK with leukonychia (including Bart-Pumphrey syndrome5,6), Papillon-Lefèvre syndrome, and some cases of mutilating keratoderma (Vohwinkel’s syndrome) without ichthyosis.7–9 Another important differential diagnosis is JadassohnLewandowsky syndrome, also known as Pachyonychia congenita type I, an autosomal-dominant keratoderma chiefly involving the plantar surfaces.10 We report successful combination therapy with a systemic retinoid and urea cream in a patient with PPK with associated deafness. The medical literature is minimal regarding treatment of the various types of PPK. There are only a small number of reports regarding systemic retinoid therapy for various types of PPK. A review of 10 patients from 10 families with bullous congenital ichthyosiform erythroderma with associated keratoderma suggested that those with Keratin 1 mutations and associated keratodermas had no benefit with oral acitretin or topical tazarotene, whereas those with Keratin 10 (K10) mutations improved.11 Contrary to this, a recent case report of a 12-year-old girl with epidermolytic hyperkeratosis with associated PPK and a K10 mutation showed poor response with acitretin.12 Isotretinoin has demonstrated efficacy in a handful of patients with Papillon-Lefèvre syndrome13,14; however, a remote case report involving an 8-year-old girl with Vohwinkel’s syndrome demonstrated only minimal decrease in the hyperkeratosis after a 12week course of isotretinoin.15 SKINmed. 2014;12:107–109

Treatment of all types of hereditary and nonhereditary keratodermas is challenging. Treatment tends to be symptomatic and may vary from simple measures such as saltwater soaks and topical keratolytics to systemic retinoids or reconstructive surgery with total excision and grafting of the hyperkeratotic skin.3 Conclusions To our knowledge, this is the first case report showing efficacy of combination therapy with isotretinoin and urea cream in PPK with associated deafness. The rarity of all the keratodermas makes the investigation of general treatment outcomes of PPKs very difficult. Cases such as the one we present here can add to the body of literature helping others find options for treatment of patients with PPK. References

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1 Krol AL. Keratoderma. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. Volume 1. 2nd ed. London: Elsevier Limited; 2008:777–789. 2 Lucker GP, Van de Kerkhof PC, Steijlen PM. The hereditary palmoplantar keratoses: an updated review and classification. Br J Dermatol. 1994;131:1–14. 3 Spitz JL. Diffuse palmoplantar keratoderma (PPK). In: Genodermatoses: A Clinical Guide to Genetic Skin Disorders. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2005:30–31. 4 Martin L, Toutain A, Guillen C, et al. Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome. Br J Dermatol. 2000;143:876–883. 5 Gibbs RC, Frank SB. Keratoderma hereditaria mutilans (Vohwinkel). Arch Dermatol. 1966;94:619–625.

Palmoplantar Papules and Hyperkeratosis in a Deaf Man

March/April 2014

CASE STUDY

6 Peris K, Salvati EF, Torlone G, Chimenti S. Keratoderma hereditarium mutilans (Vohwinkel’s syndrome) associated with congenital deaf-mutism. Br J Dermatol. 1995;132:617–620. 7 Korge BP, Ishida-Yamamoto A, Punter C, et al. Loricrin mutation in Vohwinkel’s keratoderma is unique to the variant with ichthyosis. J Invest Dermatol. 1997;109:604– 610. 8 Bart RS, Pumphrey RE. Knuckle pads, leukonychia and deafness. A dominantly inherited syndrome. N Engl J Med. 1967;276:202–207. 9 Ramer JC, Vasily DB, Ladda RL. Familial leuconychia, knuckle pads, hearing loss, and palmoplantar hyperkeratosis: an additional family with Bart-Pumphrey syndrome. J Med Genet. 1994;31:68–71. 10 Vogt HJ, Calap J. Jadassohn-Lewandowski syndrome with microphthalmos. Hautarzt. 1971;22:294–299.

11 Virtanen M, Gedde-Dahl T, Mork NJ, et al. Phenotypic/ genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression. Acta Dermatol Venereol. 2001;81:163– 170. 12 Morais P, Mota A, Baudrier T, et al. Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation. Eur J Dermatol. 2009;19:333–336. 13 Nguyen TQ, Greer KE, Fisher GB Jr, Cooper PH. Papillon-Lefèvre syndrome. Report of two patients treated successfully with isotretinoin. J Am Acad Dermatol. 1986;15:46–49. 14 Sethuraman G, Malhotra AK, Khaitan BK, Sharma VK. Effectiveness of isotretinoin in Papillon-Lefèvre syndrome. Pediatr Dermatol. 2005;22:378–379. 15 Goldfarb MT, Woo TY, Rasmussen JE. Keratoderma hereditaria mutilans (Vohwinkel’s syndrome): a trial of isotretinoin. Pediatr Dermatol. 1985;2:216–218.

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

(Continued on page 125)

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March/April 2014

Volume 12 • Issue 2

CASE STUDY

Proliferative Fasciitis in the Abdominal Region Ines Zaraa, MD;1,2 Anissa Zaouak, MD;1 Dalenda El Euch, MD;1 Ines Chelly, MD;2,3 Slim Haouet, MD;2,3 Mourad Mokni, MD;1,2 Amel Ben Osman, MD1,2

A 30-year old man with no trauma history presented to our department of dermatology with a 2-year history of abdominal painful masses. The spontaneous pain and tenderness in the abdominal region gradually worsened. Physical examination revealed 3 firm, irregular subcutaneous nodules measuring 1×0.5 cm, which were movable and unattached to the overlying skin. One of the nodules was ulcerated (Figure 1). Histopathologic examination showed spindle-shaped fibroblast cells intermingled with gangliocyte-like giant cells in the hypodermis with an infiltrate made of lymphocytes and histiocytes (Figure 2 and Figure 3). The immunohistochemical staining showed the negativity of the fusiform cells and the gangliocyte-like cells to anti-S100 protein and to anti–smooth muscle actin. (SKINmed. 2014;12:111–112)

ltogether, the clinical and histopathologic features suggested the diagnosis of proliferative fasciitis (PF), and the patient was scheduled for resection of the lesions after ruling out malignancy. No recurrence was noticed during a 4-year follow up. Discussion PF is a benign and reactive proliferative lesion of soft tissue extending from the superficial fascia into the subcutaneous tissue or muscle.1,2 It usually presents as a firm and rapidly growing mass suggesting malignancy and imposing for accurate diagnosis histology and immunohistochemistry to distinguish it from real sarcoma.3 PF is an uncommon, pseudosarcomatous fibromyofibroblastic proliferation of soft tissues.4 PF is regarded as a reactive/ reparative process. It equally affects men and women. Patients are characteristically middle-aged (57 years). Its etiopathogenesis is unknown. It is believed that local injury may trigger the fibroblastic proliferation,3 but, in our case, there was no trauma history. Clinically, it presents as a painful, unique subcutaneous nodule rapidly growing in a few weeks located in the extremities in 60%, the trunk in 30%, and the head and the neck in 10%.5

Our case is original because of the young age of onset, the multiplicity of lesions, and the abdominal site of nodules. The exact diagnosis of PF can only be made on a histopathologic examination of an excisional biopsy.3 PF is characterized by a proliferation of large ganglion-like and spindle-shaped cells that is often mistaken for a sarcoma as a result of its rapid growth, rich cellularity, and mitotic activity. The main clinical and histologic differential diagnosis is nodular fasciitis, but other diagnoses could be proposed such as pseudosarcomatous lesions including proliferative myositis, ischemic fasciitis, and fibromatosis. It may also be confused with reticulohistiocytoma, epitheliod fibrous histiocytoma, and intradermal Spitz nevus.6 PF could be differentiated from these entities on the basis of histological findings and immunohistochemical profile even though it isn’t specific of PF. Histologically, in PF, the proliferating cells extend along the fibrous fascia that compartmentalize the subcutaneous fat into the underlying fascia; however, the cells expand the epimysium and perimysium and cause the separation and isolation of atrophic muscle fibers in proliferative myositis.8 Nodular fasciitis often appears as a well-demarcated nodule that arises from the superficial fascia of the muscle. The microscopic appearance of nodular fasciitis is distinct, without the

From the Department of Dermatology La Rabta Hospital, Tunis;1 Faculté de Médecine de Tunis, Université El Manar;2 and the Department of Pathology, La Rabta Hospital, Tunis, Tunisia3 Address for Correspondence: Ines Zaraa, MD, Dermatology Department, La Rabta, Hospital, Jabbari, Bab Saadoun, Tunis, 1007 Tunisia • E-mail: inesrania@yahoo.fr

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Figure 3. Hypodermic lesions with an infiltrate made of lymphocytes and histiocytes.

