Sep / Oct, 2014

September/October 2014 • Volume 12 • Issue 5 EDITORIAL Steatocystoma Multiplex: Those Little Tumours de Moll, Lambert, and Parish

case studies Condyloma Acuminata and Mollusca Contagiosa: A Giant Manifestation in a Patient With Lupus Persechino, Abruzzese, Caperchi, Persechino, and Antonella

COMMENTARY Silas Weir Mitchell (1829–1914) Welcome to Dermatology Toodayan

ORIGINAL CONTRIBUTIONS Patient Satisfaction Following the Use of a Hair Fiber Filler Product to Temporarily Increase the Thickness and Fullness of Thinning Hair Pinski

Comparing the Efficacy of Oral Ivermectin vs Malathion 0.5% Lotion for the Treatment of Scabies Goldust, Rezaee, Raghifar, and Hemayat

CORE CURRICULUM Mohs Micrographic Surgery: History, Technique, and Advancements Patel, Patel, Franca, Chacon, and Nouri

DEPARTMENTS NEW TO THE CLINIC Omalizumab (Xolair) for the Treatment of Chronic Idiopathic Urticaria

A Turkish Patient With Hermansky-Pudlak Syndrome Akoglu, Emre, Metin, Kurtoglu, and Onursever

CORRESPONDENCE A Scarring Reaction to the Treatment of Basal Cell Carcinoma With Ingenol Mebutate Nguyen, Tremaine, and Zachary

The Washington Erythrodermics Abramovits

Bilateral Yellow Plaques on Eyelids Treated

by FDA-Approved Novel RF Pixel Technology for Skin Resurfacing Oberoi and Dharankar

BOOK REVIEW Ackerman’s Dictionary of Dermatohistology and Dermatohistopathology Collected by Charles Steffen, M.D. Petronic-Rosic

Scheinfeld

THE HEYMANN FILE Congenital Erosive and Vesicular Dermatosis With Reticulated Supple Scarring: Expanding the Database of an Enigma Heymann

COSMETIC SCIENCE A Second Look at Vitamin D

Lebanese Dermatological Society

Epstein

PHOTO CAPSULE Acquired/Post-Traumatic Ectopic Nail: Onychoheterotopia Sehgal, Chatterjee, Chaudhuri, and Chatterjee

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

TABLE OF CONTENTS September/October 2014 • Volume 12 • Issue 5

EDITORIAL

Steatocystoma Multiplex: Those Little Tumours ........................................................................................ 267

Ellen H. de Moll, BA; W. Clark Lambert, MD, PhD; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARY

Silas Weir Mitchell (1829–1914) Welcome to Dermatology........................................................................ 271

Nadeem Toodayan, MBBS

ORIGINAL CONTRIBUTIONS

Patient Satisfaction Following the Use of a Hair Fiber Filler Product to Temporarily Increase the Thickness and Fullness of Thinning Hair ........................................................................................... 278

Kevin S. Pinski, MD

Comparing the Efficacy of Oral Ivermectin vs Malathion 0.5% Lotion for the Treatment of Scabies............ 284

Mohamad Goldust, MD; Elham Rezaee, MD; Ramin Raghifar, MD; Sevil Hemayat, MD

CORE CURRICULUM

Virendra N. Sehgal, MD, Section Editor

Mohs Micrographic Surgery: History, Technique, and Advancements.......................................................... 289

Tulsie Narendra Patel, BS; Shailee Bipin Patel, BS; Katlein Franca, MD, MSc; Anna Haydee Chacon, MD; Keyvan Nouri, MD

Departments New to the Clinic

Noah Scheinfeld, MD, JD, Section Editor

Omalizumab (Xolair) for the Treatment of Chronic Idiopathic Urticaria ..................................................... 294

Noah Scheinfeld, MD, JD

The Heymann File

Warren R. Heymann, MD, Section Editor

Congenital Erosive and Vesicular Dermatosis With Reticulated Supple Scarring: Expanding the Database of an Enigma....................................................................................................... 299

Warren R. Heymann, MD

Cosmetic Science

Howard A. Epstein, PhD, Section Editor

A Second Look at Vitamin D....................................................................................................................... 302

Howard A. Epstein, PhD

Photo Capsule

Acquired/Post-Traumatic Ectopic Nail: Onychoheterotopia........................................................................ 306

Virendra N. Sehgal, MD; Kingshuk Chatterjee, DNB; Anita Chaudhuri, MD; Gautam Chatterjee, MS

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Condyloma Acuminata and Mollusca Contagiosa: A Giant Manifestation in a Patient With Lupus............... 310

Severino Persechino, MD; Claudia Abruzzese, MD; Cristiano Caperchi, MD; Flavia Persechino, MD; Tammaro Antonella, MD

262

TABLE OF CONTENTS September/October 2014 • Volume 12 • Issue 5

A Turkish Patient With Hermansky-Pudlak Syndrome................................................................................. 313

Gulsen Akoglu, MD; Selma Emre, MD; Ahmet Metin, MD; Gozde Kurtoglu, MD; Nihal Maslak Onursever, MD

CORRESPONDENCE

A Scarring Reaction to the Treatment of Basal Cell Carcinoma With Ingenol Mebutate.............................. 317

Nhan M. Nguyen, MD; Anne Marie Tremaine, MD; Christopher B. Zachary, MBBS

The Washington Erythrodermics................................................................................................................. 318

William Abramovits, MD

Bilateral Yellow Plaques on Eyelids Treated by FDA-Approved Novel RF Pixel Technology for Skin Resurfacing........................................................................................................................................ 319

Geeta Oberoi, DPD; Archana Dharankar, DNB

Book Review

Jennifer L. Parish, MD, Section Editor

Ackerman’s Dictionary of Dermatohistology and Dermatohistopathology Collected by Charles Steffen, M.D.............................................................................................................. 322

Vesna Petronic-Rosic, MD, MSc

Editorial

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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:7�

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 ≼12 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)

September/October 2014

Volume 12 • Issue 5

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ Vesna Petronic-Rosic, MD, MSc

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

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Riccarda Serri, MD Milan, Italy

Robert L. Baran, MD Cannes, France

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

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

George F. Murphy, MD Boston, MA

Robert J. Thomsen, MD Los Alamos, NM

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

Julian Trevino, MD Dayton, OH

Anthony V. Benedetto, DO Philadelphia, PA Walter H.C. Burgdorf, MD Tutzing, Germany Brian Berman, MD, PhD Miami, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel I. Cohen, MD Engelwood, CO Noah Craft, MD, PhD, DTMH Torrance, CA Natalie M. Curcio, MD, MPH Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Boni E. Elewski, MD Birmingham, AL Charles N. Ellis, MD Ann Arbor, MI

Anthony A. Gaspari, MD Baltimore, MD Michael Geiges, MD Zurich, Switzerland Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria

Joseph L. Pace, MD, FRCP Naxxar, Malta

Daniel Wallach, MD Paris, France

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

Art Papier, MD Rochester, NY

Michael A. Waugh, MB, FRCP Leeds, UK

Johannes Ring, MD, DPhil Munich, Germany

Wm. Philip Werschler, MD Spokane, WA

María Daniela Hermida, MD Buenos Aires, Argentina

Roy S. Rogers III, MD Rochester, MN

Joseph A. Witkowski, MD Philadelphia, PA

Warren R. Heymann, MD Camden, NJ

Donald Rudikoff, MD New York, NY

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Robert I. Rudolph, MD Wyomissing, PA

Ronni Wolf, MD Rechovot, Israel

Camila K. Janniger, MD Englewood, NJ

Vincenzo Ruocco, MD Naples, Italy

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

Andrew P. Lazar, MD Washington, DC

Virendra N. Sehgal, MD Delhi, India

266

Matthew J. Zirwas, MD Columbus, Ohio

September/October 2014

Volume 12 • Issue 5

Editorial

Steatocystoma Multiplex: Those Little Tumours Ellen H. de Moll, BA;1 W. Clark Lambert, MD, PhD;2 Lawrence Charles Parish, MD, MD (Hon)3

H

ardly a clinician in the 21st century would have difficulty in identifying steatocystoma multiplex (SM).

The characteristic asymptomatic yellow or skin-colored dermal papules, typically found on the trunk, upper aspects of the arms, scrotum, or chest (Figure 1), are difficult to miss, particularly when a young woman is concerned about her appearance with a low-cut blouse (Figure 2) or when a young man thinks his acne has gone astray.

Developing a Concept

The first descriptions of these “innumerable number of prominent little tumours” that vary in size from “a millet-seed to a large pea” were made by James Pringle (1855–1922), better known for having delineated the adenoma sebaceum of tuberous sclerosis.1 In 1899, he presented to the Dermatological Society of London the case of a 21-year-old man with asymptomatic “lumps” that had appeared over the previous 5 years.1 Puncture of one of these lesions revealed “abundant fluid like thin skimmilk.”1 James Galloway (1862–1922) performed the histopathologic examination on a biopsy specimen taken from this patient and decided that the lesions were caused by “hypertrophy of the sebaceous gland, liquefaction of its contents, and retention of its secretion.”1 In 1898, Pier Lodovico Bosellini (1873–1945), then in Bologna, described a 40-year-old man who was experiencing asymptomatic “multiple follicular cutaneous cysts” for 8 years.2 He concluded that it was a retention cyst caused by keratin plugging of the sebaceous glands. In Germany in 1917, Hans Günther (1884–1956), who would later distinguish himself with his work on porphyrins, analyzed the biopsy specimen of a similar patient, and suggested the term sebocystomatosis, implying the pathologic process to be analogous to lipomatosis.

Figure 1. Steatocystoma multiplex. Multiple lesions on the trunk of a young man.

Figure 2. Steatocystoma multiplex. Lesions on the breasts of a young woman.

From the University of Connecticut School of Medicine, Farmington, CT;1 the Department of Dermatology, New Jersey Medical School, Rutgers University, Newark, NJ;2 and the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA3 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1845 Walnut Street, Suite 1650, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

SKINmed. 2014;12:267–269

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© 2014 Pulse Marketing & Communications, LLC

September/October 2014

Editorial the surface. The sebum was produced and dilated the lower part of the hair follicle, the remnants of the sebaceous gland being squeezed to one side. In the end, when it reached a certain size—that of a pea—it ceased to function.”3 The term sebocystomatosis continued to be used through the 1950s, as shown by a paper in the British Journal of Dermatology and Syphilis, which described the papules as “gelatin capsules,” and defined sebocystomatosis as “a distinct clinical entity, characterized by the occurrence on various parts of the body of small cystic tumors involving the sebaceous apparatus without causing any change in the overlying skin.”4 An additional term used was hereditary epidermal polycystic disease.5 Current Concepts

Figure 3. Steatocystoma multiplex. Photomicrograph showing diagnostic feature of sebaceous gland tissue within the epithelium of a cyst. Steatocystoma simplex shows similar histology. Hematoxylin and eosin stain, original magnification ×710.

Today, SM is recognized as a benign nevoid malformation of the pilosebaceous apparatus that shows a mixture of keratinizing epithelium and sebaceous lobules attached to the epidermis by a thin epidermal strand.6 A subtype of SM, known as steatocystoma multiplex suppurativa (SMS), presents with inflamed lesions that can rupture and scar.6 On histology, SM appears as epithelial-lined sebum-filled dermal cysts, approximately 3 to 10 millimeters, with sebaceous glands present in the cyst wall (Figure 3). On the luminal side of the cyst wall is an eosinophilic cuticle with keratin, oil, and hairs in the lumen.7 A single lesion may also occur; this entity is designated “steatocystoma simplex (SS)”. In either SM or SS, the sebaceous gland tissue may be prominent or quite subtle (Figure 4).

Figure 4. Steatocystoma multiplex. Photomicrograph showing diagnostic features of sebaceous gland tissue within the epithelium of a cyst. Only a tiny fragment of sebaceous gland tissue is seen. Steatocystoma simplex may show similar histology. Hematoxylin and eosin stain, original magnification ×710.

In 1933, Isaac Muende (1901–1987) and Archibald Cathcart Roxburgh (1886–1954) in London claimed that Pringle’s nomenclature had priority to Günther’s. Their description of SM is quite detailed: “It was an affection of the hair follicle, just above the entrance of the gland, which prevented sebum from reaching SKINmed. 2014;12:267–269

SM can occur sporadically in an autosomal dominant pattern or as part of a syndrome, including Alagille syndrome (autosomal dominant microdeletion of the JAG1 gene on chromosome 20p causing gastrointestinal, cardiovascular, and facial defects).7,8 SM has also been observed in association with pachyonychia congenita type II.6 Mutations of the keratin 17 gene have been reported in familial cases of SM, although the exact origin of the spontaneous form is not fully understood. The burden of disease can vary from a handful of small cysts to more extensive disease with larger cysts. Cysts typically appear during adolescence and early adulthood, indicating a potential link to hormonal effect, and persist throughout adulthood. The classic differential diagnosis includes epidermal inclusion cysts, milia, trichilemmal cysts, and eruptive vellus hair cysts.

Although earlier concepts placed the disease as predominantly afflicting men of Northern European descent between the ages of 19 and 28,4 current thought has no sex distinction or national preference. Today, the disease is recognized as having a roughly equal sex distribution, with an average age of onset of 26 years.9

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Editorial

Treatment of SM remains unsatisfactory, with cryosurgery, aspiration, excision, incision, and laser surgery each having its proponents. Oral retinoids and tetracycline have been tried with minimal success. Similarly, intralesional steroids have some advocates.7 Conclusions What may seem merely a nuisance to some is quite bothersome to others. While SM is easily recognized, treatment options are not rewarding. The question remains: How can we rid our patients of “these gelatinous capsules?”

References 1 Pringle JJ. A case of peculiar multiple sebaceous cysts (steatocystoma multiplex). Br J Dermatol. 1899;11:381– 388.

2 Bosellini PL. Beitrag zur Lehre von den multiplen follucularen Hautcysten. Arch Dermatol Syph. 1889;45:81–96.

3 Roxburgh AC, Muende I. Sebocystomatosis in a woman aged 22. Proc R Soc Med. 1933;26:839–840.

4 Anderson DS. Sebocystomatosis. Br J Dermatol Syph.

1950;62:215–221.

5 Randazzo SD, Giardina A. [Contribution to the study of hereditary epidermal polycystic disease. On a Heredofamilial case with lesions of hyperplastic development.]

Minerva Dermatol. 1964;39:235–245.

6 Layton AM. Disorders of the sebaceous blands. Rook’s Textbook of Dermatology. Oxford, England: Wiley-Blackwell; 2010:88–89.

7 Thomas V, Snavely NR, Lee KK, Swanson NA. Benign epithelial tumors, hamartomas, and hyperplasias. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012.

8 Crawford JM, Liu C. Liver and biliary tract. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Saunders Elsevier; 2010:870.

9 Cho S, Chang SE, Choi JH, et al. Clinical and histologic features of 64 cases of steatocystoma multiplex. J Dermatol. 2002;29:152–156.

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September/October 2014

Volume 12 • Issue 5

COMMENTARY

Silas Weir Mitchell (1829–1914) Welcome to Dermatology Nadeem Toodayan, MBBS

I

n the history of the medical arts, no canvas has laid itself so widely open for personal impression as has the human skin.

Its capacity to capture generations of practitioners is made peculiarly evident by the sheer number and variety of eponymous associations it harbours, and through these disease states, signs, and syndromes, many modern dermatologists have become acquainted with important figures in medical history. One such figure, who remains to be readily linked to modern dermatology, is the great 19th century American physician, physiologist, neurologist, and novelist, Silas Weir Mitchell (1829–1914).

Otherwise a well-known Philadelphian, Mitchell’s contributions to skin disease are relatively obscure, and it is the purpose of this commentary to bring to light—in this centenary year of his passing—three eponymous dermatologic conditions relating to the man.

