Skinmed Journal - July/August 2014

July/August 2014 • Volume 12 • Issue 4 EDITORIAL A Case for History: Why We Should Remember Measles Kornreich and Parish

case studies Antinuclear Antibody Seropositivity in Men With Cutaneous B-Cell Lymphoma of the Scalp Rangwala and Duvic

COMMENTARY Intravenous Contrast and Iodine Allergy Myth Lovenstein, Beck, and Dweck

ORIGINAL CONTRIBUTIONS Jet Cryotherapy vs Clobetasol Proprionate Lotion in Alopecia Areata Faghihi and Radan

Surgical Hair Restoration and the Advent of a Robotic-Assisted Extraction Device Gupta, Lyons, Daigle, and Harris

Asymmetric Gait Nail Unit Syndrome: The Most Common Worldwide Toenail Abnormality and Onychomycosis

Linear Milia en Plaque on the Forearm Kumar and Gharami

Phytodermatitis to Euphorbia Trigona Darlenski, Kazandjieva, and Tsankov

CORRESPONDENCE Primary Localized Cutaneous Amyloidosis: A Clinical Diagnosis Grönhagen and Tey

BOOK REVIEW Dermatopathology Primer of Inflammatory Diseases Spielvogel

Zaias, Rebell, and Escovar

Tinea Lucidum or Dermatophytosis of the Stratum Lucidum: Is the Epidermal Location of Dermatophyte Infection Evolving?

Mao, Dasgupta, Keller, Lee, and Sahu

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Saying What You Know and Not What You Don’t: Clarity in Dermatopathology Reports Wassef, Sharma, and Lambert

NEW THERAPY UPDATE Efinaconazole 10% Nail Solution: A Post–FDA Approval Update

Gupta, Simpson, Abramovits, and Scheinfeld

Lebanese Dermatological Society

THE HEYMANN FILE The Autoinflammatory Assault on Conventional Diagnostic Criteria Heymann

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

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

Rosacea is with her wherever she goes .

So is Finacea . ®

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

You have made Finacea® the #1 Dermatologist-prescribed topical rosacea brand.1

INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.

Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water.

Wash hands immediately following application of Finacea®.

Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings.

In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less.

Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

Please see Brief Summary of full Prescribing Information on adjacent page.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

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

TABLE OF CONTENTS July/August 2014 • Volume 12 • Issue 4

EDITORIAL

A Case for History: Why We Should Remember Measles ........................................................................... 203

Davida A. Kornreich, MD; Jennifer L. Parish, MD

COMMENTARY

Intravenous Contrast and Iodine Allergy Myth............................................................................................ 207

Scott Lovenstein, PharmD; Richard Beck, MD; Eli Dweck, MD

ORIGINAL CONTRIBUTIONS

Jet Cryotherapy vs Clobetasol Proprionate Lotion in Alopecia Areata ...................................................... 209

Gita Faghihi, MD, and Mohammadreza Radan, MD

Surgical Hair Restoration and the Advent of a Robotic-Assisted Extraction Device..................................... 213

Aditya K. Gupta, MD, PhD, FRCPC; Danika C. A. Lyons, MSc; Deanne Daigle, MSc; James A. Harris, MD

Asymmetric Gait Nail Unit Syndrome: The Most Common Worldwide Toenail Abnormality and Onychomycosis ............................................................................................................... 217

Nardo Zaias, MD; Gerbert Rebell, MS; Sandra Escovar, MD

Tinea Lucidum or Dermatophytosis of the Stratum Lucidum: Is the Epidermal Location of Dermatophyte Infection Evolving?............................................................................................ 226

Danlin Mao, BA; Trisha Dasgupta, BA; Matthew Keller, MD; Jason B. Lee, MD; Joya Sahu, MD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Saying What You Know and Not What You Don’t: Clarity in Dermatopathology Reports............................... 231

Cindy Wassef, BA; Divya Sharma, BA; W. Clark Lambert, MD, PhD

New Therapy Update

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

Efinaconazole 10% Nail Solution: A Post–FDA Approval Update................................................................. 235

Aditya K. Gupta, MD, PhD, FRCPC; Fiona C. Simpson, HBSc; William Abramovits, MD; Noah Scheinfeld, MD, JD

The Heymann File

Warren R. Heymann, MD, Section Editor

The Autoinflammatory Assault on Conventional Diagnostic Criteria........................................................... 240

Warren R. Heymann, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Antinuclear Antibody Seropositivity in Men With Cutaneous B-Cell Lymphoma of the Scalp....................... 244

Sophia Rangwala, AB; Madeleine Duvic, MD

Linear Milia en Plaque on the Forearm....................................................................................................... 250

Piyush Kumar, MD; Ramesh Chandra Gharami, MD

198

TABLE OF CONTENTS 2013 • Volume 12 11 • Issue 4 July/August 2014

Phytodermatitis to Euphorbia Trigona........................................................................................................ 253

Razvigor Darlenski, MD, PhD; Jana Kazandjieva, MD, PhD; Nikolai Tsankov, MD, Dr Sci

CORRESPONDENCE

Primary Localized Cutaneous Amyloidosis: A Clinical Diagnosis............................................................... 257

Carina M. Grönhagen, MD, PhD; Hong Liang Tey, MBBS, MRCP(UK)

ERRATUM ................................................................................................................................................. 258

Book Review

Jennifer L. Parish, MD, Section Editor

Dermatopathology Primer of Inflammatory Diseases................................................................................. 260

Richard L. Spielvogel, MD

ABOUT OUR JOURNAL

Editorial

SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760.

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

Lebanese Dermatological Society

199

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

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

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

Indications and Usage LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum in patients 18 years of age and older.

Important Safety Information • LUZU is indicated for topical use only and is not indicated for ophthalmic, oral or intravaginal use.

• LUZU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Caution should be exercised when LUZU is prescribed for nursing mothers.

Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies. © 2014 Valeant Pharmaceuticals North America LLC.

DM/LUZ/13/0004

• The most common adverse reactions in clinical

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

Please see full Brief Summary of Prescribing Information on adjacent page.

Reference: LUZU [prescribing information]. Bridgewater, NJ: Medicis, a division of Valeant Pharmaceuticals; 2013.

S: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)

July/August 2014

Volume 12 • Issue 4

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

202

Matthew J. Zirwas, MD Columbus, Ohio

July/August 2014

Volume 12 • Issue 4

Editorial

A Case for History: Why We Should Remember Measles Davida A. Kornreich, MD;1 Jennifer L. Parish, MD2

T

he past century has seen remarkable progress in the treatment of infectious diseases, resulting in decreased pediatric mortality. Antibiotics, antisepsis, and vaccines have obliterated many previously deadly illnesses. The last case of wild type polio in the United States was in 1993; the last case of smallpox was in 1949.1 While we should be lauded for the progress made, with this elimination comes forgetfulness. The medical community no longer recognizes diseases that, for centuries, were bread-and-butter medicine. The compartmentalization of medical training into subspecialties has exacerbated this forgetfulness by narrowing our knowledge base and impairing our ability to diagnose diseases that have the potential to be fatal.

The Story of Measles

Measles exemplifies a disease that the Centers for Disease Control and Prevention (CDC) describes as “extinct”; however, unlike polio or smallpox, cities in the United States continue to experience outbreaks. Since 2000, there have been between 37 and upwards of 330 cases of measles reported annually in the United States. Between January and June of 2014 alone, 334 cases were reported, mostly in major cities such as New York and Los Angeles. In developing countries, the incidence is considerably higher. For example, between January and April of 2014, the Philippines had more than 20,000 documented cases of measles. While the mortality rate in developed countries is low (1 or 2/1000 cases), third-world countries have mortality rates as high as 25% (mostly caused by secondary infections).2 Unfortunately, the disease is not extinct within and outside of the United States, and the infection can be fatal.

While working in the emergency department this spring, the lead author observed that the surrounding community experienced an outbreak of measles. Many younger physicians did not have firsthand experience of the illness, nor did many remember details from medical school about its presentation. Posters were

placed at every workstation to educate the staff, depicting images of the classic measles signs and elucidating typical symptomatology (Figure 1). Despite these visual aids, physicians became increasingly wary of any patient with a viral prodrome and an eruption. This resulted not only in the isolation of patients indiscriminately but also the wasting of resources and workforce time. This experience emphasizes both the importance of maintaining an awareness of “historic” illnesses and the need for treating physicians to have a basic knowledge of skin diseases.

The history of measles dates back thousands of years to the river valley civilizations between the Tigris and Euphrates and to ancient Egypt. The first North American case was recorded in 1657. Measles, sometimes called rubeola, was often associated with and even mistaken for smallpox as they both presented with erythematous papular eruptions.3,4 The 1677 writings of Thomas Thacher, “A Brief Rule to Guide the Common People of New-England How to Order Themselves and Theirs in the Small Pocks, Or Measels (sic),” highlights the importance of this disease in the early colonies.5 Colonists understandably feared smallpox and measles, as the two diseases recurrently reached rampant proportions, spreading sickness and death. Early epidemics of measles occurred in 1657, 1687–1688, and 1713– 1715, each with varying fatality. In 1772, the colonists suffered severely, with mortality reaching epic proportions; Charleston, South Carolina alone reported losing 800 to 900 children to the disease.6 As with smallpox, Native Americans experienced even greater losses than the colonists, and there were reports of measles epidemics decimating entire native encampments.6 Etiology and Clinical Manifestations The epidemiology and potential severity of measles infections stem from the nature of the virus itself. The measles virus is easily transmitted through the air by talking, sneezing, or coughing. After entering its host, it exhibits a long silent phase of approximately 8

From the Department of Dermatology, Mount Sinai Hospital, New York, NY;1 and the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Davida A. Kornreich, MD, Mount Sinai Hospital, Department of Dermatology, 5 East 98th Street, 5th Floor, New York, NY 10029 • E-mail: davida.kornreich@gmail.com

SKINmed. 2014;12:203–205

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© 2014 Pulse Marketing & Communications, LLC

July/August 2014

Editorial

THINK MEASLES IN ADULTS AND CHILDREN Fever

Rash AIRBORNE ISOLATION

Measles Prodrome • Fever ≥ 101°F (38.3°C) • Coryza (runny nose) • Cough • Conjunctivitis • +/- Koplik’s spots

Measles Rash • Maculopapular rash • Typically appears 2-4 days after onset of prodrome • Begins on face (hairline) and spreads to neck, trunk, and extremities lasting 5-6 days

NOTE: Even without rash, consider in patients with prodrome symptoms and known exposure to measles.

Put suspected cases on airborne isolation immediately!

(Use a negative pressure room if available, otherwise a single room with the door closed.)

Infection Prevention & Control: NYP/CU/MSCH/ACN: 305-7025; NYP/AH: 932-5219;

NYP/LM: 212-312-5976; Figure 1.Please Measles posterNYP/WC/WD/ACN: educating746-1754 hospital staff February about 28, 2014 use the Measles webpage for additional recommendations: http://infonet.nyp.org/measles/ measles presentation.

(Reprinted with permission by the Department of Infection Prevention and Control, New York Presbyterian Medical Center, New York, NY.)

Figure 3. A young man with typical morbilliform lesions on his face.

Figure 2. The characteristic Koplik spots seen on the buccal mucosa. (Courtesy of the Centers for Disease Control and Prevention Public Health Image Library, ID# 6111.)

to 12 days, during which the virus replicates and spreads systemically within the asymptomatic patient. Following this silent phase, the patient develops a nonspecific prodrome with fever, weakness, and anorexia. The patient may then begin coughing and develop conjunctivitis, photophobia, and Koplik spots (Figure 2). By day 2 to 4 of the prodrome, the characteristic dermatitis will appear, consisting of 3- to 4-mm blanching erythematous maculopapular lesions. These lesions classically present post-auricularly or along the hairline and spread to the face, body, arms, and legs until it reaches the feet7 (Figure 3 and Figure 4).

The mortality caused by the virus is caused by its ability to suppress the host immune system. Dormant diseases such as tuberculosis and syphilis may be reactivated, and bacterial superinfections can occur, leading to pneumonia or diarrheal illnesses.

SKINmed. 2014;12:203–205

Figure 4. Typical morbilliform eruption on body. (Courtesy of the Centers for Disease Control and Prevention Public Health Image Library, ID# 3168.)

The virus can also affect the brain, resulting in encephalitis with potential residual brain damage or deafness.7 Pleural effusion, otitis media, conjunctivitis, blindness, and subacute sclerosing panencephalitis are all potential side effects. The younger the patient and the more malnourished, the greater the risk of complications and death.6

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Why We Should Remember Measles

July/August 2014

Editorial

So What Happened?

Why is the medical community today unfamiliar with measles?

The answer lies in the history of the vaccine. In 1954, John Enders (1897–1985) and his laboratory first isolated the measles virus. Over the next 5 years, the laboratory grew the virus and attenuated it, determining its immunologic effect on monkeys before immunizing the first child in 1959. Early vaccination studies proved its effectiveness. In 1963, the United States licensed the use of the attenuated vaccine.8 The vaccine program was so effective that there were 481,530 reported measles cases in the United States in 1962, and only 22,231 cases in 1968. A decade later, the CDC and the Secretary of the Department of Health, Education, and Welfare announced the goal to eliminate measles from the United States by 1982.6 Although it was behind schedule, the CDC declared that this goal was “met” in 2000.

“Let no man be so foolish as to think that he has exhausted any subject for his generation.”9 As physicians, we should remember diseases of the past for they have the potential to return to the present.

References

Unfortunately, the term extinction is misleading. In the global migration that is part of this century, it is difficult to maintain true national disease elimination without international eradication. The program has been thwarted by allegations connecting the measles, mumps, rubella vaccine with autism. The allegations have been debunked, but they have resulted in a decline in immunization rates, diminishing the “herd” effect of vaccination. As a result, the measles virus remains alive and with it the need for healthcare professionals to recognize the disease and its potential devastating effects.

Conclusions Modern medicine has made phenomenal strides over the past hundred years, but measles serves as a reminder that even extinct diseases may reemerge. As William Osler (1849–1919) said,

1 Centers for Disease Control and Prevention Web site.

CDC: 60 Years of Excellence. Available at: http://www. cdc.gov/about/pdf/resources/timelinefoldout.pdf. Accessed May 10, 2014.

2 Centers for Disease Control and Prevention Web site.

Measles (Rubeola). Available at: http://www.cdc.gov/ measles/. Accessed May 10, 2014.

3 Drutz JE. Special Articles: Measles: Its history and its eventual eradication. Semin Pediat Infect Dis. 2001;12:315–1322.

4 Gastel B. Measles: a potentially finite history. J Hist Med Allied Sci. 1973;28:34–44.

5 Thacher T. A Brief Rule to Guide the Common People of NewEngland How to Order Themselves and Theirs in the Small Pocks, Or Measels. Boston, MA: John Foster; 1677:1.

6 Cliff A, Haggett P, Smallman-Raynor M. Measles: An Historical Geography of a Major Human Viral Disease From Global Expansion to Local Retreat, 1840–1990. Cambridge, MA: Blackwell; 1993: 26, 66, 220.

7 Oldstone MBA. Viruses, Plagues, and History. New York: Oxford University Press; 2000:73–78.

8 Katz SL. The history of measles virus and the development and utilization of measles virus vaccines. In: Plotkin SA, ed. History of Vaccine Development. New York: Springer; 2011:199–206.

9 Osler W. The rise of preventive medicine. In: The Evolution of Modern Medicine: A Series of Lectures Delivered at Yale University on the Silliman Foundation in April, 1913. Available at: http://www.gutenberg.org/ files/1566/1566-h/1566-h.htm. Accessed June 3, 2014.

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

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July/August 2014

Volume 12 • Issue 4

COMMENTARY

Intravenous Contrast and Iodine Allergy Myth Scott Lovenstein, PharmD; Richard Beck, MD; Eli Dweck, MD

P

rior to the administration of intravenous (IV) iodinated contrast, patients are appropriately asked about history of allergies. There is a commonly held belief in the medical community that a specific cross-reactivity between iodinated radiographic contrast material and other substances rich in iodine, such as seafood, exists. The purpose of this commentary is to highlight the fact that the concept of an iodine allergy is FALSE and could result in the inappropriate lack of utilization of IV contrast in patients who have intolerance to antiseptics or seafood.

What Is Iodine?

Iodine is an essential trace mineral that is necessary to sustain life. It is required for the synthesis of thyroid hormone. Ingested iodine is converted to iodide in the gut. There are many dietary sources of iodine including fish, iodized salt, meats, and iodates, used as preservatives in bread. The reactions to IV contrast, seafood, or antiseptics are not related to the presence of iodine.

Contrast materials are triiodinated benzoic acid derivatives that contain a small amount of free iodide in solution. Adverse reactions to contrast may be either idiosyncratic or nonidiosyncratic in nature. The mechanism of idiosyncratic reactions is unknown, but it is unlikely attributed to a specific immune response. In fact, these types of reactions are more likely caused by activation of complement or other mediators of the nonspecific immune system.