Figure 1. Three subcutaneous firm nodules of the abdomen.

Conclusions PF is a benign and rare tumor that can be easily misdiagnosed. Because it mimics sarcoma clinically and histologically, for a proper diagnosis, PF needs a pathologist aware of the patient’s presentation in order not to mistake this benign entity. References 1 Kato K, Ehara S, Nishida J, et al. Rapid involution of proliferative fasciitis. Skeletal Radiol. 2004;33:300-302. 2 Robertson B, Roche WC, Shabb B. Nodular fasciitis: a case report. J Oral Maxillofac Surg. 1986;44:236-239. 3 Ozben V, Aydogan F, Can Karaca F, et al. Nodular fasciitis of the breast previously misdiagnosed as breast carcinoma. Breast Care. 2009;4:401-402. 4 Marchesseau AS, Franck F, Amarger S, et al. La fasciite proliférative: une tumeur spectaculaire méconnue. Ann Dermatol Venereol. 2005;132:157.

Figure 2. Double cell proliferation: fusiform, ramified and eosinophilic cells (the myofibroblastes), and the activated fibroblasts gangliocyte-like.

5 Honda Y, Oh-i T, Koga M, et al. A case of proliferative fasciitis in the abdominal region. J Dermatol. 2001;28:753-758.

large, basophilic cells seen in PF.8 Indeed, it has been noted that the ganglion-like cells of PF express actin less uniformly than the rest of the lesion.9 The treatment relies mainly, after ruling out malignancy, on surgically reduced removal of the lesion if it is painful, unaesthetic, or interfering with function. After surgery, recurrence is uncommon.7 SKINmed. 2014;12:111–112

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6 Magro G, Michal M, Alaggio R, et al. Intradermal proliferative fasciitis in childhood: a potential diagnostic pitfall. J Cutan Pathol. 2011;38:59-62. 7 Lenyoun EH, Wu JK, Ebert B, et al. Rapidly growing nodular fasciitis in the cheek of an infant: case report of a rare presentation. Eplasty. 2008;8:e30 8 Rosenberg AE. Pseudosarcomas of soft tissue. Arch Pathol Lab Med. 2008;132:579-586. 9 Kiryu H, Takeshita H, Hori Y. Proliferative fasciitis: report of a case with histopathologic and immunohistochemical studies. Am J Dermatopathol. 1997;19:396.

Proliferative Fasciitis in the Abdominal Region

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March/April 2014

Volume 12 • Issue 2

CASE STUDY

Perianal Giant Condyloma Acuminatum (Buschke-Löwenstein Tumor) Santosh Shenoy, MD

A 50-year-old heterosexual, HIV-negative man presented with a giant anal condyloma (Figure). He had iron deficiency anemia, a slow-growing anal wart for many years, and intermittent bleeding and pruritus. Esophagogastroduodenoscopy and colonoscopy findings were normal. Endoscopic ultrasound of the anorectum showed no anal sphincter involvement, and computed tomography did not reveal any pelvic inguinal lymph nodes. Wide-staged excision was performed and the patient recovered well with resolution of symptoms and no local recurrence at 1-year follow-up. Final pathology confirmed human papillomavirus (HPV) 6 strain and a giant condyloma acuminatum with mild atypia and no malignancy. Further examination of his oropharynx showed additional small HPV lesions, which were removed locally. (SKINmed. 2014;12:114–115)

ondyloma acuminatum is caused by human papillomavirus (HPV) infection. HPV encompasses a family of highly infectious and primarily sexually transmitted double-stranded DNA viruses. Giant condyloma of the anus (GCA) is a slow-growing locally destructive verrucous tumor that was first described by Buschke and Löwenstein on the penis, but may occur elsewhere in the anogenital region and also in the oropharyngeal mucosa. Untreated GCA can be locally destructive, extending into the pelvic organs and bony structures. Recurrence is common with all treatment modalities. Discussion GCA is a sexually transmitted disease that is caused by HPV subtypes 6, 11, and occasionally 16 and 18.1 Patients present with pain, pruritus, bleeding, and a mass. Anemia is an uncommon presentation. Untreated GCA can be locally destructive, extending into the pelvic organs and bony structures and carries a high morbidity rate. GCA characteristically has a marked exophytic appearance, and histological specimens show massive epidermal hyperplasia, hyperkeratosis, and parakeratosis. Keratinocytes have a large vacuolization with large cytoplasm and a nucleus with prominent nucleoli. Squamous cell carcinoma (SCC) of the anogenital area can exist concurrently with condyloma. Ulcerated lesions should be biopsied. The evaluation of treatments for condylomata acuminata is imprecise, because it is not possible to distinguish between relapse and

new infections. HPV may persist in a latent state, and all current treatments aim to clear visible lesions. In general, therapies for genital warts are somewhat unsatisfactory, resulting in recurrence rates of 30% to 70% within 6 months of treatment.2 The preferred treatment for GCA is wide surgical excision. The advantage is the ability to histologically examine the entire specimen to ensure clear margins and to evaluate for foci of SCC. Large perianal lesions with rectal involvement may need fecal diversion and a temporary colostomy.3 Preoperative endoscopic ultrasound may have a role in evaluating rectal and anal sphincter involvement. Excision may be carried out in one setting or as staged resection, if the size of the condyloma is large and where the anal canal is involved for sphincter preservation. The defect can be closed primarily or with a V-Y flap, rotational flaps, or with granulation tissue as secondary healing.4 The cure rate with surgical excision is reportedly up to 60%; however, recurrence is common and unpredictable. Oral, topical, and intralesional chemotherapeutic modalities have been used with mixed success as an adjuvant to surgery or as treatment for recurrences. Typical agents used topically include 5-fluorouracil, podophyllin, 1.5% cidofovir, bleomycin, interferon, and imiquimod. Carbon dioxide laser ablation with topical therapy has shown a favorable response in some cases. Primary radiation therapy remains controversial. Anaplastic transformation to invasive carcinoma has been reported while some case reports do show evidence of shrinkage of small lesions after radiation.5 These

From the Department of Surgery, Kansas City VA Medical Center, Kansas City, MO Address for Correspondence: Santosh Shenoy, MD, Kansas City VA Medical Center, 4801 East Linwood Boulevard, Kansas City, MO 64128 • E-mail: santosh.shenoy@va.gov

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Figure. Perianal giant condyloma acuminatum (BuschkeLöwenstein tumor).

nonsurgical modalities are useful in smaller lesions and cosmetically sensitive areas where wide excision may lead to further disfiguring and dysfunction, eg, the penis and face. Close follow-up and examination are required with these nonsurgical therapies, as destruction of the entire condyloma cannot be ensured.