Mitchell’s Disease

Mitchell’s disease—more widely known as erythromelalgia—is a rare neurovascular pain disorder of the extremities that has prominent cutaneous features (Figure 1a). Most evident during attacks, the skin overlying the affected area becomes hot and suffused with blood. This is followed by a marked reddening of the affected part—usually the feet or hands—which later darkens into a dusky color before settling. Patients with the condition experience burning pain with swelling and tenderness of the tissues involved. Characteristically, warm conditions bring on the episodes, which are alleviated with cooling. Pendency and mild exercise also bring on attacks, whereas elevation and rest bring relief. The disease is often classified into primary (idiopathic/familial) and secondary forms. In the latter group, it is important to exclude thrombocythemic erythromelalgia, which is amenable to aspirin therapy. The exact pathophysiology of Mitchell’s disease remains unknown.

Silas Weir Mitchell first lectured on the condition in 1872.1 As would later become apparent to Mitchell himself, some of his original patients in fact had what we would now call plantar fasciitis. In 1878, Mitchell authored his famous essay2 on the disease in which he introduced the term erythromelagia—roughly meaning red painful member—and vividly set the diagnostic criteria for the condition (Figure 1b). Owing in no small part to his brilliant observatory powers, Mitchell’s thorough account made the disease more recognizable and therefore more diagnosable.

In 1893, he differentiated the condition from Raynaud’s disease and suggested that it might be an expression of terminal neuritis.3 Mitchell’s last paper on erythromelalgia was co-authored in 1899, at which time he presented pathologic findings.4 A more detailed historic synopsis of Mitchell’s disease is given in Silas Weir Mitchell: The Man and His Malady5—a small book that was written in anticipation of the Mitchell centenary.

Weir-Mitchell’s Skin We can hardly hope for a more obvious dermatologic association. Although rarely used nowadays, this eponym refers to the specific skin changes that occur in causalgia, a disease state that Mitchell was first to describe, name, and manage through his experience with gunshot wounds in the American Civil War. The skin changes, which are best described as red, glossy, and perspiring (Figure 2a), commonly affect limbs with partial nerve injury and occur secondary to underlying vasomotor changes. Burning pain, swelling of the affected limb, and hypersensitivity to touch are other well-known features of causalgia, a condition that is better known today by the more modern name of complex regional pain syndrome (CRPS) type II. Other less well-recognized skin changes known to occur in CRPS include xerosis, abnormal nail growth, ulcerating erythematous papules, and reticulate hyperpigmentation.6

From the University of Queensland School of Medicine, Southern Clinical School, Brisbane, Australia Address for Correspondence: Nadeem Toodayan, MBBS, 87 Sunflower Cr. Calamvale, Brisbane, QLD, Australia 4116 • E-mail: nadeem_toodayan@hotmail.co.uk

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Figure 1. (a) Mitchell’s disease affecting the foot. (Courtesy of The Erythromelalgia Association.) (b) The first page of Mitchell’s classic 1878 essay on the disease. (From The American Journal of the Medical Sciences.)

Figure 2. (a) The atrophic and red, “glossy,” perspiring skin of Weir-Mitchell here seen in a case of complex regional pain syndrome affecting the neck. (Courtesy of the International Research Foundation for RSD/CRPS Inc.) (b) Mitchell’s classic 1864 text described many cases of “burning pain” following partial nerve injury. Detailed dermatologic observations are recorded in chapter VI. (From the National Library of Medicine.)

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Mitchell’s experience with causalgia was primarily drawn from his work at Turner’s Lane Hospital,* where neurologic cases were concentrated during the American Civil War. In companionship with Morehouse and Keen, and after several months of painstaking clinical observations, Mitchell produced his classic 1864 neurologic text Gunshot Wounds and Other Injuries of Nerves (Figure 2b). Chapter VI of this work is dedicated to the effects of nerve wounds on the Nutrition of the Skin and its Appendages and includes superbly well-recorded examinations of the integumentary system. Critically, Mitchell was sure to realize “the connection of burning pain with glossy skin”7 and first definitively linked the changes to partial peripheral nerve injury. He introduced the term causalgia in 1867.8 The Weir-Mitchell Phenotype of Acquired Partial Lipodystrophy There is certainly no shortage of grandiloquence in the dermatologic nosology and the Weir-Mitchell phenotype of acquired partial lipodystrophy (APL) is just another one of those won-

derful orotundities. APL—also known as Barraquer-Simons syndrome—is a condition characterized by selective atrophy of body fat stores in a cephalothoracic distribution. Typically, the condition is more often seen in women and presents after a febrile illness. Facial changes are characteristic, with paucity of the buccal and periorbital fat giving prominence to the zygomas and chin, as well as something of a “haggard appearance” to the face (Figure 3a). The neck, upper limbs, and thorax are further involved, whereas the abdomen and lower limbs are usually spared. In some cases, especially in women, there is concomitant hypertrophy of fat stores in the lower body, and this is known as the Laignel-Lavastine phenotype.9 The Weir-Mitchell phenotype is the more common and refers to acquired cephalothoracic lipodystrophy without these lower body changes. The pathophysiology of lipodystrophy is complex and poorly understood but the clinical differentiation between different subtypes is important because a number of known associations have come to be recognized. APL, for instance, is particularly associated with membranoproliferative

Figure 3. (a) A patient exhibiting the characteristic facial features of APL. (Courtesy of Dr. Kenneth Greer.) (b) Mitchell’s original paper on APL. (From The American Journal of The Medical Sciences.)

*Turner’s Lane Hospital stood about half a mile north from Girard College—close to modern-day Turner Street. This location is given by Hermann Bokum (1807–1878) on page 63 of his interesting contemporary account of the hospital in Philadelphia: Wanderings North and South (1864). Bokum had been chaplain to the hospital.

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glomerulonephritis, which has been linked to high levels of circulating C3 nephritic factor.10 The prime significance of this eponymous designation rests not so much in matters of clinical distinction as it does in priority.

This is because Weir Mitchell was the first to report on APL when he presented “a singular case of absence of adipose matter in the upper half of the body”11 during a meeting of the Philadelphia Neurological Society on Monday, March 23, 1885 (Figure 3b).

His patient was a 12-year-old school girl who had experienced a peculiar emaciating process in the months following a prolonged flu-like illness. The account is short but characteristically brilliant and should be read by every dermatologist seriously interested in this rare but fascinating condition.

The Man Silas Weir Mitchell (Figure 4) was a man of many talents. He exerted a profound influence on the customs and cultures of his time and so impressed the medical world that his name continues to be spoken of highly a hundred years after his death.12 At different stages in his long life, Mitchell found himself foremost amongst American physiologists, neurologists, and later novelists (Figure 5). His rising prominence had him presiding over several of the country’s leading medical societies and he became nationally renowned for his literary works and sometimes for his poetry.

Today, Mitchell is often remembered in the medical profession for instituting the “rest cure” for states of nervous exhaustion—the Weir-Mitchell treatment. Although an obsolete form of medical therapy, the treatment has a long, controversial, and interesting history that continues to be studied to this very day.

Perhaps the most agreeable feature of Mitchell’s long and distinguished career was his tireless dedication to work. It was precisely this aspect of his that had him making important advances in physiology at a relatively young age, and so when he entered the army medical department with the rise of the American Civil War in 1861, he was already well trained in the art of making accurate observations. Mitchell’s wartime work drew him to the study of the human nervous system, and, given that he was later crowned the Father of American Neurology, we may begin to appreciate the value of his contributions during this period.

Having been born into a family of noteworthy physicians, Mitchell was on intimate terms with the medical fraternity, and, as a respected trustee at the University of Pennsylvania, he was instrumental in bringing William Osler (1849–1919) to the medical chair in October of 1884. He was highly regarded abroad and lauded by men of such respectable stature as Sir James Paget (1814–1899) and Jean Martin Charcot (1825–1893).

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Figure 4. Silas Weir Mitchell (1829–1914)—A Philadelphian Great, c.1900. (Courtesy of the University of Pennsylvania Archives.)

Later in life, Mitchell revived his childhood love of literature and authored a number of American best sellers. His success as a novelist only added to his prominence as a physician, and, by the end of his life, he was revered by both medical professionals and laymen alike. Mitchell died from influenza in the early hours of Sunday, January 4, 1914. He was a few weeks shy of his 85th birthday and had been seeing patients only a week before falling ill.

To fully contemplate a life as long and diverse as Mitchell’s we need only turn the pages of any one of his six, full-length biographies. He excelled not only as a physician but also as a celebrated writer of fiction, and through both these avenues brought hope and happiness to countless numbers of lives. In this centenary year of his passing, he is sincerely remembered for his work and devotion, and with so irresistible a legacy at hand, we proudly induct him into dermatologic echelons.

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Figure 5. In 1902, Mitchell helped to found and became inaugural president to The Franklin Inn Club—a high-profile literary society that was established to entertain Philadelphia’s leading intellectuals. The club had once erected this plaque in Mitchell’s memory on the sight of his former residence at 1524 Walnut Street, where it can still be seen today. (Photo

by Lawrence Charles Parish, MD, MD (Hon), May 2014.)

References 1 Mitchell SW. Clinical lecture on certain painful affections of the feet.” Philadelphia Med Times. 1872;3:81–82, 113–115.

2 Mitchell SW. On a rare vasomotor neurosis of the extremities, and on the maladies with which it may be confounded. Am J Med Sci. 1878;76:2–36.

3 Mitchell SW. Erythromelalgia: red neuralgia of the extremities; vasomotor paralysis of the extremities; terminal neuritis (?). Med News. 1893;63:197–202.

7 Mitchell SW, Morehouse GR, Keen WW. Gunshot Wounds and Other Injuries of Nerves. Philadelphia, PA: J. B. Lippincott and Co; 1864: 88.

8 Mitchell SW. On the Diseases of nerves, resulting from injuries. In: Flint A, ed. Contributions Relating to the Causation and Prevention of Disease, and to Camp Diseases.

Chapter 12. New York, NY: Hurd and Houghton; 1867: 439.

4 Mitchell SW, Spiller WG. A case of erythromelalgia, with microscopical examination of the tissue from an amputated toe. Am J Med Sci. 1899;117:1–13.

9 Weedon DD. Partial lipodystrophy: In: Weedons Skin Pathology. Third Edition. Section 4, Chapter 17. Lipodystrophy Syndromes. China: Elsevier; 2010: 470.

5 Toodayan N. (March 2013) Silas Weir Mitchell: The Man and His Malady. L.O.B. Publishing: Brisbane (ISBN 9780992467807). This work has been the primary basis for this contribution. All references for the biographical section of this contribution are to be found in this book.

If needed, please contact author for a copy.

10 Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350:1220–1234.

6 Webster GF, Schwartzman RJ, Jacoby RA, Knobler RL, Uitto JJ. Reflex sympathetic dystrophy, occurrence of inflammatory skin lesions in patients with stages II and III disease. Arch Dermatol. 1991;127:1541–1544.

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11 Mitchell SW. Singular case of absence of adipose matter in the upper half of the body. Am J Med Sci. 1885;90:105–106.

12 Kline DG. In Memoriam: A Centenary Tribute to Silas Weir Mitchell. World Neurology. 2014;29:12– 13.

Silas Weir Mitchell (1829–1914)

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September/October 2014

Volume 12 • Issue 5

Original contribution

Patient Satisfaction Following the Use of a Hair Fiber Filler Product to Temporarily Increase the Thickness and Fullness of Thinning Hair Kevin S. Pinski, MD Abstract Hair loss can have a negative effect on self-image and self-esteem for both men and women. The results of a recent randomized, placebocontrolled, double-blind study demonstrated the ability of a new oral dietary supplement to increase hair growth in women with thinning hair after 90 days. A companion hair fiber filler product has been designed to be applied to areas of thinning hair to provide the temporary appearance of fuller-looking hair until their own hair is replenished. Forty men and women from a dermatology and cosmetic surgery clinic were asked to use the product and afterward complete quality-of-life, self-assessment, and product satisfaction questionnaires. Mean quality-of-life and self-assessment results were favorable. Hair qualities showing the greatest improvement were scalp coverage and hair fullness. The product satisfaction questionnaire indicated a high level of satisfaction and most patients (35 [88%]) were pleased with the way the product matched their natural hair color. Based on the results reported here, use of the product is likely to increase the quality of life of men and women with thinning hair. (SKINmed. 2014;12:278–281)

H

air loss can have a devastating effect on self-image and self-esteem for both men and women. Hair loss is associated with diminished quality of life in men,1 although the psychological impact of hair loss may be more severe for women.2,3 A proprietary oral compound consisting of proteins and glycosaminoglycans of marine origin has been developed to treat hair loss (Viviscal Hair Nourishment System; Lifes2good, Inc, Chicago, IL) and a recent randomized, placebocontrolled, double-blind study demonstrated the ability of this product to increase hair growth in women with thinning hair after 90 days.4 A companion hair fiber filler product has been developed for consumers undergoing treatment with Viviscal Hair Supplement. The product is designed to be applied to areas of thinning hair and temporarily provide the appearance of fuller, thickerlooking hair until they see results from the dietary supplement product. A series of questionnaires were developed to determine the degree of user satisfaction following the application of the hair fiber filler product to temporarily increase the fullness and thickness of thinning hair and to assess the effects of thinning hair on quality of life.

Methods Participants were recruited from among patients treated at a dermatology and cosmetic surgery clinic. Each patient completed a pretreatment quality-of-life questionnaire prior to applying the hair filler fiber product to their hair under the supervision of the clinic staff. To match hair color as closely as possible, the hair fiber filler was available in black, brown, blonde, auburn, and grey colors (Viviscal Hair Filler Fibers; Lifes2good, Inc, Chicago, IL). Pretreatment and post-treatment photos were obtained and patients completed post-treatment satisfaction questionnaires. Each enrolled patient received a modest stipend and free product sample for participating.

Results The study patients included 20 men and 20 women. The pretreatment quality-of-life questionnaire showed that thinning hair had the greatest impact on being embarrassed, feeling unattractive, and having a negative effect on self-esteem (Table I). Following the application of the hair fiber filler, mean scores on the selfassessment questionnaire were all very favorable (Table II). Hair qualities showing the greatest improvement were scalp coverage and hair fullness while the area showing the least improved change

From Pinski Dermatology and Cosmetic Surgery, Chicago, IL Address for Correspondence: Kevin S. Pinski, MD, Pinski Dermatology and Cosmetic Surgery, 150 North Michigan Avenue, Suite 1200, Chicago, IL 60601 • E-mail: bquaranto@pinskiderm.com

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Table I. Quality-of-Life Questionnaire Please complete the following questions by circling the number in the column that best describes your opinion for each characteristic from 0 (not relevant) to 4 (very much): Mean

Median (Minimum, Maximum)

1. I am embarrassed by my thinning hair.

2.6

2 (1, 4)

2. I avoid social gatherings because of my thinning hair.*

1.3

1 (0, 4)

3. I don’t like meeting new people as I feel they are judging me because of my thinning hair.

1.5

1 (1, 4)

4. I avoid going out during the day because of my thinning hair.

1.3

1 (0, 4)

5. My condition negatively impacts my emotional state at work.

1.5

1 (0, 4)

6. I feel my thinning hair has negatively impacted my ability to succeed in interviews.

1.2

1 (0, 4)

7. My condition has prevented my participation in a sports activity.*

1.1

1 (0, 4)

8. My condition has a negative impact on my self-esteem.

2.2

2 (1, 4)

9. My thinning hair has a negative effect on my sex life.

1.3

1 (0, 4)

10. I fear being the center of attention because of my thinning hair.

1.7

1.5 (0, 4)

11. I feel my thinning hair has a negative effect on my personal relationships.

1.5

1 (0, 4)

12. I am less outgoing than I would like to be because of my thinning hair.

1.7

1.5 (0, 4)

13. I feel unattractive because of my thinning hair.

2.3

2 (1, 4)

*N=39.