Nonidiosyncratic Reactions With regard to nonidiosyncratic reactions, the mechanism is more defined. Specifically, these reactions are caused by direct toxic or osmolar (ionic content of dye) effects. Adverse reactions to IV dye are observed in 5% to 8% of patients. They can be described as mild, moderate, and severe. With mild reactions, patients complain of warmth, nausea, and vomiting. With moderate reactions, symptoms include severe vomiting, swelling, and urticaria. These types of reactions occur in 1% of patients

receiving contrast dyes and frequently require treatment with antihistamines and steroids. Severe, life-threatening reactions (ie, anaphylaxis) occur in 0.1% of patients receiving contrast.1 Although iodine is not the cause of the allergy with contrast dyes, the iodine concentration has an effect on the severity of the reaction. The higher the iodine concentration, the greater the risk of adverse reaction.2 Hypersensitivity reactions to seafood always begin within 2 hours of exposure, are true allergies, and are likely immunoglobulin E– mediated.3 For example, 85% of patients with shellfish sensitivity have positive skin-prick tests to shrimp extract.4 This is the method of choice for determining tissue immunoglobulin E. The primary antigen in shellfish that is responsible for stimulating allergic reactions is the muscle protein tropomyosin. Although seafood may contain relatively high levels of iodine compared with other foods, the allergenic proteins are not iodinated, and seafood allergy does not depend on the iodine content of the seafood.5 What about the possibility of a relation between contrast material sensitivity and allergy to seafood? In an older study published approximately 40 years ago, 5% of 112,003 cases of intravascular ionic contrast administration resulted in a reaction. The relative risk of a reaction with seafood was 3%, which was comparable to that observed in patients with other food allergies;6 therefore, seafood allergy should be considered no differently from other food allergies, when considering the risk of reaction to iodinated contrast.

Antiseptics and Allegenicity How do antiseptics cause allergenicity? First, one needs to know some basics. The active agent in antiseptics is polyvinylpyrrolidone-iodine, of which povidone iodine or Betadine (Purdue Products L.P., Stamford, CT) is an example. Polyvinylpyrrolidone acts as a carrier that delivers complexed diatomic iodine directly to the bacterial cell surface.6 The reactions are not caused by iodine but rather other substances in the solution. These

From ARIA Health System, Philadelphia, PA Address for Correspondence: Eli Dweck, MD, Aria Health, 10800 Knights Road, Philadelphia, PA 19114.

• E-mail: Eli.Dweck@vrad.com

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substances are noniodinated copolymers (PVC/eicosene, PVP hexadecene) and have been reported to cause skin irritation and contact dermatitis.5 Severe anaphylactoid reactions to antiseptics are rare but several reports exist in which patients experience generalized urticaria and anaphylactic shock.

Less severe food and drug allergies (including mild or moderate seafood allergy) are not premedicated. Patients with a history of allergic-like reaction to iodinated contrast should not get contrast dyes, however, unless it is deemed absolutely necessary. If they must receive it, they should be premedicated.

References

Conclusions There is little evidence that elemental iodine or iodine is responsible for idiosyncratic reactions or povidone iodine dermatitis and zero evidence exists that iodine is the responsible agent in seafood allergy. Any cross-reactivity between iodine and contrast, seafood allergies, and povidone is unfounded. Due to this, shellfish allergy and sensitivity to iodine containing solutions are therefore not an absolute contraindication to iodinated contrast.

Patients reporting iodine or seafood allergy should be questioned as to the nature/severity of the reaction. A history of anaphylaxis to any food places the patient at a 3-fold risk of an adverse reaction to contrast material. At our institution, any patient with a known severe allergic reaction to any food or medication, requiring hospitalization or epinephrine, is premedicated with steroids.

1 Boehm I. Seafood allergy and radiocontrast media: are physicians propagating a myth? Am J Med. 2008;121:e19.

2 Brockow K. Contrast media hypersensitivity: scope of the problem. Toxicology. 2005;209:189–192.

3 Daul CB, Morgan JE, Lehrer SB. Hypersensitivity reactions to crustacea and mollusks. Clin Rev Allergy.

1993;1:201–222.

4 University of California San Francisco. Iodine Allergy and Contrast Administration. http://radiology.ucsf.edu/ patient-care/patient-safety/contrast/iodine-allergy. Accessed March 18, 2013.

5 Katelaris CH. ‘Iodine allergy’ label is misleading. Aust Presc. 2009;32:125–128.

6 Shehadi WH. Adverse reactions to intravascularly administered contrast media. Am J Roentgenol Radium Ther Nucl Med. 1975;24:145–152.

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Volume 12 • Issue 4

Original contribution

Jet Cryotherapy vs Clobetasol Proprionate Lotion in Alopecia Areata Gita Faghihi, MD,1 and Mohammadreza Radan, MD2 Abstract Alopecia areata (AA) is a common disease of hair follicles. Cryotherapy has been employed to stimulate hair regrowth. The current investigation evaluated the efficacy of this method in patchy AA. Forty patients older than 5 years and with 120 recalcitrant patches were enrolled in the study. AA covered less than 50% of the patients’ scalps. In each individual, one lesion was treated with N2 jet cryotherapy once a week for a period of 12 weeks, while another lesion was treated with topical 0.05% clobetasol proprionate lotion. All patients were followed from weeks 2 to 16. Thirty-eight of 40 patients completed therapy. The overall response rate of patches was 80% in the cryotherapy group and 91.5% in the clobetasol group. Complete recovery (>95% terminal hair growth) was not obtained in any patient. Results from chi-square test showed no significant difference between improvements in AA in the two groups (reliability 95%). Pearson measurement showed a significant reverse relationship between diameter and duration of patches and the improvement rate in both groups. Liquid nitrogen jet cryotherapy can be a helpful modality in the treatment of AA. (SKINmed. 2014;12:209–211)

A

lopecia areata (AA) is a chronic inflammatory disease of the hair follicle usually manifesting as round or ovoid patchy areas of hair loss with discrete borders. AA is a common condition with no uniformly successful form of therapy.1,2 It is estimated to affect almost 2% of the US population.3 Mild, limited involvement of the scalp is the most common presentation; multiple patches may become confluent over time.

Regression may occur, with new hair growth taking place, and recurrences in different locations occur. More severe forms of the disorder, involving the entire scalp, eyebrows, eyelashes, axillary, pubic areas, or entire body also exist.4–6 AA, especially when severe, often profoundly affects the lives of those afflicted. Patients with AA who have a history of atopy may have a less favorable prognosis.7 Current investigative efforts strongly implicate CD4 and CD8 T-cell lymphocytes in the etiology of this disorder. The CD4+ killer T cell is an effector cell that causes hair bulb injury, triggering the AA.8,9 Although autoantibodies are postulated to play an integral role in the disease process, current research implicates a cell-mediated autoimmune mechanism as the underlying pathogenic etiology.

CD44v10 is believed to be involved in the activation mechanism of CD4 and CD8 lymphocyte migration into tissue and the initiation of the subsequent defense response against antigenic stimuli.10 Supporting this theory is that activated CD4 and CD8 T lymphocytes

have been found in a characteristic perifollicular and intrafollicular inflammatory infiltrate of anagen hair follicles.

Materials and Methods The inclusion criteria were as follow: age older than 5 years, AA coverage <50% of the scalp area, presence of at least 2 symmetrical patches over the scalp, maximum diameter of each lesion <9 cm, absence of any other severe medical illness, and no simultaneous immune-suppressive agent use, and discontinuation of any other treatment at least 8 weeks earlier.

Exclusion criteria included pregnancy, lactation, any new-onset medical systemic illness, progression of AA into >50% of the scalp area, severe hemorrhagic bulla, or any documented hypersensitivity to each of these procedures.

In each individual, one lesion was treated with N2 jet cryotherapy once weekly for a period of 12 weeks. The patients were matched by age and sex. A cryojet gun sprayed the liquid nitrogen onto the area for 3 to 5 seconds, until it became slightly frozen. After the frozen area thawed (about 3 to 5 seconds), a second spray was administered in the same manner. Meanwhile, another lesion on the same patient was treated with topical 0.05% clobetasol proprionate lotion twice daily for 8 weeks. All patients signed a written consent sheet and were followed every 3 weeks from weeks 2 to 16.

From the Department of Dermatology, Skin and Leishmaniasis Research Center,1 and Supervision Council in Medical Practice,2 Isfahan University School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Address for Correspondence: Gita Faghihi, MD, Department of Dermatology, Skin and Leishmaniasis Research Center, Isfahan University School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran • E-mail: g_faghihi@med.mui.ac.ir

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We recorded the side effects and amount of hair regrowth during the study. The evaluation was performed with clinical examination.

According to the extent of terminal hair growth, the lesions were grouped into 4 categories: good response (regrowth of >75% terminal hair), moderate response (regrowth of 50%–75% terminal hair), poor response (regrowth of 25%–50% terminal hair), and no response (regrowth of <25% terminal hair).

Results Thirty-eight of 40 patients (16 men, 22 women) completed the study. The patients’ ages ranged from 9 to 58 years. The mean age was 21 ± 3 years. The duration of disease ranged from 3 months to 10 years, and the average disease duration was 10 months. The two groups were not significantly different in regard to demographic characteristics and size and patterns of patches at baseline.

The average diameter of lesions in the cryotherapy group was not statistically different from the betamethasone group (3 cm and 3.5 cm). The partial hair regrowth was seen in 88% of patches in the cryotherapy group and 90% in the clobetasol group. No patients attained full hair regrowth in either group. One patient (2.5%) discontinued cryotherapy due to pain during cryojet spraying and dissatisfaction. The results in lesions treated with cryotherapy were classified as: good response, 21.5% (regrowth of >75% terminal hairs); moderate response, 30% (regrowth of 50%–75% terminal hairs; poor response, 34% (regrowth of 25%–50% terminal hairs; and no response, 14.5% (regrowth of <25%). In the group of lesions treated with topical clobetasol, results were as follow: good response, 32% (regrowth of >75% terminal hairs); moderate response, 35 % (regrowth of 50%–75% terminal hairs); poor response, 23% (regrowth of 25%–50% terminal hairs); and no response, 10% (regrowth of <25%).

Comparison of improvement rates between the two groups showed no significant difference (P=.75) by chi-square test (reliability coefficiency 95%). The response of lesions according to disease duration is presented below.

Good Response in the Cryotherapy Group A good response was seen in 41.5% of patients with lesions of less than 6 months’ duration, 32% of patients with lesions of 6 and 24 months’ duration, and 18% of patients with lesions of more than 24 months’ duration.

Analyses by Pearson measurement test showed that there was a reverse relationship between lesion duration and the rate of hair regrowth (r=–0.25, P=.037; r=–0.75, P=.045, respectively). In both groups there was a significant improvement compared with baseline status.

The response of lesions according to the diameter of patches is presented below.

Good Response in the Cryotherapy Group A good response was seen in 38% of patients with lesions <2.5 cm in diameter, 25% of patients with lesions between 2.5 and 5 cm in diameter, and 23.5% of patients with lesions >5 cm in diameter.

Good Response in the Topical Clobetasol Group A good response was seen in 45% of patients with lesions <2.5 cm in diameter, 37% in patients with lesions between 2.5 and 5 cm in diameter, and 18.5% in patients with lesions >5 cm in diameter.

Analyses by Pearson measurement test showed that there was a reverse relationship between lesion diameter and rate of hair regrowth (r=–0.25, P=.03; r=–0.8, P=.025; respectively). In both groups there was a significant improvement compared with the baseline status.

The Recurrence (by Definition) A loss of >50% of hairs or an increase of <50% in extent and size of the patches after good terminal hair regrowth occurred in 41% of patients in the cryotherapy group and 68% of patients in the betamethasone group; however, betamethasone-treated patches were more likely to show recurrences than cryotherapy-treated patches (chi-square reliability coefficient 95%; P<.05%).

The most frequent side effects in the cryotherapy group were short-term, transient erythema and mild stinging pain. There were no significant side effects associated with N2 application or betamethasone administration. One patient in the cryotherapy group discontinued treatment due to dissatisfaction and painful sensation.

In addition, no dyspigmentation occurred in areas treated by liquid nitrogen cryotherapy at the end of the trial.

Discussion

Good Response in the Topical Clobetasol Group A good response was seen in 45% of patients with lesions of less than 6 months’ duration, 28% of patients with lesions of 6 and 24 SKINmed. 2014;12:209–211

months’ duration, and 15% of patients with lesions of more than 24 months’ duration.

Various therapeutic agents have been described for the treatment of AA but none are curative or preventive. Cryotherapy has also been employed to stimulate hair growth in AA.13,14

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One investigation studying both children and adults revealed that hair regrowth in >60% of affected areas in 70 of 72 patients after 6 months only 3 of 66 patients had relapsed. The average size of their studied lesions was 2×3 cm.15 In our study, 23% of lesions showed a good response (regrowth of >75% terminal hairs) and 33.5% showed only a moderate response (ie, regrowth of 50%–75% terminal hairs) with cryotherapy treatment. The average diameter of our studied lesions were 3 and 3.5 cm in the cryotherapy and betamethasone groups, respectively.

A longer follow-up to see whether there are sustained results with cryotherapy is needed.

Acknowledgment The Vice Chancellory of Research and Technology of the Isfahan University of Medical Sciences supported our idea and provided the facilities to perform this trial.

References

The cause of such significant difference could be racial variation of response in autoimmune diseases, criteria of inclusion (eg, severity of hair loss at the start of trial), or a technical difference in the mode of treatment. In a Korean study, patients older than 50 years who underwent more than 3 weeks of treatment seemed to have a relatively poor response rate. Other patient-related factors such as sex, age, and demographic characteristics were not significant. There were no significant side effects, except for slight pain, swelling, and erythema.13 The overall improvement rate seen in the Korean study was significantly higher than that seen in our study.

In another study, the overall response rate was 66.7%. There seemed to be good response rates of 70.0% in women and 71.4% in AA multiplex. These data showed a better outcome than ours and the difference may be the result of shorter intervals of cryo application.14 The best mechanisms to explain the efficacy of cryotherapy in AA are vascular changes and immunomodulation.

According to some researchers, if cryotherapy is applied to diseases of the hair superficially, one can expect regrowth of the hair. The supposed mechanism is that cryotherapy dilates the vessels around hair follicles, thus improving follicular nutritional status. Their report showed superficial cryotherapypromote eyebrow hair growth in several patients with AA.13 In general, N2 cryotherapy in patients with AA can be an effective treatment. It is a simple and convenient method and has relatively good therapeutic response with fewer side effects than other treatments. We have reported our recent experience, which shows that cryotherapy with liquid nitrogen appears to promote hair growth in patients with AA. Cryotherapy in AA may be regarded as a safe, effective, and easily available treatment.

Conclusions We recommend superficial cryotherapy as an effective treatment for patients with a mild isolated form of AA, especially in children who are vulnerable to side effects caused by immunosuppressive drugs.

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1 Schwartz RA, Janniger CK. Alopecia areata. Cutis.

1997;59:238–241.

2 McElwee KJ. Third International Research Workshop on Alopecia Areata. J Invest Dermatol. 1999;112:822–844.

3 Safavi KH, Muller SA, Suman VJ, et al. Incidence of alopecia areata in Olmstead County, Minnesota, 1975 through 1989. Mayo Clin Proc. 1995;70:628–633.

4 Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol. 2000;42:549–570.

5 Sharma VK, Kumar B, Dawn G. A clinical study of childhood alopecia areata in Chandigarh, India. Ped Dermatol. 1996;13:372–377.

6 Shapiro J, Madani S. Alopecia areata: diagnosis and management. Int J Dermatol. 1999;38(suppl 1):19–24.

7 Tosti A, Morelli R, Bardazzi F, Peluso AM. Prevalence of nail abnormalities in children with alopecia areata. Pediatr Dermatol. 1994;11:112–115.

8 Todes-Taylor N, Turner R, Wood GS, et al. T cell subpopulations in alopecia areata. J Am Acad Dermatol.

1984;11:216–223.

9 McElwee KJ, Spiers EM, Oliver RF. Partial restoration of hair growth in the DEBR model for alopecia areata after in vivo depletion of CD4+ T cells. Br J Dermatol.

1999;140:432–437.

10 Gilhar A, Ullmann Y, Berkutzki T, et al. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest.

1998;101:62–67.

11 Kuflik EG. Cryosurgery updated. J Amer Acad Dermatol.

1994;31:925–944.

12 Lee BJ, Lee WS, Yoo MS, Ahn SK. Cryotherapy of alopecia areata. Korean J Dermatol. 1994;32:416–420.

13 Hong SP, Jeon SY, Oh TH, Lee WS. A retrospective study of the effect of superficial cryotherapy on Alopecia Areata. Korean J Dermatol. 2006;44:274–280.

14 Hyung OK, Seok D, Won S. Effect of cryotherapy with liquid nitrogen on alkopecia areata. Korean J Dermatol.1994;32:421–426.

15 Lei Y, Nie Y, Zhang JM, et al. Effect of superficial hypothermic cryosurgery with liquid nitrogen on alopecia areata. Arch Dermatol. 1991;127:1851–1852.

Jet Cryotherapy vs Clobetasol Proprionate Lotion

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July/August 2014

Volume 12 • Issue 4

Original contribution

Surgical Hair Restoration and the Advent of a Robotic-Assisted Extraction Device Aditya K. Gupta, MD, PhD, FRCPC;1,2 Danika C. A. Lyons, MSc;2 Deanne Daigle, MSc;2 James A. Harris, MD3 Abstract The number of surgical hair restorations performed worldwide is ever-increasing. Today’s gold standard in surgical hair restoration is follicular unit transplantation (FUT). FUT refers to the transplantation of individual follicular units (FUs) from the donor region to the recipient region. Strip extraction and manual FU extraction (FUE) are the most common methods for FU production. While strip extraction and manual FUE both hold individual merits, they are also associated with a number of limitations. The introduction of a robotic surgical assistive device may circumvent many of the limitations associated with traditional strip and manual FUE methods. As with all new technologies, however, the robotic device will require further independently funded, peer-reviewed, clinical testing to establish its efficacy relative to existing hair restoration methods in clinical practice. (SKINmed.