Two prophylactic HPV vaccines are commercially available. Gardasil (Merck & Co., Whitehouse Station, NJ) is a quadrivalent vaccine against HPV types 6, 11, 16, and 18 and is recommended for use in women to prevent cervical, vulvar, and vaginal cancers and condyloma acuminata, starting at age 9 up to 26 years. It is also approved in men aged 9 to 26 years to prevent genital warts. Quadrivalent HPV vaccine is effective in preventing genital warts in young men and anal intraepithelial neoplasia among men who have sex with men. There are no data on the efficacy of bivalent vaccine to prevent anal intraepithelial neoplasia in men.10–11 Cervarix (GlaxoSmithKline, Research Triangle Park, NC) is a bivalent vaccine approved for the prevention of cervical cancer and precancerous lesions caused by HPV types 16 and 18 in women aged 10 to 25 years. They are most effective when given before the onset of sexual activity and provide long-term protection. References

Complications of GCA are a result of uncontrolled growth. Fistulization, foul odor, and secondary infections are common. Large exophytic masses may interfere with defecation, sexual intercourse, and difficulty with perianal hygiene. Progression to verrucous carcinoma or invasive SCC has been reported. Individuals with genital warts from HPV have a long-term increased risk of anogenital and head and neck cancers.6 Malignant transformation is reported in up to 50% of patients with large lesions. GCA represents a spectrum between simple condyloma acuminata to SCC. The HPV proteins E6 and E7 of the high-risk serotypes HPV 16 and 18 have been shown to inactivate the host’s tumor suppressor proteins p53, which could possibly result in unregulated proliferation and malignant transformation.7 Lowrisk subtypes HPV 6 and 11 do not integrate in the host genome and it is not clear whether increased viral gene expression or inability of the host to mount a cytotoxic immune response changes the oncogenic potential of HPV type 6 and 11, causing progressions of small condyloma to GCA.8 Patients with anorectal and genital HPV should be closely monitored every 3 months initially for recurrences locally as well as other areas such as oropharyngeal mucosa. Among men and women aged 14 to 69 years in the United States, the overall prevalence of oral HPV infection is 6.9%, and the prevalence is higher among men than among women.9 In addition, these patients should be checked for other sexually transmitted diseases such as herpes simplex virus, syphilis, and HIV. Whenever feasible, sexual partners should be evaluated and treated appropriately. SKINmed. 2014;12:114–115

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1 Majewski S, Jablonska S. Human papillomavirus-associated tumors of the skin and mucosa. J Am Acad Dermatol. 1997;5:659–685. 2 Jablonska S. Traditional therapies for the treatment of condylomata acuminata (genital warts. Australas J Dermatol. 1998;39 suppl 1:S2. 3 Trombetta LJ, Place RJ. Giant condyloma acuminatum of the anorectum: trends in epidemiology and management. Report of a case and review of the literature. Dis Colon Rectum. 2001:12:1878–1886. 4 Wietfeldt ED, Thiele J. Malignancies of the anal margin and perianal skin. Clin Colon Rectal Surg. 2009;2:127– 135. 5 Tytherleigh MG, Birtle AG, Cohen CE, et al. Combined surgery and chemoradiation as a treatment for the Buschke-Löwenstein tumour. Surgeon. 2006;6:378– 383. 6 Blomberg M, Friis S, Munk C, Bautz A, Kjaer SK. Genital warts and risk of cancer: a Danish study of nearly 50 000 patients with genital warts. J Infect Dis. 2012;10:1544–1553. 7 Vousden KH. Regulation of the cell cycle by viral oncoproteins. Semin Cancer Biol. 1995;2:109–116. 8 Martin JM, Molina I, Monteagudo C, et al. Buschke-Lowenstein tumor. J Dermatol Case Rep. 2008;4:60–62. 9 Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;7:693–703. 10 Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-2):1–24. 11 Saslow D, Castle PE, Cox JT, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007;57:7–28.

Perianal Giant Condyloma Acuminatum

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March/April 2014

Volume 12 • Issue 2

CASE STUDY

Aplastic Anemia and Hoyeraal-Hreidarsson Syndrome Baris Malbora, MD; Zekai Avci, MD; Namik Ozbek, MD

A 2-year-old girl patient was admitted with intractable diarrhea, respiratory infections, and seizures. She was the first child of the first-degree parents. She was born at term with a birth weight of 2300 g. Physical examination revealed weight 6800 g, height 76 cm, and head circumference 41 cm, below the third percentile. Findings included sparse and dull hair, nail dystrophy, and proximally located thumbs (Figure). Aphthous lesions were observed on the oral mucosa. Neurologic examination disclosed poor head control. She could not sit without support and had hyper-reactive deep tendon reflexes. (SKINmed. 2014;12:117–118)

omplete blood cell count revealed hemoglobin of 7.32 g/dL, mean corpuscular volume of 87.4 fL, red blood cell distribution width of 15, white blood cell count of 360/mm3, and platelet count of 12.300/mm3. Bone marrow aspiration was performed and hypocellularity, granulocytic vacuolization, erythroid dysplasia, and vacuolization were noted. No megacaryocyte was seen; however, there were hemophagocytic histiocytes. Erythroid/myeloid cell ratio was 2/7. Peripheral blood lymphocyte subset analysis showed reduction in B-cell lineage (CD19 1.7%). Findings from biochemical tests, quantitative immunoglobulins, and tandem mass spectrometry were normal. Results from diepoxybutane test were normal and viral serology was negative. Results from cytogenetic analysis were normal (46, XX). The gene responsible for the autosomal-dominant form of dyskeratosis congenita (encoding the RNA component of telomerase [TERC]) were screened for mutation by denaturing HPLC analysis. No abnormal patterns were detected in our patient. Unfortunately, telomerase reverse transcriptase (TERT) and DKC1 mutation analyses were not performed. Cranial magnetic resonance imaging was performed and showed cerebral white matter demyelinization, hypoplasia of cerebellar hemispheres, vermis and corpus callosum, and dilatation at the third and lateral ventricles. Psychometric evaluation was compatible with 6 months. During follow-up, coagulase-negative staphylococci were detected in blood cultures during a febrile neutro-

penic episode, and appropriate antibiotics were started. Due to a lack of B cells, presence of hemophagocytosis, and prolonged infection, 2 g/kg intravenous immunoglobulin was administered within 2 days. The patient was transferred to another center for the rest of treatment. Two weeks after discharge, it was learned that the patient had died from sepsis. Discussion Dyskeratosis congenita is a clinically and genetically heterogeneous inherited bone marrow failure syndrome that is classically characterized by a mucocutaneous triad of abnormal skin pigmentation, leukoplakia, and nail dystrophy.1 Hoyeraal-Hreidarsson syndrome is a severe clinical variant of dyskeratosis congenita.2,3 Even though it is often known to be inherited as X-linked, autosomal-dominant and recessive forms have also been defined.4 We describe a severe and very rare form of aplastic anemia with Hoyeraal-Hreidarsson syndrome in a 2-year-old girl. In the majority of patients, the disease is caused by mutations in the X-linked dyskeratosis congenita gene DKC15; however, other inheritances should be kept in mind.4 Researchers4 have identified novel homozygous TERT mutations in two unrelated consanguineous families, where the index cases presented with classical dyskeratosis congenita, or the more severe variant, Hoyeraal-Hreidarsson syndrome. These TERT mutations resulted in reduced telomerase activity and extremely short telomeres. As these mutations are homozygous, these patients were predicted to have sig-

From the Department of Pediatric Hematology, Baskent University Faculty of Medicine, Ankara, Turkey Address for Correspondence: Baris Malbora, MD, Baskent University, Department of Pediatrics, 6. Cadde, No: 72/3, 06490, Bahcelievler, Ankara, Turkey • E-mail: barismalbora@gmail.com

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CASE STUDY they were clinically asymptomatic with normal blood cell counts. She went on to develop progressive trilineage hematopoietic bone marrow failure with profound thrombocytopenia. Conclusions In our patient, we diagnosed Hoyeraal-Hreidarsson syndrome with intrauterine growth retardation, microcephalia, psychomotor retardation, progressive pancytopenia, B-cell reduction, hypoplasia of the cerebellum, vermis, and corpus callosum, and cerebral white matter demyelinization. This case is presented as a very rare form of aplastic anemia.