Table II. Self-Assessment Questionnaire

Table III. Product Satisfaction

Please review each of the parameters below and check the most appropriate answer from 1 (greatly decreased) to 7 (greatly increased):

Please rank the following questions on a scale of 1 to 5 that matches your opinion for each characteristic with 5 being the highest:

Mean

Median (Minimum, Maximum)

Mean

Median (Minimum, Maximum)

1. Overall hair volume

5.7

6 (0, 7)

1. Was this product easy to use?

2. Scalp coverage

6.3

7 (2, 7)

4.6

5 (4, 5)

3. Thickness of hair body*

5.6

6 (0, 7)

2. Would you use it yourself?

4.4

5 (4, 5)

4. Softness of hair

4.7

4 (0, 7)

5. Hair quality*

5.2

5 (0, 7)

3. Would you recommend it to a friend?

4.4

5 (4, 5)

6. Hair fullness

6.0

6 (0, 7)

4. Overall product rating?

4.5

5 (4, 5)

7. Personal attractiveness

5.7

6 (1, 7)

8. Confidence*

5.7

6 (3, 7)

*N=39

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ORIGINAL CONTRIBUTION

was softness of hair. The results of the product satisfaction questionnaire indicate a high level of satisfaction (Table III). In response to multiple choice questions regarding their experience, approximately one half of patients required less than 20 seconds to apply the hair fiber filler and one half required more than 20 seconds (Table IV). Although patients wore their hair at various lengths ranging from tight to the head to past the shoulders and a range of hair colors, most patients (35 [88%]) were pleased with the way the product matched their hair color. The ability of the hair fiber product to effectively cover the scalp and match hair color is shown in Figures 1–3.

Patients were also provided an opportunity to respond to two open-ended questions regarding their experience after using the product. The first question inquired about possible lifestyle changes based on the results they achieved. Among the 38 respondents, 10 indicated that they would do nothing differently while 28 reported possible lifestyle changes such as the use of hats or new hairstyles. The second open-ended question asked about their overall feelings about their results. Among the 40 responses received, 3 indicated no change and the remaining 37 provided generally positive comments.

Conclusions A companion hair fiber filler product temporarily provides the appearance of fuller, thicker-looking hair in consumers using a

Table IV. Patient Experiences 1. How much time was required to apply the hair fiber product?

No. (%) a) 10 seconds

10 (25.0)

b) 20 seconds

11 (27.5)

c) 30 seconds

8 (20.0)

c) 1 minute +

11 (27.5)

2. What is the best description of the length of your hair? a) Tight to the head

18 (45.0)

b) Level with the chin

9 (22.5)

c) Level with shoulders

5 (12.5)

d) Past shoulders

7 (17.5)

3. What best describes your hair color? a) Black

8 (20.0)

b) Brown

21 (52.5)

c) Blonde

8 (20.0)

d) Auburn

1 (2.5)

e) Grey

3 (7.5)

4. Were you happy that the Viviscal Fibers matched your hair color effectively? a) Yes

35 (87.5)

b) No

5 (12.5)

Figure 1. Application of the hair fiber product to a woman with dark brown hair (before and after).

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Figure 2. Application of the hair fiber product to a woman with grey hair (before and after).

Figure 3. Application of the hair fiber product to a man with brown hair (before and after).

proprietary hair growth dietary supplement. Overall, consumer satisfaction of the product was high, noting increased scalp coverage and hair fullness and approval with the ability of the product to match hair color.

logical characteristics of women with androgenetic alopecia: a controlled study. Br J Dermatol. 1991;125:248– 252.

3 Reid EE, Haley AC, Borovicka JH, et al. Clinical sever-

Acknowledgment

ity does not reliably predict quality of life in women

Sponsored by Lifes2good, Inc, Chicago, IL. Dr Carl Hornfeldt assisted in the preparation of this manuscript.

with alopecia areata, telogen effluvium, or androgenic alopecia. J Am Acad Dermatol. 2012;66:e97– e102.

References 1 Han SH, Byun JW, Lee WS, et al. Quality of life assessment in male patients with androgenetic alopecia: result of a prospective, multicenter study. Ann Dermatol.

2012;24:311–318.

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2 van der Donk J, Passchier J, Knegt-Junk C, et al. Psycho-

281

4 Ablon G. A double-blind, placebo-controlled study evaluating the efficacy of an oral supplement in women with self-perceived thinning hair. J Clin Aesthet Dermatol.

2012;5:28–34.

The Use of a Hair Fiber Filler Product

collagenpin.com

September/October 2014

Volume 12 • Issue 5

Original contribution

Comparing the Efficacy of Oral Ivermectin vs Malathion 0.5% Lotion for the Treatment of Scabies Mohamad Goldust, MD;1 Elham Rezaee, MD;2 Ramin Raghifar, MD;1 Sevil Hemayat, MD3 Abstract Scabies is found worldwide among people of all groups and ages. It is curable with scabicide medications. This study aimed to compare the efficacy and safety of oral ivermectin vs malathion 0.5% lotion for the treatment of scabies. In total, 148 patients with scabies were enrolled and randomized into two groups: the first group received a single dose of oral ivermectin 200 µg/kg body weight, and the second was treated with two applications of topical lindane lotion 1%, with a 1-week interval between applications. Treatment was evaluated at intervals of 2 and 4 weeks, and if there was treatment failure at the 2-week follow-up, treatment was repeated. A single dose of ivermectin provided a cure rate of 60.8% at the 2-week follow-up, which increased to 89.1% at the 4-week follow-up after repeating the treatment. Treatment with two applications of lindane lotion 1%, with a 1-week interval between them, was effective in 47.2% of patients at the 2-week follow-up, which increased to 72.9% at the 4-week follow-up after this treatment was repeated.

A single dose of ivermectin was as effective as two applications of lindane lotion 1% at the 2-week follow-up. After repeat treatment, ivermectin was superior to lindane lotion 1% at the 4-week follow-up. The delay in clinical response with ivermectin suggests that it may not be effective against the parasite at all stages in the life cycle. (SKINmed. 2014;12:284–287)

S

cabies is a relatively contagious infection caused by a tiny mite (Sarcoptes scabiei). The mites that cause scabies burrow into the skin and deposit their eggs, forming a burrow that looks like a pencil mark.1,2 Eggs mature in 21 days. The itchy eruption is an allergic response to the mite. It can travel from an infected person to another person. Most people get scabies from direct, skin-to-skin contact. Less often, people pick up mites from infested items such as bedding, clothes, and furniture.3,4 The mite can survive for about 48 to 72 hours without human contact.

Worldwide, there are millions of cases of scabies each year. Anyone can get scabies. It strikes people of all ages, races, and income levels.5,6 People who are very clean and neat can get scabies. It tends to spread easily in nursing homes and extended-care facilities. The good news is that a dermatologist can successfully diagnose and treat scabies.7,8 With today’s treatments, scabies need only cause short-term distress. Other conditions are sometimes confused with scabies. The scabies mite has no relation to body lice, although the treatment of the resulting skin disease is sometimes the same.9,10 Scabies is also different from bedbug bites. In

contrast to scabies, bedbugs are visible to the naked eye and can live for long periods without feeding. Scabies may be diagnosed clinically in geographical areas where it is common when diffuse itching presents along with either lesions in two typical spots or there is itchiness of another household member.11,12 The classical sign of scabies is the burrows made by the mites within the skin. A definitive diagnosis is made by finding either the scabies mites or their eggs and fecal pellets. Searches for these signs involve either scraping a suspected area, mounting the sample in potassium hydroxide, and examining it under a microscope, or using dermoscopy to examine the skin directly.13,14 Products used to treat scabies are called scabicides because they kill scabies mites; some also kill mite eggs.15,16 Permethrin cream and malathion lotion are the two most widely used treatments for scabies. Malathion is an organophosphate parasympathomimetic, which binds irreversibly to cholinesterase. Malathion is an insecticide of relatively low human toxicity. Malathion is applied to the whole body and washed off after 24 hours.17,18

From the Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran;1 Medicinal Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran;2 and Thran Azad University of Medical Sciences, Tehran, Iran3 Address for Correspondence: Mohamad Goldust, Medical Student, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran • E-mail: Drmgoldust@yahoo.com

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ORIGINAL CONTRIBUTION

Oral ivermectin is an effective and cost-comparable alternative to topical agents in the treatment of scabies infection. It may be particularly useful in the treatment of severely crusted scabies lesions in immunocompromised patients or when topical therapy has failed.11,19 This study aimed to compare the efficacy of oral ivermectin vs malathion 0.5% lotion in the treatment of scabies.

The first group received a single dose of 200 µg/kg body weight oral ivermectin and the second group received topical malathion 0.5% lotion and were told to apply this twice at 1-week intervals. The treatment was given to both patients and their close family members, and they were asked not to use any antipruritic drug or any other topical medication.

Methods

Evaluation

This study was approved by the ethics committee of Tabriz University of Medical Sciences. Informed consent was obtained from the patients or their parents.

The clinical evaluation after treatment was made by experienced investigators who were blinded to the treatments received. Patients were assessed at 2 and 4 weeks after the first treatment. At each assessment, the investigators recorded the sites of lesions on body diagram sheets for each patient, and compared the lesions with those visible in the pretreatment photograph. New lesions were also scraped for microscopic evaluation. Patients were clinically examined and evaluated based on the previously defined criteria (see Patient recruitment). Cure was defined as the absence of new lesions and healing of all old lesions, regardless of presence of post-scabetic nodules. Treatment failure was defined as the presence of microscopically confirmed new lesions at the 2-week follow-up. In such cases, the treatment was repeated at the end of week 2 and patients were evaluated again at week 4. Reinfestation was defined as a cure at 2 weeks but development of new lesions with positive microscopic findings at 1 month. Any patients with signs of scabies (whether as a result of treatment failure or reinfestation) would then be treated with permethrin.

Patient recruitment This was a single-blind, randomized controlled trial. Between August 2009 and October 2012, any patients with scabies who were older than 2 years of age and attending the dermatology outpatient department of Sina Hospital, Tabriz University of Medical Sciences, were assessed for enrolment in the study.

Exclusion criteria were age younger than 2 years; pregnancy or lactation; history of seizures, severe systemic disorders, immunosuppressive disorders, or presence of crusted scabies; and use of any topical or systemic acaricide treatment for 1 month prior to the study.

Before entry into the study, patients were given a physical examination and their history of infestations, antibiotic treatment, and other pertinent information was recorded. Age, sex, height, and weight were recorded for demographic comparison, and photographs were taken for later clinical comparison. None of the patients had been treated with pediculicides, scabicides, or other topical agents in the month preceding the trial. The diagnosis of scabies was made primarily by the presence of the following 3 criteria: presence of a burrow and/or typical scabietic lesions at the classic sites of infestation, report of nocturnal pruritus, and history of similar signs and symptoms in the patient’s families and/or close contacts. Infestation was confirmed by demonstration of eggs, larvae, mites, or fecal material under light microscopy. Patients who satisfied the above criteria were randomly divided into two groups: group A were to receive ivermectin, and group B were to receive malation 0.5% lotion.

Randomization and treatment In total, 378 patients were initially enrolled. Of these, 38 patients were not able to return after the first follow-up examination, and were therefore excluded from the study. The remaining 340 patients (210 men, 130 women; mean±standard deviation age 44.86±14.47 years, range 4–72 years) constituted the final study population.

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Statistical analysis The χ² test or the Fisher exact test was used as appropriate to examine the difference between groups, and P<.05 was considered significant. SPSS software (version 16; SPSS Inc, Chicago, IL) was used for all analysis.

Results There were no significant differences in age or sex between the two groups (Table I). On entry into the study, the number of patients in each treatment group who were graded as having mild, moderate, or severe infestation was also not significantly different (Table II).

At 2-week follow-up, the treatment was effective in 108 patients (63.5%) in the ivermectin group and 75 patients (45.8%) in the malathion 0.5% lotion group, with no significant difference between the groups (P=.41). The treatment was repeated for the 157 patients (90 men, 67 women; 62 in the ivermectin group and 95 in the malathion 0.5% lotion group) who still had infestation.

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ORIGINAL CONTRIBUTION proved for this use. Oral ivermectin has been reported effective in the treatment of crusted scabies; its use should be considered for patients who have failed treatment with or who cannot tolerate FDA-approved topical medications for the treatment of scabies.20,21 Malathion is an underrecognized and underutilized therapy for head lice infestation and scabies largely due to misperceptions about its safety profile. Specifically, its pure form as it exists in pharmaceutical preparations is nontoxic to humans in the low doses available.

Table I. Demographic Characteristics of the Study Population Ivermectin (n=170)

Malathion (n=170)

Age

38.26±12.53

33.22±13.99

Men

95

115

Women

55

75

Height, cm

173±35

176±26

Weight, kg

75±28

69±24

At the second follow-up, at 4 weeks, only 25 of the 62 patients in the ivermectin group still had severe itching and skin lesions, compared with 65 of the 95 patients in the malation 0.5% lotion group; thus, the overall cure rate was 145 of 170 patients (85.3%) in the ivermectin group and 105 of 170 (61.8%) in the malathion 0.5% lotion group (P<.05).

The remaining 90 patients who were considered to have treatment failure in the study were retreated with open-label permethrin cream, which cured the infestation in 2 to 3 weeks.

Adverse events The treatments were considered cosmetically acceptable by both patients and parents. None of the 340 participants experienced allergic reactions. The main adverse event was irritation, reported by 40 patients (30 in the ivermectin group and 10 in the malathion group), but this was not serious and did not affect compliance.

None of the patients had worsening of the infestation during the study; even the treatment failures were improved compared with their pretreatment status, and none had >50 new lesions.

While labeled for ages 6 and up, recent studies showed no cholinesterase inhibition in patients with head lice infestation aged 2 to 6 years treated with malathion.17,22 In this study, two applications of malathion in 1-week intervals was as effective as a single oral dose of ivermectin by 2 weeks (P>.05). The lack of efficacy of a single dose of ivermectin in some patients may be caused by the lack of ovicidal action of ivermectin.23,24 Ivermectin, due to its specific site of action, may not be effective against the parasite in younger stages inside the egg because the nervous system has not yet developed. The concentration achieved in the skin may also be variable because ivermectin is orally administered. These factors could also explain the temporal delay in complete recovery observed in the ivermectin group.25,26 In our patients, we found that oral ivermectin was superior to malathion 0.5% lotion after repeating the medication over a period of 4 weeks. The data from the fourth week showed that ivermectin continued to decrease both the lesions and the degree of pruritus as compared with malathion (P<.05).

Discussion

In one study, a higher number of patients showed clearance of lesions as compared with our results.27 This could be explained by the longer follow-up. In another study, 100% cure was seen in the treatment group with ivermectin possibly because the study was carried out in a smaller number of patients with follow-up of 2 weeks and ages 12 years or older, when the activity of sebaceous glands is higher.28

Ivermectin is an oral antiparasitic agent approved for the treatment of worm infestations. Evidence suggests that oral ivermectin may be a safe and effective treatment for scabies; however, ivermectin is not Food and Drug Administration (FDA)–ap-

Regarding side effects, malathion was found to be significantly more safe than ivermectin (P<.05). Although ivermectin was as effective as malathion at 2-week follow-up, it has few outweighing advantages over malathion.

Table II. Severity of Infestation Pretreatment of All Patients Lesions, No.

Ivermectin (n=170)

Crotamiton (n=170)

Total Patients (n=340)

Mild <50

30

30

60

Moderate 50–100

45

40

85

Severe >100

95

100

195

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Conclusions Ivermectin is cost-effective and can be given to masses with better compliance with or without supervision. It can be considered as first-line medication for the treatment of scabies. It can also be given safely in patients with scabies who have secondary eczematization, erosions, or ulcers in whom topical therapies such as permethrin, lindane, and benzyl benzoate can cause serious cutaneous and systemic side effects in addition to the problem of compliance.

References 1 Gould D. Prevention, control and treatment of scabies.

Nurs Stand. 2010;25:42–46.

2 Albakri L, Goldman RD. Permethrin for scabies in children. Can Fam Physician. 2010;56:1005–1006.

3 Goldust M, Ranjkesh MR, Amirinia M, et al. Sertaconazole 2 % cream vs. hydrocortisone 1% cream in the treatment of seborrheic dermatitis. J Dermatolog Treat. 2012.

4 Fourie JJ, Horak IG, de la Puente Redondo V. Efficacy of a spot-on formulation of pyriprole on dogs infested with Sarcoptes scabiei. Vet Rec. 2010;167:442–445.

5 Hong MY, Lee CC, Chuang MC et al. Factors related to missed diagnosis of incidental scabies infestations in patients admitted through the emergency department to inpatient services. Acad Emerg Med. 2010;17:958–964.