2014;12:213–216)

I

n their annual census, the International Society of Hair Restoration Surgery reported that more than 270,000 hair restoration surgeries were performed in 2010, and 85% were performed to treat androgenetic alopecia-related (AGA) hair loss.1 In Canada, the number of surgical hair restorations (SHRs) performed in 2010 had increased 63% from 2008;1 thus, it is evident that AGA-related hair loss is widespread and that the demand for minimally invasive, effective, and aesthetically pleasing hair restoration treatments are at an all-time high. This contribution will review recent advancements in the field of SHR, with a specific focus on robotically assisted SHR. Follicular Unit Transplantation: Strip/ Linear Extraction and Manual Follicular Unit Extraction

SHR procedures have improved substantially over the past 60 years or more. In the past, large 4.0 mm diameter circular grafts (also known as punch grafts) were excised from the donor region and transplanted onto the recipient region. Although successful in principle, the sizable grafts left an unnatural appearance and substantial scarring on the donor region. Today, individual, microscopically sized follicular units (FUs) (naturally occurring entities of 1 to 4 hairs) are excised and transplanted into carefully allocated recipient sites.3 FU transplantation (FUT) is the process whereby FUs are harvested individually and transplanted onto the recipient region. FUT is considered the gold standard in modern SHR, yielding the most natural-looking results. The two methods most often employed to produce FUs from the donor region are strip removal and manual FU extraction (FUE).1

Conventionally in SHR, scalp tissue from an area bearing “permanent” hair (also referred to as the donor region) is excised and transplanted into areas of the scalp bearing “nonpermanent” hair (also known as the recipient region).2,3 The rationale for transferring the hair in this way is based on the principle of donor dominance. Donor dominance refers to the robust phenomenon where a graft of hair-bearing tissue, when excised from the donor region and transplanted onto the balding scalp, continues to grow despite the relocation.2

During a strip excision, a lateral strip of hair-bearing tissue is excised from the donor region. The “safe zone” for excision is a lateral strip of scalp between the top and bottom of the ears that is considered at least risk for future miniaturization.4 The size of the excised strip is determined by first estimating donor density, which is the average number of FUs in the donor region (FU/cm2). To estimate donor density, a hand-held illuminated magnifier or digital imaging densitometer is used to view a 1.0 cm2 region of the donor scalp. The number of visible FUs in that

From the Division of Dermatology, Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 Hair Sciences Center of Colorado, Greenwood Village, Colorado3 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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region is tallied and extrapolated to estimate the number of total FUs on the donor scalp. To estimate the number of FUs required to adequately cover the balding region, a mathematical formula is applied that takes into account the estimation of donor density, the average distance between FUs on a typical human scalp, and the surface area of the balding region.5 From these parameters, the surgeon can estimate how many FUs will be required to cover the balding region to achieve a natural-looking distribution of hair.

Once the strip is excised, individual FUs are dissected under an illuminated binocular microscope. The FUs are cautiously separated from one another, trimmed to remove excess tissue, and stored in a preservative solution. A carefully designed pattern of recipient sites is then created with a needle or small slit blade and the FU grafts are inserted into these sites.

Strip extractions allow for cautious and accurate dissection of FUs from the donor strip with low rates of follicle transection; however, postsurgical scarring from the excision site can deter patients from pursuing the procedure. Specifically, if patients wish to wear a short hairstyle, the scarring left by the strip extraction can be difficult to conceal. Multiple surgical procedures are often required to adequately cover the recipient region; therefore scalp laxity must be considered prior to the original surgery to avoid scarrelated complications in the donor region. In addition, utilization of techniques such as the “single-scar technique” and trichophytic closure are necessary to avoid leaving multiple scars and/or highly visible scars on the donor region.

Robotically Assisted Follicular Unit Extraction An innovative robotic surgical assistive device, the ARTAS Robotic System from Restoration Robotics Inc. (San Jose, CA), may change the way SHRs are performed (Figure). The robotic system received 510(k) Food and Drug Administration clearance in 2011 and Canadian Medical Device Licensing in 2012.7,8 It may offer a means by which the demand for minimally scarring SHR can be offered to patients by reducing the time, complexity, and training constraints associated with the FUE. The robotic device is a physician-controlled, computer-assisted surgical tool equipped with an image-guided robotic arm and dissection tool.6,9 While undergoing a robotically assisted hair restoration procedure, patients are seated in a semi-prone position.

The hair in the donor region is shaved to approximately 1.0 mm long and a skin tensioning device is placed on the scalp that uses printed symbols on its borders to provide a frame of reference for the computer system. These markings ensure that the computer

In an FUE procedure, FUs are individually extracted from the donor region using a handheld punch measuring 0.8 mm to 1.1 mm and are stored in a preservative solution. In a similar fashion to a strip excision, the FUs are transplanted into carefully allocated recipient sites. A FUE procedure does not leave a postsurgical linear scar; therefore, patients are able to comfortably wear short hairstyles following surgery. FUEs are complex procedures, however, that require a great deal of training and practice to perform well. Less-experienced surgeons frequently experience high rates of follicle transection when performing an FUE. Indeed, even highly experienced surgeons can have difficulty in extracting individual FUs because although the hair may enter the skin at a particular angle, the follicle will often splay subdermally, increasing the likelihood for follicle transection during dissection. The success rate of manual FUE is highly dependent on the skill of the transplant surgeon and is associated with intersurgeon and intra-surgeon variability. Time, complexity, and training constraints associated with FUE can make it difficult for hair transplant surgeons to accommodate the demand for the procedure.6 SKINmed. 2014;12:213–216

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Figure. The ARTAS Robotic System from Restoration Robotics Inc. Surgical Hair Restoration

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targets only FUs within the parameters outlined by the skin tensioning device. Computer algorithms calculate the ideal angle of approach as well as the pressure and depth required to dissect the FU without transecting the follicle. A specialized dissection tool further assists in avoidance of follicle transection by breaking the dissection into two steps. First, a sharp inner needle scores the skin, then a blunt outer punch cores deep into the dermis, severing the connections that hold the FU in place.6,9 The FU is then manually removed and placed into a storage solution.

For many surgeons, the robotic device may decrease the time to complete an FUE procedure. A robotic-assisted device may offer increased accuracy and specificity in FU dissection, thereby minimizing the need for additional time and training associated with manual FUE. The robotic device could therefore offer physicians an effective, accurate, consistent, and minimally invasive means for performing an FUE procedure.

Robotically Assisted Follicular Unit Extraction in Clinical Practice

As with any surgical procedure, considerable precautions must be taken to avoid undesirable complications following surgery.

While using the robotic assistive device, dissection from areas bordering the “safe zone” of the donor region must be carefully monitored.11 Although FUs can feasibly be harvested from anywhere on the scalp, doing so heightens the risk of obtaining FUs susceptible to future hair loss. If “nonpermanent” hair were transplanted onto the recipient region, the hair would eventually miniaturize and result in a patchy and unnatural appearance.

The portion of the donor region considered at least risk for future miniaturization is a lateral strip of scalp between the top and bottom of the ears.4 In this region, the average number of FUs per square centimeter ranges from 65 to 85, although this number varies between ethnic groups.5 Careful assessment of the patients’ current degree of hair loss as well as their age, ethnicity, and family history are necessary to establish reasonable expectations for future hair loss.

Conclusions

Preliminary evaluation of the robotic device in clinical practice has led to optimistic performance and safety reports. A lead researcher in the development of the device performed a number of surgeries to compare his overall experience using robotic assistance for FUE with his experience performing manual FUE.9 He reported that the robotic device had comparable overall performance of FUE, improved consistency and a decreased overall rate of follicle transection.9,10 Preliminary reports have suggested that robotically assisted FUE consistently yields transection rates of ≤10%.7 It is important to note, that the robotic system is an assistive device only and not a substitute for the proficiency and attention to detail of a skilled surgeon. A robotic device is capable of aiding in the dissection of FUs under the guidance of a knowledgeable surgeon. A certain level of expertise is required to tactfully remove, trim, store, and insert FU grafts into recipient sites. It cannot reasonably be assumed that a surgeon with little or no experience in this field could perform an entire SHR with results comparable to that of a surgeon with many years of experience.

Robotically assisted FUE is a unique innovation in the field of SHR. Robotic assistance may not only circumvent many of the limitations associated with traditional strip extraction and manual FUE, but may also facilitate accessibility of the procedure to patients. As with all new procedures, technologies, and tools, however, robotically assisted FUE is not without limitations. As such, the robotic device should be recognized as an additional method of SHR and not as a replacement for existing techniques or skilled personnel.

Conflicts of Interest Authors Gupta, Lyons, and Daigle have no conflicts of interest to declare. Dr Harris is a principal investigator, consultant, and stockholder for Restoration Robotics.

References

There are few hair restoration clinics able to accommodate the demand for FUEs due in large part to the complexities associated with manual FUE. A robotic assistive device may facilitate accessibility of the procedure to the public. While robotic assistance may offer inexperienced surgeons a means for circumventing the complexities associated with manual FUE, it may not offer equivalent benefits to experienced surgeons. In fact, experienced FUE surgeons may observe little or no improvement in their overall performance.

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1 Relevant Research, Inc. International Society of Hair Restoration Surgery (ISHRS). 2013 Practice Census Statistics. 2013.

2 Orentreich N. Autografts in alopecias and other selected dermatological conditions. Ann N Y Acad Sci. 1959;83:463–479.

3 Rassman WR, Bernstein RM, McClellan R, et al. Follicular unit extraction: minimally invasive surgery for hair transplantation. Dermatol Surg. 2002;28:720–728.

4 Avram M, Rogers N. Contemporary hair transplantation.

Dermatol Surg. 2009;35 1705–1719.

5 Jimenez F, Ruifernández JM. Distribution of human hair in follicular units. A mathematical model for estimating the donor size in follicular unit transplantation. Dermatol Surg. 1999;25:294–298.

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ORIGINAL CONTRIBUTION

6 Vandruff C. How technology is changing the hair restoration industry. Aesthetic Trends Technol Anti-Aging.

2011:1–5.

9 Harris JA. Robotic-assisted follicular unit extraction for hair restoration: case report. Cosmet Dermatol.

2012;25:284–287.

7 Winnington P. Robotic surgery: with new technology come new opportunities. Pract Dermatol. 2012:1–2.

10 Berman D. New computer assisted system may change the hair restoration field. Pract Dermatol. 2011:32–35.

8 Harris JA. Robotic-assisted FUE may be the future of hair transplantation. Natl Hair J. 2011:1–6.

11 Harris JA. The risk of overharvesting with FUE. Hair Transpl Forum Int. 2013;23:86–87.

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Volume 12 • Issue 4

Original contribution

Asymmetric Gait Nail Unit Syndrome: The Most Common Worldwide Toenail Abnormality and Onychomycosis Nardo Zaias, MD; Gerbert Rebell, MS; Sandra Escovar, MD Abstract Asymmetric gait nail unit syndrome (AGNUS) is the result of asymmetric shoe pressure on the toes and foot caused by ubiquitous uneven flat feet that affect the gait. The pressure produces clinical changes in the toenails, which are identical to all clinical types of dermatophyte and opportunistic onychomycosis, yet they are dermatophytes-free. AGNUS produces additional signs that make it easy to identify. Its coexistence with fungal disease has resulted in reports describing new clinical types of onychomycosis, identifying signs of drug resistance, assessing severity index, and defining complete clinical cure when taking a systemic or topical antifungal, as well as “retronychia.” These signs are typically seen in the toenails of patients with AGNUS. AGNUS has a mechanical etiology and can coexist with dermatophytosis, which is a hereditary disease. AGNUS can coexist with any other disease affecting the toenails and results in greater clinical severity than each condition individually. AGNUS is and has been the most common worldwide toenail abnormality in shoe-wearing societies. (SKINmed. 2014;12:217–223)

M

ost patients with abnormal toenails who seek advice from physicians or their nail care professionals believe it is caused by a fungus. In reality, the most common worldwide toenail abnormality is caused by the pressure that closed shoes exert on specific areas of the toes and nails while walking. It is hard to believe that it wasn’t until recently that the asymmetric gait nail unit syndrome (AGNUS) has been described.1

In our medical education, it was never stressed enough that one side of our body is not a mirror image of the other. We examined patients with uneven eyes, mouths, and breasts, for example. We experienced the dissimilarities of one foot compared with the other when buying shoes. It was not until 2012, however, that this was scientifically proven—that one side of our body is not a mirror image of the other,2 and this is true for the soles of the feet. We are all born with uneven flat feet (Figure 1). While walking in closed shoes, the flatter foot changes its biomechanics and initiates pressure points to the foot and the toenails.

Depending on hereditary, each patient will develop clinical signs in the feet and toes, shortly followed by vertebral symptoms (fleeting skeletal pain). How can such a simple abnormality really exist? The investigators of evolutionary development who described the development of vertebrae in fish showed unequiv-

ocally that the ossification of each vertebra occurs asymmetrically;2 thus, one can say that we are born with a quantum of scoliosis. To prove this point, stand in front of a mirror with no shoes, feet together, and hands at the sides—you will be amazed to see that one of your shoulders is higher than the other. How does AGNUS affect dermatologists in particular? Because onychomycosis is in our territory of care, and AGNUS toenail changes are identical to all of the clinical types of onychomycosis as well as other conditions described in the literature. This has caused investigators unaware of AGNUS to describe new clinical types of onychomycosis and even toe nail conditions such as retronychia.

Onychomycosis In 1972, a clinical description of the clinical forms of dermatophyte onychomycosis was reported based on a biological approach of the host-parasite relationship,3 which included distal subungual onychomycosis (DSO). This infection solely of the nail bed (NB) corneocytes, producing varying degrees of NB keratosis, at times elevating the emergence angle of the nail plate (NP) but not causing onycholysis. Cases that show NP damage and onycholysis are caused by the host picking out the subungual debris. Figure 2 shows dermatophyte-negative AGNUS that is clinically identical to DSO.1

From the Division of Dermatology, Mount Sinai Medical Center, Miami Beach, FL Address for Correspondence: Nardo Zaias, MD, Department of Dermatology, Mount Sinai Medical Center, 4308 Alton Road, Suite 750, Miami Beach, FL 33140 • E-mail: nardozaias@aol.com

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ORIGINAL CONTRIBUTION

Figure 3.Clinical-like white superficial onychomycosis yet dermatophyte-free asymmetric gait nail unit signs. Note the curved nail plate (3 arrows) on left and onycholysis on right toe.

Figure 1. Uneven flat feet in a 2-year-old girl.

Figure 2. Dermatophyte-free asymmetric gait nail unit signs. Distal subungual onychomycosis–like presentation on left and characteristic medial bending of the nail plate matrix on the right (arrows). Shoe trauma results in onycholysis and nail bed keratosis.

Figure 4. Dermatophyte-free asymmetric gait nail unit signs. Severe onycholysis showing hallux with the characteristic medial bending of the nail plate and dyskeratosis caused by pressure, exactly as in white superficial onychomycosis.

White Superficial Onychomycosis White superficial onychomycosis (WSO) initially affects the onychocytes of the surface of the NP. It clinically appears as isolated whitish islands but also confluent large white areas of the surface. In the United States, Trichophyton mentagrophytes var. interdigitale, is the most common dermatophyte to produce WSO.4 Figure 3 and Figure 4 show dermatophyte-negative WSO-like AGNUS.1 At present, we are having doubts about the ability of a fungus to establish a sustainable infection of the surface of SKINmed. 2014;12:217–223

the NP without the association of friction or other trauma. It is interesting to note that in an attempt to reproduce dermatophyte onychomycosis, earlier investigators5 occluded toenails with live cultures of many dermatophytes. They scored the surface of the NP and found that after time, that as long as they had the toe occluded, the focus of “infection” on the NP surface remained.

When the occlusion was removed, however, it disappeared. The authors, swayed by the fact that T mentagrophytes destroys NP and Trichophyton rubrum rarely does,6 were confident in describ-

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ing T mentagrophytes as the most common dermatophyte in the United States to produce WSO at that time.

Proximal Subungual Onychomycosis Proximal subungual onychomycosis (PSO) is the presentation of a nail infection in an immunodeficient host. The invasion of the deeper layers of the NP are shaped like the lunula, suggesting an invasion originating proximally from the proximal nail fold and not distally from the hyponychium, as is seen in DSO. Patients have the fungus before they become immunodeficient. Figure 5 and Figure 6 show PSO-like dermatophyte-free AGNUS. Prevalence of AGNUS and Dermatophyte Onychomycosis The ability to recover a dermatophyte from a toenail that is clinically identical to any clinical type of onychomycosis has always been a challenge to physicians. In a small study in 1969, investigators studied 187 patients with clinical toenail abnormalities resembling onychomycosis.7 The recovery of dermatophyte fungi from patients with clinical onychomycotic toenails was only 23%.

Later studies investigating onychomycosis by various investigators of 5598 patients found similar results (23%–30%),8–11 leaving approximately 70% of dystrophic toenails that look like onychomycosis worldwide. It would appear logical to conclude that in shoe-wearing societies, AGNUS accounted for the overwhelming majority of these cases; however, it was not considered until much later. Aside from the clinical appearance of onychomycosis, it typically shows the mechanical influence of the closed shoe on the flatter foot. Shoes put pressure on the NP matrix and cause curving of the NP on one side only (Figure 7). The prevalence of AGNUS was so high that investigators believed they were describing “newer” clinical types of onychomycosis.

