Skinmed Sep / Oct 2016

Chinese Society of Dermatology

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

Chang

ORIGINAL CONTRIBUTIONS Hair and Aging Turner and Bhogal

Terra Firma-Forme Dermatosis in Singaporean Patients: The “Alcohol Wipe” Sign

Oh, Oon, Ng, Tee, Jhingan, and Chong

Woronoff Ring: A Novel Manifestation of Molluscum Contagiosum Zawar, Goyal, and Doda

Dermatomyositis––Part 2: Diagnosis, Association With Malignancy, and Treatment

African Association for Dermatology

Atarzadeh, Daneshfard, Dastgheib, Jaladat, and Amin

PERILS OF DERMATOPATHOLOGY The Skin: A Time Capsule

Singh, John, Lai, Handler, and Lambert

NEW THERAPY UPDATE What Is New in the Management of Alopecia Areata Gupta, Carviel, and Abramovits

THE HEYMANN FILE Becoming Wiser About the Wiesner Nevus

Unna Nevus: Early Presentation in a 10-Year-Old Girl Chatterjee, Koley, and Madke

Focal Epithelial Hyperplasia in Adult Patients With HIV Infection: Clearance With Topical Imiquimod Méndez-Flores, Esquivel-Pedraza, Hernández-Salazar, Charli-Joseph, and Saeb-Lima

CORRESPONDENCE Consequences Boyd

Bernhardt

CORE CURRICULUM Alopecia Areata––Part III: Prognosis and Treatment

case studies A Pigmented Subcutaneous Nodule on the Scalp

Estefan, Ribeiro, Abad, Saintive, and Ramos-e-Silva

Kumaran, Narang, and Parsad

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Trench Foot

Self Assessment Examination Lambert

Contact Urticaria With Paraphenylene Diamine, Rare or Underreported?

Heymann

PHOTO CAPSULE Desquamative Dermatitis Caused

by Erlotinib: An Underreported Cutaneous Adverse Event

Ramos-e-Silva, Pinto, Pirmez, Cuzzi, and Carneiro

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

September/October 2016 • Volume 14 • Issue 5

September/October 2016 • Volume 14 • Issue 5 EDITORIAL DEPARTMENTS Campbell de Morgan Spot, Better HISTORICAL VIGNETTE Known As a Cherry Angioma Early Description of Diet-Induced Karadag and Parish Blistering Skin Diseases in Medieval Persia: Avicenna’s Point of View COMMENTARY Proximal Nail Fold Hematoma Due to Pulse Oximeter

North American Clinical Dermatologic Society

Vega, Yin, and Keller

Wang, Harvell, Friedman, Kirkorian, and Milgraum

Scan this QR code with your QR reader

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

The first and only prescription foam approved by the FDA for the treatment of rosacea In the art of rosacea therapy...

Proven efficacy has another profile with Finacea Foam ®

IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin Reactions: There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Eye and Mucous Membranes Irritation: Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea® Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a healthcare professional if eye irritation persists.

Flammability: The propellant in Finacea® Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

Most Common Adverse Reactions In clinical studies, the most frequently observed adverse reactions in ≥ 0.5% of subjects treated with Finacea® Foam included local site pain (6.2%), pruritus (2.5%), dryness (0.7%), and erythema (0.7%).

For Topical Use Only Finacea® Foam is not for oral, ophthalmic or intravaginal use.

Avoid the use of occlusive dressings or wrappings at the application site.

Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents.

Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

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.

For important risk and use information, see the full Prescribing Information at www.finaceafoam.com.

For important risk and use information, see the Brief Summary on the following page.

Discover The Foamulation www.finaceafoam.com

© 2016 Bayer. Whippany, NJ 07981.

Bayer, the Bayer Cross, and Finacea are registered trademarks of Bayer.

All rights reserved. PP-825-US-0518 January 2016

FINACEAÂŽ

(azelaic acid) Foam, 15% for topical use

For Topical Use Only–Not for Oral, Ophthalmic or Intravaginal Use Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Finacea (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.