15 Currie BJ, McCarthy JS. Permethrin and ivermectin for scabies. N Engl J Med. 2010;362:717–725.

16 Bouvresse S, Chosidow O. Scabies in healthcare settings. Curr Opin Infect Dis. 2010;23:111–118.

17 Idriss S, Levitt J. Malathion for head lice and scabies: treatment and safety considerations. J Drugs Dermatol.

2009;8:715–720.

18 Burgess I, Robinson RJ, Robinson J, et al. Aqueous malathion 0.5% as a scabicide: clinical trial. Br Med J (Clin Res Ed). 1986;292:1172.

19 Chhaiya SB, Patel VJ, Dave JN, et al. Comparative efficacy and safety of topical permethrin, topical ivermectin, and oral ivermectin in patients of uncomplicated scabies. Indian J Dermatol Venereol Leprol. 2012;78:605– 610.

20 Worth C, Heukelbach J, Fengler G, et al. Acute morbidity associated with scabies and other ectoparasitoses rapidly improves after treatment with ivermectin. Pediatr Dermatol. 2012;29:430–436.

21 Gonzalez P, Gonzalez FA, Ueno K. Ivermectin in human medicine, an overview of the current status of its clinical applications. Curr Pharm Biotechnol. 2012;13:1103– 1109.

6 Sampathkumar K, Mahaldar AR, Ramakrishnan M, et al.

Norwegian scabies in a renal transplant patient. Indian J Nephrol. 2010;20:89–91.

22 Hanna NF, Clay JC, Harris JR. Sarcoptes scabiei infestation treated with malathion liquid. Br J Vener Dis. 1978;54:354.

7 Goldust M, Golforoushan F, Ranjkesh MR, et al. Comparative trial of Permethrin 5% vs. Lindane 1 % for the treatment of scabies. J Dermatolog Treat. 2012.

23 Sharma R, Singal A. Topical permethrin and oral ivermectin in the management of scabies: a prospective, randomized, double blind, controlled study. Indian J Dermatol Venereol Leprol. 2011;77:581–586.

8 Meyer EP, Heranney D, Foegle J, et al. [Management of a scabies epidemic in the Strasbourg teaching hospital, France]. Med Mal Infect. 2011;41:92–96.

9 Wolf R, Davidovici B. Treatment of scabies and pediculosis: facts and controversies. Clin Dermatol. 2010;28:511– 518.

10 Mounsey K, Ho MF, Kelly A, et al. A tractable experimental model for study of human and animal scabies. PLoS Negl Trop Dis. 2010;4:e756.

11 Goldust M, Rezaee E, Hemayat S. Treatment of scabies: comparison of permethrin 5% versus ivermectin. J Dermatol. 2012;39:545–547.

12 Micali G, Tedeschi A, West DP, et al. The use of videodermatoscopy to monitor treatment of scabies and pediculosis. J Dermatolog Treat. 2011;22:133–137.

13 Orrico JA, Krause-Parello CA. Facts, fiction, and figures of the Sarcoptes scabiei infection. J Sch Nurs.

2010;26:260–266.

14 Jin SP, Choi JE, Won CH, et al. Scabies in a 2-month-old infant successfully treated with lindane. Ann Dermatol.

2009;21:200–202.

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24 Martinez BG, Di Martino OB, Rodriguez MM, et al.

[Erythrodermic crusted scabies induced by corticosteroids treated with ivermectin. A case report]. Rev Esp Geriatr Gerontol. 2011;46:174–175.

25 Behera SK, Dimri U, Singh SK, et al. The curative and antioxidative efficiency of ivermectin and ivermectin + vitamin E-selenium treatment on canine Sarcoptes scabiei infestation. Vet Res Commun. 2011;35:237– 244.

26 Lekimme M, Farnir F, Marechal F, et al. Failure of injectable ivermectin to control psoroptic mange in cattle. Vet Rec. 2010;167:575–576.

27 Walker GJ, Johnstone PW. Interventions for treating scabies. Cochrane Database Syst Rev. 2000;CD000320.

28 Strong M, Johnstone P. Interventions for treating scabies. Cochrane Database Syst Rev. 2007;CD000320.

Comparing the Efficacy of Oral Ivermectin vs Malathion 0.5%

Discussions in Dermatology December 3-6, 2014

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Marc Darst, MD

H.L. Greenberg, MD

Jeanine Downie, MD

Candace Spann, MD

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Erin Gilbert, MD

Allan Wirtzer, MD

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September/October 2014

Volume 12 • Issue 5

Core curriculum Virendra N. Sehgal, MD, Section Editor

Mohs Micrographic Surgery: History, Technique, and Advancements Tulsie Narendra Patel, BS; Shailee Bipin Patel, BS; Katlein Franca, MD, MSc; Anna Haydee Chacon, MD; Keyvan Nouri, MD

Mohs micrographic surgery is an excision technique that has been widely adapted as the recommended treatment for basal and squamous cell carcinomas and other skin cancers. It was developed by Frederic E. Mohs in the 1930s and has since advanced in its methods and applications. Mohs developed the practice in the process of determining a method to treat various neoplasms. Mohs micrographic surgery is a modality that involves serial excision of a tumor followed by microscopic evaluation of the tissue. It is a complicated surgical technique that involves scrupulous training and constant adaptation. It has greatly expanded since its inception to include new imaging techniques such as immunohistochemistry and confocal mosaicing microscopy. Further advancements include its application to other medical specialties, such as otolaryngology. This technique began as a revolutionary practice but has since become the standard treatment for a variety of skin cancers. (SKINmed. 2014;12:289–292)

M

ohs micrographic surgery is a surgical technique that was pioneered and founded by Frederic E. Mohs in the early 1930s.1,2 Mohs established this excision technique while working alongside Professor Michael F. Guyer at the University of Wisconsin.1 Mohs and Guyer studied the fixative properties of various substances that were injected into neoplasms.1 This idea was inspired by the use of chemicals to treat tumors as illustrated by the Egyptians with arsenic and by Sir Humphrey Davy using zinc chloride.3 Various chemical combinations were applied and studied.1 Eventually, Mohs found that zinc chloride was especially potent, as it allowed for a tumor to be sequentially excised after the fixative process was complete.1,4 The excised tissue was then examined under a microscope to ensure that the entire tumor had been removed.2,4 The technique of using chemicals in order to remove the tumor was coined “chemosurgery.”4 Mohs, a general surgeon, wanted to introduce a new practice into the field of general surgery for the treatment of tumors that were previously considered untreatable.1,3 Through his efforts, Mohs was able to illustrate an incredibly high cure rate, >97%, associated with chemosurgery.1,3 He was able to cure patients with late-stage disease who were previously deemed incurable.3

As Mohs surgery became better known, Mohs created the American College of Chemosurgery in 1968.3 Due to the precarious nature of tumors of the skin, it was important to Mohs that all who practiced chemosurgery be methodically trained.1 The American College of Chemosurgery therefore created a specific fellowship program under which dermatologists could study the precise art of Mohs surgery.1 This focused training program has been vital towards the widespread recognition of this practice as a viable option for the treatment of skin cancers by all medical specialties.1 The first Mohs surgery fellowship was initiated at New York University by a dermatologist, Perry Robbins.5 The program began as a 1-year fellowship in which fellows were trained in all aspects of the technique including surgery, dermatopathology, and wound care.5 Today, these programs range between 1 and 2 years of training and are accredited by the American College of Mohs Surgery (ACMS) and the Accreditation Council for Graduate Medical Education (ACGME).6 Although training under the ACMS and the ACGME varies slightly, both require that their fellows treat a variety of cases and at least 500 Mohs cases per year.6

From the Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL Address for Correspondence: Tulsie Narendra Patel, BS, University of Miami Miller School of Medicine, 1600 NW 10th Avenue #1140, Miami, FL 33136 • E-mail: tnpatel@med.miami.edu

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In 1970, dermatologists Theodore A. Tromovitch and Sam Stegman, members of the American College of Chemosurgery, boosted the popularity and acceptance of a fresh tissue technique, previously demonstrated by Mohs.3,5 They presented 102 cases of surgery “without using zinc chloride chemical fixative” at the annual Chemosurgery Conference.5 This led to their revolutionary paper on the effective “chemosurgery fresh tissue technique” in which there were astonishingly only 3 recurrences in their 102 surgeries.5,7 This technique provided improvements in efficiency and patient comfort, compared with the previously accepted fixed-tissue technique (chemosurgery).3 This surgical technique officially became known as Mohs micrographic surgery because of its dependence on microscopes and mapping.3 The mapping technique was an organizational practice incorporated into the method to ensure that all of the cancerous regions were excised without affecting healthy, normal tissue.3 The scope of the American College of Chemosurgery began to expand, and in 1985 the organization was changed to the American College of Mohs Micrographic Surgery and Cutaneous Oncology.3 Changes continued to occur as fellows were required to not only undergo vast training in frozen section dermatopathology but also cutaneous oncology and reconstructive surgery.3 Thus, through Mohs’ perseverance and vision, the treatment of a variety of skin cancers officially changed.1 Technique Mohs surgery was initially known as chemosurgery because of its fixed-tissue technique.4 The fixed-tissue technique involves the use of a black paste composed of zinc chloride, stibnite, and bloodroot.4 Zinc chloride is used because it is safe for the patient and physician and because it preserves the histological features of the tissue.1 It permits secondary intention healing, therefore allowing superior cosmetic results.1 The use of the paste is also associated with numerous complications including local inflammation and pain.1 In chemosurgery, the black paste is applied to the tumor and set for 12 to 24 hours.4 After the paste sets, serial excisions of the tumor are completed.4 Serial excisions are required to ensure that the entire tumor has been removed, especially as this technique targets large tumors.1 Once the fixed tissue has been excised, its horizontal layers are carefully mapped and then examined under a microscope.4 After the entire excision process is complete, the patient’s wound is healed through secondary intention wound healing.4 Even though the fixed-tissue technique presents concerns as a result of the length of time required for treatment and the painful nature of the treatment, the cure rates for this method are in the 99th percentile.4 SKINmed. 2014;12:289–292

Soon after the popularity of the fixed-tissue technique, a fresh tissue technique was introduced.2 This technique used frozen specimens.8 Mohs initially used this technique in the treatment of small tumors of the eyelid.4 This process was innovative because it did not require the use of the zinc chloride paste and thus offered benefits in terms of pain, timing (the whole procedure could be completed in 1 day), and reconstruction.4 In addition, this technique illustrated similar cure rates to the fixedtissue method.4 Today, the Mohs surgery technique can be summarized.

• A patient’s skin tumor is identified through visual and tactile inspection.9 • The area around the tumor is then anesthetized before an angled blade is used to excise the tissue.9 • The tissue is then mapped in order to maintain proper orientation.9,10 • The tissue is examined in a histopathology laboratory using various staining techniques and light microscopy to ensure correct and complete removal of the tumor.9,10 Application Mohs surgery has been used for the treatment of a variety of skin cancers; namely, basal cell carcinomas, squamous cell carcinomas, cutaneous lesions, verrucous carcinomas, and paracutaneous neoplasms.4,11 It is frequently used for the treatment of basal cell carcinomas most often located on the patient’s head and neck.4,11 There is overwhelming evidence that demonstrates its high cure rates (around 99%) for the treatment of basal cell carcinomas, especially for cases of primary occurrence of the disease.11 This procedure has also been used for the treatment of incompletely excised or recurrent basal cell carcinomas.4 In addition, this technique has been shown to have similar results in the treatment of squamous cell carcinomas.10,12 The benefits of using Mohs micrographic surgery for these conditions include the complete removal of all tumor cells, minimal disturbance to the surrounding normal tissue, and better aesthetic outcomes.12 Mohs surgery has also become the accepted mode of treatment for squamous cell carcinoma, the second most common skin cancer.4 Although traditional surgical techniques tend to be used on smaller tumors, larger and more aggressive primary squamous cell carcinoma and recurrent squamous cell carcinoma tend to be managed with Mohs micrographic surgery.4 It is the treatment of choice for squamous cell carcinomas in certain anatomical areas, affecting the mucosa and vulva.4

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There has also been a recent increase in the incidence of other skin cancers.1 Accordingly, Mohs surgery has been adapted for the treatment of a variety of associated conditions.1 It has been used for the treatment of neoplasms including atypical fibroxanthoma, melanoma, and leiomyosarcoma.1,8 Further, it has been used for the treatment of rare but aggressive cutaneous disorders such as dermatofibrosarcoma protuberans, microcystic adnexal carcinoma, sebaceous carcinoma, Merkel cell carcinoma, and extramammary Paget’s disease.1,13 This technique has also been applied to a variety of other cutaneous conditions as well. For example, this technique was recently adapted for the treatment of nonmelanoma skin cancers in organ transplant recipients.14 These patients have a higher risk of developing basal and squamous cell carcinomas.14 In addition, it has been used in delicate situations such as the management of cutaneous carcinomas of mixed histology in which a clear diagnosis cannot be made.15 Future Challenges Mohs micrographic surgery continues to modify itself with advances in the medical sciences.4,14 With new imaging techniques, it has become more efficient and timely.10,16 The next step will be the widespread application and acceptance of these new techniques by Mohs surgeons.4 Immunohistochemistry techniques have recently been adopted during laboratory testing for the benefits they offer regarding identification, tissue sparing, and recurrence.10,17 It works by targeting a specific antigen in the excised tissue and can therefore track tumor cells that could otherwise be missed or masked by other processes, such as inflammation.17 Immunohistochemistry allows for enhanced staining of the frozen sections such that the diseased tissue can be visualized more clearly.17 Specifically, it increases the sensitivity of the surgery by allowing better delineation of the margins of the tumor.10 Immunohistochemistry is not yet widely adapted in Mohs micrographic surgery as a result of cost and timing issues, but it is being considered an adjunct identifier in various conditions including basal and squamous cell carcinomas and malignant melanoma.10,17 At this time, application of immunohistochemistry in Mohs surgery has taken place most often in the treatment of melanoma, squamous, and basal cell carcinomas.17 Immunohistochemistry will undoubtedly contribute to the advancement of Mohs surgery with the discovery of new markers that will allow for Mohs surgery to be used to treat even more conditions.10,17 The use of confocal mosaicing microscopy has also led to advancements in Mohs surgery.16 It provides nuclear imaging in SKINmed. 2014;12:289–292

less time and permits more rapid interpretation as relates to frozen histology.16 Mohs micrographic surgery allows for the construction of large mosaic images of an entire tumor in order to examine large areas at a time using low magnification.16 This microscopy is especially helpful in the identification of various sizes and types of basal cell carcinoma tumors16; hence, this imaging technique provides yet another outlet for rapid identification of tumors treated with Mohs surgery.16 Further advancements in this field to better suit Mohs surgery involve the improvement of contrast for various types of tissues.16 Current efforts are placed on the development of a “positive” and a “negative” contrast mode that will indicate the presence of a tumor or lack thereof, respectively.16 Additional efficiency may be attained through the use of a single computer for the acquisition and development of the mosaic, thus decreasing the time for the treatment, as well.16 The biggest goal for proponents of the use of confocal mosaicing microscopy, however, is the approval for its application for the treatment of squamous cell carcinomas through the development of multimodal contrast that can detect cellular processes occurring in both the nuclei and cytoplasm.16 Imaging has also advanced with use of high-resolution ultrasound before Mohs micrographic surgery.18,19 Ultrasound has been found to be accurate in determining the margins of large tumors with subclinical dermal involvement.19 A recent study at the Mount Sinai Medical Center found that basal cell carcinomas may be detected in real time by the presence of characteristic weak reflecting spots within an echo-poor tumor region.18 Ultrasound has the potential to be used as a predictive tool for all kinds of nonmalignant skin cancers.19 This indicates the use of high-resolution ultrasound as a diagnostic tool for Mohs surgery as it could reduce treatment costs and also indicate tumor characteristics, such as size, preoperatively18,19; however, much work is still required in the field of ultrasound. It still needs to advance in its imaging of various layers of the skin to allow for proper distinction of the entire tumor from all other pathophysiological processes that may be associated with the affected tissue.19 Other issues that must be addressed include advancements in high-resolution ultrasound that will allow for greater cellular resolution to allow for tumor typing, application to small tumors, standardized training in operation of the ultrasound with regards to Mohs surgery, and ability to accurately determine surgical outlines18; thus, the use of ultrasound shows great potential, but its true application remains to be seen.18,19 The number of Mohs surgeons has greatly increased in recent years.20 According to the ACMS Web site, there are more than 900 practicing Mohs surgeons in the United States today.20 Internationally, the numbers have also increased.21–23 Most surgeons

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from around the world are trained in the United States through the American College of Mohs Surgery, and there are now more than 20 Mohs surgeons in Australia, more than 15 in Canada, and more in South America.23–24 There are also approved fellowship programs in Australia, New Zealand, and Canada.22 Mohs surgeons have also been trained outside of the American College of Mohs Surgery in Europe.21 These various outlets for training opportunities have helped greatly to expand Mohs surgery’s international reach.22,23

9 Pennington BE, Leffell DJ. Mohs micrographic surgery: established uses and emerging trends. Oncology (Williston Park). 2005;19:1165–1171; discussion 1171–1162, 1175.