Figure 5. Dermatophyte-free asymmetric gait nail unit signs. Clinical appearance of proximal subungual onychomycosis.

Figure 6. Clinically proximal subungual onychomycosis yet dermatophyte free asymmetric gait nail unit signs.

Note hyperkeratosis caused by shoe pressure and asymmetric gait.

AGNUS and Onychomycosis Onychomycosis is a term that describes the physical inclusion of a member of the order Mycota in the nail unit. There are clinical syndromes where the appearance of the nail unit identifies a host-parasite relationship. Dermatophyte fungi and species of Scytalidium have evolved into a relationship with the skin, hair, and nails in humans and other animals where they can sustain a chronic course that is not self-healing.

In 1959, the first systemic antimycotic agent, griseofulvin, was used for the treatment of skin, hair, and nail infections caused by dermatophyte fungi.12 This initiated the decline of mycology in dermatology departments in the United States, because there was no longer a need to identify dermatophyte fungus, being that griseofulvin is effective for all of the conditions.

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Figure 7. Typical curvature of the nail plate in asymmetric gait nail unit signs.

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ORIGINAL CONTRIBUTION

Present Day Concept of Chronic Dermatophyte Syndrome by T rubrum T rubrum, a human obligate parasite, is worldwide in a normal host and causes superficial skin dermatophytosis and hair and nail disease that follows an autosomal dominant hereditary susceptibility pattern.13,14 If a patient does not have susceptibility, no sustainable contagion is possible. The fungus inhabits only the “dead” stratum corneum, as a “serum factor” prevents its deeper penetration in the epidermis.15 Metabolites produced by the fungus act as antigens and result in similar lesions as contact dermatitis16 but spread peripherally as the fungus grows on the surface of the skin. The clinical lesion, wherever it occurs, is the immunological response of the host and therefore can range from minimal to severe inflammation and scaling.

The initial infection of fungus is on the soles of the feet, typically acquired in the patient’s own household.13–17 Data on tinea pedis11 show a prevalence of 30% (T rubrum) at young ages, with a very small percentage of patients having onychomycosis. With increased age (50 years), onychomycosis rises to 30% and tinea pedis remains the same. The infection spreads from the soles to distant areas such as the groin (tinea cruris) and the glabrous skin (tinea corporis). Tinea palmaris and finger onychomycosis is less frequent. On the other hand, an immunocompromised host who asymptomatically had the fungus before becoming immunosuppressed may produce a severe clinical inflammatory reaction.

Figure 8. Dermatophyte-negative asymmetric gait nail unit signs appearing as distal lateral onychomycosis-like (the proposed 1998 classification).

Scytalidium sp (Hendersonula toruloidea), a soil saprophyte, can also cause a clinical picture identical to T rubrum dermatophytosis and onychomycosis.

Dermatophytes affect children differently than adults. Tinea capitis is found only in children. There are reported cases of children with unusual clinical presentations as WSO caused by T rubrum in the fingernails.18 The usual presentation is Trichophyton interdigitale in adult toenails. Candida albicans has been reported to produce the same type of onychomycosis in the fingernails of infants.19

Figure 9. Dermatophyte-free asymmetric gait nail unit signs appearing as total or endonyx onychomycosis look alike (the proposed new classification). It strongly suggests that patients can have both mechanical changes and dermatophyte infection.

New Classifications of Onychomycosis or Coexistence With AGNUS In 1998, distal lateral subungual onychomycosis was described,20 theorizing that the infecting agent comes from the lateral nail fold stratum corneum and invades the NB corneocytes. Unfortunately, the authors did not produce any evidence to validate this assumption. The name is misleading and they were likely describing a case of DSO and AGNUS. Figure 8 shows a toe with dermatophyte-free AGNUS that is identical to distal lateral subungual onychomycosis.

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In 1988, total invasion of the NP was a term coined to describe characteristic Trichophyton soudanense invasion of the entire thickness of the NP.21 It was later reclassified as endonyx onychomycosis in 1999.22 Thirteen years earlier, however, a description of a case of onychomycosis by T soudanense from Venezuela was characterized as DSO, not endonyx.23 Figure 9 shows dermatophyte-free endonyx-like AGNUS.

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Clinical Drug Resistance In 1996, a report associated drug resistance with a lateral lytic nail clinical sign that is characteristic of AGNUS (Figure 10).

Another report in 199624 explained the reason for drug resistance from a histologic cross section where some layering of the stratum corneum of the lateral nail fold epidermis was seen and believed that this layering of the horny layer of the proximal nail fold prevented passage of the antifungal agents into the NB. This is a common cutting artifact when the stratum corneum is cut near a harder structure such as the NP. Reclassification of the Clinical Types of Onychomycosis Reclassification of the clinical types of onychomycosis is again based on appearances rather than proof. Baran and colleagues included nails that, by appearance only, could have more than fungal involvement. In their original publication, Figure 5 shows an obvious AGNUS with its characteristic hyperkeratosis of the tip of the toe and the incurved NP. Also their Figure 7 shows a total dystrophic onychomycotic toe with distal hyperkeratosis, proximal nail fold paronychia and friction of the area.20 The investigators had no knowledge of AGNUS at that time.

Figure 10. Dermatophyte-free asymmetric gait nail unit signs with lateral onycholysis, supposedly a sign of drug resistance.

Definition of Cure A group of onychomycosis investigators have attempted to reclassify the definition of “a clinical cure” as being fungus-negative with some persisting clinical lesions.25,26 Figure 11 and Figure 12 show AGNUS and associated dermatophytosis, treated until cure of the dermatophyte was achieved but persisting with AGNUS. Clinical Severity Index To standardize patients for inclusion in studies, some investigators decided to create a clinical formula for the severity index for onychomycosis.27,28 The arbitrary classifications never considered AGNUS and therefore a new severity index is needed to only include dermatophyte onychomycosis and not both.

Opportunistic Onychomycosis The “opportunistic fungi” reported to produce onychomycosis are only commensals that can survive in the keratinous environment of the nail unit niche provided by AGNUS but did not initiate the infection. Retronychia,29 described as an unusual presentation of a toenail abnormality, is seen in cases of AGNUS (Figure 13 and Figure 14).

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Figure 11. Hallux with Trichophyton rubrum distal subungual onychomycosis and characteristic curvature in asymmetric gait nail unit signs. The dotted line shows junction-infected nail bed. Patient only received 7 consecutive days of terbinafine HCl 250 mg every 3 months.

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Figure 15. Asymmetric gait nail unit sign before treatment with open-toe shoes.

Figure 12. Results after 8 months of treatment in the same patient in Figure 11. Dermatophyte-free but clinical remnants of asymmetric gait nail unit signs still exist.

Figure 16. Same patient as in Figure 15, showing corrected asymmetric gait nail unit signs after 7 months using only open-toe shoes.

Figure 13. Asymmetric gait nail unit signs. Dermatophytefree left hallux, initial clinical (similar to retronychia).

Figure 17. Asymmetric gait nail unit signs cleared after 1 year using personalized insoles. (Pretreatment picture shown in Figure 8.)

Figure 14. Retronychia. Asymmetric gait nail unit signs in a 15-year-old female with scoliosis.

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Conclusions Correction of AGNUS can be achieved by wearing open-toe shoes or personalized insoles for the period of time that normal nail growth replaces the NP. Figure 15 and Figure 16 demonstrate the improvement 7 months after using open-toe shoes. Figure 17 shows improvement of AGNUS after using insoles for 1 year.

Disclosure Dr Zaias has been a consultant and an investigator for all major pharmaceutical companies that produce systemic antimycotics.

References 1 Zaias N, Rebell G, Casal G, Appel J. The asymmetric gait nail sign, a survey of fungus negative nail unit signs related to skeletal correctable abnormalities. SKIN/med.

2012;10:1–52.

2 Vilhais-Neto W, Maruhashi M, Smith KT, et al. Rere controls retinoic acid signaling and somite bilateral symmetry. Nature. 2010;463:953–957.

3 Zaias N. Onychomycosis. Arch Derm. 1972;105:263– 274.

13 Zaias N, Rebell G. Chronic dermatophytosis caused by Trichophyton rubrum. J Am Acad Dermatol. 1996;35:S17– S20.

14 Zaías N, Tosti A, Rebell G, et al. Autosomal dominant pattern of distal subungual onychomycosis caused by T. Rubrum. J Am Acad Derm. 1996;34:302–304.

15 Blank H, Sagami S, Boyd C, Roth F Jr. The pathogenesis of superficial fungus infection in cultured human skin.

Arch Derm. 1959;80:132.

16 Swerlick R. A review of cellular and molecular events in contact allergic dermatitis. Cutis. 2001;67(5S):25.

17 Ghannoum MA, Muherjee PK, Korman NJ, et al. Molecular analysis of dermatophyte spread of infection among household members. Cutis. 2013;91:237–239.

18 Ploysangam T, Lucky AW. Childhood white superficial onychomycosis caused by Trichophyton rubrum. Arch Dermatol. 1997;36:29–31.

19 Minomiya S, Nabekura K, Soh Y, et al. Does infantile onychomycosis recovers spontaneously. Skin Res.1968;10:655.

20 Baran R, Hay RJ, Tosti A, Haneke E. A new classification of onychomycosis. Br J Dermatol. 1998;139:567–571.

4 Zaias N. Superficial white onychomycosis. Sabouradia.

1966;5:99–103.

21 Kalter RJ, Hay RJ.Onychomycosis due to Tricophyton soudanense (and T violaceum) Clin Exp Dermatol.

1988;13:221–227.

5 Vilanova X, Cassanovas M, Francino F. Onychomycosis, an Experimental Study. J Invest Dermatol. 1956;27:77– 101.

22 Tosti A, Baran R, Piraccini BM, Fanti PA. Endonyx, a new modality of nail invasion by dermatophytes. Acta Derm Venereol. 1999;79;52–53.

6 Zaias N. The Nail in Health and Disease. 2nd ed. Appleton and Lange: Norwalk, CT; 1990.

23 de Albornoz MB, Diaz E, Cabral NA. [Onychomyosis caused by Trichopyton soudanense. 1st isolation in Venezuela]. Med Cutan Ibero Lat Am. 1975;3:1–6.

7 Zaias N, Oertel I, Elliot DF. Recovery of dermatophytes, molds and yeasts from 182 abnormal toe nails not psoriasis. J Invest Dermatol. 1969;53:140–142.

8 Gupta AK, Konnikov N, MacDonald P, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicenter survey. Br J Dermatol.

1998;139:665–671.

9 Gupta AK, Summerbell RC. Combined distal and lateral subungual and white superficial onychomycosis in toenails. Am Acad Dermatol. 1999;41:938–994.

24 Baran R, DeDoncker P. Lateral edge nail involvement indicates poor prognosis for treating onychomycosis with systemic drugs. Acta Derm Venereol (Stockh).

1995;76:82–83.

25 Elewski BE. A full “cure” for onychomycosis is not always possible. Arch Dermatol. 1999;135:852–853.

26 Scher R, Tavakkol A, Sigurgeirsson B, et al. Onychomycosis diagnosis and definition of cure. J Am Acad Dermatol.

2007;56:939–944.

10 Scherer WP, McCreary JP, Hayes WW. The diagnosis of onychomycosis in a geriatric population. A study of 450 cases in South Florida. J Am Podiatr Med Assoc.

2001;91:456–466.

27 Baran R, Hay R, Garduno JL. Review of antifungal therapy and the severity index for assessing onychomycosis: part 1. J Dermatol Treat. 2008;19:72–81.

11 Haneke E, Roseeuw D. The scope of onychomycosis: epidemiology and clinical features. Int J Dermatol.

1999;38(S2):7–12.

28 Carney C, Tosti A, Daniels R, et al. A new classification system for grading the severity of onychomycosis. Arch Dermatol. 2011;147:1277–1281.

12 Blank K, Roth FJ Jr, Bruce WW, et al. The treatment of dermatomycoses with orally administrated griseofulvin.

Arch Derm. 1959;79: 256–266.

29 de Becker DA, Richart B, Duhard F, et al. Retronychia, proximal ingrowing of the nail plate. J Am Acad Dermatol.

2008;58:9778–9983.

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COMING SOON

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July/August 2014

Volume 12 • Issue 4

Original contribution

Tinea Lucidum or Dermatophytosis of the Stratum Lucidum: Is the Epidermal Location of Dermatophyte Infection Evolving?

Danlin Mao, BA; Trisha Dasgupta, BA; Matthew Keller, MD; Jason B. Lee, MD; Joya Sahu, MD Abstract Dermatophyte infections are traditionally localized to the stratum corneum. The advent of immunosuppressants and topical steroid/antifungal preparations, however, has created a new phenomenon: dermatophytosis in the stratum lucidum. This atypical presentation manifests in 3 clinical scenarios: oral immunosuppression and/or medical comorbidities, lesions/body sites with lichenification, and sites on/near acral skin. In each setting, superficial potassium hydroxide (KOH) preparations have proved ineffective in diagnosis, despite high indices of suspicion for dermatophytosis. It is only under histologic examination that florid hyphal elements are identified. The authors propose a modified KOH technique requiring a sample of deeper, pathological scale-containing fungal elements to be used in scenarios where tinea lucidum or dermatophyte infection of the stratum lucidum may be present.

(SKINmed. 2014;12:226–230)

T

he potassium hydroxide (KOH) preparation in which a sample of stratum corneum is digested in 10% KOH and analyzed is typically used as a diagnostic test for fungal infections.

While renown as the tool of choice in determining dermatophytosis, the KOH examination was surprisingly insufficient within our clinical practice when we encountered several cases of suspected dermatophyte infection, which were only later diagnosed histologically.

Those cases shared significant similarities; for example, immunosuppressed patients refractory to topical antifungal treatment and patients treated with topical antifungal therapies both resulted in repeatedly negative KOH results. KOH detects fungal elements normally restricted to the stratum corneum. Closer histologic examination of the cases, however, revealed dermatophyte colonization of the stratum lucidum (Figures 1 and 2).

Hence, in this specific constellation of clinical and histopathological attributes, we are proposing the new term tinea lucidum to describe such atypical dermatophyte location.

Additionally, we recommend that a modified KOH preparation should be performed in potential tinea lucidum cases. This involves repeated scrapings at the lesion site until the colonized scale reaches the level of the stratum lucidum, resulting in an immediate and cost-effective diagnostic alternative to biopsy.

Historical Perspective Throughout medical literature from the 19th century to those of contemporary dermatology, superficial dermatophytosis has been characterized as the presence of fungal elements in the stratum corneum. While literature referring specifically to dermatophyte infection in immunosuppressed patients cites cases of invasion into the reticular dermis and subcutaneous tissue, no literature describing colonization into the stratum lucidum has been identified.

The technique for KOH preparation of suspected dermatophyte infection in the acral skin was well delineated in early 20th century literature. Ormsby and Mitchell, for example, advised that “caseous magma and… white, sodden epithelium should be discarded… The superficial scales should be removed with the curet [sic] down to the point where the squames become pinkish and are attached rather firmly.”1 In contrast, current dermatology textbooks merely imply that the “scraping with a dull edge of a scalpel outward from the advancing margins of a lesion”2 or obtaining “copious dry scale”3 from affected sites is sufficient for a KOH-based diagnosis, missing the importance of sampling deeper epidermis in suspected dermatophytosis. Bolognia and Lever omitted the description of the KOH examination technique altogether.4,5

From the Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Joya Sahu, MD, Department of Dermatology and Cutaneous Biology, Jefferson Medical College of Thomas Jefferson University, 833 Chestnut Street, Suite 704, Philadelphia, PA 19107 • E-mail: joya.sahu@jefferson.edu

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Figure 2. (Top) Numerous pustules studded on a pink scaly polycyclic plaque on dorsal foot. (Bottom) Hematoxylin and eosin, 400× magnification. Note the hyphal elements present between the stratum corneum and the granular layer (arrows).

Figure 1. (Top) Pink scaly serpiginous plaques on the palmar surface of a SLE patient on mycophenolate mofetil.

(Bottom) PAS, 200× magnification. Note the highlighted hyphal elements in the stratum lucidum (arrows).

Methods We conducted a retrospective analysis of all dermatophytosis cases diagnosed histologically and archived electronically within our academic clinical practice from 2002 to 2010 in order to establish the prevalence of tinea lucidum or dermatophyte infection within the stratum lucidum.

Specimens with the final diagnosis of “dermatophytosis” (n=133) and “dermatophytosis, bullous” (n=2) were included, while diagnoses of “Majocchi’s granuloma” (n=4) and “tinea capitis” (n=3) were excluded. An institutional review board waiver was obtained prior to performing this retrospective review.

Of the 135 dermatophytosis cases, 27 were from sites on or near SKINmed. 2014;12:226–230

acral skin surfaces. Two additional specimens, classified as bullous dermatophytosis, were also from acral sites, for a total of 29 cases of acral skin. For the purposes of this study, acral skin surfaces were defined as the areas between the wrists and fingertips and between the ankles and the tips of the toes.

Joint microscopic examinations were performed for each histologic specimen. The primary analysis involved stratifying the dermatophyte location to the stratum corneum, the stratum lucidum, or both.

Specimens with dermatophytes localized to the stratum corneum were further analyzed to determine whether they were present throughout the full thickness of the stratum corneum or a specific fraction of the layer (eg, the superior or inferior half ).