5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

5.2 Eye and Mucous Membranes Irritation Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists.

5.3 Flammability The propellant in Finacea Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the prescribing information: t )ZQPQJHNFOUBUJPO [see Warnings and Precautions (5.1)]. t Eye and Mucous Membranes Irritation [see Warnings and Precautions (5.2)].

6.1 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.

Finacea Foam was evaluated for the treatment of papulopustular rosacea in two multicenter, randomized, double-blind, vehicle-controlled, 12-week clinical trials involving a total of 1362 (Finacea Foam, 15%: 681; vehicle: 681) subjects. Overall, 95.7% of subjects were White, 73.4% were female, and the mean age was 50.6 years.

Table 1: Adverse Reactions Occurring in ≼ 0.5% of Subjects Treated with Finacea Foam Compared with Subjects Treated with Vehicle System/Organ Class Preferred

Finacea Foam, 15% (N=681) n (%)

Vehicle (N=681) n (%)

General disorders and application site conditions Application site pain* Application site pruritus Application site dryness Application site erythema

42 (6.2%) 17 (2.5%) 5 (0.7%) 5 (0.7%)

10 (1.5%) 2 (0.3%) 5 (0.7%) 6 (0.9%)

* “Application site pain� is a term used to describe disagreeable skin sensations, including burning, stinging, paraesthesia and tenderness.

6.2 Post-Marketing Experience )ZQFSTFOTJUJWJUZ SBTI BOE XPSTFOJOH PG BTUINB IBWF CFFO SFQPSUFE GSPN the postmarketing experience of azelaic acid-containing formulations.

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.

Local Tolerability Studies In a 21-day cumulative irritation study under occlusive conditions, mildto-moderate irritation was observed for azelaic acid pre-foam emulsion. In B IVNBO SFQFBU JOTVMU QBUDI UFTU )3*15 TUVEZ OP TFOTJUJ[BUJPO QPUFOUJBM was observed for azelaic acid pre-foam emulsion.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.

Therefore, Finacea Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% foam. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 UJNFT UIF NBYJNVN SFDPNNFOEFE IVNBO EPTF .3)% CBTFE PO CPEZ surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times UIF .3)% CBTFE PO #4" BOE DZOPNPMHVT NPOLFZT HJWFO NH LH EBZ UJNFT UIF .3)% CBTFE PO #4" B[FMBJD BDJE /P UFSBUPHFOJD FGGFDUT were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys.

An oral peri- and post-natal developmental study was conducted in rats.

Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was PCTFSWFE JO SBUT BU BO PSBM EPTF PG NH LH EBZ UJNFT UIF .3)% based on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/ LH EBZ BOE UJNFT UIF .3)% CBTFE PO #4" /P FGGFDUT PO TFYVBM maturation of the fetuses were noted in this study.

8.3 Nursing Mothers It is not known if azelaic acid is secreted into human milk in vivo /P XFMM controlled studies of topically administered azelaic acid in nursing women BSF BWBJMBCMF /FWFSUIFMFTT UIF EFDJTJPO UP EJTDPOUJOVF OVSTJOH PS UP discontinue the drug should take into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Finacea Foam in children below the age of 18 years have not been established.

8.5 Geriatric Use Of the total number of subjects in clinical studies of Finacea Foam, 18.8 QFSDFOU XFSF BOE PWFS XIJMF QFSDFOU XFSF BOE PWFS /P PWFSBMM 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.