Mohs micrographic surgery often involves collaboration between physicians from different specialties.8 Recently, greater involvement has come from the otolaryngology community that deals with skin cancers of the face and neck.8 As a result of the rising incidence of cutaneous malignancies, otolaryngologists have begun to probe further into Mohs micrographic surgery because of its reliability in high-risk cases.8 Although complete implementation of this technique has not occurred in otolaryngology, the incidence continues to rise.8

13 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.

Conclusions Mohs micrographic chemosurgery is an innovative extraordinary excision technique ever since its inception. Adaptation of the fresh tissue technique, through new applications and advancements in imaging, is an outcome of its proven efficacy, fastening itself as a standard treatment for a variety of cutaneous neoplasms auguring well for its future.

References 1 Trost LB, Bailin PL. History of Mohs surgery. Dermatol Clin. 2011;29:135–139, vii.

2 Shriner DL, McCoy DK, Goldberg DJ, Wagner RF Jr. Mohs micrographic surgery. J Am Acad Dermatol. 1998;39:79– 97.

3 Brodland DG, Amonette R, Hanke CW, Robins P. The history and evolution of Mohs micrographic surgery. Dermatol Surg. 2000;26:303–307.

4 Swanson NA. Mohs surgery. Technique, indications, applications, and the future. Arch Dermatol. 1983;119:761–773.

5 Robins P. 44 years in dermatologic surgery: a retrospective. J Drugs Dermatol. 2009;8:519–525.

6 Ibrahimi OA, Eisen DB, Avram MM, Robins P. Ten pearls for identifying the right dermatologic surgery fellowship for you. J Drugs Dermatol. 2010;9:421–424.

7 Tromovitch TA, Stegeman SJ. Microscopically controlled excision of skin tumors. Arch Dermatol. 1974;110:231–232.

8 Minton TJ. Contemporary Mohs surgery applications.

Curr Opin Otolaryngol Head Neck Surg. 2008;16:376–380.

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10 Sroa N, Campbell S, Ravitskiy L. Immunohistochemistry in mohs micrographic surgery: a review of the literature.

J Clin Aesthet Dermatol. 2009;2:37–42.

11 Perkins W. Who should have Mohs micrographic surgery?

Curr Opin Otolaryngol Head Neck Surg. 2010;18:283–289.

12 Lawrence CM. Mohs’ micrographic surgery for basal cell carcinoma. Clin Exp Dermatol. 1999;24:130–133.

14 Bangash HK, Colegio OR. Management of non-melanoma skin cancer in immunocompromised solid organ transplant recipients. Curr Treat Options Oncol.

2012;13:354–376.

15 Cohen PR, Schulze KE, Nelson BR. Cutaneous carcinoma with mixed histology: a potential etiology for skin cancer recurrence and an indication for Mohs microscopically controlled surgical excision. South Med J. 2005;98:740– 747.

16 Gareau DS, Li Y, Huang B, et al. Confocal mosaicing microscopy in Mohs skin excisions: feasibility of rapid surgical pathology. J Biomed Opt. 2008;13:054001.

17 Thosani MK, Marghoob A, Chen CS. Current progress of immunostains in Mohs micrographic surgery: a review.

Dermatol Surg. 2008;34:1621–1636.

18 Marmur ES, Berkowitz EZ, Fuchs BS, et al. Use of highfrequency, high-resolution ultrasound before Mohs surgery. Dermatol Surg. 2010;36:841–847.

19 Jambusaria-Pahlajani A, Schmults CD, Miller CJ, et al.

Test characteristics of high-resolution ultrasound in the preoperative assessment of margins of basal cell and squamous cell carcinoma in patients undergoing Mohs micrographic surgery. Dermatol Surg. 2009;35:9–15; discussion 15–16.

20 About the ACMS (Mohs College). http://www.mohscollege.org/acms/ Accessed March 31, 2013.

21 Langtry JA. International Perspective of Mohs Micrographic Surgery: Europe. In: Nouri K, ed. Mohs Micrographic Surgery. New York, NY: Springer; 2011:497–501.

22 Goodman GJ, Morgan VA, Rutherford TJ, et al. International perspective of Mohs micrographic surgery: Australia and New Zealand. In: Nouri K, ed. Mohs Micrographic Surgery. New York, NY: Springer; 2011:509– 518.

23 Kopke LFF, Nestor G. International perspective of Mohs micrographic surgery: South America. In: Nouri K, ed.

Mohs Micrographic Surgery. New York, NY: Springer; 2011:493–495.

Mohs Micrographic Surgery

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Volume 12 • Issue 5

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

Omalizumab (Xolair) for the Treatment of Chronic Idiopathic Urticaria Noah Scheinfeld, MD, JD

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malizumab (Xolair, Novartis Pharmaceuticals, East Hanover, NJ; Genentech Inc, South San Francisco, CA) is a recombinant humanized monoclonal antibody that blocks the immunoglobulin E (IgE) high-affinity Fc receptor.1 Omalizumab stops free-serum IgE from attaching to mast cells and other immune cells by preventing IgE-mediated inflammatory changes.

Omalizumab was originally approved in 2003 for patients 12 years and older with moderate to severe persistent allergic asthma caused by year-round allergens in the air not controlled by asthma medicines such as inhaled steroids. More recently, studies have been directed toward patients with chronic idiopathic urticaria (CIU), where upwards of 50% of CIU patients have inadequate response to H1-antihistamines, previously the only approved therapy for CIU.2 Women are twice as likely as men to experience CIU, and most develop symptoms between the ages of 20 and 40 years.2 The agent has now been approved since March 2014 for the treatment of CIU in patients 12 years and older) who remain symptomatic despite H1-antihistamine treatment.

Omalizumab 150 mg or 300 mg is administered by the physician as a subcutaneous injection every 4 weeks. Dosing appears to be a decision that the physician makes, with the 300-mg dose being more effective for CIU than the 150-mg dose. Most patients will likely receive the 300-mg dose, as side effects do not appear to be dose related. In addition, dosing of omalizumab for CIU patients is not dependent on serum IgE (free or total) level or body weight.

Mechanism of Action A variety of studies have found that omalizumab decreases inflammatory mediators. The result of blocking the IgE high-

affinity Fc receptor is manifold. Omalizumab treatment downregulates dendritic cell FcεRI expression.3 The combined effect of specific immunotherapy and omalizumab is associated with prevention of nasal eosinophilic cationic protein increase and decreased tryptase levels in nasal secretions.4 Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of specific immunotherapy allergen used.5 In a study assessing the immunologic effects of omalizumab on airway inflammation in allergic asthma, the mean percentage sputum eosinophil count decreased significantly from 6.% to 1.7% in the omalizumab group, a reduction significantly greater than that with placebo (8.5% to 7.0%). This was associated with a significant reduction in tissue eosinophils, FcεRI+ cells, CD3+, CD4+ and CD8+ T lymphocytes, B lymphocytes, and cells staining for IL-4+, but not with improvement in airway hyper-responsiveness to methacholine.6 Treatment with omalizumab normalized the number of myeloid dendritic cells during the grass-pollen season.7 Omalizumab induces complex changes in interleukin (IL) levels and does not decrease all Th-2–related ILs. In a study of patients with asthma, circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13, and soluble intercellular adhesion molecule-1 (s-ICAM) were measured before and after 16 weeks of treatment.7 In addition, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. The results of the aforementioned study were interesting: IL-13 decreased significantly, IL-5 and IL-8 decreased in the omalizumab group compared with baseline, and other circulating mediators did not change.3–7 The mechanism with which omalizumab induces long-term remission is also unclear. Most patients may require ongoing maintenance dosing.8 The drug did not seem to alter the natural history of the disease.8

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

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As in patients with asthma, some authors correlated the clinical improvement induced by omalizumab in patients with CIU with the reduction in free IgE levels; however, numerous patients with CIU successfully treated with omalizumab in published case reports or studies exhibited neither increased total IgE levels nor IgE specific to allergens. Omalizumab may also serve as a mast cell stabilizer by downregulating the high-affinity IgE receptors on mast cells and basophils.

Omalizumab and CIU In this phase 3, multicenter, randomized, double-blind study,9 researchers evaluated omalizumab’s efficacy and safety in patients with CIU despite H-antihistamine therapy (ie, fexofenadine 180 mg or cetirizine 10 mg once a day). The investigators randomized 323 patients to receive three subcutaneous injections, spaced 4 weeks apart, of omalizumab dosed at 75 mg, 150 mg, or 300 mg or placebo. They monitored the patients for 16 weeks, with the primary efficacy metric as the change from baseline in weekly validated itch-severity score of the urticaria (score 0–21).

Patients’ 7-day itch-severity score was approximately 14 in each of the four CIU groups. At 3 months, the mean (±standard deviation) change from baseline in the weekly itch-severity score was 5.1±5.6 in the placebo group, –5.9±6.5 in the 75-mg group, –8.1±6.4 in the 150-mg group (P=.001), and –9.8±6.0 in the 300-mg group. The 300-mg group had the lowest P value.

A number of case reports and series have also reported that omalizumab is highly effective at a dose of 300 mg/kg for CIU. Improvement in quality-of-life impairment was followed by relapse with 6-month periodic administration of omalizumab for severe treatment-refractory CIU and urticarial vasculitis.10 With long-term and continued use, 300 mg of omalizumab controlled CIU in 7 patients.11 How to Use Omalizumab Dermatologists should be prepared for possible anaphylaxis after administration of omalizumab and have an epinephrine autoinjector on hand. The patient should remain in the office for observation for 30 minutes following each injection. After the first injection, the time the patient must wait in the office should be extended to 2 hours after each of the first 3 injections; however, it could be modified based on a physician’s clinical judgment after discussing the risks with the patient. It should not be used in patients who are infected with helminthes, ie, strongylosis, and if used in patient with a high risk of infection with helminthes, must be monitored closely. Omalizumab is not indicated for the treatment of other allergic conditions or other forms of SKINmed. 2014;12:294–297

urticaria. In addition, it is not indicated for the relief of acute bronchospasm or status asthmaticus or for use in pediatric patients younger than 12 years.

How to Reconstitute Omalizumab Omalizumab comes as a powder that must be reconstituted with Sterile Water for Injection (SWFI), USP, only, that the physician must prepare for subcutaneous injection. Each vial of omalizumab is for single use only and contains no preservatives.12 The lyophilized product takes 15 to 20 minutes to dissolve. The fully reconstituted product will appear clear or slightly opalescent, and it is acceptable if there are a few small bubbles or foam around the edge of the vial. The reconstituted product is somewhat viscous. In order to obtain the full 1.2-mL dose, all of the omalizumab combined with saline must be withdrawn from the vial before expelling any air or excess solution from the syringe.12 The solution must be used within 8 hours following reconstitution when stored in a vial at 2°C to 8°C (36°F–46°F) or within 4 hours of reconstitution when stored at room temperature. Reconstituted Xolair vials should be protected from sunlight. Following are the steps for reconstituting omalizumab.12 Step 1: Draw 1.4 mL of SWFI, USP, into a 3-mL syringe equipped with a 1-inch, 18-gauge needle.

Step 2: Place the vial upright on a flat surface using the standard aseptic technique, insert the needle, and inject the SWFI, USP, directly onto the product.

Step 3: Keeping the vial upright, gently swirl the upright vial for approximately 1 minute to evenly wet the powder. Do not shake.

Step 4: After completing Step 3, gently swirl the vial for 5 to 10 seconds approximately every 5 minutes in order to dissolve any remaining solids. There should be no visible gel-like particles in the solution. Do not use if foreign particles are present.

Note: If it takes longer than 20 minutes to dissolve completely, repeat Step 4 until there are no visible gel-like particles in the solution. Do not use if the contents of the vial do not dissolve completely by 40 minutes.

Step 5: Invert the vial for 15 seconds in order to allow the solution to drain toward the stopper. Using a new 3-mL syringe equipped with a 1-inch, 18-gauge needle, insert the needle into the inverted vial. Position the needle tip at the very bottom of the solution in the vial stopper when drawing the solution into the syringe. Before removing the needle from the vial, pull the

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plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.

Step 6: Replace the 18-gauge needle with a 25-gauge needle for subcutaneous injection.

Step 7: Expel air, large bubbles, and any excess solution in order to obtain the required 1.2-mL dose. A thin layer of small bubbles may remain at the top of the solution in the syringe.

Three steps need to be taken for each 150-mg dose of omalizumab. Because 300 mg is given, these steps must be performed for each vial. Omalizumab is then administered by subcutaneous injection. The injection may take 5 to 10 seconds to administer because the solution is slightly viscous. Each vial delivers 1.2 mL (150 mg) of omalizumab. Do not administer more than 150 mg per injection site. Divide the 2 doses of 150 mg between 2 injection sites.

Side-Effect Profile Omalizumab has a favorable side-effect profile and is classified as pregnancy category B.12 Its specific side effects are listed below.

A U.S. Food and Drug Administration (FDA) review in September of 2014 of safety studies suggests a slightly increased risk of problems involving the heart and blood vessels supplying the brain among patients being treated with the asthma drug omalizumab than in those who were not treated with omalizumab. As a result, the FDA added information about these potential risks to the drug label.

Other Side Effects

Eosinophilic Conditions Fever, Arthralgia, and Dermatitis A constellation of signs and symptoms including arthritis/arthralgia, dermatitis (urticaria or other forms), fever, and lymphadenopathy similar to serum sickness have been reported in post-approval use of omalizumab.21 Severe thrombocytopenia and hair loss have been linked to omalizumab. Malignant neoplasms were observed in 20 of 4127 (0.5%) omalizumab-treated patients compared with 5 of 2236 (0.2%) control patients in clinical studies of adults and adolescents (12 years and older) with asthma and other allergic disorders.21 A variety of malignancies were seen in patients treated with omalizumab including several cases of breast cancer, nonmelanoma skin cancer, prostate cancer, melanoma, and parotid cancer occurring more than once, and five other types occurring once each. The majority of patients were observed for less than 1 year.21 it is unclear whether these cancers were related to omalizumab. The impact of longer exposure to omalizumab or use in patients at higher risk for malignancy (eg, elderly and current smokers) is not known.

Worm Infections and Omalizumab

Anaphylaxis Anaphylaxis13,14 occurred in approximately 0.09% of patients receiving omalizumab injections for asthma, with 61% of these reactions occurring within the first 2 hours after the first 3 injections and 14% occurring within 0.5 hours after the fourth or later injection. Food and Drug Administration (FDA) and World Health Organization experts expect that the rate of anaphylaxis will be the same for CIU patients. The Omalizumab Joint Task Force report published in 2007, which focused on asthma, recommended 5 steps for physicians prescribing omalizumab (Xolair) injections to ensure the safety of patients receiving omalizumab injections. When Xolair is given (1) informed consent should be obtained; (2) patients should be made aware that Xolair can induce anaphylaxis, the symptoms of which should be explained to the patients; (3) patients who take Xolair should have an epinephrine autoinjector in case anaphylaxis occurs; and (4) before injection, the state of health of patients should be assessed by the administering doctor, with vital signs taken and lung function (eg, peak expiratory flow or forced exSKINmed. 2014;12:294–297

piratory volume in 1 second) established. After taking Xolair, patients should wait in the doctor’s office for 2 hours after the first 3 injections and then change to 30 minutes after each injection; however, this can be modified based on the physician’s judgment after discussing the risks of anaphylaxis with the patient.13 The anaphylaxis warning is a black box warning for asthma and CIU.