A Figure. The general appearance of the patient, with sparse, discolored hair (A) and feet showing nail dystrophy (B). The mottled depigmentation reflects dyskeratosis on the feet.

References 1 Marrone A, Dokal I. Dyskeratosis congenita: a disorder of telomerase deficiency and its relationship to other diseases. Expert Rev Dermatol. 2006;1:463–479.

nificantly reduced telomerase activity in vivo. The first patient was a 13-year-old Libyan girl from a consanguineous marriage. She was underweight and short for her age. Investigations showed that she had hypocellular bone marrow and thrombocytopenia. Her parents and an older sister had mild clinical and laboratory abnormalities. The death of an older sister was from unknown causes at 6 years of age. The second patient was a 3-year-old girl with an Iranian-Jewish ethnic background who was also from a consanguineous marriage. She was found to have cerebellar hypoplasia, early bone marrow failure, and leukoplakia after further investigations to elucidate her failure to thrive. Microcephaly, dysphagia, learning disabilities, and developmental delay were also noted. Clinical investigation of the rest of the family found that

2 Hoyeraal HM, Lamvik J, Moe PJ. Congenital hypoplastic thrombocytopenia and cerebral malformations in two brothers. Acta Paediatr Scand. 1970;59:185–191. 3 Hreidarsson S, Kristjansson K, Johannesson G, Johannsson JH. A syndrome of progressive pancytopenia with microcephaly, cerebellar hypoplasia and growth failure. Acta Paediatr Scand. 1988;77:773–775. 4 Marrone A, Walne A, Tamary H, et al. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood. 2007:15;110:4198–4205. 5 Knight SW, Heiss NS, Vulliamy TJ, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol. 1999;107:335–339.

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March/April 2014

Volume 12 • Issue 2

CASE STUDY

Merkel Cell Carcinoma Ardalan Minokadeh, PhD;1 Adam J. Wulkan, MD;2,3 Kenneth Beer, MD;2,4,5 Jill S. Waibel, MD2,3 A 92-year-old man presented for evaluation with a 1-month history of a rapidly growing asymptomatic pink nodule on his forearm. Biopsy results of the lesion demonstrated pathology consistent with Merkel cell carcinoma (MCC). Immunohistochemical studies displayed positive cytoplasmic staining for cytokeratin AE1/AE3, positive dot-like perinuclear staining for cytokeratin-20, diffuse cytoplasmic staining for neuron specific enolase, and no significant staining for S-100. Subsequent positron emission tomography did not reveal evidence of metastatic disease. Wide excision of the lesion was performed along with a sentinel node biopsy of his left axilla. The sentinel nodes were negative for MCC. Adjuvant radiation treatment of the tumor site was provided because the pathologist noted MCC within 2 mm of the deep margin. (SKINmed. 2014;12:120–121)

ix months after his first nodule was discovered, the patient presented with a 1-week history of an 8-mm pink papule on his right pre-auricular area (Figure 1). A shave biopsy was performed, which revealed Merkel cell carcinoma (MCC) (Figures 2 and 3). Immunohistochemical studies revealed a strong expression for cytokeratin-20 within the atypical cells and there was no evidence of thyroid transcription factor-1 expression. Results from repeat positron emission tomography (PET) were negative for metastatic disease. The patient underwent a wide local excision of this second tumor with reconstruction, without complications. Subsequently, he completed a course of adjuvant radiation therapy. In the 6 months after that surgery, the patient had no recurrences, metastases, or new lesions in the sites of either of his cancers. While it has been presumed that these are two primary MCCs, this cannot be verified. Discussion MCC is a rare, aggressive neuroendocrine tumor arising from Merkel cells, which are specialized neuroreceptors located in the basal layer of the epidermis. A 33% mortality rate is associated with this diagnosis, higher than that of melanoma.1 There are about 1500 new cases of MCC in the United States each year, and the incidence of this cancer is on the rise.2 Recent studies in the etiology of this malignancy have identified that the Merkel cell polyomavirus (MCV) may be responsible for inducing MCC.3 DNA sequences of the MCV have been detected in 80% of tumors compared with only 8% to 16% of controls. In the following case discussion, we present a patient with two MCC lesions

each lacking the MCV, with a discussion of the etiology and treatment of this malignancy. At present, it is believed that many MCCs have a viral etiology. The identification of the MCV at the University of Pittsburgh has renewed interest in MCC.3 Initial studies have demonstrated a monoclonal pattern of DNA integration into MCCs, suggesting that the viral integration occurs prior to clonal tumor growth. This supports the idea that the virus is responsible for MCC, as opposed to MCCs merely having increased susceptibility to be secondarily infected by MCV.4 In a recent review of MCC, the incidence of MCC is estimated to be 0.6 per 100,000,5 representing a rise from historic incidence rates. The need for novel therapeutic interventions is clear. Indeed, a potential outcome of this testing will be the development of antiviral therapy for MCV-positive patients, significantly altering the therapeutic landscape for MCC. Histochemical staining of the two tumors in this patient failed to demonstrate viral protein (Figure 3). Thus, it is likely that our patient is one of the approximately 15% to 25% of MCC patients who are MCV negative. One other possibility is that the patient in this report had infection with MCV that was not detected with present methodologies. While wide excision remains the mainstay of treatment for MCC, several studies have shown superior results utilizing Mohs surgery.6,7 Mohs surgery with adjunctive radiation has been shown to decrease recurrence rates. Sentinel node mapping in patients with MCC has been advocated by the new National Comprehensive Cancer Network (NCCN) guidelines for the management of

From Tulane University, New Orleans, LA;1 Department of Dermatology & Cutaneous Surgery, University of Miami, Miami FL;2 Miami Dermatology & Laser Institute, Miami, FL;3 Palm Beach Esthetic Dermatology & Laser Center, West Palm Beach, FL;4 Department of Medicine, Duke University, Durham, NC5 Address for Correspondence: Adam Wulkan, MD, 1600 NW 10th Avenue, Room 2023, Miami, FL 33136 • Email: AJWulkan@med.miami.edu

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Figure 1. Pink, dome-shaped papule in the right preauricular area.

Figure 3. Completed immunohistochemical staining using CM2B4 monoclonal antibody. This antibody was developed at the University of Pittsburgh against the T-antigen protein of the recently discovered Merkel cell polyomavirus. Results were unable to identify any positive staining in the tumors cells with this antibody, and an appropriate positive control was concurrently performed.

References 1 De Wolf-Peeters C, Marien K, Mebis J. A cutaneous APUDoma or Merkel cell tumor? A morphologically recognizable tumor with biologic and histologic malignant aspect in contrast with its clinical behavior. Cancer. 1980;46:1810–1816.