17 PATIENT COUNSELING INFORMATION Inform patients using Finacea Foam of the following information and instructions: t 'PS FYUFSOBM VTF POMZ t $MFBOTF BGGFDUFE BSFB T XJUI B WFSZ NJME TPBQ PS B TPBQMFTT DMFBOTJOH lotion and pat dry with a soft towel. t 4IBLF XFMM CFGPSF VTF t "WPJE VTF PG BMDPIPMJD DMFBOTFST UJODUVSFT BOE BTUSJOHFOUT BCSBTJWFT BOE peeling agents. t "WPJE DPOUBDU XJUI UIF FZFT NPVUI BOE PUIFS NVDPVT NFNCSBOFT *G Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye irritation persists. t *G BMMFSHJD SFBDUJPOT PDDVS EJTDPOUJOVF VTF BOE DPOTVMU ZPVS QIZTJDJBO t 8BTI IBOET JNNFEJBUFMZ GPMMPXJOH BQQMJDBUJPO PG 'JOBDFB 'PBN t $PTNFUJDT NBZ CF BQQMJFE BGUFS UIF BQQMJDBUJPO PG 'JOBDFB 'PBN IBT ESJFE t "WPJE UIF VTF PG PDDMVTJWF ESFTTJOHT BOE XSBQQJOHT t 5P IFMQ NBOBHF SPTBDFB BWPJE BOZ USJHHFST UIBU NBZ QSPWPLF FSZUIFNB flushing, and blushing. These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic beverages. t 5IF QSPQFMMBOU JO 'JOBDFB 'PBN JT nBNNBCMF "WPJE mSF nBNF PS smoking during and immediately following application. t %JTDBSE QSPEVDU XFFLT BGUFS PQFOJOH Š #BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD "MM SJHIUT SFTFSWFE Manufactured for:

#BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD 8IJQQBOZ /+ Manufactured in Switzerland

6798100BS

TABLE OF CONTENTS September/October 2016 • Volume 14 • Issue 5

EDITORIAL

Campbell de Morgan Spot, Better Known As a Cherry Angioma ................................................................ 331

Ayse Serap Karadag, MD; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARy

Proximal Nail Fold Hematoma Due to Pulse Oximeter ............................................................................... 335

Patricia Chang

ORIGINAL CONTRIBUTIONS

Hair and Aging .......................................................................................................................................... 338

Graham A. Turner, PhD; Ranjit K. Bhogal, PhD

Terra Firma-Forme Dermatosis in Singaporean Patients: The “Alcohol Wipe” Sign ................................... 345

Choon Chiat Oh, MBBS; Hazel H. Oon, MD (Toronto); See Ket Ng, MBBS; Shang Ian Tee, MBBS; Anjali Jhingan, MBBS; Wei-Sheng Chong, MBBS

Woronoff Ring: A Novel Manifestation of Molluscum Contagiosum ............................................................ 349

Vijay Zawar, MD; Tarang Goyal, MD; Dimple Doda

Dermatomyositis––Part 2: Diagnosis, Association With Malignancy, and Treatment .................................. 354

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

Self Assessment Examination ................................................................................................................... 359

Lambert

CORE CURRICULUM Virendra N. Sehgal, MD, Section Editor

Alopecia Areata––Part III: Prognosis and Treatment .................................................................................. 361

Juliany Estefan, MD; Marcia Ribeiro, MD, PhD; Eliane Abad, MD; Simone Saintive, MD; Marcia Ramos-e-Silva, MD, PhD

Departments Historical Vignette

Charles Steffen, MD, Section Editor

Early Description of Diet-Induced Blistering Skin Diseases in Medieval Persia: Avicenna’s Point of View ........................................................................................................................... 367

Fatemeh Atarzadeh, MD, PhD; Babak Daneshfard, MD, PhDc; Ladan Dastgheib, MD; Amir-Mohammad Jaladat, MD, PhD; Gholamreza Amin, PhD

Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

The Skin: A Time Capsule ......................................................................................................................... 372

Parmvir Singh, BS; Ann M. John, BA; Yi C. Lai, MPH; Marc Z. Handler, MD; W. Clark Lambert, MD, PhD

New Therapy Update

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

What Is New in the Management of Alopecia Areata .................................................................................. 375