Patients at risk for infections with helminthes, eg, geohelminth strongylosis, should be monitored for such infection while on omalizumab therapy. Insufficient data are available to determine the length of monitoring required for geohelminth infections after stopping Xolair treatment. In a one-year clinical trial conducted in Brazil in patients at high risk for geohelminthic infections (roundworm, hookworm, whipworm, threadworm), 53% (36/68) of Xolair-treated patients experienced an infection, as diagnosed by standard stool examination, compared to 42% (29/69) of placebo controls. Response to appropriate anti-geohelminth treatment of infection as measured by stool egg counts was not different between treatment groups. Insufficient data are available to determine the length of monitoring required for helminthes infections after stopping omalizumab treatment.

The point estimate of the odds ratio for infection was 1.96, with a 95% confidence interval (0.88–4.36), indicating that a patient who had an infection in this study was anywhere from 0.88 to 4.36 times as likely to have received omalizumab than a patient

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who did not have an infection. Response to appropriate antigeohelminth treatment of infection as measured by stool egg counts was not different between treatment groups.12

4 Bez C, Schubert R, Kopp M, et al. Effect of anti-immunoglobulin E on nasal inflammation in patients with seasonal allergic rhinoconjunctivitis. Clin Exp Allergy. 2004;34:1079–1085.

Omalizumab Compared With Other Agents for CIU Omalizumab, an agent that has been on the market for asthma related to elevated IgE levels since 2003, is a promising treatment for CIU. Its rate of side effects is low, and since it is pregnancy category B, for women considering pregnancy, omalizumab can succeed when other treatments have failed (eg, cyclosporine). In a series of 30 patients treated with omalizumab for CIU,22 all patients had moderate to severe symptoms at least 4 times per week despite the use of immunosuppressive medications including cyclosporine, prednisone, and methotrexate. It should be noted that after treatment with omalizumab, 10 patients had complete resolution of their symptoms, 8 had a significant response, 4 had a partial response, and 8 had no response. These findings provide evidence on the use of omalizumab in cases other than chronic idiopathic urticaria and in cases that are refractory to standard immunosuppressive medications.15 Mycophenolate mofetil was not a treatment used in this study. It should be mentioned that mycophenolate mofetil has been used to successfully treat CIU but is pregnancy category D and is part of the FDA Risk Evaluation and Mitigation Strategy program.16 Conclusions Medically minded dermatology should view omalizumab as a new and useful treatment for CIU but should follow the guidelines in the package insert when using omalizumab. The risk profile of omalizumab is favorable when compared with other immunosuppressive agents. Omalizumab injections must be monitored in the office and might be suited for dermatologists who have experience in infusing infliximab or intravenous immunoglobulin in their office with equipment such as epinephrine autoinjectors, heart rate monitors, and a crash cart. This is not necessary but could be helpful if a patient has anaphylaxis caused by omalizumab. Omalizumab is expensive ($20,000+ a year) and is not without rare but serious side effects. When used within the guidelines, it can be used safely and effectively and is a useful agent for the treatment of CIU. References 1 Milgrom H, Berger W, Nayak A, et al Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108:E36.

2 Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy. 2011;66:317–330.

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3 Prussin C, Griffith DT, Boesel KM, et al. Omalizumab treatment downregulates dendritic cell FcepsilonRI expression. J Allergy Clin Immunol. 2003;112:1147–1154.

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5 Kopp MV, Brauburger J, Riedinger F, et al. The effect of anti-IgE treatment on in vitro leukotriene release in children with seasonal allergic rhinitis. J Allergy Clin Immunol. 2002;110:728–735.

6 Djukanovic R, Wilson SJ, Kraft M, et al. The effects of anti-IgE (omalizumab) on airways inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170:583–593.

7 Feuchtinger T, Bartz H, von Berg A, et al. Treatment with omalizumab normalizes the number of myeloid dendritic cells during the grass pollen season. Allergy Clin Immunol. 2003;111:428–430.

8 Groffik A, Mitzel-Kaoukhov H, Magerl M, et al. Omalizumab—an effective and safe treatment of therapy resistant chronic spontaneous urticaria. Allergy. 2011;66:303–305.

9 Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368:924–935.

10 Kai AC, Flohr C, Grattan CE. Improvement in quality of life impairment followed by relapse with 6-monthly periodic administration of omalizumab for severe treatmentrefractory chronic urticaria and urticarial vasculitis. Clin Exp Dermatol. 2014 Apr 23 [Epub ahead of print].

11 Silva PM, Costa AC, Mendes A, et al. Long-term efficacy of omalizumab in seven patients with treatment-resistant chronic spontaneous urticaria. Allergol Immunopathol (Madr). 2014 Apr 11. [Epub ahead of print].

12 Xolair [package insert]. East Hanover, NJ: Novartis Pharmaceuticals; 2014 13 Cox L, Lieberman P, Wallace D, et al. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report. J Allergy Clin Immunol. 2011;128:210–212.

14 Cox L, Platts-Mills TA, Finegold I, et al. American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis. J Allergy Clin Immunol. 2007;120:1373–1377.

15 Altman MC, Naimi DR. Omalizumab for chronic urticaria. N Engl J Med. 2013;368:2528–2530.

16 Zimmerman AB, Berger EM, Elmariah SB, et al The use of mycophenolate mofetil for the treatment of autoimmune and chronic idiopathic urticaria: experience in 19 patients. J Am Acad Dermatol. 2012;66:767–770.

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September/October 2014

Volume 12 • Issue 5

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

Congenital Erosive and Vesicular Dermatosis With Reticulated Supple Scarring: Expanding the Database of an Enigma Warren R. Heymann, MD

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hree children with “extensive crusted erosions and vesicles at birth that healed with supple reticulated scarring restricted to the skin and tongue” were detailed by researchers in 1985.1 More recently, the literature on congenital erosive and vesicular dermatosis with reticulated supple scarring (CEVDRSS) was reviewed, in which nine additional cases were added to the 19 cases already published, and the clinical spectrum of the disorder was further refined.2 One of the most daunting challenges for a dermatologist is to assess the neonate presenting with vesicles. The spectrum of these infectious and noninfectious disorders is discussed in an excellent review.3 If one takes a methodical approach to these patients, always being concerned about infectious etiologies first (with Herpes simplex of paramount concern), a Tzanck preparation, potassium hydroxide stain (congenital candidiosis), Gram stain (Staphylococci), appropriate cultures, direct fluorescent antibody staining, polymerase chain reaction, and skin biopsies (routine and direct immunofluorescence) should render a precise diagnosis. A Tzanck preparation alone will determine whether there are any multinucleated giant cells (Herpes simplex infection, congenital varicella, or zoster), eosinophils (erythema toxicum neonatorum, eosinophilic pustular folliculitis, incontinentia pigmenti), or neutrophils (transient neonatal pustular melanosis, impetigo).

Making a Diagnosis Dermatologists search for primary lesions to establish a diagnosis. CVEDRSS is unusual in that the characteristic scars enable the diagnosis to be made only retrospectively, once the vesicular

and erosive phase has resolved and other causes of neonatal bullous disorders have been ruled out. These scars had been aptly described by Cohen and colleagues as “cobblestonelike and, in some areas, oriented along cleavage lines. On the limbs, the reticulated pattern followed the long axes of the extremities.”1 I am confident that I have seen one such patient. By the time I had examined the patient, only scarring was noted, but it was so striking that I was reasonably sure of the diagnosis. Establishing such a diagnosis, however, does not always translate to understanding its pathogenesis, nature, extent, or prognosis.

In a recent review of 28 patients,2 Tlougan and colleagues noted the following : preterm birth (79%), nail abnormalities (46%), hyperthermia/hypohidrosis (46%), a history of maternal chorioamnionitis (43%), alopecia (43%), neurodevelopmental and ophthalmologic abnormalities (36% each), and tongue atrophy (29%). Histopathology of late lesions demonstrated scars with diminished hair follicles and absent eccrine glands. From the 9 patients added to the literature, the following features had not been previously reported: (1) erosive lichen planus (observed in one 2-year-old boy on severely involved areas); (2) gangrene of the left index finger in the same boy; and (3) hydronephrosis of the left kidney in a preterm (28 week) male. The authors acknowledge that it may be impossible to determine whether prematurity is responsible for these features or whether CEVDRSS results in prematurity.

I asked Dr Cohen whether he had any further knowledge about the original patients. He graciously replied: “My last information on the 2 kids from Baltimore was in the early 1990s when they were quite stable and doing well. They had no lesions and

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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no recurrent lesions. The scarring was quite stable and still supple without symptoms except problems with cooling during the summer.”

Conclusions CEVDRSS is an enigma. It remains to be determined whether it is secondary to a yet-undefined infectious etiology, placental disease, or toxic insult or whether there is a genetic predisposition.

Tlougan and colleagues are to be congratulated on expanding our database for clinical features of the disorder. Until such time that a registry be developed detailing the long-term prognosis of these patients, combined with modern molecular techniques applied to initial vesicular and erosive lesions to assess the ge-

netics and/or the potential infectious nature of the disorder, we will only be able to label the disease. Unlocking the mysteries of CEVDRSS will be most enlightening both intellectually and practically.

References 1 Cohen BA, Esterly NB, Nelson PF. Congenital erosive and vesicular dermatosis healing with reticulated supple scarring. Arch Dermatol. 1985;121:361–367.

2 Tlougan BE, Paller AS, Schaffer JV, et al. Congenital erosive and vesicular dermatosis healing with reticulated supple scarring: Unifying clinical features. J Am Acad Dermatol. 2013;69:909–915.

3 Hussain S, Venepally M, Treat JR. Vesicles and pustules in the neonate. Semin Perinatol. 2013;37:8–15.

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September/October 2014

Volume 12 • Issue 5

COSMETIC SCIENCE Howard A. Epstein, PhD, Section Editor

A Second Look at Vitamin D Howard A. Epstein, PhD

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he physiology of vitamin D from its synthesis in skin to its active form, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], was fully elucidated just prior to the 1980s. The vitamin D receptor (VDR) was found to be important for calcium homeostasis, bone development and mineralization, control of cell growth, and differentiation.

factors, the best known example being the retinoid X receptor.

Other coactivators provide tissue and target gene specificity.1 Identified in 1969, the VDR is a family of more than 150 proteins that includes receptors for steroid hormones including the retinoids, cholesterol metabolites, bile acids, isoprenoids, fatty acids, and eicosanoids.

Recent advances in gene transcriptional regulation are providing new insight into the vitamin and how it regulates gene transcription. There is considerable debate regarding the effects of vitamin D on skeletal and nonskeletal tissue. Skin contains the enzymatic machinery to metabolize vitamin D to its active metabolite, which regulates proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, and promotion of hair follicle cycling.

There are common polymorphisms identified with the human VDR. These polymorphisms, perhaps at one time considered minor genetic differences between individuals, may have health implications that vary depending on the nature of the polymorphism. For example, FokI, a vitamin D–related receptor, is a polymorphism correlated with reduced bone mineral density.1 FokI appears to be associated with influencing insulin secretion and insulin resistance. It has some regulatory involvement associated with the severity of metabolic syndrome via high-density lipoprotein cholesterol.2 VDR function is moderated by protein complexes that act as coactivators or co-repressors. A co-repressor termed hairless is found in skin and may regulate 1,25-(OH)2D– mediated epidermal proliferation and differentiation as well as hair follicle cycling.1

Exposure to UV-B radiation (280–320 nm) was shown to be the action spectrum for the generation of the active form of vitamin D. More than 1 million skin cancers are estimated to occur annually in the United States. Despite the risk of skin cancer, sun exposure to avoid vitamin D deficiency is recommended by some physicians.

This practice has led to a scientific discussion. The debate has extended into the cosmetics field as consumers and formulators of sunscreen products request guidance with respect to the most appropriate use of sunscreens and general sun protection and the desire to maintain appropriate levels of vitamin D in their body.

Function of the VDR The VDR is found in many tissues of the body. Most of the effects of 1,25-dihydroxyvitamin D are mediated by the VDR acting by regulating the expression of genes whose promoters contain specific DNA sequences termed vitamin D response elements. The VDR works in association with other transcription

Vitamin Pathway in Skin Skin is the only tissue currently known to complete the UV-B– induced pathway from 7-dehydrocholesterol to hormonally active calcitriol (1α, 25-dihydroxyvitamin D3, 1α,25(OH)2D3).

Calcitriol regulates cellular functions in keratinocytes. The antiproliferative effect of calcitrol is useful for treating psoriasis. D3 synthesis is important in the prevention of skin malignancies.2 Vitamin D analogs including calcitriol, calcipotriol, tacalcitol, and maxacalcitol have been synthesized for topical treatment of psoriatic skin, further supporting the theory of the importance of calcitriol function in skin.

From EMD Chemicals, Philadelphia, PA Address for Correspondence: Howard A. Epstein, PhD, EMD Chemicals, Cosmetic Actives, Performance Materials DivisionNAFTA Region, Philadelphia, PA • E-mail: hepsteinskincare@yahoo.com

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Low Vitamin D Levels Globally and UV Exposure Approximately one third of the world’s population has low vitamin D levels.3 Exposure of the body in a bathing suit to one minimal erythemal dose (MED) was reported to be eqivalent to ingesting approximately 10,000 IU of vitamin D3. Exposure of less than 18% of the body surface, hands, arms ,and face for 2 or 3 times per week to one third MED in the spring, summer, and autumn is predicted to provide more than adequate synthesis of vitamin D3.3,4 UV-B exposure increases calcitriol in several internal organs, which is postulated to provide antioxidant protection against various cancers.5,6 Exposure to higher levels of UV radiation is known to result in harmful effects to skin. An alternative approach to providing sufficient vitamin D is through oral supplementation; however, the long-term effects of vitamin D supplementation is not well understood. There is a report that such long-term vitamin D3 supplementation may even have adverse effects on serum lipids.7

of vitamin D–containing food was similar between both groups.

The SLC24A5Ala111 allele was negatively associated with nonsummer serum levels of 25(OH)D3.9 SLC24A5 and SLC45A2 genes are correlated with skin melanin index. In this study, only SLC24A5 remained significantly associated with serum vitamin D metabolite levels after adjustment for race/ethnicity, genetic ancestry, and melanin index.

Conclusions A survey of data published during the past few years appears to report contradictory findings. Frequently, the rationale for the contradictions is explained by the variation of study protocol, vitamin D assay techniques, and other related factors.

Perhaps it is appropriate to say that we have a vitamin D conumdrum.

References 1 Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: an endocrine society scientific statement. Endocrine Rev. 2012;33:456–492.

People with darker skin types produce less vitamin D related to their pigmentation. One study reported that there was no significant correlation between UV-B exposure and increase in vitamin D production in the skin (25-hydroxyvitamin-D3) of constituent or facultative pigmentation (light and dark) skin types.8 There was a positive correlation with baseline level of cholesterol.

A low natural level of cholesterol was found to be correlated with low vitamin D production.

2 Segaert S, Bouillon R. Epidermal keratinocytes as source and target cells for vitamin D. In: Vitamin D Endocrine System: Structural, Biological, Genetic and Clinical Aspects: Proceedings of the Eleventh Workshop on Vitamin D, Nashville, TN, USA, May 27–June 1, 2000. Norman AW, Bouillon R, Thomasset M, eds. 2000:583–590.

Another study conducted in the United States compared serum vitamin D (25(OH)D) levels in individuals with African ancestry with those with European ancestry.9 There were no significant differences between African American and European American participants with respect to age, sex, fish liver oil intake, vitamin D supplement use, calcium supplement use, glucocorticoid use, hours per week spent outdoors, current tobacco use, systolic blood pressure, and mean number of days past summer solstice when blood was drawn. None of the participants reported taking cholesterol-lowering drugs. Serum levels of 25(OH)D3 and 24,25(OH)2D3 were significantly higher among European American volunteers compared with African American volunteers for men and women in both groups. There was a higher frequency of African Americans with the SLC45A2374Phe/ Phe genotype and SLC24A5Ala/Thr and 111Ala/Ala genotypes. Intake

5 Hanada K, Sawamura D, Nakano H, Hashimoto I. Possible role of 1,25-dihydroxyvitamin D3–induced metallothionein in photoprotection against UVB injury in mouse skin and cultured rat keratinocytes. J Dermatol Sci. 1995;9:203–208.