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Table I. Clinical and Histologic Characteristics on Non-Acral Sites Characteristics

SC Only

SC + Stratum Lucidum

Stratum Lucidum Only

Specimen distribution

41 of 106

64 of 106

1 of 106

Superior SC only

11

0

N/A

Inferior SC only

8

31

N/A

Full thickness of SC

22

33

N/A

1

5

0

Relevant comorbidities

0

b

4

N/A

Immunosuppressive treatment

1a

3c

N/A

Localization in SC

Internal cases

Abbreviations: N/A, not applicable; SC, stratum corneum. a Pretreated with 1% hydrocortisone cream. b Patient 1: history of lung cancer, brain cancer, coronary artery disease status post myocardial infarction; Patient 2: recent history of idiopathic thrombocytopenic purpura on prednisone taper; Patient 3: rheumatoid arthritis; Patient 4: ankylosing spondylitis. c Patient 1: had been treated with clotrimazole/betamethasone dipropionate 1–0.05% ×1 month on biopsied skin was potassium hydroxide negative; Patient 2: Prednisone 5 mg/d; had been using triamcinolone ointment 0.1% soak and smear on biopsied skin 2 to 3 times a week since September 22, 2010, for “dermatitis;” Patient 3: treated previously with methylprednisolone dose pack.

Table II. Clinical and Histologic Characteristics on Acral Sites Characteristics

SC Only

SC + Stratum Lucidum

Stratum Lucidum Only

Specimen distribution

10/29

16/29

3/29

Localization in SC

7

7

N/A

Superior SC only

0

0

N/A

Inferior SC only

4

4

N/A

Full thickness of SC

3

3

N/A

Internal cases

2

1

1

Relevant comorbidities

1a

1c

1e

Immunosuppressive treatment

1

2

1f

b

d

Abbreviations: N/A, not applicable; SC, stratum corneum. a History of squamous cell carcinoma in situ; previously diagnosed with tinea pedis. b Clotrimazole-betamethasone 1–0.05% cream, econazole nitrate 1%. c Systemic lupus erythematosus/discoid lupus erythematosus. d Patient 1: history of cellcept for systemic lupus erythematosus, ketoconazole; fluocinonide 0.05% gel twice a day diagnosed at baseline visit; Patient 2: dermatophytosis previously diagnosed as “dyshidrosis” and treated with clobetasol propionate 0.05% ointment; fluocinonide 0.05% ointment; hydrocortisone-iodoquinol 1–1%. e Baseline-proven pustular psoriasis of hands treated with clobetasol at time of baseline. f Clobetasol propionate 0.05% ointment per day.

Lastly, a review of electronic medical records (available only for cases from 2008 onward) was conducted for specimens from patients within our practice, which are referred to as “internal cases.” This allowed us to determine whether patients with tinea lucidum had medical histories significant for (1) relevant comorbidities (malignancy, human immunodeficiency virus, autoimSKINmed. 2014;12:226–230

mune, or inflammatory disease) and/or (2) immunosuppressive therapy and/or (3) prior antifungal treatment for dermatophyte infection prior to biopsy.

Patient demographics are presented in Tables I and II by anatomical location—acral vs non-acral, respectively—of the biopsied specimens.

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Results

Non-acral Sites Review of non-acral site biopsy specimens revealed that 65 (61.32%) of the 106 cases contained fungal elements in the stratum lucidum, with 64 cases displaying dermatophytosis in both the stratum corneum and stratum lucidum. Only 1 case demonstrated restriction of dermatophytes solely to the stratum lucidum. The remaining 41 non-acral specimens (38.68%) revealed hyphal elements limited to the stratum corneum.

Review of the 105 non-acral specimens with hyphal elements in the stratum corneum demonstrated the following: only 11 (10.48%) showed dermatophytosis exclusively within the superior half of the stratum corneum; 39 (37.14%) of the specimens had fungal elements that could only be detected at a deeper level in the inferior half of the stratum corneum; and the remaining 55 specimens (52.38%) contained hyphal elements throughout the full thickness of the stratum corneum.

Additionally, a review was conducted to identify the correlations with potential co-morbidities and/or treatment with immunosuppressive or antifungal medications on patients who had accessible electronic medical records. Out of the 6 non-acral patients with such records, one had fungal elements evident only in the stratum corneum, which penetrated the full thickness of this layer; the patient had been treating the affected skin with topical 1% hydrocortisone cream at the time of biopsy. For the remaining 5 cases, in which dermatophytes were visualized extending from the stratum corneum into the stratum lucidum, 4 (80%) had chart documentation of medical co-morbidities; 3 of these 4 patients were on an immunosuppressive medication at the time of biopsy (Table I).

Acral Sites Review of acral site biopsy specimens revealed that 19 (65.52%) of the 29 cases contained dermatophytes in the stratum lucidum, with 16 cases showing fungal elements in both the stratum corneum and the stratum lucidum. Only 3 cases demonstrated dermatophytes solely in the stratum lucidum. The remaining 10 acral specimens (34.49%) revealed dermatophytosis confined to the stratum corneum.

Of the 4 cases with electronic medical records available for review there was one with fungal elements evident only in the stratum corneum (but spanning its entirety). Active treatment with both topical steroids and antifungals to the affected skin had been documented at the time of biopsy. Additionally, 2 cases demonstrated evidence of dermatophytosis in both the stratum corneum and lucidum. One had a medical history significant for systemic lupus erythematosus and discoid lupus erythematosus and was taking multiple immunosuppressive medications, while the other had been misdiagnosed with dyshidrosis and was applying multiple topical steroid agents to the site prior to biopsy (Table II).

Discussion Defining-associated patient characteristics with which tinea lucidum, or dermatophyte infection of the stratum lucidum, can present is crucial in recognizing tinea lucidum in clinical practice.

The analyses we performed on a local population of patients biopsied for suspicious skin lesions, diagnosed histopathogically as dermatophytosis, revealed that 32.1% (34 of 106) of non-acral specimens and 64.7% (11 of 17 in the subset analysis) of acral specimens had fungal elements limited to the inferior half of the stratum corneum and below, often extending into the stratum lucidum. Although limited by the small number of cases available for ancillary chart review, our study supports a possible relationship between certain medical comorbidities and/or immunosuppressive therapies to the unprecedented location of dermatophytosis described herein.

Our objective was to support the hypothesis that superficial skin scrapings collected for KOH examination in cases of suspected dermatophytosis may not be adequate for visualization of fungal elements. A modified KOH examination requiring repeat scrapings of the affected site until deeper layers of scale from the inferior stratum corneum or stratum lucidum are exposed should be considered in 3 specific clinical settings of suspected dermatophyte infection.

To determine dermatophyte location within the nonviable epidermis, 14 (50%) cases were randomly selected for review and none showed restriction to only the superior half of the stratum corneum. Eight cases (57.14 %) revealed dermatophytes limited to the inferior half of the stratum corneum of the acral skin and the remaining 6 showed fungal elements scattered throughout its full thickness.

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â&#x20AC;˘ On acral surfaces: Just as Ormsby and Mitchell advised nearly a century ago, a sampling of colonized squamous cells along characteristically hyperkeratotic acral surfaces warrants clearing away surface scale to reach deeper levels of the stratum corneum and/or stratum lucidum.1 â&#x20AC;˘ Lichen simplex chronicus: Similar to cases of tinea lucidum, patients with lichen simplex chronicus and other dermatologic conditions where histopathologically, lichenification, or a recapitulation of acral-like skin is observed with corresponding prominence of the stratum lucidum may require deeper scrapings for adequate KOH diagnosis.

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• Immunosuppressive therapies: Distinct from the entities of tinea incognito (in which the clinical appearance of the superficial fungal infection is altered through inappropriate treatment with topical steroids) or of Majocchi’s granuloma (in which fungal elements invade dermal and subcutaneous tissues), tinea lucidum may potentially be a consequence of local or systemic immunosuppressive medication, modifying the pattern of dermatophyte colonization to deeper layers of the stratum corneum or to the stratum lucidum.

currently thought, to the stratum corneum. In cases where superficial scrapings for KOH examination may be negative but clinical suspicion remains high for dermatophytosis, we urge consideration of a modified KOH examination as described above, instead of immediate pursuit of biopsy, sparing cost, pain, and delayed diagnosis to the patient.

While constrained by the limits of a retrospective analysis and review of single-laboratory specimens, these preliminary findings ultimately permit us to alert our colleagues to settings in which this previously uncharacterized phenomenon of tinea lucidum may emerge.

2 Wolff K, Goldsmith L, Katz S, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw Hill; 2007.

3 James WD, Berger T, Elston D. Andrews’ Diseases of the Skin. 10th ed. Philadelphia, PA: Elsevier Saunders; 2006.

Conclusions

4 Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology.

2nd ed. Philadelphia, PA: Mosby; 2008.

Dermatophyte location appears to have shifted to deeper cornified layers of the nonviable epidermis and is not limited, as

5 Elder D, Elenitsas R, Johnson B, Murphy G, Xu X. Lever’s Histopathology of the Skin, 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

References 1 Ormsby OS, Mitchell JH. Ringworm of hands and feet.

JAMA. 1916;LXVII:711–717.

Wax Moulage

“Calcinosis and Sklerodermie”, Moulage No. 170, made by Lotte Volger in 1926 in the Clinic for Dermatology Zurich. Demonstrating a calcified plaque by pressing with a finger on the patiens left temple. Museum of Wax Moulages Zurich. www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2014;12:226–230

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Volume 12 • Issue 4

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

Saying What You Know and Not What You Don’t: Clarity in Dermatopathology Reports Cindy Wassef, BA;1 Divya Sharma, BA;2 W. Clark Lambert, MD, PhD3 “… the truth, the whole truth, and nothing but the truth” Witness oath, Black’s Law Dictionary “When I use a word,” Humpty Dumpty said in rather a scornful tone. “It means just what I choose it to mean—neither more or less.”

Lewis Carroll, Through the Looking Glass (1871)

D

ermatopathology reports may provide essential information for the clinician when making management and treatment decisions. Such reports often include information regarding patient demographics, clinical history, macroscopic and microscopic features, and final diagnosis.

Sometimes, however, suggestions are included regarding the management of such lesions, such as “re-excise.”1 Such recommendations are given by dermatopathologists based on the small sample given to them. No information may be available regarding the part of the lesion removed, whether the whole lesion was taken out, or whether there are areas other than that biopsied associated with the presented specimen.1,2 These comments raise questions regarding the role of dermatopathologists in management.

Clinical Aspects While dermatopathologists offer invaluable diagnostic aid, their role in clinical therapy is less clear. Although they do possess valuable diagnostic information, dermatopathologists rarely get the opportunity to examine the patients from whom the biopsies are obtained. Indeed, beyond the information provided by the clinician and the specimen received, little is mentioned in pathology requisition forms regarding patient comorbidities, treatment preferences, or resources available. Another issue is the vast array of other nonsurgical treatments available. While a dermatopathologist may simply suggest a re-excision, various other topical treatments, radia-

tion, or periodic monitoring of the lesion may also be acceptable options.

Whereas dermatopathologists may comment voluntarily about management of lesions, dermatologists often specifically request that certain items be reported, for example, whether lesional tissue is present in the margins of biopsy samples. Depending on the specimen presented, identifying whether margins are involved can be challenging. For example, the type of biopsy may not be conducive to identifying margins because it is too shallow. In one survey of dermatopathologists it was found that while 93.4% commented regarding surgical margins on an excised melanoma specimen, only 77.6% commented on the margins of shaved or punch biopsies of melanoma specimens.3,4 Routine reporting of margins of melanocytic nevi were much lower: only 32.2% in shave specimens of melanocytic nevi and 33.6% in punch biopsies of melanocytic nevi. The type of lesion also dictated the extent to which dermatopathologists commented on margins. In this same survey, reporting rates of margins were greater for suspected dysplastic nevi than for nondysplastic melanocytic nevi.3,4 Therapeutic Suggestions Dermatopathology treatment suggestions can be helpful or harmful. One example in which dermatopathology suggestions may be needed for proper management is in stasis dermatitis.

Within a lesion of stasis dermatitis, there is not infrequently an ulcer.

From the Department of Dermatology, State University of New York – Stoney Brook, Stoney Brook, NY;1 the Departments of Dermatology and Pathology,2 and the Department of Laboratory Medicine,3 Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Department of Dermatology and Pathology, Rutgers University – New Jersey Medical School, Room C520 MSB, UMDNJ – NJMS, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@umdnj.edu

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perils of dermatopathology

Area of biopsy

Lesion

Figure 2. Depiction of a biopsy of a cutaneous lesion.

The excised portion may give rise to a section in which the margins are clear, although the lesion is not at all excised. It is important that such a specimen not be reported as an excision.

margins may be clear in that section, the same may not be true for the margins of the larger lesion (Figure 2).

These issues may make dermatopathologists vulnerable to possible medicolegal action. When reporting negative margins, dermatopathologists may use vague, unclear terms such as “appears completely excised.” In contrast, language used for positive margins tends to be much more clear and concise. Such hesitancy in the reporting of negative margins is indicative of the dermatopathologists’ concern about making such a definitive statement.

Figure 1. Molluscum contagiosum occurring in a patient with undiagnosed ichthyosis. (Hematoxylin and eosin, original magnification ×135.)

Legal Implications Healthcare providers, especially nonphysicians, often make the mistake of overcleaning the ulcer so as to impede the healing process. This can be detected on the dermatopathology specimen and may constitute an indication for the dermatopathologist to clarify management and treatment techniques for the referring clinician. Alternatively, the dermatopathologist may observe evidence of a second disorder, not suspected by the submitting physician or healthcare provider (not necessarily a physician) that impacts the disease at hand. For example, a patient with a viral disorder, such as molluscum contagiosum, may also have an ichthyosis, which makes them susceptible to the viral disease. The dermatopathologist would be remiss in reporting only the viral disease without commenting on evidence of the ichthyosis (Figure 1). In contrast, dermatopathologists may declare “margins clear” without taking into consideration or being aware of the portion of the lesion present in the sample. Biopsy samples may contain only a section of the lesion, not an excision. While the SKINmed. 2014;12:231–233

Due to legal implications, dermatopathologists are often much more cautious and prone to overreporting findings rather than underreporting. This may create problems itself Sue to the unnecessary procedures that such reporting may spur.3,4 One suggested approach is a statement indicating that the dermatopathologist does not feel comfortable reporting on margins for punch and shave biopsies because in these samples margins cannot be accurately seen.4 Such a statement explains ones reasoning and indicates to clinicians the validity and honesty of all evaluations.

Some institutions, such as the University of Colorado, have adopted the approach of stating in their comments section that “this is a difficult case.” Such a statement makes others aware that there may be differing opinions if such a lesion is examined by another dermatopathologist and that the clinician should be more cautious with what they tell the patient and with treat-

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ment and follow-up. To be sure the comments section is read, a brief statement such as “(see Comment)” may be added to the diagnosis section.

Conclusions

between dermatologists and dermatopathologists should lead to accurate diagnosis and effective patient care.

References

We suggest that the best approach is to state in the diagnosis only what the dermatopathologist can identify, nothing more and nothing less. If margins cannot be seen, stating so is better for both the clinician and the patient. Commenting about margins only to satisfy the referring clinician is a disservice to both clinician and patient. In addition, physicians must be aware and accepting of the limitations of the reporting based on the biopsy sample submitted. If a clinician desires a statement regarding the margin, an appropriate sample must be submitted and the request should be made then, not later.5 On the other hand, where the dermatopathologist can make genuinely constructive suggestions, such statements may be added to the comments section.

We recommend doing so with a good dose of humility and with generous use of modifying statements such as “It may be appropriate to consider….” A mutual understanding of limitations

1 Fernandes H, Fernandes N, Bhattacharya S, et al.

Molec1 Wiland HO 4th, Grant-Kels JM. Ethical issues in dermatopathology. Clin Dermatol. 2012;30:476–481.

2 High WA. Malpractice in dermatopathology: principles, risk mitigation and opportunities for improved care for the histologic diagnosis of melanoma and pigmented lesions. Clin Lab Med. 2008;28:261–284.

3 Sellheyer K, Bergfeld WF, Stewart E, et al. Evaluation of surgical margins in melanocytic lesions: a survey among 152 dermatopathologists. J Cutan Pathol. 2005;32:293– 299.

4 Sellheyer K, Bergfeld WF. When to ask your dermatopathologist to evaluate for surgical margins and when not: a matter of confusion for dermatologists and dermatopathologists alike. J Am Acad Dermatol. 2005;52:1095– 1097.

5 Sharma A, Jow T, Chen J, et al. Once a biopsy, always a biopsy. Skinmed. 2010;8:345–346.

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OR

July/August 2014

Volume 12 • Issue 4

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

Efinaconazole 10% Nail Solution: A Post–FDA Approval Update Aditya K. Gupta, MD, PhD, FRCPC;1,2 Fiona C. Simpson, HBSc;2 William Abramovits, MD;3,4,5 Noah Scheinfeld, MD, JD6

E

finaconazole 10% nail solution (Jublia; Valeant, Laval, Quebec, Canada) is a new topical antifungal for the treatment of onychomycosis.1–5 Onychomycosis is the most common cutaneous foot disorder and affects an estimated 2% to 8% of the global population.6 It is caused by colonization of the nail plate and bed by dermatophytes, yeasts, and nondermatophyte molds.7-9 Individuals with pre-existing medical comorbidities, such as diabetes,10 poor peripheral vascular circulation,11 and immunosuppression caused by the human immunodeficiency virus12 or transplant,13 as well as the elderly,14 are at increased risk for contracting onychomycosis. The oral antifungals traditionally used to treat onychomycosis may be associated with adverse events and drug-drug interactions that sometimes make them undesirable in individuals undergoing polypharmacy.15 Topical antifungals reduce the systemic exposure of the drug and are associated with fewer adverse events; however, the current options of efinaconazole and ciclopirox have modest efficacy. Efinaconazole was designed as a nail solution to improve on the efficacy of topical antifungals.16 In vitro, efinaconazole has lower or equivalent minimum inhibitory concentrations (MIC) than terbinafine, itraconazole, ciclopirox and amorolfine.