Aditya Gupta, MD, PhD, FRCPC; Jessie Carviel, PhD; William Abramovits, MD

322

TABLE OF CONTENTS September/October 2016 • Volume 14 • Issue 5

The Heymann File

Warren R. Heymann, MD, Section Editor

Becoming Wiser About the Wiesner Nevus ................................................................................................ 379

Warren R. Heymann, MD

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

Trench Foot ............................................................................................................................................... 381

Mark Bernhardt, MD

Photo Capsule

Desquamative Dermatitis Caused by Erlotinib: An Underreported Cutaneous Adverse Event ..................... 383

Miriam L. Vega, MD, MPH; Natalie C. Yin, BS; Matthew Keller, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

A Pigmented Subcutaneous Nodule on the Scalp ...................................................................................... 385

Shuwei Wang, BS; Jeff D. Harvell, MD; Kenneth J. Friedman, MD; A. Yasmine Kirkorian, MD; Sandy Milgraum, MD

Contact Urticaria With Paraphenylene Diamine, Rare or Underreported? .................................................. 389

Muthu Sendhil Kumaran, MD; Tarun Narang, MD; Davinder Parsad, MD

Unna Nevus: Early Presentation in a 10-Year-Old Girl ............................................................................... 392

Kingshuk Chatterjee, MNAMS, MRCPS (Glasgow); Sankha Koley, MD; Bhushan Madke, MD

Focal Epithelial Hyperplasia in Adult Patients With HIV Infection: Clearance With Topical Imiquimod .................................................................................................................................... 395

Silvia Méndez-Flores, MD; Lilly Esquivel-Pedraza, DDS, MSc; Amparo Hernández-Salazar, MD; Yann Charli-Joseph, MD; Marcela Saeb-Lima, MD

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

Consequences............................................................................................................................................ 399

Alan S. Boyd, MD

323

IMPORTANT SAFETY INFORMATION Contraindications

exposed to Otezla, compared to none in placebo-treated patients (0/506). Suicidal behavior was observed in 0.1% (1/1308) of ◆ Otezla® (apremilast) is contraindicated in patients on Otezla, compared to 0.2% (1/506) patients with a known hypersensitivity to on placebo. One patient treated with Otezla apremilast or to any of the excipients in attempted suicide; one patient on placebo the formulation committed suicide Warnings and Precautions – Carefully weigh the risks and benefits ◆ Depression: Treatment with Otezla is of treatment with Otezla for patients associated with an increase in adverse with a history of depression and/or suicidal reactions of depression. During clinical thoughts/behavior, or in patients who trials, 1.3% (12/920) of patients treated with develop such symptoms while on Otezla.

Otezla reported depression compared to Patients, caregivers, and families should 0.4% (2/506) on placebo; 0.1% (1/1308) of be advised of the need to be alert for the Otezla patients discontinued treatment emergence or worsening of depression, due to depression compared with none on suicidal thoughts or other mood changes, placebo (0/506). Depression was reported and they should contact their healthcare provider if such changes occur as serious in 0.1% (1/1308) of patients

Otezla® is a registered trademark of Celgene Corporation. © 2016 Celgene Corporation 01/16 USII-APR150244

Weight Decrease: Body weight loss of 5-10% occurred in 12% (96/784) of patients treated with Otezla and in 5% (19/382) of patients treated with placebo. Body weight loss of ≥10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) of patients treated with placebo. Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla ◆ Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of Otezla efficacy may occur. Concomitant use of Otezla with CYP450 enzyme inducers (eg, rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended ◆

References: 1. Information derived from Symphony Health Solutions PrescriberSource PatientFocus data, Celgene proprietary methodology. April 2014 through December 2015. 2. Otezla [package insert]. Summit, NJ: Celgene Corporation; 2015. 3. Data on file, Celgene Corporation. 4. Papp K, Reich K, Leonardi CL, et al.

J Am Acad Dermatol. 2015;73(1):37-49.