Figure 2. Hematoxylin and eosin stain of the preauricular tumor: tumor composed of uniform, small, round to oval cells. Mitotic figures are abundant.

patients with MCC; this modality has utility in monitoring MCC patients to determine the likelihood of distant metastasis. Conclusions MCCs tend to be highly aggressive. Both early recognition and surgical excision remain the mainstay of curative treatments. In this report, we document a patient with two MCC lesions and no evidence of metastatic or recurrent disease 20 months after his initial diagnosis. Evaluation of this patient was extensive and included multiple PET scans and sentinel node evaluations. Despite a report of basal cell carcinoma discovered by PET scan, more information about the utility of this modality for patients with multiple MCC is needed to help determine optimal technology and intervals for evaluation with PET scans for MCC. In addition, evaluation of sentinel nodes using DNA probes for the MCV will also need to be included in patient staging procedures. Continued studies will further our knowledge of how to approach and treat this aggressive cancer. SKINmed. 2014;12:120–121

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2 Lemos B, Nghiem P. Merkel cell carcinoma: more deaths but still not pathway to blame. J Invest Dermatol. 2007;127:2100–2103. 3 Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–1100. 4 Shuda M, Feng H, Kwun HJ, et al. Antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A. 2008;105:16272–16277. 5 Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010;37:20–27. 6 Thomas CJ, Wood GC, Marks VJ. Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg. 2007;33:333–339. 7 O’Connor WJ, Roenigk KK, Brodland DG. Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg. 1997;23:929–933.

Merkel Cell Carcinoma

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March/April 2014

Volume 12 • Issue 2

CASE STUDY

Bilateral Zosteriform Extragenital Lichen Sclerosus Piyush Kumar, MD; Abhijeet Kumar Jha, MD; Sambeet Kumar Mallik, MD; Mohammed Raihan, MD

A 35-year-old man presented with asymptomatic eruption on both forearms and lower aspects of the legs for 6 months. The lesions first appeared on his inner aspects of the wrist, the dorsal surface of the hands, and legs and progressed to involve proximal aspects of the extremities. There was no significant past history. On examination, multiple pearly white papules and depigmented atrophic plaques were found bilaterally on the flexors of the arms and the extensors of the legs. The lesions were arranged in a linear manner, following the lines of Blaschko (Figures 1 and 2). The surface of the atrophic plaques was notable for prominent telangiectasia, giving an erythematous appearance. The genitalia, oral cavity, palms, and soles were spared. Systemic examination was noncontributory. Lichen striatus and extragenital lichen sclerosus (ELS) were considered the differential diagnosis. Clinically, the age of the patient, the absence of scaling, and the presence of atrophic plaques and telangiectasia were in favor of ELS. A punch biopsy from an atrophic plaque was performed, and it revealed hyperkeratosis, atrophic epidermis, basal layer vacuolar degeneration, mild lymphocytic infiltration in the dermis, edema, and homogenization of collagen of the upper portion of the dermis (Figures 3 and Figure 4). Histopathologic findings were consistent with lichen sclerosus. A diagnosis of bilateral zosteriform ELS was made. (SKINmed. 2014;12:123–125)

xtragenital lichen sclerosus (ELS) is an uncommon condition that may or may not be seen with genital lichen sclerosus (LS).1,2 The clinical presentation of ELS is varied and mimics many other conditions. Classically, initial ELS presents with porcelain white papules, which coalesce to form an atrophic plaque, and mimics a plaque type of morphea. Variation in morphology is well known, and bullous lesions,2 generalized folliculocentric papular type3 (PK has seen such a case4), and even keratotic papules5 have been described. Palm and sole involvement, as well as scalp involvement leading to scarring alopecia, have been reported with LS. Linear or zosteriform ELS is a rare variant found as an isotopic response after herpes virus infection/herpes zoster or as a primary event and is considered to be the result of genetic mosaichism.1,6,7 Bilateral zosteriform ELS is an even rarer variant, and only a few cases have been described in the literature.1,8 At times, such lesions may be associated with underlying bone atrophy and may mimic “en coup de sabre” (morphea on the face).9

Histopathology is diagnostic. Both genital LS and ELS have almost indistinguishable histopathology.10,11 Some rarer histopathologic findings include massive melanin incontinence and vascu-

litis.10 When melanin incontinence is prominent, LS lesions may be pigmented, rather than leukodermic.10 Because genital LS is frequently pruritic, the epidermis may show changes of lichen simplex chronicus and absence of atrophy.12 At times, the epidermis may even be acanthotic, and such a change may indicate subsequent development of malignancy. Epidermal atrophy is the rule in ELS and thus differs from genital LS.12 ELS is often asymptomatic and has no malignant potential.13 This has been attributed to the decreased expression of Ki-67 and p53 in extragenital lesions as compared with genital lesions.13 ELS usually requires treatment only if it is very pruritic or cosmetically of concern. Various treatment modalities have been used in extragenital LS with variable success including acitretin, methotrexate, topical tacrolimus, calcipotriene, UVA phototherapy, psoralen-UVA (PUVA) therapy, and narrow-band UVB therapy.10,13 The use of potent corticosteroids, such as 0.05% clobetasol propionate, has been proven to be a safe and effective therapeutic option13; however, widespread lesions may limit its usefulness. Camouflage may be helpful in such cases.8 Combined treatment of tacrolimus ointment and PUVA may be a good option in extensive cases of LS.14

From the Department of Dermatology, Katihar Medical College, Katihar, India Address for Correspondence: Piyush Kumar, MD, Assistant Professor of Dermatology, Katihar Medical College and Hospital, Katihar 854105, India • E-mail: docpiyush@gmail.com

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Figure 1. .Atrophic plaques in a linear manner on the inner side of both forearms. Note the prominent telangiectasia, giving an erythematous appearance. Figure 3. Hyperkeratosis, epidermal atrophy, basal layer degeneration, and mild infiltration in the upper portion of the dermis. Note the pallor of the upper dermis (hematoxylin and eosin stain ×100).

Figure 2. Atrophic plaques on the dorsum of the hands. Note the closely set white papules and discrete atrophic plaques on the inner side of the right forearm.

Conclusions The clinical presentation of ELS can be quite varied, making it difficult to diagnose. A high index of suspicion and histopathologic study are needed to establish the diagnosis. Acknowledgments Dr Paritosh Kumar Banerjee and Dr Ramesh Chandra Gharami assisted in the case discussion and diagnosis. Dr Rajesh Kumar Mandal assisted in the literature search. SKINmed. 2014;12:123–125

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Figure 4. Epidermal atrophy, basal layer degeneration, and infiltration in the upper portion of the dermis. Edema and homogenization of collagen is appreciable. Colloid body (arrow) and prominent pigmentary incontinence are atypical findings (hematoxylin and eosin stain ×400). Bilateral Zosteriform Extragenital Lichen Sclerosus

March/April 2014

CASE STUDY

References 1 Chen JF, Chiang CP, Chen YF. Bilateral zosteriform extragenital lichen sclerosus et atrophicus: a new clinical presentation. J Dermatol. 2010;37:480–483. 2 Ballester I, Bañuls J, Pérez-Crespo M, Lucas A. Extragenital bullous lichen sclerosus atrophicus. Dermatol Online J. 2009;15:6. 3 Mann DJ, Vergilis-Kalner IJ, Wasserman JR, PetronicRosic V. Folliculocentric lichen sclerosus et atrophicus. Skinmed. 2010;8:242–244. 4 Kumar P, Debbarman P, Mondal AK, et al. White papules and atrophic plaques on trunk and extremities. J Pakistan Assoc Dermatologists. 2012;22:293–297.

8 Chan YH, Yau KC. Dermato-venereological quiz. Hong Kong J Dermatol Venereol. 2006;14:98–99. 9 Kim CR, Jung KD, Kim H, et al. Linear lichen sclerosus along the Blaschko’s line of the face. Ann Dermatol. 2011;23:222–224. 10 Weedon D. Disorders of collagen. In: Weedon D, ed. Weedon’s Skin Pathology. 3rd ed. London, England: Churchill Livingstone Elsvier Limited; 2010:313–316. 11 Winfield H, Jaworsky C. Connective tissue disease. In: Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of Skin. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins Publishers; 2009:303–306.