For dermatophytes, efinaconazole is the most effective antifungal against Trichophyton rubrum, Trichophyton mentagrophytes, Epidermphyton floccosum and Microsporum spp.17 Against Candida spp., including C. albicans, efinaconazole has an MIC value an order of magnitude less than competitors. Efinaconazole was also equivalent or better than competitors for NDMs including Fusarium oxysporum, Scopulariopsis brevicaulis, and Aspergillus spp.17 Efinaconazole also has a low keratin binding profile and decreased surface tension, which allow it to effectively penetrate the nail plate.1,2,18

Clinical Studies Phase I, II, and III clinical trials and a contact sensitization study have been conducted for efinaconazole. The phase I study was conducted in 10 healthy volunteers and 20 individuals with severe onychomycosis to assess the safety profile of onychomycosis.19 The phase I study determined that efinaconazole and its H3 metabolite have low plasma accumulation and systemic exposure.

The phase II trials were conducted in 135 adult Mexican participants with mycologically confirmed onychomycosis.20 This study compared efinaconazole 10%, 10% with semi-occlusion, 5%, and placebo, with participants randomized in a 2:2:2:1 ratio. Participants applied the nail solution daily for 36 weeks followed by a 4-week follow-up period. The most effective trial arm was efinaconazole 10% with a mycologica cure rate of 87.2% and a complete cure rate of 25.6%. All trial arms were superior to placebo.

Efficacy Efinaconazole 10% nail solution was tested in duplicate, randomized, parallel-group, multicenter phase III clinical trials.16 This study enrolled 1655 participants with mycologically confirmed mild to moderate onychomycosis (20% to 50% of the nail plate). Participants were randomized to receive efinaconazole 10% nail solution or placebo in a 2:1 ratio. The nail solution was applied daily for 48 weeks with a 4-week wash-out period. The main study outcome was complete cure, with mycologic cure, complete or almost complete cure, treatment success, and unaffected nail growth as secondary outcomes. Pooled

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc., London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center;3 the Departments of Dermatology & Family Practice, University of Texas Southwestern Medical School;4 Dermatology Treatment & Research Center, Dallas, TX;5 Department of Dermatology, Weill Cornell Medical College, New York, NY6 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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analysis of the study population resulted in a complete cure rate of 18.5% for efinaconazole vs 4.7% for placebo.21 The mycologic cure rates were 56.3% and 16.6% for efinaconazole and placebo, respectively.

Safety Treatment-emergent adverse events (TEAEs) were reported for the phase I through III clinical trials.5,16,19,20 Across all trials, the most common TEAEs were nasopharyngitis, upper respiratory tract infection, and headache, which were considered unrelated to the drug.

The drug-associated TEAEs were mild and localized to the application site, including application site dermatitis and vesicles.

A contact sensitization trial comprised of two studies was conducted to determine whether efinaconazole or the vehicle were potential allergens.22 In the first study, participants had an occlusive patch containing efinaconazole or vehicle applied at 9 visits over 3 weeks. After a 17- to 24-day wash-out period, the participants were re-challenged for 48 hours. Irritation scores below 0.5 (barely perceptible) were achieved by 91.6% of patients in the efinaconazole group and 95.0% of patients in the placebo group.

No contact sensitization was observed in 99.5% and 99.0% of the efinaconazole and vehicle groups, respectively.

onychomycosis, with or without lunula involvement. Efinaconazole may also be useful in mixed infections, as it has strong in vitro activity against NDMs and yeasts. In individuals who are at higher risk for recurrence of onychomycosis, eg, diabetics, those with severe peripheral vascular disease, and immunocompromised individuals, efinaconazole may be considered as a prophylactic agent.

Conclusions Efinaconazole 10% nail solution is a safe and effective treatment for mild to moderate onychomycosis. It is the first topical drug for onychomycosis to be approved as topical monotherapy without debridement. Efinaconazole 10% nail solution will provide prescribers with increased options to treat patients who cannot use oral drugs or who prefer a topical approach.

Conflict of interest Dr Gupta was an advisor to and has performed clinical trials for Valeant Pharmaceuticals International Inc. References

In the second study, participants were randomized to receive patches of efinaconazole 10%, 5%, or 1%; 0.2% sodium lauryl sulfate (positive control); or deionized water (negative control) every weekday for 3 weeks. The outcome measure was the cumulative irritation score. The scores were 1.18, 1.26, and 1.12 for efinaconazole 10%, 5%, and 1%, and 2.77 for 0.2% sodium lauryl sulfate, respectively. Efinaconazole was not associated with contact sensitization in this study.

Indications and Administration Efinaconazole 10% nail solution was approved by Health Canada on October 3, 2013, and the Food and Drug Administration on June 9, 2014.1,2,23,24 It is indicated for “the topical treatment of mild to moderate onychomycosis (tinea unguium) of toenails without lunula involvement due to Trichophyton rubrum and Trichophyton mentagrophytes in immunocompetent adult patients.”1,2 Efinaconazole nail solution should be applied daily at bedtime for 48 weeks to “completely cover the toenail, the nail folds, nail bed, hyponychium, and the undersurface of the nailplate.”1,2 Long-term use of efinaconazole has not yet been evaluated, but there is a potential for increased cure rates with application for 72 weeks. Potential off-label uses include adjunctive therapy with an oral antifungal agent when there is severe onychomycosis. Additionally, efinaconazole may be used when there is incomplete cure or failure with an oral agent in severe SKINmed. 2014;12:235–237

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1 Valeant Canada LP. JUBLIA Efinaconazole Topical Solution, 10% w/w. 2013.

2 Valeant Pharmaceuticals. JUBLIA® (efinaconazole) topical solution, 10%. 2014. Available at: http://www.accessdata. fda.gov/drugsatfda_docs/label/2014/203567s000lbl. pdf. Accessed July 4, 2014.

3 Gupta AK, Simpson FC, Abramovits W. Efinaconazole 10% nail solution. Skinmed. 2013;11:239–241.

4 Gupta AK, Simpson FC. Efinaconazole: a new topical treatment for onychomycosis. Skin Therapy Lett. 2014;19:1–4.

5 Gupta AK, Simpson FC. Efinaconazole (Jublia) for the treatment of onychomycosis. Expert Rev Anti Infect Ther.

2014;12:743–752.

6 Sigurgeirsson B, Baran R. The prevalence of onychomycosis in the global population - A literature study. J Eur Acad Dermatol Venereol. 2013 Nov 28. [Epub ahead of print].

7 Zaias N. Onychomycosis. Arch Dermatol. 1972;105:263– 274.

8 Gupta AK, Drummond-Main C, Cooper EA, Brintnell W, Piraccini BM, Tosti A. Systematic review of nondermatophyte mold onychomycosis: diagnosis, clinical types, epidemiology, and treatment. J Am Acad Dermatol.

2012;66:494–502.

9 Gupta A, Nakrieko K-A. Molecular determination of mixed infections of dermatophytes and nondermatophyte moulds in individuals with onychomycosis. J Am Podiatr Med Assoc. 2014 (In press).

10 Gulcan A, Gulcan E, Oksuz S, Sahin I, Kaya D. Prevalence of toenail onychomycosis in patients with type 2 diabetes mellitus and evaluation of risk factors. J Am Podiatr Med Assoc. 2011;101:49–54.

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11 Gupta AK, Gupta MA, Summerbell RC, et al. The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol. 2000;14:466–469.

19 Jarratt M, Siu WJ, Yamakawa E, et al. Safety and pharmacokinetics of efinaconazole 10% solution in healthy volunteers and patients with severe onychomycosis. J Drugs Dermatol. 2013;12:1010–1016.

12 Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals.

Int J Dermatol. 2000;39:746–753.

20 Tschen EH, Bucko AD, Oizumi N, et al. Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study. J Drugs Dermatol. 2013;12:186–192.

13 Güleç AT, Demirbilek M, Seçkin D, et al. Superficial fungal infections in 102 renal transplant recipients: a casecontrol study. J Am Acad Dermatol. 2003;49:187–192.

14 Baran R. The nail in the elderly. Clin Dermatol.

2011;29:54–60.

15 Shear N, Drake L, Gupta AK, Lambert J, Yaniv R. The implications and management of drug interactions with itraconazole, fluconazole and terbinafine. Dermatology.

2000;201:196–203.

16 Elewski BE, Rich P, Pollak R, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies.

J Am Acad Dermatol. 2013;68:600–608.

17 Jo Siu WJ, Tatsumi Y, Senda H, et al. Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis. Antimicrob Agents Chemother. 2013;57:1610– 1616.

18 Sugiura K, Sugimoto N, Hosaka S, et al. The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment. Antimicrob Agents Chemother. 2014;58:3837– 3842.

21 Gupta AK, Elewski BE, Sugarman JL, et al. The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials. J Drugs Dermatol.

2014;13:815–20.

22 Del Rosso JQ, Reece B, Smith K, Miller T. Efinaconazole 10% solution: a new topical treatment for onychomycosis: contact sensitization and skin irritation potential. J Clin Aesthet Dermatol. 2013;6:20–4.

23 Valeant Pharmaceuticals Inc. Valeant Pharmaceuticals Announces Approval of Jublia® for the Treatment of Onychomycosis in Canada]. 2013. Available at: http:// ir.valeant.com/investor-relations/news-releases/newsrelease-details/2013/Valeant-Pharmaceuticals-Announces-Approval-Of-Jublia-For-The-Treatment-Of-Onychomycosis-In-Canada/default.aspx. Accessed October 18, 2013.

24 Valeant Pharmaceuticals, Inc. Valeant Pharmaceuticals Announces FDA Approval of Jublia® for the Treatment of Onychomycosis. 2014. Available at: http://ir.valeant. com/investor-relations/news-releases/news-release-details/2014/Valeant-Pharmaceuticals-Announces-FDAApproval-Of-Jublia-for-the-Treatment-of-Onychomycosis/ default.aspx. Accessed June 27, 2014.

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SKINmed. 2014;12:235–237

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July/August 2014

Volume 12 • Issue 4

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

The Autoinflammatory Assault on Conventional Diagnostic Criteria Warren R. Heymann, MD

T

he concept of autoinflammatory disorders has blossomed since the late 1990s with the identification of genes that are involved in inflammation and apoptotic processes. Vast knowledge has accrued regarding activation of the inflammasome—the intracellular complex that synthesizes interleukin (IL) 1, a master cytokine that affects virtually all cell types.1 Autoinflammatory diseases affect the innate immune system as opposed to autoimmune diseases, such as lupus erythematosus or rheumatoid arthritis, which affect the adaptive immune system and cause immunodysregulation via autoreactive lymphocytes and specific autoantibodies.2

There are two forms of IL-1: IL-1α and IL-1β. IL-1α is expressed as a precursor and is constitutively present in most cells of healthy individuals, as opposed to IL-1β, which is not present in normal, healthy cells. IL-1β is produced by monocytes, tissue macrophages, and dendritic cells in response to stimuli, such as infection. The IL-1β precursor is activated by caspase-1, an intracellular cysteine protease. Before caspase-1 can cleave the IL-1β precursor into the active cytokine, it must be activated.

Activation of caspase-1 occurs following the oligomerization of a complex of intracellular proteins that comprise the inflammasome. An inflammasome component, cryopyrin (NLRP3), plays a critical role in the secretion of IL-1β. Mutations of cryopyrin result in enhanced IL-1β secretion, resulting in autoinflammatory disorders.3 Monogenic autoinflammatory syndromes are characterized by the childhood onset of febrile episodes and involvement of the skin, mucous membranes, eyes, joints, gastrointestinal tract, and nervous system.1 Currently, at least a dozen such disorders have been elucidated, although inevitably more will be identified as mutational analysis and the pathophysiology of innate immunity is further refined. Each autoinflammatory disorder displays

“characteristic” features, although, as described below, it may behoove the clinician not to be too rigid about diagnostic criteria when correlating the mutation with the clinical phenotype.

Classification The autoinflammatory diseases may be classified based on the following clinical features.2 The periodic fever syndromes manifest as eruptions with recurrent episodic fever and abdominal pain: familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome, and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome.

The cryopyrin-associated periodic syndromes present with neutrophilic urticaria: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease.

Pediatric granulomatous arthritis is associated with minimal or low-grade febrile attacks: Blau syndrome.

Disorders that present with cutaneous pustules associated with episodic fever include deficiency of IL-1 receptor antagonist; Majeed syndrome; pyogenic arthritis, and pyoderma gangrenosum and acne syndrome; deficiency of IL-36 receptor antagonist; CARD14-mediated psoriasis; and early-onset inflammatory bowel disease.

Inflammatory disorders caused by mutations in proteosome components—the proteasome-associated autoinflammatory syndromes—manifest as an atypical neutrophilic dermatosis with a histiocytic-like infiltrate: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature.

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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Conditions presenting with autoinflammation and immunodeficiency based on a mixed phenotype determined by the effect of different immune cells: PLCγ2-associated antibody deficiency and immune dysregulation and autoinflammation and PLCγ2associated antibody deficiency and immune dysregulation.

Investigators reported the familial Mediterranean fever (FMF) case of an infant who presented with warm, tender, erythematous contusiform nodules of the face and extremities that coincided with periodic febrile episodes that lasted from 3 days to several weeks. The lesions healed as gray macules without lipoatrophy. Results from skin biopsy demonstrated a lobular neutrophilic panniculitis with negative microbial stains. The differential diagnosis included pancreatic panniculitis, α-1 antitrypsin deficiency, infectious panniculitis, Sweet syndrome, idiopathic infantile febrile panniculitis, and autoinflammatory disease. The family history was unremarkable. Genetic testing revealed a single allelic mutation at M694V in the MEFV gene associated with FMF. The patient responded to colchicine following inadequate responses to corticosteroids, methotrexate, and nonsteroidal anti-inflammatory drugs.4 FMF is the most common monogenic autoinflammatory disease. Its inheritance is autosomal recessive, although a single mutation may be associated with the clinical phenotype. Although most frequently occurring in people of eastern Mediterranean descent, it may also be observed in European and Asian populations. The responsible mutation is in the MEFV gene, which encodes pyrin. The M694V mutation is associated with the most severe disease course with a greater risk of developing secondary amyloidosis. As discussed earlier, such pyrin mutations in the inflammasome are associated with increased IL-1β production.5 FMF characteristically commences before 20 years of age with sudden febrile episodes, serositis (manifesting as peritonitis, arthritis, or pleuritis), and/or dermatitis that may last between 6 and 96 hours. The rash eruption may be seen in approximately 50% of patients, with FMF being described as “erysipelas-like.”

The eruption may be associated with swelling and tenderness.6

It is increasingly important to diagnose autoinflammatory disorders because many patients respond to specific blockade of IL-1β. Three IL-1 blockers have been approved: (1) anakinra, which blocks the IL-1 receptor, thereby reducing the activity of IL-1α and IL-β; (2) rilonacept, a soluble decoy receptor; and (3) canakinumab, a neutralizing monoclonal IL-1β antibody.3 Specifically for FMF, colchicine is the mainstay of therapy for the prevention of painful attacks and the development of amyloidosis.

According to the investigators, their case is the first report of FMF presenting with lobular panniculitis as the main clinical expression. The diagnosis of FMF would not have been considered even with its being classified as “probable” based on the Tel Hashomer criteria for diagnosing FMF. The authors deserve credit for considering an autoinflammatory etiology for their patient. It also demonstrates that our diagnostic constructs will constantly need revision as we incorporate mutational analyses of autoinflammatory diseases.

Conclusions Clinicians should keep in mind these disorders as diagnostic possibilities in patients with unexplained febrile episodes, dermatitis, and systemic symptoms. Undoubtedly, we will be expanding the diagnostic criteria for existing entities and defining new disorders based on correlating phenotypes with new mutations.

References

The Tel Hashomer criteria for diagnosing FMF include major criteria (1: recurrent febrile episodes with serositis; 2: amyloidosis of AA type without predisposing disease; 3: favorable response to colchicine treatment) and minor criteria (1: recurrent febrile episodes; 2: erysipelas-like erythema; 3: FMF in a firstdegree relative). The diagnosis is definitive if there are 2 major or 1 major and 2 minor criteria present. The diagnosis is considered probable if 1 major and 1 minor criterion are evident.6 The case presented above was believed to be FMF.

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1 Caso F, Rigante D, Vitale A, et al. Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues. Int J Rheumatol.

2013;2013:513782.

2 de Jesus AA, Goldbach-Mansky R. Monogenic autoinflammatory diseases: Concept and clinical manifestations. Clin Immunol. 2013;147:155–174.

3 Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol.

2013;25:469–484.

4 Leiva-Salinas M, Betlloch I, Arribas MP, Francés L, Pascual JC. Neutrophilic lobular panniculitis as an expression of a widened spectrum of familial Mediterranean fever. JAMA Dermatol. 2014;150:213–214.

5 Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin.

Nat Rev Rheumatol. 2014;10:135–147.

6 Portincasa P, Scaccianoce G, Palasciano G. Familial Mediterranean fever: a fascinating model of inherited autoinflammatory disorder. Eur J Clin Invest. 2013;43:1314–1327.

The Autoinflammatory Assault

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

Rosacea is with her wherever she goes .