◆

Otezla was evaluated in 2 multicenter, double-blind, placebo-controlled trials of similar design. Patients with moderate to severe plaque psoriasis (N = 1257) were randomized 2:1 to Otezla 30 mg or placebo twice daily for 16 weeks, after a 5-day titration2,4

◆

Inclusion criteria: Age ≥18 years, BSA involvement ≥10%, sPGA ≥3, PASI score ≥12, candidates for phototherapy or systemic therapy2,4

◆

Results were similar between ESTEEM 1 and ESTEEM 22,3

BSA, body surface area; PASI, Psoriasis Area and Severity Index; ScPGA, Scalp Physician Global Assessment; sPGA, static Physician Global Assessment.

Adverse Reactions ◆

Adverse reactions reported in ≥5% of patients were (Otezla%, placebo%): diarrhea (17, 6), nausea (17, 7), upper respiratory tract infection (9, 6), tension headache (8, 4), and headache (6, 4)

Use in Specific Populations ◆

Pregnancy and Nursing Mothers: Otezla is

Pregnancy Category C; it has not been studied in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether apremilast or its metabolites are present in human milk.

Caution should be exercised when Otezla is administered to a nursing woman

a Results were consistent between ESTEEM 1 and ESTEEM 2. b Week 16: secondary endpoint; all other timepoints: exploratory endpoints. c Baseline mean PASI scores: Placebo, 19; Otezla, 19; Total, 19. d During weeks 16 through 32 (maintenance phase), all patients received Otezla. e Causes of patient dropout include adverse events, lack of efficacy, and patient withdrawal. f 95% confidence interval. g FAS; LOCF. h Week 16: Prespecified exploratory endpoint. In the planned hierarchical statistical testing sequence for ESTEEM 1 and ESTEEM 2, efficacy analyses preceding ScPGA were statistically significant, allowing for control of the overall type 1 error rate at 0.05 significance level in analysis of ScPGA. i Baseline ScPGA ≥3.

Get the latest news at otezlapro.com

◆

Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min); for details, see Dosage and Administration, Section 2, in the Full Prescribing Information

Please turn the page for Brief Summary of Full Prescribing Information.

Rx Only OTEZLA® (apremilast) tablets, for oral use The following is a Brief Summary; refer to Full Prescribing Information for complete product information.

INDICATIONS AND USAGE OTEZLA® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

CONTRAINDICATIONS OTEZLA is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation [see Adverse Reactions (6.1)].

WARNINGS AND PRECAUTIONS Depression: Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients.

Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider.

Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur. During the 0 to 16 week placebocontrolled period of the 3 controlled clinical trials, 1.3% (12/920) of patients treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of patients treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated patients (0/506). Depression was reported as serious in 0.1% (1/1308) of patients exposed to OTEZLA, compared to none in placebo-treated patients (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of patients while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated patients. In the clinical trials, one patient treated with OTEZLA attempted suicide while one who received placebo committed suicide.

Weight Decrease: During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of patients treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of ≥10% of body weight occurred in 2% (16/784) of patients treated with OTEZLA 30 mg twice daily compared to 1% (3/382) patients treated with placebo. Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.

Drug Interactions: Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONS Clinical Trials Experience in Psoriasis: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of patients with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for patients treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated patients.

Table 3: Adverse Reactions Reported in ≥1% of Patients on OTEZLA and With Greater Frequency Than in Patients on Placebo; up to Day 112 (Week 16) Preferred Term

Placebo (N=506) n (%)

OTEZLA 30 mg BID (N=920) n (%)

Diarrhea

32 (6)

160 (17)

Nausea

35 (7)

155 (17)

Upper respiratory tract infection

31 (6)

84 (9)

Tension headache

21 (4)

75 (8)

Headache

19 (4)

55 (6)

Abdominal pain*

11 (2)

39 (4)

Vomiting

8 (2)

35 (4)

Fatigue

9 (2)

29 (3) (continued)

Table 3: Adverse Reactions Reported in ≥1% of Patients on OTEZLA and With Greater Frequency Than in Patients on Placebo; up to Day 112 (Week 16) Placebo (N=506) n (%)