5 Criado PR, Lima FH, Miguel DS, et al. Lichen sclerosus-a keratotic variant. J Eur Acad Dermatol Venereol. 2002;16:504–505.

12 Carlson JA, Lamb P, Malfetano J, et al. Clinicopathologic comparison of vulvar and extragenital lichen sclerosus: histologic variants, evolving lesions, and etiology of 141 cases. Mod Pathol. 1998;11:844–854.

6 Gutte R, Khopkar U. Extragenital unilateral lichen sclerosus et atrophicus in a child: a case report. Egyptian Dermatol J. 2011;7:10.

13 Bergstorm KG, Mengden SJ, Kamino H, Ramsay D. Extragenital lichen sclerosus et atrophicus. Dermatol Online J. 2008;14:23.

7 Cabanillas González M, Monteagudo B, de las Heras C, Chacharrón JM. Blaschkoid, zosteriform linear lichen sclerosus et atrophicus. Actas Dermosifiliogr. 2009;100:155–157.

14 Valdivielso-Ramos M, Bueno C, Hernanz JM. Significant improvement in extensive lichen sclerosus with tacrolimus ointment and PUVA. Am J Clin Dermatol. 2008;9:175– 179.

Historical Diagnosis and treatment: epithelioma

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Bilateral Zosteriform Extragenital Lichen Sclerosus

MEDIA PARTNER

March/April 2014

Volume 12 • Issue 2

correspondence

Traumatic Panniculitis in a Chinese Woman Choon Chiat Oh, MBBS, MRCP;1 Kong Bing Tan, MBBS, FRCPA, FRCPath;2 Thamotharampillai Thirumoorthy, MBBS, FRCP;1 Shiu Ming Pang, MBBS, FRCP;1 Haur Yueh Lee, MRCP1 To the Editor:

Discussion

A 28-year-old Chinese woman was admitted to the hospital for painful swelling over her left leg for 1 month. She was otherwise systemically well and denied any trauma to the affected area. Prior to dermatology consult, she was treated for various diagnoses including cellulitis, erythema nodosum, and cutaneous vasculitis. On physical examination, she had an ill-defined tender erythematous plaque on her left leg, with localized hypertrichosis on the plaque (Figure 1). Laboratory markers including full blood cell count, antinuclear antibodies, and extractable nuclear antigen profile were unremarkable. She was previously seen for persistent pain and swelling of her left hand and Secretans syndrome was diagnosed by her managing physician. Histology of the affected area (Figure 2) showed lipomembranous changes in the subcutis, and Perls stain was positive for iron (Figure 2 inset).

Traumatic panniculitis is rare. This condition was first described in 1985, with 5 cases reported in the literature.1

Figure 1. An ill-defined tender erythematous plaque on the patient’s left leg, with localized hypertrichosis on the plaque.

Figure 2. Histology of the skin biopsy showing changes in the subcutaneous adipose tissue. Inset: Perl’s stain for iron. (Original magnification, 400x.)

The intensity of traumatic injury is not necessarily related to the development or the intensity of the cutaneous lesions. History of trauma helps in the diagnosis, although the antecedent is often minor or unnoticed.2 Clinically, the lesions appear at the site of injury as painful indurated nonspecific plaques and nodules. Localized hypertrichosis associated with traumatic panniculitis is very rare. The mechanism of hypertrichosis is poorly understood. One suggestion is that local inflammation induces abundant and localized arterial hyperemia, which provides nutrients that stimulate the affected follicles and cause hypertrichosis. Another sugges-

From the Dermatology Unit, Singapore General Hospital;1 and the Pathology Department, National University Hospital,2 Singapore Address for Correspondence: Choon Chiat Oh, Dermatology Unit, Singapore General Hospital, Outram Road, Singapore 169608 • E-mail: oh.choon.chiat@sgh.com.sg

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tion is that inflammation increases angiogenesis and causes a prolonged anagen phase of the lesion, affecting the hair growth cycle.3 Histologically, the features are not specific, although late lesions typically show lipomembranous changes of the subcutaneous adipose tissue. Other features include lobular panniculitis without vasculitis. Hemosiderin-laden macrophages may be abundant.4 Lipomembranous change per se, is a nonspecific manifestation of adipose tissue damage and is also characteristically present in membranous panniculitis and lipodermatosclerosis. In the appropriate clinicopathological context, a traumatic etiology should be considered.

hypertrichosis. Although she denied any form of trauma, further history revealed a strong history of family violence, for which she was once admitted for traumatic head injury. conclusions This case illustrates localized hypertrichosis as a feature of traumatic panniculitis. An in-depth evaluation for possible underlying psychosocial issues may be necessary in cases of repeated consults. References 1 Winkelmann RK, Barker SM. Factitial traumatic panniculitis. J Am Acad Dermatol. 1985;13:988–994.

A recent paper characterized 4 young Korean women with traumatic panniculitis and localized hypertrichosis. The authors suggested that there are more reports in Asian women as detection of localized dark hair is relatively easier in this population.4

2 Moreno A, Marcoval J, Peyri J. Traumatic panniculitis. Dermatol Clin. 2008;26:481–483. 3 Lee DJ, Kim YC. Traumatic panniculitis with hypertrichosis. Eur J Dermatol. 2011;21:258–259.

Our patient continued to return to hospital for repeated episodes of new tender erythematous plaques on the same leg, which subsequently resolved to brown plaques with localized

4 Lee JH, Jung KE, Kim HS, et al. Traumatic panniculitis with localized hypertrichosis: two new cases and considerations. J Dermatol. 2013;40:139–141.

Rosacea: Could Topical Azelaic Acid and Oral Tetracyclines Modify Videocapillaroscopic Pattern? Giulia Ganzetti, MD; Katia Giuliodori, MD; Anna Campanati, MD; Annamaria Offidani, MD To the Editor: Rosacea is a common chronic skin disease characterized by flushing, persistent erythema, telangiectasia, and inflammatory papules and pustules that affect the central face.1 It is considered a cutaneous vascular disorder principally caused by persistent inflammation linked to reactive oxygen species production by neutrophils.2,3 purpose The aim of our study was to evaluate the action of a standardized combination therapy on the qualitative and quantitative microvessel alterations in patients affected by rosacea.

We compared 20 patients with papulopustular rosacea, stage II according to Plewig and Kligman classification1 (10 men and 10 women; mean age, 39.5±7.8 years), with 20 patients with papulopustular acne vulgaris (12 men and 8 women; mean age, 28.7±8.5 years). No patients received any topical or systemic therapy in the 3 months prior to the first assessment. Combination therapy with oral minocycline (100 mg twice daily for 4 weeks followed by 50 mg twice daily for 4 weeks and 50 mg/d for a further 4 weeks) and topical application of azelaic acid 15% (once a day for 12 weeks) were administered to both groups. At baseline and after 12 weeks of combination therapy, we performed videocapillaroscopy in the same cheek area, evaluating the background color,

From the Dermatological Clinic, Department of Medical Sciences, Polytechnic University of Marche, Ancona, Italy Address for Correspondence: Katia Giuliodori, Dermatological Clinic, Department of Medical Sciences, Polytechnic University of Marche, via Conca 71, 60126 Ancona, Italy • E-mail: katiagiuliodori79@yahoo.it

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Table. Qualitative (A and B) and Quantitative (C) Videocapillaroscopic Parameters in Rosacea and Acne Groups Before and After Targeted Therapy Rosacea Group (Baseline) (Patients, No.)