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3 Reichrath J. Protecting against adverse effects of sun protection? J Am Acad Dermatol. 2003;49:1204–1206.

4 Holick MF, Jenkins M. The UV Advantage. iBooks. New York, NY: Simon & Schuster Inc; 2003:94–120.

6 Lee JH, Youn JI. The photoprotective effect of 1, 25-dihydroxyvitamin D3 on ultraviolet light B-induced damage in keratinocyte and its mechanism of action. J Dermatol Sci. 1998;18:11–18.

7 Bogh MK, Schmedes AV, Philipsen PA, Thieden E, Wulf HC. Vitamin D production after UVB exposure depends on baseline vitamin D and total cholesterol but not on skin pigmentation. J Invest Dermatol. 2010;130:536– 553.

8 Wilson RT, Roff AN, Dai PJ, et al. Genetic ancestry, skin reflectance and pigmentation genotypes in association with serum vitamin D metabolite balance. Horm Biol Clin Investig. 2011;7:279–293.

A Second Look at Vitamin D

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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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September/October 2014

Volume 12 • Issue 5

PHOTO CAPSULE

Acquired/Post-Traumatic Ectopic Nail: Onychoheterotopia Virendra N. Sehgal, MD;1 Kingshuk Chatterjee, DNB;2 Anita Chaudhuri, MD;2 Gautam Chatterjee, MS2

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19-year-old native Indian reported a slow-growing, painless, hard projection over the distal phalanx of the left thumb following a fish bone prick 6 years ago. It progressed since then from a pinhead to the present size. A family history of any similar disorder was denied. He had no past consultation for the condition. Skin surface examination of the dorsum of the left thumb revealed a well-defined, shiny keratotic plaque 2×2 mm along the length of the medial aspect of the distal phalanx. It had a depression over the proximal end. Its color, shape, texture, and thickness resembled the nail plate (Figure 1a and 1b). It was nontender, and the skin surrounding the plaque was normal. Anteroposterior and oblique views on radiography of the left hand did not show any bony abnormality of the left thumb or distal phalanx or any connection between the plaque and the underlying soft tissue/bone (Figure 2). No visible rudimentary/supernumerary structure was identified.

Acquired/post-traumatic ectopic nail (onychoheterotopia/onychoheterotropia) is a rare and challenging disorder.1,2 It may sometimes present as ectopic plantar/calcaneal nail.3,4 The term onychoheterotopia suggests nail tissue growth outside the classic nail unit of the dorsal fingers and toes, presenting either as small outgrowths of a, unusual nail or a complete double fingernail malformation.5 Nail biology6 is important in the understanding and identification of such morphological abrasions. The current report is an extraordinary example triggered by a fish bone prick injury. It was insidious and became apparent only after years of progression. It is therefore worthwhile to take stock of congenital ectopic nail.7–9 It may either be exclusive or associated with other well-establish congenital anomalies, namely congenital palmar nail syndrome8 and ectopic nail with polydactyly.9 The surgical resection of the accessory nail deformity and underlying nail matrix is the procedure of choice for treatment.1

Figure 1. Keratotic plaque on the medial aspect of the distal phalanx of the left thumb.

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, India;1 and the Department of Dermatology, Burdwan Medical College and Associated Hospital, Burdwan, West Bengal, India2 Address for Correspondence: Virendra N. Sehgal, MD, 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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Photo capsule References 1 Mahdi S, Beardsmore J. Post-traumatic double fingernail deformity. J Hand Surg Br. 1997;22:752–753.

2 Rajashekar M, Bhandary S, Shenoy M, Sali AR. Posttraumatic ectopic nail. J Postgrad Med. 2006;52:218.

3 Ena P, Mazzarello V, Dessy LA. Ectopic plantar nail: a report of two cases. Br J Dermatol. 2003;149:1071– 1074.

4 Kopera D, Soyer HP, Gerz HK. Ectopic calcaneal nail. J Am Acad Dermatol. 1996;35:484–485.

5 Riaz F, Rashid RM, Khachemoune A. Onychoheterotopia: pathogenesis, presentation, and management of ectopic nail. J Am Acad Dermatol. 2011;64:161–166.

6 Sehgal VN, Aggarwal AK, Srivastava G, Chatterjee K. Nail biology, morphologic changes and clinical ramifications: Part 1. Skinmed. 2012;9:39–46.

7 Tomita K, Inoue K, Ichikawa H, Shirai S. Congenital ectopic nails. Plast Reconstr Surg. 1997; 00:1497– 1499.

8 Al-Qattan MM, Hassanain J, Hawary MB. Congenital palmar nail syndrome. J Hand Surg Br. 1997;22:674– 675.

Figure 2. Anteroposterior/oblique view of the left hand showing the left thumb.

9 Narang T, Kanwar AJ. Ectopic nail with polydactyly. J Am Acad Dermatol. 2005;53:1092–1093.

VINTAGE LABEL

Courtesy of Lawrence Charles Parish, MD, MD (Hon) SKINmed. 2014;12:306–307

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September/October 2014

Volume 12 • Issue 5

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

Condyloma Acuminata and Mollusca Contagiosa: A Giant Manifestation in a Patient With Lupus Severino Persechino, MD;1 Claudia Abruzzese, MD;1 Cristiano Caperchi, MD;1 Flavia Persechino, MD;2 Tammaro Antonella, MD1 A 27-year-old woman with systemic lupus erythematosus since childhood and treated with immunosuppressive therapy for many years was referred to our clinic for the presence of widespread condylomatosis and mollusca contagiosum localized in the genital area. These lesions appeared 4 years before and had been treated with both surgery and topical immunomodulation therapy without resolution.

The patient stated that she had two sexual partners in that period, who showed no skin lesions. Cutaneous examination showed about 30 to 40 molluscoid lesions of 0.5 cm to 2 cm in diameter and widespread cauliflower-like condyloma acuminata (Figure) spread on the vulvovaginal and perianal region without any symptoms. At the time of observation, she was under treatment with corticosteroids and mycophenolate mofetil. (SKINmed. 2014;12:310–311)

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spectrum of hematologic examinations was performed, including complete blood cell count, hepatitis B and C markers, syphilis serology, and human immunodeficiency virus (HIV) antibodies; results were normal except for severe lymphocytopenia (lymphocytes were 8.7% in white blood cell count) and positivity for direct Coombs test, antinuclear antibodies, and Epstein-Barr virus antibodies IgG type. The patient was also screened for possible infection with chlamydia, with negative results.

Skin biopsy for each type of lesion was performed and histological examination confirmed the clinical diagnosis of condyloma acuminata and mollusca contagiosum. We also evaluated the human papillomavirus (HPV) genotype, to exclude the presence of oncogenic HPV within the skin lesions, with negative results.

We decided to treat the patient with weekly sessions of diathermocoagulatory therapy for genital warts and curettage for mollusca contagiosum, keeping the same dose of immunosuppressive therapy. At the present follow-up, she experienced complete resolution of the skin lesions.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with an unpredictable course that should be treated with corticosteroids or/and immunosuppressive agents, espe-

cially in the severe form of the disease.1 One of the main side effects of pharmacologic treatment is a decrease in immune system activity, particularly cell-mediated immunity and increased risk of infections.

In the case we described, molluscum contagiosum virus (MCV) and HPV occurred in our patient simultaneously. HPV genital lesions usually present with cauliflower-like condyloma involving the moist surfaces or keratotic and smooth papular warts localized on dry surfaces.2 MCV lesions in the genital area are characterized by translucent papules, typically umbelicated in the central area. In immunodepressed patients, mainly those with the human immunodeficiency virus, warty papules as well as giant mollusca are also observed.3,4 Patients with persistent cell-mediated immune defects caused by HIV infection or persistent iatrogenic immunosuppression are at increased risk for developing viral infections. Moreover, both viruses seem to have developed specific ways to escape host immune mechanism. HPV is able to avoid antigen presentation, to induce anti-inflammatory and immune inhibitory mechanisms, and inhibit cytotoxic T-cell function locally.5 MCV encodes specific proteins that can interfere with cytotoxic T-cell killing of MCV-infected cells and inhibit inflammation.6 Mycophenolate

From the Dermatology Unit, NESMOS Department, Sant’Andrea Hospital, University of Rome “Sapienza”1 and the Dermatologic Clinic, Policlinico Umberto I, University of Rome “Sapienza”, Rome, Italy2 Address for Correspondence: Claudia Abruzzese, MD, Dermatology Unit, NESMOS Department, Sant’Andrea Hospital, University of Rome “Sapienza,” Via di Grottarossa, 1035 00189 Rome, Italy • E-mail: abruzzeseclaudia@gmail.com

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Case Study mofetil, used to treat our patient, is an immunosuppressive drug with a prevalent cytotoxic action on lymphoid cells, the main effectors of cell-mediated immune response. Therefore, many factors are involved in the development of these skin lesions, related to the hematologic alterations in SLE, immunosuppressive therapy, and peculiar features of HPV and MCV. The case we present is not so unusual for the emergence of viral infections in an immunocompromised patient, with the simultaneous coinfection by the two viruses and widespread clinical manifestation.

References 1 D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007;369:587–596.

2 Handsfield HH. Clinical presentation and natural course of anogenital warts. Am J Med. 1997;102:16–20.

3 Lewis EJ, Lam M, Crutchfield CE 3rd. An update on molluscum contagiosum. Cutis. 1997;60:29–34.

4 Dlova NC. Giant molluscum in an HIV-positive patient.

Skinmed. 2010;8:350.

5 Frazer IH. Interaction of human papillomaviruses with the host immune system: a well evolved relationship. Virology. 2009;384:410–414.

Figure 1. Cauliflower-like condyloma involving the genital area associated with translucent papules, typically umbelicated in their central area, which are clinically compatible with the diagnosis of molluscum contagiosum virus infection.

6 Smith KJ, Yeager J, Skelton H. Molluscum contagiosum: its clinical, histopathologic, and immunohistochemical spectrum. Int J Dermatol. 1999;38:664–672.

“Incontinentia pigmenti Bloch Sulzberger.”

Moulage No. 245, made by Lotte Volger in 1924 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2014;12:310–311

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Volume 12 • Issue 5

CASE STUDY

A Turkish Patient With Hermansky-Pudlak Syndrome Gulsen Akoglu, MD;1 Selma Emre, MD;1 Ahmet Metin, MD;1 Gozde Kurtoglu, MD;1 Nihal Maslak Onursever, MD2

A 34-year-old woman presented to our outpatient clinic with photosensitivity, photophobia, and facial pruritus (Figure 1). She had brown eyes and fair skin, hair, eyelashes, and eyebrows since birth. Her sister had similar skin and hair pigments. The patient had no systemic disease and was not taking any medication. Her parents were second-degree relatives. A dermatologic examination revealed small hyperkeratotic papules with an erythematous background, minimal desquamation, and some excoriation over the nose, zygomatic arch, and forehead consistent with actinic keratosis and solar damage. An ophthalmological examination demonstrated impaired visual acuity (60/100 in both eyes, reaching 80/100 in the left eye with best correction). Hypopigmentation at the albinotic retinal midperiphery (Figure 2) by fundoscopy was noted. She had no nystagmus or strabismus. The patient had no complaints or symptoms of the neurological, gastrointestinal, or respiratory system, and she had no recurrent skin or systemic infection. (SKINmed. 2014;12:313–315)

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he had a history of abnormal gingival bleeding during oral surgery. Total blood cell count, liver and kidney function tests, fasting glucose and lipid profiles, and urinalysis were within normal limits. Results from stool occult blood tests were negative. Prothrombin time (PTT) was 10.3 seconds (11.2–13.2 seconds), the international normalized ratio (INR) was 0.9 (0.85–1.15), the activated partial thromboplastin time (aPTT) was 23.6 seconds (22–31 seconds), and the bleeding time was 1 minutes and 27 seconds (2–9 min). Results from platelet function tests showed that aggregation declined to 31.7% (83% to 100%) in the presence of adenosine diphosphate (ADP), 9.2% (80 % to 100%) with collagen, 12.1% (70% to 100%) with adrenalin, and 60.5% (70% to 100%) with ristocetin.

Based on these clinical and laboratory findings, the patient was diagnosed with Hermansky-Pudlak syndrome (HPS). Findings from chest radiography and pulmonary function tests were normal. Thoracic computed tomography (CT) revealed a bilateral emphysematous appearance without fibrosis. Findings from abdominal CT were normal.

The patient’s actinic keratosis had nearly disappeared after 1 session of cryotherapy and 3% diclofenac gel twice daily for 3

months. She was informed regarding the avoidance of drugs, such as aspirin and other anti-inflammatory agents; the risk of abnormal bleeding during surgery and physical trauma; the importance of using sunscreen and wearing sunglasses; and the need for periodic dermatologic examinations.

Discussion HPS is a rare, autosomal, recessively inherited disorder that presents as heterogeneous genetic mutations and clinical phenotypes.

The classical triad of HPS symptoms comprises tyrosinase-positive oculocutaneous albinism (OCA), a tendency toward bleeding that is secondary to dysfunctional platelet aggregation, and the accumulation of ceroid-like pigment (lipofuscin) in various cells.1,2 The syndrome was first described by Hermansky and Pudlak in 1959,2 and most reported cases originate in Puerto Rico, where the prevalence is approximately 1:1800.3 HPS is a form of syndromic albinism that combines features of albinism with extrapigmentary complications. Eight subtypes of HPS (HPS 1–8) have been defined recently, of which HPS1 is the most common and severe,3 characterized by restrictive pulmonary disease, granulomatous colitis, and bleeding diathesis. The clinical hallmarks

From the Dermatology1 and Second Ophthalmology Clinic,2 Ankara Ataturk Training and Research Hospital, Ankara, Turkey Address for Correspondence: Gulsen Akoglu, MD, Dermatology Clinic, Atatürk Training and Research Hospital, Bilkent, Ankara, Turkey • E-mail: gusemd@yahoo.com

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Case Study

Figure 1. Cutaneous albinism and actinic keratoses on the face of a patient with Hermansky-Pudlak syndrome (a, b).

Figure 2. Hypopigmentation at the albinotic retinal mid-periphery is seen in the fundoscopic examination of the right (a) and left eye (b).

of HPS4 are similar to HPS1, and HPS2 is the only subtype that is associated with immunodeficiency, presenting as neutropenia and recurrent infections. The other subtypes are mild in severity and have been reported in few patients.1,4,5 The clinical manifestations of HPS are attributed to defects in the development and function of lysosome-related organelles in various cells, such as melanocytes, platelets, neutrophils, type 2 lung epithelial cells, and macrophages.1 The development of melanocytes is normal, but pigment formation is impaired in melanosomes.

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The degree of cutaneous albinism varies between patientsâ&#x20AC;&#x201D;even in the same patient during their lifetime. Some patients can develop depigmentation that is similar to those with tyrosinasenegative OCA, especially in early childhood. In contrast, certain patients have obvious pigmentation, and their light skin color might be noticeable compared with close relatives. Many premalignant and malignant skin growths can develop on the skin of these patients.6 The ocular findings of HPS can present as translucent irides, hypopigmentation at the midperiphery, and albinoid retina caused

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Case Study

by pigment dilution. Nystagmus and strabismus can also be observed.7 In our case, the patient had OCA, actinic keratoses, and albinoid sections of the retina, which are oculocutaneous hallmarks of HPS.

complications and severe immunodeficiency. Melanosomes are also normal, but their transfer to keratinocytes is impaired. In our case, the typical oculocutaneous and hematologic findings supported our diagnosis of HPS.