OTEZLA 30 mg BID (N=920) n (%)

Dyspepsia

6 (1)

29 (3)

Decrease appetite

5 (1)

26 (3)

Insomnia

4 (1)

21 (2)

Back pain

4 (1)

20 (2)

Migraine

5 (1)

19 (2)

Frequent bowel movements

1 (0)

17 (2)

Depression

2 (0)

12 (1)

Bronchitis

2 (0)

12 (1)

Tooth abscess

0 (0)

10 (1)

Folliculitis

0 (0)

9 (1)

Sinus headache

0 (0)

9 (1)

Preferred Term

*Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain.

Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) patients following discontinuation of treatment with OTEZLA (apremilast).

DRUG INTERACTIONS Strong CYP 450 Inducers: Apremilast exposure is decreased when OTEZLA is co-administered with strong CYP450 inducers (such as rifampin) and may result in loss of efficacy [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C : OTEZLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to OTEZLA during pregnancy.

Information about the registry can be obtained by calling 1-877-311-8972.

Nursing Mothers: It is not known whether OTEZLA or its metabolites are present in human milk. Because many drugs are present in human milk, caution should be exercised when OTEZLA is administered to a nursing woman. Pediatric use: The safety and effectiveness of OTEZLA in pediatric patients less than 18 years of age have not been established. Geriatric use: Of the 1257 patients who enrolled in two placebo-controlled psoriasis trials (PSOR 1 and PSOR 2), a total of 108 psoriasis patients were 65 years of age and older, including 9 patients who were 75 years of age and older. No overall differences were observed in the efficacy and safety in elderly patients ≥65 years of age and younger adult patients <65 years of age in the clinical trials. Renal Impairment: Apremilast pharmacokinetics were characterized in subjects with mild, moderate, and severe renal impairment as defined by a creatinine clearance of 60-89, 30-59, and less than 30 mL per minute, respectively, by the Cockcroft–Gault equation.

While no dose adjustment is needed in patients with mild or moderate renal impairment, the dose of OTEZLA should be reduced to 30 mg once daily in patients with severe renal impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Hepatic Impairment: Apremilast pharmacokinetics were characterized in patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment. No dose adjustment is necessary in these patients.

OVERDOSAGE In case of overdose, patients should seek immediate medical help. Patients should be managed by symptomatic and supportive care should there be an overdose.

Manufactured for: Celgene Corporation, Summit, NJ 07901 OTEZLA® is a registered trademark of Celgene Corporation.

Pat. http://www.celgene.com/therapies ©2015 Celgene Corporation, All Rights Reserved.

Based on APRPI.005

OTZ_PsO_HCP_BSv.004 12_2015

September/October 2016

Volume 14 • Issue 5

Editorial

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

Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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

Chinese Society of Dermatology

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A POWERFUL FIRST RESPONDER Prescribe once-daily Enstilar ® for proven efficacy in an elegant vehicle for adult patients with plaque psoriasis1 Eligible* patients may get their prescription for as little as $0.

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INDICATION AND USAGE Enstilar® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older.

Apply Enstilar® to affected areas once daily for up to 4 weeks.

Patients should discontinue use when control is achieved. Instruct patients not to use more than 60 g every 4 days.

IMPORTANT SAFETY INFORMATION For topical use only. Enstilar® is not for oral, ophthalmic, or intravaginal use. Instruct patients to avoid use on the face, groin, or axillae, or if atrophy is present at the treatment site, and not to use with occlusive dressings, unless directed by a physician.

The propellants in Enstilar® are flammable. Instruct patients to avoid fire, flame, or smoking during and immediately after using this product.

Hypercalcemia and hypercalciuria have been observed with use of Enstilar®. If hypercalcemia or hypercalciuria develop, patients should discontinue treatment until parameters of calcium metabolism have normalized.