Parameter

A Background colour

Rosacea Group (After 12 Weeks of Therapy) (Patients, No.)

Acne Group (Baseline) (Patients, No.)

Acne Group (After 12 Weeks of Therapy) (Patients, No.)

Pink

Red

Pink

Red

Pink

Red

Pink

Red

Abs (0)

Mild (1)

Mod (2)

Sev (3)

Abs (0)

Mild (1)

Mod (2)

Sev (3)

Abs (0)

Mild (1)

Mod (2)

Sev (3)

Abs (0)

Mild (1)

Mod (2)

Sev (3)

Vessel tortuosity

Neoangiogenesis

B Vessel distribution irregularity

C Vessel diameter

<50 μm (0)

>50 <100 μm (1)

>100 μm (2)

<50 μm (0)

>50 <100 μm (1)

>100 μm (2)

<50 μm (0)

>50 >100 μm <100 μm (2) (1)

<50 μm (0)

>50 <100 μm (1)

>100 μm (2)

Abs = Absent; Mod = Moderate; Sev = Severe

morphological irregularities (irregularity of vessel distribution, vessel tortuosity, neoangiogenesis), and vessel diameter. Background color was evaluated using a 2-color scale (pink and red), morphological irregularities using a 4-point scale for each parameter (0 absent, 1 mild, 2 moderate, and 3 severe), and vessels’ diameters using a 3-point scale (0 vessel diameter <50 μm; 1 vessel diameter >50 μm and <100 μm [dilation]; and 2 vessel diameter >100 μm [telangiectasia]). In the rosacea group at baseline, videocapillaroscopy showed a diffuse and intense reddish background not detectable in the acne group (Table, A). The evaluation of morphological features identified mild to severe irregular vessel distribution, vessel tortuosity, and neoangiogenesis (Table, B), each of which were statistically significantly different between the two study groups (P<.005). The mean vessel diameter was signiﬁcantly increased in the skin affected by rosacea compared with that affected by acne vulgaris (52.3±8.92 μm vs 32.4±5.73 μm) (P<.005) (Table, C, and Figure 1A and 1B). SKINmed. 2014;12:127–130

After 12 weeks of combination therapy in the rosacea group, videocapillaroscopy showed an important reduction in the reddish background in both groups, whereas no modifications were detectable in the vessel diameter or morphological aspects (P>.005) (Table and Figure 1C–1D). Rosacea is a chronic inflammatory skin dermatosis that is frequently difficult to manage and has a significant impact on patients’ quality of life. Acne vulgaris shows skin lesions strictly resembling rosacea, although the underlying physiopathological pathway seems to be different.4,5 Videocapillaroscopy is a noninvasive technique that has been shown to be useful in visualizing and to studying microcirculatory aspects in many skin diseases.6–9 Few studies have been conducted on videocapillaroscopic evaluation of rosacea and, to the best of our knowledge this is the first paper to emphasize the videocapillaroscopic pattern before and after a targeted therapy. Azelaic acid is a dicarboxylic agent effective for the treatment of rosacea through its anti-inflammatory effects achieved by reducing reactive oxygen species.10 It is well known that the applica-

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CORRESPONDENCE References 1 Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol. 2002;46:584–587. 2 Young CN, Koepke JI, Terlecky LJ, et al. Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J Invest Dermatol. 2008;128:2606–2614.

3 Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009;55:77–81. 4 Campanati A, Marconi B, Penna L, Paolinelli M, Offidani A. Pronounced and early acne in Apert’s syndrome: a case successfully treated with oral isotretinoin. Eur J Dermatol. 2002;12:496–498.

5 Campanati A, Giuliodori K, Ganzetti G, Liberati G, Offidani AM. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol. 2010;11(suppl 1):46–48.

Figure 1. Videocapillaroscopic findings in rosacea (A) and acne (B) patients at baseline. Videocapillaroscopic findings in rosacea (C) and acne (D) patients after 12 weeks of topical azelaic acid and oral tetracyclines.

tion of azelaic acid in rosacea may induce a significant improvement in number of inflammatory lesions and erythema without any influence on the neo-angiogenic phenomenon.11 Tetracyclines are able to modulate angiogenesis in several dermatological diseases: rosacea, bullous dermatoses, pyoderma gangrenosum, and sarcoidosis.12 Conclusions Our study confirmed that azelaic acid 15% in combination with oral tetracycline represents a valid therapeutic option in the treatment of rosacea, reducing anti-esthetic facial flushing and videocapillaroscopic background redness, without reducing either morphologic irregularities or neoangiogenesis in the course of rosacea. This failure may be linked to many, still mysterious pathophysiologic pathways of rosacea, of which currently available therapies are not able to act.

6 Campanati A, Savelli A, Sandroni L, et al. Effect of allium cepa-allantoin-pentaglycan gel on skin hypertrophic scars: clinical and video-capillaroscopic results of an open-label, controlled, nonrandomized clinical trial. Dermatol Surg. 2010;36:1439–1444. 7 Campanati A, Goteri G, Simonetti O, et al. Angiogenesis in psoriatic skin and its modifications after administration of etanercept: videocapillaroscopic, histological and immunohistochemical evaluation. Int J Immunopathol Pharmacol. 2009;22:371–377. 8 Ganzetti G, Campanati A, Offidani A. Alopecia areata: a possible extraintestinal manifestation of Crohn’s disease. J Crohns Colitis. 2012;6:962–963. 9 Orciani M, Campanati A, Salvolini E, et al. The mesenchymal stem cell profile in psoriasis. Br J Dermatol. 2011;165:585–592. 10 Gollnick H, Layton A. Azelaic acid 15% gel in the treatment of rosacea. Expert Opin Pharmacother. 2008;9:2699–2706. 11 Gupta AK, Gover MD. Azelaic acid (15% gel) in the treatment of acne rosacea. Int J Dermatol. 2007;46:533–538. 12 Korting HC, Schöllmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22:287–294.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2014;12:127–130

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(8 8

44 ll ur tio 4sp n t 44 h

l g ad ift for

March/April 2014

Volume 12 • Issue 2

Book Review Jennifer L. Parish, MD, Section Editor

Lasers and Energy Devices for the Skin By Goldman MP, Fitzpatrick RE, Ross EV, Kilmer SL, and Weiss RA. Second Edition. London, England: Informa Healthcare. 2013. Pages 394. $179.95 The field of lasers and other energy devices has grown at a remarkable pace as technical developments continue to rapidly change the way dermatologists approach and treat cutaneous conditions. The armamentarium available to the practicing physician continues to expand as new developments and refinements produce impressive results, once considered unattainable. In the second edition of Lasers and Energy Devices for the Skin, renowned experts have pooled their knowledge to offer an up-to-date and exceptionally comprehensive reference for this exciting field. Organization The book is organized into 17 chapters, covering a broad range of topics from laser treatment of vascular lesions, benign pigmented lesions, leg telangiectasias, and scars to the removal of tattoos and hair. Principles of laser-tissue interactions are discussed in great detail, offering both new practitioners and seasoned dermatologists the fundamentals needed to use these devices while obtaining minimal adverse effects. Specific chapters are dedicated to ablative lasers, ablative fractional lasers, and nonablative fractional lasers. In addition, the book discusses important aspects surrounding the use of laser devices, including pain management, safety standards, and medicolegal issues that are essential to any practicing physician. An entire chapter is devoted to the burgeoning field of noninvasive body contouring. The science behind cryolipolysis, nonthermal focused ultrasound, thermal focused ultrasound, low-level laser therapy, infrared lasers, and radiofrequency is explored and the latest studies supporting their efficacy are described. Practical pictures of the actual devices are provided as well. Observations A particular highlight of the book is the chapter on the specific use of lasers on Asian skin. Ranging from Fitzpat-