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

You have made Finacea® the #1 Dermatologist-prescribed topical rosacea brand.1

INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea.

Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water.

Wash hands immediately following application of Finacea®.

Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings.

In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less.

Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

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

July/August 2014

Volume 12 • Issue 4

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

Antinuclear Antibody Seropositivity in Men With Cutaneous B-Cell Lymphoma of the Scalp Sophia Rangwala, AB; Madeleine Duvic, MD

Patient 1: A 65-year-old Caucasian man presented with a 2-month history of large erythematous patches of the right temporal scalp. The patient was otherwise in good health and taking no medications. He denied a family history of lymphomas or autoimmune diseases. No hepatosplenomegaly or lymphadenopathy was appreciated. A complete blood cell count, serum protein electrophoresis, peripheral blood flow cytometric analysis, bone marrow biopsy, Helicobacter pylori titers, and Borrelia burgdorferi titers were within normal range. The antinuclear antibody titer was positive at 1:640 and showed a homogenous pattern. Rheumatoid factor, SSA (Ro), and SSB (La) antibody titers were negative. Computed tomography scans of the chest, abdomen, and pelvis were unremarkable. Two punch biopsies from different time points demonstrated an atypical lymphocytic infiltrate forming clusters in the dermal and subcutaneous tissue. These cells had a (14;18) translocation and were mostly positive for CD20 and bcl-6, but not bcl-2. The patient was diagnosed with low-grade primary cutaneous follicle center lymphoma based on clinicopathological evidence, and achieved complete remission after local radiation and 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. The patient has had no evidence of recurrence for 6 years. (SKINmed. 2014;12:244–248)

P

atient 2: A 43-year-old Caucasian man presented with a 3-month history of nonpruritic erythematous nodules of the right parietal scalp (Figure 1). The patient was taking 800 mg mesalamine daily for treatment of ulcerative colitis, and had completed 5 cycles of 500 mg intravenous infliximab 3 months before. There was no family history of lymphomas or autoimmune diseases. No hepatosplenomegaly or lymphadenopathy was appreciated. A complete blood cell count, serum protein electrophoresis, peripheral blood flow cytometric analysis, and Helicobacter pylori titers were normal. Borrelia burgdorferi serum IgG was positive (1:64) but IgM was negative, indicating a possible past infection with Lyme disease. Antinuclear antibody (ANA) titer was 1:160 with a homogenous pattern, while SSA and SSB antibody titers were negative. Computed tomography scans of the chest, abdomen, and pelvis were unremarkable. Two punch biopsies from different time points both revealed a moderately dense lymphocytic infiltrate comprising predominantly small and few large lymphocytes in the dermal and subcutaneous tissue, with most staining for CD20. The B cells were not immunoreactive to bcl-2 or CD10, but many were positive for bcl-6. Clinical and histopathology findings

were consistent with low-grade primary cutaneous follicle center lymphoma. The patient was given doxycycline for 1 month for possible Lyme disease; local radiation therapy; and 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). He underwent complete remission with no recurrence for 6 years (Figure 2).

Patient 3: A 36-year-old Caucasian man with Down syndrome presented with a 3-month history of a shiny pink nodule with surrounding erythema of the occipital scalp. Past treatments with antibiotic ointments, topical corticosteroids, oral erythromycin, and oral terbinafine were ineffective. Review of systems was positive for mild diarrhea. The patient was taking no medications. His family history was negative for lymphomas and autoimmune diseases. No hepatosplenomegaly or lymphadenopathy was appreciated. A complete blood cell count, peripheral blood flow cytometric analysis, and bone marrow biopsy were normal. The patient had a positive ANA titer of 1:80 with a nucleolar pattern. SSA and SSB antibody titers were normal. A positron electron tomography scan demonstrated mediastinal and bilateral hilar adenopathy. Two punch biopsies from differ-

From the Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX Address for Correspondence: Sophia Rangwala, AB, 7575 Cambridge Street, Apartment 502, Houston, TX 77054 • E-mail: srangwala@gmail.com

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Figure 1. An ANA-positive patient with primary cutaneous follicle center lymphoma before local radiation and chemotherapy.

Figure 2. An ANA-positive patient with primary cutaneous follicle center lymphoma after local radiation and chemotherapy.

ent time points both revealed a dense lymphocytic infiltrate in dermal and subcutaneous tissue that was predominantly positive for CD20. Many of these B cells were positive for bcl-6 and CD10, and most were negative for bcl-2. Clinical, radiological, and pathological evidence suggested a diagnosis of stage IVA follicular lymphoma, grade 2. After 6 cycles of R-CHOP, the patient went into complete remission with no recurrence for 3 years.

Introduction Cutaneous B-cell lymphomas comprise a diverse group of nonHodgkin lymphomas (NHLs), which involve clonal expansion of malignant B cells in the skin. The 2005 World Health Organization and European Organization for the Research and Treatment of Cancer classification guidelines categorize primary cuSKINmed. 2014;12:244â&#x20AC;&#x201C;248

taneous B-cell lymphomas as primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type, and primary cutaneous diffuse large B-cell lymphoma, other.1 Systemic B-cell lymphomas with secondary dissemination to the skin are less common and are generally associated with a worse prognosis.2 Past reports have evaluated the significance of ANAs with NHL, particularly systemic B-cell lymphomas3,4 and cutaneous T-cell lymphomas.5 After seeing two ANA-positive adult men present with primary cutaneous follicle center lymphoma within a month, we conducted a retrospective review to determine the frequency and clinical relevance of ANA titers in patients with cutaneous B-cell lymphoma.

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Methods A cutaneous lymphoma database of 254 M.D. Anderson Cancer Center patients that excluded mycosis fungoides/Sézary syndrome was queried to find patients who had been clinicohistologically diagnosed with primary or secondary cutaneous B-cell lymphoma from January 1999 to March 2011. Computerized chart reviews were performed under institutional review board approval to determine lymphoma subtype and availability of ANA titers. ANA levels were categorized as ANA-positive if titers were ≥1:40, and ANA-negative if <1:40, which was consistent with the range defined by the MD Anderson laboratory. The serum was assayed with indirect immunofluorescence of HEp-2 human cell lines. Because NHL treatments such as fludarabine, radiation, and interferon-α4 may correspond with autoantibody production and/or autoimmune clinical features, only serum samples collected prior to lymphoma therapy were used. ANApositive patients were further investigated for possible reasons for the seropositivity.

Results Of the 58 patients with primary or secondary cutaneous B-cell lymphoma, 35 (60%) were men and 23 (40%) were women (Table I). Predisposition to the scalp was most common with primary cutaneous follicle center lymphoma, with 40% of the 15 patients with this lymphoma subtype demonstrating such an association. ANA testing was performed in 23 (40%) of the 58 patients, and ANA positivity was seen in 2 of 3 patients with

primary cutaneous follicle center lymphoma and in 1 of 2 patients with secondary follicular B-cell lymphoma. Of interest, all 3 ANA-positive patients were men, had low-grade disease, and had skin lesions exclusive to the scalp. The medical history and clinical course of these patients are detailed below.

Discussion In addition to autoimmune disorders, ANA seropositivity is seen with infections, prescription drug use, malignancies, and advanced age and at times with no identifiable factors.6-8 Lymphoproliferative diseases are the most common malignancies with this antibody association and are often linked to autoimmune disturbances, such as immune thrombocytopenia, autoimmune hemolytic anemia, and systemic rheumatic diseases.9 A prospective case-control study found that of 64 patients with NHL, 39% were seropositive for one or more autoimmune markers, especially ANA (21%). All ANA positivity followed a homogenous distribution, and men with low-grade lymphoma tended to be more susceptible (P=.035). ANA seropositivity was not associated with specific clinical findings or an effect on remission rate.3 A larger case-control study of 347 NHL patients showed that 19% were ANA-positive prior to treatment, compared with 5.6% of the control group (P<.0001). Prevalence was most significant with follicular and mantle cell lymphoma, and 28% with positive ANA serologies displayed autoimmune symptoms, although this was mostly limited to marginal zone lymphoma patients.4

Table I. Cutaneous B-Cell Lymphoma Patients Cutaneous B-Cell Lymphoma

Subtype

Primary

Follicle center ANA negative ANA positive Marginal zone ANA negative ANA positive Diffuse large B cell, leg ANA negative ANA positive Diffuse large B-cell, other ANA negative ANA positive

Secondary

Follicular ANA negative ANA positive Diffuse large B-cell ANA negative ANA positive SKINmed. 2014;12:244–248

Sex

246

Men

Women

10 1 (of the scalp) 2 (of the scalp) 16 6 (1 of the scalp) — 1 — — 3 2 —

5 — — 13 9 (2 of the scalp) — 2 — — 1 — —

4 1 1 (of the scalp) 1 1 —

— — — 2 — —

Antinuclear Antibody Seropositivity in Men

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Case Study

Table II. Patient Characteristics Patients

Age/Sex

Cutaneous Lymphoma Subtype

Autoimmune Symptoms

ANA Pattern

1

65/Man

Primary cutaneous follicle center lymphoma

None

1:640, homogenous

2

43/Man

Primary cutaneous follicle center lymphoma

None

1:160, homogenous

3

37/Man

Follicular lymphoma, stage IVA

None

1:80, nucleolar

As far as we are aware, we are the first to demonstrate ANA seropositivity in cutaneous B-cell lymphoma patients. A retrospective chart review found elevated ANA titers in 3 patients with cutaneous B-cell lymphoma of follicular origin: 2 with primary cutaneous follicle center lymphoma and 1 with secondary cutaneous follicular lymphoma (Table II). Notably, the study also saw positive ANA titers particularly in patients with follicular lymphoma. The centrocytes and centroblasts characteristically seen in follicular lymphoma may be inducing ANA expression, perhaps secondary to lymphoma cells expressing autoimmune immunoglobulins10 or apoptotic lymphoma cells causing crosspresentation of intracellular antigens.11 The latter explanation may be supported by the observation that in our ANA-positive patients, malignant B cells did not typically express the antiapoptotic protein bcl-2. This differs from other studies, which have demonstrated bcl-2 to be strongly expressed in skin biopsies of secondary cutaneous follicular lymphoma and low-grade cutaneous primary follicle center lymphoma.12

Conclusions ANA titers may be elevated in patients with cutaneous B-cell lymphoma, particularly men with low-grade primary or secondary follicular lymphoma affecting the scalp. Previous studies have shown ANA seropositivity to correlate with NHL, but we believe we are the first to describe this in cutaneous B-cell lymphoma. Due to our small sample size, larger studies are needed to assess statistical significance. Finally, it would be interesting to know whether ANA titers decrease after rituximab treatment, a finding that has been reported in patients with systemic lupus erythematosus.15 References

We found ANA seropositivity to be associated with low-grade lymphoma in men and to follow a homogenous distribution when coupled with primary cutaneous follicle center lymphoma.

Of note, the ANA for patient 3 was only mildly elevated (1:80), had a nucleolar pattern, and was associated with secondary follicular lymphoma. To our knowledge, a similar clinical constellation has been described only once before in a patient with systemic follicular lymphoma who also had a positive ANA (1:160) with a nucleolar distribution.4 Interestingly, all 3 of our ANApositive patients had cutaneous B-cell lymphoma exclusive to the scalp. Although ANA is a sensitive marker of rheumatologic disease, none exhibited signs or symptoms characteristic of collagen vascular disease. Patient 1 and patient 3 had no implicating comorbidities or medications that we could find. Patient 2 had a history of ulcerative colitis and infliximab treatment, however, which have both been associated with ANA seropositivity.13,14 The fact that all 3 patients resolved after R-CHOP suggests that elevated ANA levels do not alter treatment response.

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1 Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood.

2005;105:3768–3785.

2 Richmond HM, Duvic M, Macfarlane DF. Primary and metastatic malignant tumors of the scalp: an update.

Am J Clin Dermatol. 2010;11:233–246.

3 Timuragaoglu A, Duman A, Ongut G, et al. The significance of autoantibodies in non-Hodgkin’s lymphoma.

Leuk Lymphoma. 2000;40:119–122.

4 Guyomard S, Salles G, Coudurier M, et al. Prevalence and pattern of antinuclear autoantibodies in 347 patients with non-Hodgkin’s lymphoma. Br J Haematol.

2003;123:90–99.

5 Peterson SR, Talpur R, Duvic M. Antinuclear antibody seropositivity in patients with cutaneous T-cell lymphoma.

J Am Acad Dermatol. 1998;39:434–438.

6 Peng YC, Hsieh SC, Yang DY, et al. Expression and clinical significance of antinuclear antibody in hepatitis C virus infection. J Clin Gastroenterol. 2001;33:402–406.

7 Kulthanan K, Jiamton S, Omcharoen V, et al. Autoimmune and rheumatic manifestations and antinuclear antibody study in HIV-infected Thai patients. Int J Dermatol.

2002;41:417-422.

8 Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum.

1997;40:1601–1611.

9 Jardin F. Development of autoimmunity in lymphoma.

Expert Rev Clin Immunol. 2008;4:247–266.

Antinuclear Antibody Seropositivity in Men

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Case Study

10 Dighiero G, Hart S, Lim A, et al. Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas. Blood. 1991;78:581–585.

11 Rovere P, Sabbadini MG, Vallinoto C, et al. Delayed clearance of apoptotic lymphoma cells allows cross-presentation of intracellular antigens by mature dendritic cells.

J Leukoc Biol. 1999;66:345–349.

12 Kim BK, Surti U, Pandya A, et al. Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol. 2005;29:69–82.

13 Barahona-Garrido J, Camacho-Escobedo J, Garcia-Martinez CI, et al. Antinuclear antibodies: a marker associated with steroid dependence in patients with ulcerative colitis. Inflamm Bowel Dis. 2009;15:1039–1043.

14 Viana VS, de Carvalho JF, de Moraes JC, et al. Autoantibodies in patients with psoriatic arthritis on anti-TNFα therapy. Rev Bras Reumatol. 2010;50:225–234.

15 Weide R, Heymanns J, Pandorf A, et al. Successful longterm treatment of systemic lupus erythematosus with rituximab maintenance therapy. Lupus. 2003;12:779– 782.

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Volume 12 • Issue 4

CASE STUDY

Linear Milia en Plaque on the Forearm Piyush Kumar, MD; Ramesh Chandra Gharami, MD

A 64-year-old man presented with asymptomatic eruption on his right forearm and the dorsum of the hand present for 2 weeks. There was no history of trauma, prolonged sun exposure, or application of or contact with any substance prior to the development of lesions.

He was a known hypertensive and diabetic and was taking treatment for these conditions. The rest of his history was noncontributory.

On examination, multiple grouped tiny white papules were found on both normal skin and on the erythematous plaque. These papules were of almost uniform size (2–4 mm) and were notable for absence of umbilication. The erythematous plaque was roughly 15 cm in length and was extending along the ulnar border of forearm and dorsum of hand in a linear pattern (Figure 1). The surface temperature of the plaque appeared similar to the surrounding area, and the surface was studded with multiple tiny white papules. There were no lesions suggestive of chronic actinic damage in the surrounding area. The papules revealed solid whitish material on expression with a needle. The rest of the mucocutaneous examination was noncontributory. Based on clinical presentation, a diagnosis of linear milia en plaque was made. (SKINmed. 2014;12:250–251)

H

istopathology findings were consistent with milia.

Considering the patient’s age and comorbidities, physical and topical modes of treatment were chosen. First, electrodessication (ED) was done for treating most of the milial lesions. Surprisingly, it also resulted in some reduction in the size of the erythematous plaque. After 1 week of ED, medical therapy with clobetasol propionate ointment in the morning and tretinion 0.05% cream at night was advised for 3 weeks. This therapy resulted in drastic reduction in the size of the plaque; however, new milia lesions were developing (Figure 2). After that, only tretinoin 0.05% cream was continued for another 3 weeks. There was almost complete clinical resolution; however, the lesions had healed with residual hyperpigmentation (Figure 3). All treatments were stopped on the second follow-up visit (total of 6 weeks), and the patient was under follow-up for another 2 years. No recurrence was noted in this period.

Discussion Milia are small keratin-filled cysts caused by obstruction of a hair follicle or eccrine gland duct.1 Multiple eruptive milia (MEM) and milia en plaque (MEP) are the rare presentations of the otherwise common dermatologic condition milia. While MEM is characterized by development of numerous milia during a short span, MEP typically presents as erythematous-edematous or infiltrated erythematous plaque containing numerous milia with

or without comedones, usually in the head and neck region.1,2 Although it is reported in various age groups, it is more common in middle-aged adults, with a female predominance.2 The etiopathogensis is unknown; however, association with pseudoxanthoma elasticum, discoid lupus erythematosus, lichen planus, trauma, renal transplantation, and cyclosporine therapy has been documented.1,2 The most common presentation is similar to that in our case. The classic location is the postauricular area; however, lesions at the preauricular, supraclavicular, periorbital, and submandibular areas; nasal bridge; eyelids; and forehead are known.2 It is usually unilateral and may be several centimeters in diameter.1,3 The bilateral distribution is known, but is very rare.3 Only 1 case with linear distribution has been documented.4 No systemic complications have been reported. MEP should be differentiated from nevus comedonicus and Favre-Racouchot disease. The clinical examination is usually sufficient to differentiate these conditions.1 The histopathology is diagnostic in doubtful cases.1,2 Histologically, MEP is characterized by keratinous cysts (epidermal) and lymphocytic infiltration. The infiltration is usually most dense beneath the epithelium of cysts, showing lichenoid pattern.1,2 Chronic granulomatous inflammation of the foreign body type is found when the cysts are ruptured.