Patients with HPS are usually diagnosed when detailed tests are performed for abnormal or recurrent bleeding,1,8–10 of which bleeding diathesis is a well-defined clinical feature. There are fewer or smaller dense bodies in the platelets than normal or none at all. Thrombocyte aggregation tests of HPS patients are abnormal because of the absence or scarcity of molecules, such as ADP and serotonin, which mediate secondary aggregation of platelets. Mild or massive life-threatening bleeding can occur.

Bleeding time is usually prolonged, but coagulation tests are within normal limits. Despite thrombocyte infusions and desmopressin therapy, which are usually needed to control bleeding, 10% of deaths in HPS are attributed to bleeding complication.

The bleeding diathesis in our patient was confirmed by coagulation test, and she was warned about the hemorrhagic complications of her disorder.

Conclusions Because HPS is linked to hemorrhagic manifestations and possible life-threatening complications, it should be part of the differential diagnosis of patients with albinism. Patients with HPS need periodic follow-ups to identify new skin growths and assess whether their organ systems are functioning properly.

References

In HPS, ceroid material can accumulate in various organ systems, particularly the lungs, intestines, kidneys, and heart.1,2 Pulmonary function tests, radiography, and thoracic CT show restrictive lung disease.11 Pulmonary fibrosis is the most common complication (50%) that causes death. Intestinal involvement presents as granulomatous colitis, for which infliximab is an effective treatment.12 In our case, only emphysematous changes in the lungs were observed, and the patient was advised to have regular follow-ups.

Eighteen Turkish patients with HPS have been reported in the Turkish and English literature,5,8–12 in 2 of whom interstitial lung disease11 and granulomatous colitis12 were noted. As in our case, most patients were diagnosed with HPS while they were examined to identify the cause of bleeding diathesis. The actual number of reported cases may be low, because HPS may be overlooked in Turkish patients; thus, its prevalence is likely to be higher than expected.

The differential diagnosis of HPS includes nonsyndromic OCA disorders (OCA 1–4) and syndromic OCA disorders, such as Chediak-Higashi (CHS) and Griscelli syndrome (GS), both of which have systemic manifestations.6 To some extent, patients with nonsyndromic OCA present with findings of OCA; however, no systemic or laboratory abnormalities are detected. CHS and GS are autosomal, recessively inherited syndromes, like HPS, but they are usually accompanied by serious neurological

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1 Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syndrome and related disorders of organelle formation.

Traffic. 2000;1:823–835.

2 Hermansky F, Pudlak P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: report of two cases with histochemical studies. Blood. 1959;14:162–169.

3 Carmona-Rivera C, Golas G, Hess RA, et al. Clinical, molecular, and cellular features of non-Puerto Rican Hermansky-Pudlaksyndrome patients of Hispanic descent.

J Invest Dermatol. 2011;131:2394–2400.

4 Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res. 2006;19:19–42.

5 Korswagen LA, Huizing M, Simsek S, et al. A novel mutation in a Turkish patient with Hermansky-Pudlak syndrome type 5. Eur J Haematol. 2008;80:356–360.

6 Toro J, Turner M, Gahl WA. Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene.

Arch Dermatol. 1999;135:774–780.

7 Izquierdo NJ, Townsend W, Hussels IE. Ocular findings in the Hermansky-Pudlak syndrome. Trans Am Ophthalmol Soc. 1995;93:191–200.

8 Harrison C, Khair K, Baxter B, et al. Hermansky-Pudlak syndrome: infrequent bleeding and first report of Turkish and Pakistani kindreds. Arch Dis Child. 2002;86:297– 301.

9 Celebi H, Celebi S, Elkiran T, et al. Case report of a Hermansky-Pudlak Syndrome with ocular albinism and bleeding diathesis. Ret-Vit. 2006;14:63–66.

10 Kucuk N, Suher M, Koc E, et al. A case with HermanskyPudlak Syndrome. Turkish Med J. 2007;1:168–170.

11 Ciledag A, Cirit Kocer B, Kokturk N, et al. A rare cause of interstitial lung disease: Hermansky-Pudlak syndrome.

Tuberk Toraks. 2011;59:85–88.

12 Erzin Y, Cosgun S, Dobrucali A, et al. Complicated granulomatous colitis in a patient with Hermansky-Pudlak syndrome, Successfully treated with infliximab. Acta Gastroenterol Belg. 2006;69:213–216.

Hermansky-Pudlak Syndrome

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September/October 2014

Volume 12 • Issue 5

correspondence

A Scarring Reaction to the Treatment of Basal Cell Carcinoma With Ingenol Mebutate Nhan M. Nguyen, MD;1 Anne Marie Tremaine, MD;2,3 Christopher B. Zachary, MBBS2 To the Editor: Basal cell carcinoma (BCC) is the most common human malignancy. Current treatment modalities, depending on risk, include surgical techniques, such as excision, Mohs micrographic surgery, and curettage and electrodessication. For nonsurgical candidates, treatment options include radiation therapy and topical therapies, such as 5-fluorouracil, imiquimod, photodynamic therapy, and vigorous cryotherapy.1 Ingenol mebutate gel (Picato; LEO Pharma, Ballerup, Denmark) is approved by the Food and Drug Administration for the treatment of actinic keratosis but has been found to be effective in the treatment of nonmelanoma skin cancers (NMSCs), including its emerging use in the treatment of superficial BCC.2,3 The treatment regimen for superficial BCC with ingenol mebutate is once daily for 2 days (either consecutive days or 1 week apart).2,4 In a phase IIa study, the incidence of adverse events was low, where one patient treated with ingenol mebutate gel 0.05% on consecutive days for superficial BCC experienced severe flaking, scaling, and dryness, extending beyond the application site.2 There have been no reports of treatment-related scarring with the use of ingenol mebutate. We report a patient who was treated with ingenol mebutate gel for BCC and developed a scarring reaction at the treatment site.

Clinical Record A 62-year-old Caucasian woman presented with a 2-month history of a 1-cm pearly pink thin plaque on the chest. Results from biopsy confirmed the diagnosis of superficial and micronodular BCC. The patient had two previous excision scars on the chest and requested a nonsurgical therapy. The BCC was treated with light curettage, and the patient was instructed to use ingenol mebutate gel 0.05% the following day, once daily for 2 consecutive days. Three days later, the patient returned complaining of

Figure 1. One day post-treatment with curettage and ingenol mebutate for basal cell carcinoma.

a vigorous reaction on the chest, as well as fever, chills, and insomnia. On examination, the patient was afebrile; the skin was erythematous with areas of erosion (Figure 1). The reaction extended 2 cm beyond the area of treatment, and there was no evidence of infection. Her systemic symptoms resolved spontaneously after 7 days. At 3-month follow-up, the patient presented with a pruritic, linear, pink, indurated, and raised scar measuring 9 mm at the BCC site (Figure 2). The scar was treated with intralesional kenalog on two occasions (2.5 mg/mL and 10 mg/mL), 2 months apart, with three treatments with a nonablative 1550 nm fractional laser device (settings: 70 mJ, 11%–26% overlap, 4–6 passes) used in combination with a nonablative 1927 nm fractional device (settings 10 mJ, 40%–50% overlap, 4 passes).

The scar softened gradually with each treatment.

Topical ingenol mebutate gel therapy in the treatment of actinic keratosis and NMSCs has generally been regarded as safe and

From the Department of Medicine, University of California School of Medicine, San Francisco, Fresno, CA;1 the Department of Dermatology, University of California Irvine School of Medicine, Irvine, CA;2 and the Department of Dermatology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA3 Address for Correspondence: Anne Marie Tremaine, MD, Massachusetts General Hospital, Harvard Medical School, Department of Dermatology, Boston, MA 02114 • E-mail: amt1998@gmail.com

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correspondence come occurred from increased absorption of ingenol mebutate in a wound. Going forward, we recommend allowing the site to fully heal before initiating treatment with ingenol mebutate.

The potential adverse events of combination treatment should be discussed with the patient when selecting treatment options.

Further studies are needed to assess the safety profile and adverse events of ingenol mebutate. Topical ingenol mebutate remains a promising short-course therapy in the management of actinic keratosis and NMSCs. References 1 National Comprehensive Cancer Network. Basal and squamous cell skin cancers, version 2.2012. http:// www.nccn.org/professionals/physician_gls/pdf/nmsc. pdf. Accessed September 1, 2012.

Figure 2. Three months post-treatment with curettage and ingenol mebutate for basal cell carcinoma.

2 Siller G, Rosen R, Freeman M, et al. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol. 2010;51:99–105.

effective, with common side effects that are well-tolerated. The most common local skin reactions are erythema, scabbing/crusting, flaking/scaling, and vesiculation.4 Our patient illustrates the potential for acute systemic symptoms and scarring that can occur in treating BCCs with curettage in combination with topical ingenol mebutate gel applied the following days. The combination treatment is useful but it is likely that the patient’s out-

3 Ramsay JR, Suhrbier A, Aylward JH, et al. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br J Dermatol.

2011;164:633–636.

4 Ogbourne SM, Hampson P, Lord JM, et al. Proceedings of the First International Conference on PEP005. Anticancer Drugs. 2007;18:357–362.

The Washington Erythrodermics William Abramovits, MD To the Editor:

Pros:

While driving to work and listening to National Public Radio, I heard sports commentator extraordinaire Frank Deford expound upon the oh-so-relevant issue of the renaming of a football team whose name is deemed politically incorrect by some. I had an epiphany—I should propose “Washington Erythrodermics” to Mr Daniel Snyder, the team owner, and to the National Football League.

1. Erythroderma can affect everyone, regardless of racial, economic, social, regional, and age barriers.

1. It may take a while for the general public to grasp the concept. Erythroderma does not exactly roll off of the tongues of the populace with the ease that redskin does.

2. Erythroderma crosses disease barriers, as it can complicate psoriasis (7.4 million people affected in the United States), eczema (31.6 million), contact dermatitis (everybody is at risk), stasis dermatitis (10 to 20 million, depending on who you read), seborrheic dermatitis (30+ million, more if we include the one related to HIV), pemphigus and pemphigoid (40,000), CTCL/Sézary syndrome (200,000), and drug eruptions (everybody is at risk).

That still does not include the idiopathic (another everybody)!!

2. Surely, the reader will find a few others.

As at least one third of the US population is at risk for eryth-

Cons:

From the Dermatology Treatment & Research Center, Dallas, TX Address for Correspondence: William Abramovits, MD, Dermatology Treatment & Research Center, 5310 Harvest Hill Road, Suite 160,Dallas, TX 75230 • E-mail: dra@DermCenter.us

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correspondence

roderma, this would be a good opportunity to become familiar with the term.

What a conscientizing campaign! The American Academy of Dermatology should get behind it, and the NFL will get the kudos.

Of course, you may think this political correctness is nonsense

and that the Washington team should stay as named.

In my next essay, I may take on the issue of the Atlanta Pluckys, a name that has to do with “hair plucking disorder.” For now, avoid the term trichotillomania, because it is not a mania—a psychotic behavior.

Bilateral Yellow Plaques on Eyelids Treated

by FDA-Approved Novel RF Pixel Technology for Skin Resurfacing Geeta Oberoi, DPD; Archana Dharankar, DNB To the Editor: A 52-year-old woman presented to us with bilateral symmetrical soft, creamy yellow plaques on the upper and lower eyelids, present for 10 years (Figure 1). The plaques had progressed slowly in size, were permanent, and had coalesced over time, with no preceding history of trauma. Her medical history revealed generalized vitiligo, present since the age of 6.

Examination revealed the plaque sizes to be horizontal length by vertical length): left eye: upper eyelid=1.7x1 cm, lower eyelid=2.5x1.8 cm/corner 0.5 cm; right eye: upper eyelid=1.5x0.7 cm/lower eyelids=2.3x1 cm/corner 0.6 cm.

Figure 1. Patient with Xanthelasma palprebrum involving bilateral upper and lower eyelids before treatment.

Results from laboratory tests revealed serum cholesterol to be 281.5 mg/dL in 2013 (normal range up to 200 mg/dL) and high-density lipoprotein triglycerides 82.1 mg/dL in 2011 to 63.5 mg/dL in 2013.

Low-density lipoprotein cholesterol increased from 129.4 mg/dL to 203.1 mg/dL. The patient underwent a cardiovascular consultation and was started on atorvastatin 10 mg and aspirin 75 mg.

Our patient was concerned about the cosmetic changes of the lesion, therefore she elected to be treated by novel fractional microplasma radiofrequency technology device (Pixel RF; Alma Lasers, Caesarea, Israel), which is a minimally ablative fractional technology that uses unipolar radiofrequency (RF) technology to provoke plasma sparks, creating multiple controlled microperforations on the skin (Figure 2). The depth and diameter of these, depending on the RF power, vary from

Figure 2. Patient during treatment showing crusting and oozing in the affected areas.

From the Skin & You Clinic, Maharashtra, India Address for Correspondence: Geeta Oberoi, DPD, Skin & You Clinic, 115-B-Mittal Court, Nariman Point, Mumbai-21, Maharashtra, India • E-mail: dr.geeta.oberoi@gmail.com

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Figure 4. After 4 treatments and a follow-up of 1 year, no scar tissue was seen; however, repigmenting slowly appeared caused by history of vitiligo in the patient.

Figure 3. Clearing of the Xanthelasma palpebrarum after 2 treatments.

100 mm to 150 mm in depth and from 80 mm to 120 mm in diameter.

The technology was applied using a 12-mm stationary tip or roller tip. The first session was started with 35 W to 40 W using the stationery tips and the roller at the edges, and a total of 24 KJ to 27 KJ of energy was delivered to each eye. The clinical end point was erythema to pinpoint bleeding. Each treatment was

performed at 3- to 4-week intervals for 4 sessions (Figure 3). Post care was advised. A preliminary study using reflectance confocal microscopy showed that, at 50 W, most of the epidermis and some of the papillary layers ablated and a collateral coagulation zone formed.

At the end of the 4 sessions, the patient was satisfied with the results (Figure 4).

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

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Volume 12 • Issue 5

Book Review Jennifer L. Parish, MD, Section Editor

Ackerman’s Dictionary of Dermatohistology and Dermatohistopathology Collected by Charles Steffen, M.D.

By Steffen C. Oceanside, CA: private printing. 2014. Page 136. charlessteffen@cox.net

C

harles Steffen, MD, has been a prolific contributor in the realms of dermatology and dermatopathology, often writing about giants in the fields from both a professional and historical perspective. His latest contribution is an exhaustive compilation of terms, definitions, and viewpoints of the infamous A. Bernard Ackerman (1936–2008) with whom he collaborated for many years.

Doctor Steffen honors the late Dr Ackerman with a concise and straightforward collection of “Bernie-isms” that those of us who knew him, worked with him, or studied his work, recognize with due sorrow or a heartfelt chuckle. Some of them decades old, they still carry the same bite, clarity, and logical simplicity that defined him. Bernie himself in his everlasting search for truth in dermatohistopathology redefined others.

There are only 14 references, a fraction of Bernie’s published works, but, from within them, Dr Steffen captured the world of dermatohistology and dermatohistopathology that Bernard Ackerman built and many of his views that were the subject of profound, spirited controversy.

The work is admirably comprehensive and a true dictionary of terms, a project Bernard Ackerman himself pursued for decades but failed to complete. Through this book, Ackerman’s concepts and definitions will live on, even though most of his texts are out of print and almost impossible to obtain. Equally so, it will continue to be a thorn in the side of the ill-fated who came into his crossfire and were hopeful the disputes would remain buried with him (“Words, terms and phrases to avoid”). From the viewpoint of a reasonably impartial reader, it is fascinating to see which of Bernie’s observations were “survivors” and which the test of time proved wrong.

It is a pity the section entitled “When you see - think” is not longer, as it provides such valuable practice pearls for daily sign-outs.

There are many typos and some leftover highlighting throughout the work, so a thorough copyediting would be much appreciated, but otherwise, the book is a must-have for Bernie Buds, dermatopathologists in training and in practice (who will find epiphany in some of the beautiful definitions), and all who are thirsty for knowledge in the field and a historical perspective of some of the battles of the giants.

Reviewed by Vesna Petronic-Rosic, MD, MSc, Associate Professor of Dermatology, University of Chicago Pritzker School of Medicine, Chicago, IL 60637 • E-mail: vprosic@yahoo.com

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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.