rick skin types III to V, Asian skin is well-known to have a high risk of pigmentary alterations and scarring following laser procedures. This chapter first describes the basic differences of pigmented skin. It then proceeds to discuss how the different lasers—vascular-specific lasers, pigmentspecific lasers, ablative and nonablative laser systems, and hair removal lasers—should be used in higher Fitzpatrick skin types. Potential complications to be wary of are thoroughly discussed and measures needed to prevent such consequences are provided. Recommendations Additional highlights include the large number of high-resolution before and after photos with laser parameters, which provide readers with a good sense of the results that can be achieved with appropriate applications of these devices. The tables within each chapter succinctly summarize important content in an easy-toview manner. Sections within the book also contain highlighted case scenarios, featuring actual patient encounters. Finally, the evidence of clinical studies is consistently summarized throughout the chapters to provide the reader with a current understanding of the published literature. This book is a must-have for any practitioner hoping to attain a strong and thorough understanding of how to best treat patients with lasers and other energy devices. With a growing population interested in such procedures, physicians must continually keep abreast of these novel concepts and innovation devices. This book offers it all. It provides the necessary combination of historical, scientific, and practical knowledge needed for physicians to understand and use these devices effectively. Most importantly, it provides insight from experts in the field accumulated from years of experience; these pearls are invaluable to this book.

Reviewed by Krystle Wang, MD, Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University 840 Chestnut Street, Philadelphia, PA 19107 • E-mail: krysjeff@gmail.com

SKINmed. 2014;12:132

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IMPORTANT INFORMATION ABOUT ®

Mirvaso

(Brimonidine) Topical Gel, 0.33%* *Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base BRIEF SUMMARY This summary contains important information about MIRVASO (Mer-VAY-Soe) Gel. It is not meant to take the place of the full Prescribing Information. Read this information carefully before you prescribe MIRVASO Gel. For full Prescribing Information and Patient Information please see package insert. WHAT IS MIRVASO GEL? MIRVASO (brimonidine) Topical Gel, 0.33% is a prescription medicine that is used on the skin (topical) to treat facial redness due to rosacea that does not go away (persistent). WHO IS MIRVASO GEL FOR? MIRVASO Gel is for use in adults ages 18 years and older. WHAT WARNINGS AND PRECAUTIONS SHOULD I BE AWARE OF? MIRVASO Gel should be used with caution in patients that: • • • • • • • • •

have depression have heart or blood vessel problems have dizziness or blood pressure problems have problems with blood circulation or have had a stroke have dry mouth or Sjögren’s Syndrome have skin tightening or Scleroderma have Raynaud’s phenomenon have irritated skin or open sores are pregnant or plan to become pregnant. It is not known if MIRVASO Gel will harm an unborn baby. • are breastfeeding. It is not known if MIRVASO Gel passes into breast milk. You and your female patient should decide if she will use MIRVASO Gel or breastfeed. She should not do both. Ask your patient about all the medicines they take, including prescription and over-the-counter medicines, skin products, vitamins and herbal supplements. Using MIRVASO Gel with certain other medicines may affect each other and can cause serious side effects. Keep MIRVASO Gel out of the reach of children. If anyone, especially a child, accidentally swallows MIRVASO Gel, they may have serious side effects and need to be treated in a hospital. Get medical help right away if you, your patient, a child, or anyone else swallows MIRVASO Gel and has any of these symptoms:

MIRVASO Gel can lower blood pressure in people with certain heart or blood vessel problems. See “What warnings and precautions should I be aware of?” These are not all of the possible side effects of MIRVASO Gel. Remind your patients to call you for medical advice about side effects. You are also encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. HOW SHOULD MIRVASO GEL BE APPLIED? • Remind your patients to use MIRVASO Gel exactly as you instruct them. They should not use more MIRVASO Gel than prescribed. • Patients should not apply MIRVASO Gel to irritated skin or open wounds. • Important: MIRVASO Gel is for use on the face only. Patients should not use MIRVASO Gel in their eyes, mouth, or vagina. They should also avoid contact with the lips and eyes. • Instruct your patients to see the detailed Instructions for Use that come with MIRVASO Gel for information about how to apply MIRVASO Gel correctly. GENERAL INFORMATION ABOUT THE SAFE AND EFFECTIVE USE OF MIRVASO GEL Remind your patients not to use MIRVASO Gel for a condition for which it was not prescribed and to not give MIRVASO Gel to other people, even if they have the same symptoms. It may harm them. WHAT ARE THE INGREDIENTS IN MIRVASO GEL? Active Ingredient: brimonidine tartrate Inactive Ingredients: carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, purified water, sodium hydroxide, titanium dioxide. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT MIRVASO GEL? • Go to www.mirvaso.com or call 1-866-735-4137 GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177 USA Revised: August, 2013 HCP

• Lack of energy, trouble breathing or stops breathing, a slow heart beat, confusion, sweating, restlessness, muscle spasms or twitching. WHAT ARE THE POSSIBLE SIDE EFFECTS OF MIRVASO GEL? The most common side effects of using MIRVASO Gel include: • redness, flushing, burning sensation of the skin, skin irritation Skin redness and flushing may happen about 3 to 4 hours after applying MIRVASO Gel. Ask your patients to tell you if they get skin redness and flushing that is uncomfortable. Mirvaso and Galderma are registered trademarks. ©2013 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 MIR-164B Printed in USA 08/13 Mirvaso Brief Summary HCP R3.indd 1

References: 1. Fowler J Jr, Jackson JM, Moore A, et al; Brimonidine Phase III Study Group. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656. 2. Mirvaso [package insert]. Galderma Laboratories, L.P. Fort Worth, TX; 2013.

9/4/13 11:51 AM

Help your patients with facial erythema of rosacea experience...

Not an actual patient. Individual results may vary. Results are simulated to show a 2-grade improvement of erythema. At hour 12 on day 29, 22% of subjects using Mirvaso Gel experienced a 2-grade improvement of erythema compared with 9% of subjects using the vehicle gel.*

RAPID AND SUSTAINED ERYTHEMA REDUCTION BROUGHT TO YOU BY ® M I R V A S O ( b r i m o n i d i n e ) T O P I C A L G E L , 0 . 3 3 %† • The first and only FDA-approved topical treatment specifically developed and indicated for the facial erythema of rosacea1 • Fast results that last up to 12 hours1 • The most commonly reported adverse events in controlled clinical studies included erythema (4%), flushing (2%), skin-burning sensation (2%), and contact dermatitis (1%)2 Important Safety Information Indication: Mirvaso® (brimonidine) topical gel, 0.33% is an alpha-2 adrenergic agonist indicated for the topical treatment of persistent (nontransient) facial erythema of rosacea in adults 18 years of age or older. Adverse Events: In clinical trials, the most common adverse reactions (≥1%) included erythema, flushing, skin-burning sensation, and contact dermatitis. Warnings/Precautions: Mirvaso Gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Alpha-2 adrenergic agents can lower blood pressure. Mirvaso Gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease. Serious adverse reactions following accidental ingestion of Mirvaso Gel by children have been reported. Keep Mirvaso Gel out of the reach of children. Not for oral, ophthalmic, or intravaginal use. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see brief summary of full Prescribing Information on the following page.

See for yourself. Visit www.mirvaso.com/hcp. *Phase 3 clinical studies of 553 subjects 18 and older. Subjects were randomized 1:1 to either Mirvaso Gel or vehicle for 29 days. Subjects and clinicians were asked to grade the improvement they saw at 30 minutes and hours 3, 6, 9, and 12 following application. † Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base.