MEP may regress spontaneously; however, it usually remains unchanged if untreated.5 Various treatment modalities have been described for MEP and include topical tretinoin, etretinate, mi-

From the Department of Dermatology, Medical College, Kolkata, India Address for Correspondence: Piyush Kumar, MD, Department of Dermatology, Medical College and Hospital, Kolkata, West Bengal, India 700033 • E-mail: docpiyush@gmail.com

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Case Study with respect to the optimal treatment for MEP, and the choice of therapy needs to be individualized.1,2 Conclusions MEP itself is a rare entity, and linear MEP is even rarer. The diagnosis is mainly clinical, and based on distinctive morphology. There is no consensus on optimal mode of therapy, in part due to the few cases in medical literature and short follow-up period after treatment. The dense lymphocytic infiltration in the dermis prompted us to use topical clobetasol propionate for a brief period, despite the fact that milia are a known complication of topical corticosteroid therapy. Our patient responded well to topical clobetasol and led to faster resolution, without much adverse effect. Based on our experience, we recommend combined modalities of treatment for MEP and include topical clobetasol propionate for a brief period, if not contraindicated. We could not find any cases of recurrent MEP in the medical literature.

No recurrence, as in our case, led us to believe that MEP may be a reaction pattern to a one-time assault/damage, which is yet to be identified. Our follow-up period was small and may limit the validity of our inference.

Figure 1. Erythematous linear plaque along the ulnar border of the patient’s forearm and hand. Note the multiple tiny white papules on both the erythematous plaque and normal-appearing skin.

Figure 2. After 3 weeks of treatment.

References 1 Martins LE, Werner B, Fonseca GP. Milia en plaque. An Bras Dermatol. 2010;85:895–898.

2 Berk DR, Bayliss SJ. Milia: a review and classification. J Am Acad Dermatol. 2008;59:1050–1063.

3 Hallaji Z, Akhyani M, Jamshidi S, Modabbernia A, Kamyab K. Bilateral retro-auricular milia en plaque: a case report and review of the literature. Dermatol Online J. 2010;16:12.

4 Kautz O, Muller S, Braun-Falco M, Nashan D. Milia en plaque in a linear pattern. J Eur Acad Dermatol Venereol.

2009;23:1335–1336.

Figure 3. After 6 weeks of treatment.

nocycline, simple extraction, electrodessication, carbon dioxide laser, erbium:YAG laser, dermabrasion, photodynamic therapy, and cryosurgery.1,6 Some authors have advocated use of 30% trichloracetic acid for the treatment of MEP as an inexpensive and effective modality7; however, no consensus has been reached

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5 Fujita H, Iguchi M, Kenmochi Y, Fukunaga Y, Asahina A. Milia en plaque on the forehead. J Dermatol. 2008;35:39– 41.

6 Mendiratta V, Sarkar R, Sharma RC, Koranne RV. Milia en plaque- an unsual presentation. Ind J Dermatol.

1999;44:64–65.

7 Sharma R, Kumar B. Milia en Plaque. Indian J Dermatol Venereol Leprol. 1995;61:365–366.

Linear Milia en Plaque on the Forearm

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July/August 2014

Volume 12 • Issue 4

CASE STUDY

Phytodermatitis to Euphorbia Trigona Razvigor Darlenski, MD, PhD;1 Jana Kazandjieva, MD, PhD;2 Nikolai Tsankov, MD, Dr Sci1 A 56-year-old Caucasian woman presented with acute onset of dermatitis on her face accompanied by intense itching. The patient reported that the condition began after cleaning a decorative plant, Euphorbia trigona, and contact with some drops of the plant’s latex sap released upon cutting its leaves. The clinical examination revealed erythema and edema of the infraorbital and perioral regions (Figure 1). The patient was in otherwise good general health, had no personal or family history of systemic or skin disease, and was not receiving any concomitant medications. Therapy with topical methylprednisolone aceponate 0.1% cream once daily was initiated and systemic desloratadine 5 mg tablets once daily was administered for the intense itch. Seven days after the introduction of the treatment a significant improvement was noticed (Figure 2). Patch testing with the leaves of the plant as well as with the latex sap was undertaken in order to prove the causative role (Figures 3 and 4). Strongly positive reactions with bulla formation were observed on day 2 and 3, most likely suggesting acute irritation instead of true delayed hypersensitivity. (SKINmed. 2014;12:253–255)

C

ontact dermatitis caused by plants, also known as phytodermatitis, is a relatively uncommon reaction that develops through different mechanisms (ie, irritation, contact allergy, phototoxicity, and photoallergy) and included a variety of etiologic agents. The prevalence of phytodermatitis is between 5% and 10% of all dermatitis cases.1 Euphorbia trigona, also known as Euphorbia hermentiana Lem and African milk tree, is a succulent plant belonging to the family of Euphorbiaceae. Its origin is the tropical and subtropical areas of East India and Africa. The plant is often mistaken for a cactus due to the many thorns coming out of the stem. It is a popular plant for indoor decoration in Europe and the United States.

stituents of the plant’s latex sap have been identified as 5 different ingenane derivates.6 Patients with latex allergy (not the case with our patient) are advised to avoid contact with Euphorbia spp.5 It is advisable that labels on sold plants from the Euphorbiaceae family contain warnings that the plant be handled with protective gloves. If skin or eye contact occurs with the sap, immediate washing is mandatory.

The spectrum of irritant skin reactions caused by contact with plants encompasses variable clinical manifestations varying from strong acute reactions with blistering, ulceration, and necrosis to granuloma formation (cactus plants) and subacute/chronic irritant dermatitis.2 The Table summarizes the different plants that cause skin irritation.

Acute irritant reactions from Euphorbia spp. have been formerly described.3,4 Dermatitis is produced when the sap of the plant comes into contact with the skin. Eye involvement has also been observed.5 The exact mechanism of the skin toxicity of the latex sap remains unknown. The dermatitis-producing chemical con-

Table. Plants that Cause Irritant Skin Reactions Family

Species

Agavaceae

Agave americana

Amaryllidaceae

Narcissus pseudo-narcissus

Araceae

Dieffenbachia picta, Philodendron spp.

Bromeliaceae

Ananas cosmosus

Brassicaceae

Armoracia rusticana, Brassica oleracea, Brassica nigra, Raphanus sativus, Sinapis alba

Euphorbiaceae

Euphorbia spp., Codiaeum variegatum, Hippomane mancinella, Ricinus communis

Liliaceae

Hyacinthus orientalis

Polygonaceae

Rheum rhaponticum

Ranunculaceae

Anemone pavonina, Ranunculus acer, Aquilegia vulgaris, Caltha palustris

Solanaceae

Capsicum frutescens, Capsicum annuum

From the Department of Dermatology and Venereology, Tokuda Hospital Sofia, Bulgaria;1 and the Department of Dermatology and Venereology, Faculty of Medicine, Medical University, Sofia, Bulgaria2 Address for Correspondence: Razvigor Darlenski, MD, PhD, Tokuda Hospital, Department of Dermatology and Venereology, Sofia, Bulgaria, 51B, Nikola Vaptsarov Boulevard, 1407 Sofia, Bulgaria • E-mail: darlenski@gmail.com

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CASE STUDY

Figure 1. General view of the patient’s face before treatment.

Figure 2. General view of the patient’s face after treatment.

Figure 3. Prepared plaster with the plant material for patch testing (lowest part, paper disc soaked with the plant’s latex).

Figure 4. Reactions on day 2 of the testing presented with erythema, edema, and blister formation.

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CASE STUDY

Figure 6. Closer view of the cut leaf with the latex sap (milk) flow.

References 1 Coz CJ, Ducombs G. Contact dermatitis.In: Frosch PJ, Menné T, Lepoittevin JP, eds. Plants and Plant Products.

Berlin Heidelberg: Springer-Verlag; 2006:751–780.

2 Sasseville D. Clinical patterns of phytodermatitis. Dermatol Clin. 2009;27:299–308, vi.

3 Worobec SM, Hickey TA, Kinghorn AD, Soejarto DD, West D. Irritant contact dermatitis from an ornamental euphorbia. Contact Dermatitis. 1981;7:19–22.

4 Smirnov LD, Efremov AI. Dermatitis due to euphorbia rigida M.B. Vestn Dermatol Venerol. 1970;44:67–69.

5 Kesler CJ. How do euphorbia plants cause contact dermatitis? Nursing. 2009;39:13.

6 Lin LJ, Marshall GT, Kinghorn AD. The dermatitis-producing constituents of euphorbia hermentiana latex. J Nat Prod. 1983;46:723–731.

Figure 5. Euphorbia trigona: general view.

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July/August 2014

Volume 12 • Issue 4

correspondence

Primary Localized Cutaneous Amyloidosis: A Clinical Diagnosis Carina M. Grönhagen, MD, PhD; Hong Liang Tey, MBBS, MRCP(UK)

To the Editor:

Table. Demographics of Patients

Primary localized cutaneous amyloidosis (PLCA) is characterized by the cutaneous deposition of amyloid protein within the papillary dermis without systemic involvement.1,2 It is more prevalent in populations in South America and Southeast Asia, especially in patients of Chinese origin.3 Currently, in most regions of the world, the diagnosis of PLCA is made histologically. In this article, we present in a series of patients a descriptive analysis that indicates PLCA can be diagnosed clinically with a high degree of accuracy without necessity of skin biopsies.

During the period of January 1, 2013, to December 31, 2013, consecutive patients in a general clinic who were clinically diagnosed to have PLCA were offered biopsy. Thirteen patients consented to the procedure (Table) and their clinical and histologic diagnoses were correlated. The skin lesions were most commonly located on the legs (pretibial area) (n=11), followed by the upper back (n=9) and arms (n=9); all but 1 patient had multiple locations of involvement. The duration of PLCA ranged from 1 to 20 years, and the majority of the patients (n=10 [77 %]) reported pruritus as the main symptom. Histologic studies were performed using hematoxylin and eosin as well as Congo red stains. In all 13 patients, the histologic diagnosis was consistent with the clinical diagnosis of PLCA. PLCA is a chronic condition that is often pruritic. There are three major forms: lichen, macular and the rare nodular form.

The lichenoid form is most common and consists of hyperpigmented, closely set, firm keratotic papules typically located on the shins and may also involve other extensor surfaces of the lower and upper limbs (Figure). In our study, 85% (n=11) of the patients had lichenoid lesions.2 The macular form is less often pruritic and is characterized by dark brown hyperpigmentation typically arranged in a rippled pattern, most often located over the upper arms and the upper back.4 In this study, 69% (n=9) of

Patients

N=13

Sex Female

9

Male

4

Mean age, (range), y

57.2 (39–75)

Ethnicity Chinese

12

Indian

1

Family history of primary cutaneous amyloidosis

3

the patients had the macular form. The lichen and macular forms are not distinct entities, often coexisting in the same patient, and are termed biphasic amyloidosis.2 The cause of PLCA is unclear, although different etiologic factors have been proposed, including genetic predisposition, prolonged friction, virus, and environmental factors.2 In this cohort, a subgroup of patients had a family history of the condition (23% [3 of 13], and 27% (12 of 44) of cases in our previous study were familial in nature.5 The clinical manifestations of PLCA, comprising the combination of the morphology and distribution of the lesions, are distinct. The differential diagnoses, consisting of lichen simplex chronicus, hypertrophic lichen planus, papular mucinosis, scleromyxedema, epidermolysis bullosa prupriginosa, and pityriasis versicolor are typically significantly different in appearance.

In Asian and South American patients presenting with chronic, often pruritic clinically typical lesions (congregation of hyperpigmented macules or papules, sometimes forming a rippled configuration) at the typical locations (symmetrical involvement of the extensor aspects of the arms and legs and the upper

From the National Skin Center, Singapore Address for Correspondence: Hong Liang Tey, MBBS, MRCP(UK), National Skin Center, 1 Mandalay Road, 308 205 Singapore • E-mail: teyhongliang111@yahoo.com

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CORRESPONDENCE back, often in more than one of these locations), the diagnosis of PLCA can be clinically distinguished from other dermatoses with a high degree of accuracy and the diagnosis can be made without the routine need for biopsies.

In summary, in our cohort of patients with PLCA, the clinical diagnosis correlated with the histologic findings in all cases. The routine diagnosis of PLCA can be made clinically without the need for histologic studies, especially in populations of patients in whom the disease is more prevalent.

References 1 Vijaya B, Dalal BS, Sunila, Manjunath GV. Primary cutaneous amyloidosis: a clinico-pathological study with emphasis on polarized microscopy. Indian J Pathol Microbiol. 2012;55:170–174.

2 Bolognia JL, Jorizzo JL, Rapini RP. In: Dermatology. 2nd ed. St. Louis, MO: Mosby Elsevier; 2008.

3 Tan T. Epidemiology of primary cutaneous amyloidoses in southeast Asia. Clin Dermatol. 1990;8:20–24.

4 Kibbi AG, Rubeiz NG, Zaynoun ST, Kurban AK. Primary localized cutaneous amyloidosis. Int J Dermatol.

1992;31:95–98.

Figure. Lichen amyloidosis with multiple hyperpigmented papules on the thighs in a Chinese man. The rippled pattern of arrangement of the papules seen here is classically described, but this is not a consistent feature of the condition.

5 Chia B, Tan A, Tey HL. Primary localized cutaneous amyloidosis: association with atopic dermatitis. J Eur Acad Dermatol Venereol. 2014;28:810–813.

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ERRATUM Skinmed. 2014;12:191.

Kafka and the Enigmatic Case of Cutaneous Myiasis.

Angel Fernandez-Flores, MD, PhD; Marcela Saeb-Lima, MD Two references were inadvertently dropped by the compositor. They appear below.

5. Felices RR, Ogbureke KU. Oral myiasis: report of case and review of management. J Oral Maxillofac Surg. 1996;54:219–220.

6. Tichý M. PB, Sládek P. The case of myiasis in spinocelulary carcinoma of the aurical. Otorinolaryng a Foniat (Prague).

2004;1:34–36.

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July/August 2014 2014

Volume 12 • Issue 4

Book Review Jennifer L. Parish, MD, Section Editor

Dermatopathology Primer of Inflammatory Diseases

By Feldman SR, Sangueza OP, Pichardo-Geisinger R, Kinney MA, Feneran A, Narahari S. Boca Raton, FL: CRC Press; 2014: 94p. $79.95

O

ne of Webster’s online dictionary definitions of a primer is “a small introductory book on a subject” and this aptly titles this small dermatopathology paperback text. The authors have drawn on their many years of dermatopathology practice and teaching to compile an introductory text primarily for individuals planning to enter a dermatology residency program or those in the first year of such a program.

Practitioners wishing a brief review prior to taking a recertification examination may also find it useful. This booklet provides a framework for understanding the various patterns of inflammation in the skin and proceeds in an orderly fashion to delineate the basic histologic findings of the most common clinical diseases demonstrating these specific patterns.

The histologic patterns are similar to those of Dr A. Bernard Ackerman’s groundbreaking textbook, Histologic Diagnosis of Inflammatory Skin Diseases: A Method by Pattern Analysis, originally published in 1978. They have simplified the subdivisions that Ackerman used in both his original and subsequent editions, pointing out only the major and most critical histologic findings.

Patterns described include superficial perivascular dermatitis with its subtypes, superficial and deep perivascular dermatitis, vasculitis, nodular and diffuse dermatitis, bullous and vesicular dermatitis, panniculitis, sclerosing dermatitis, and folliculitis. Under each pattern, several of the most commonly encountered clinical entities that are biopsied are presented with a brief description of the epidemiology, pathophysiology, clinical features, special studies, and clinical variants of each entity. The most important histologic features are illustrated with a relatively low magnification (usually ×10) and a higher magnification (usually ×40). These are accompanied by a written listing of the key microscopic features utilizing numbered arrows pointing to the features. A single low- or high-powered photomicrograph of one or two different histologic differential diagnostic entities is also presented. Helpful hints are

provided as “Good Things to Know” about the histologic examination of each disease.

Although dermatopathologists may quibble about the predominant pattern of a specific entity, such as placing pityriasis lichenoides under superficial perivascular dermatitis instead of superficial and deep perivascular dermatitis, the authors have selected entities that most often present with the histopathologic pattern used and can be clearly recognized by the beginner in dermatopathology.

As a result of the size constraints of a small introductory text, some of the photomicrographs appear blurred or overstained, making it difficult to identify cell types with certainty. Although this is obviously important in making a final diagnosis, the patterns are clearly illustrated in each of these entities and, with a little trust, the identification of the cells described as spindled, multinucleated, or containing granules is not so important. Some of the best highpowered photomicrographs demonstrate deep fungal organisms.

Many of these slides were obtained from the Graham Dermatopathology Library at Wake Forest School of Medicine, WinstonSalem, North Carolina, courtesy of Dr James H. Graham and Dr Gloria F. Graham who donated their life-long collections. Compilation of this material in a concise pattern format with each clinical entity and its histologic findings presented on a single page allows the reader to review the entire primer in a single sitting of 2 to 3 hours. The illustrated glossary of terms is placed at the end of the booklet, although it might have been more helpful for the reader at the beginning.

Overall, I can recommend this book to those students planning on entering or beginning a dermatology residency and to seasoned clinicians wanting to refresh their memories. Once properly categorized, additional histologic findings of a specific disease entity and ancillary information may be acquired from more definitive tests.

Reviewed by Richard L. Spielvogel, MD, Clinical Professor of Dermatology and Pathology, Drexel University, College of Medicine, Philadelphia, PA • E-mail: rlspiel@verizon.net

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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.