Topical corticosteroids can produce reversible hypothalamicpituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. Risk factors include use of highpotency topical corticosteroids, use over a large surface area or on areas under occlusion, prolonged use, altered skin barrier, liver failure, and use in pediatric patients. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of Reference: 1. Enstilar® [prescribing information]. Parsippany, NJ: LEO Pharma Inc.; October 2015.

LEO, the LEO Lion Design, and Enstilar are registered trademarks of LEO Pharma A/S. ©2016 LEO Pharma Inc. All rights reserved. March 2016 MAT-02406

application, or substitute with a less potent steroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroidcontaining product at the same time may increase total systemic corticosteroid exposure.

Adverse reactions reported in <1% of subjects treated with Enstilar® in clinical trials included application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis.

Patients who apply Enstilar® to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. You may wish to limit or avoid use of phototherapy in patients who use Enstilar®.

There are no adequate and well-controlled studies of Enstilar® in pregnant women. Enstilar® should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Because many drugs are excreted in human milk, caution should be exercised when Enstilar® is administered to a nursing woman. Do not use Enstilar® on the breast when nursing.

The safety and effectiveness of Enstilar® in pediatric patients have not been studied.

Please see Brief Summary on following page. *Must be 18 years of age or older to be eligible. For specific eligibility requirements and program restrictions, visit Enstilar.com or call 1-855-772-7224.

Enstilar ® (calcipotriene and betamethasone dipropionate) Foam, 0.005%/0.064% for topical use Initial U.S. Approval: 2006 BRIEF SUMMARY: Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE Enstilar ® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Flammability The propellants in Enstilar ® Foam are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application.

Hypercalcemia and Hypercalciuria Hypercalcemia and hypercalciuria have been observed with use of Enstilar ® Foam. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Enstilar ® Foam treatment of more than 4 weeks has not been evaluated.

Effects on Endocrine System Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of the topical corticosteroid. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria.

Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios.

Use of more than one corticosteroid-containing product at the same time may increase total systemic corticosteroid exposure.

Allergic Contact Dermatitis Allergic contact dermatitis has been observed with topical calcipotriene and topical corticosteroids. Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Corroborate such an observation with appropriate diagnostic patch testing.

Risks of Ultraviolet Light Exposures Patients who apply Enstilar ® Foam to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The rates of adverse reactions given below were derived from three randomized, multicenter, prospective vehicle and/or active-controlled clinical trials in subjects with plaque psoriasis. Subjects applied study product once daily for 4 weeks, and the median weekly dose of Enstilar ® Foam was 24.8 g.

Adverse reactions reported in <1% of subjects treated with Enstilar ® Foam included: application site irritation, application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, and exacerbation of psoriasis.

Postmarketing Experience Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing reports for local adverse reactions to topical steroids include atrophy, striae, telangiectasia, dryness, perioral dermatitis, secondary infection, and miliaria.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C There are no adequate and well-controlled studies in pregnant women.

Pregnant women were excluded from the clinical studies conducted with Enstilar ® Foam. Enstilar ® Foam should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with Enstilar ® Foam. Enstilar ® Foam contains calcipotriene that has been shown to be fetotoxic and betamethasone dipropionate that has been shown to be teratogenic in animals when given systemically.

Nursing Mothers Systemically administered corticosteroids appear in human milk and can suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when Enstilar ® Foam is administered to a nursing woman. Instruct the patient not to use Enstilar ® Foam on the breast when nursing.

Pediatric Use Safety and effectiveness of the use of Enstilar ® Foam in pediatric patients have not been studied. Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency with the use of topical corticosteroids. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients treated with topical corticosteroids.

Local adverse reactions including striae have been reported with use of topical corticosteroids in pediatric patients.

Geriatric Use Of the total number of subjects in the controlled clinical studies of Enstilar ® Foam in plaque psoriasis, 97 were 65 years or older, while 21 were 75 years or older. No overall differences in safety or effectiveness of Enstilar ® Foam were observed between these subjects versus younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

PATIENT COUNSELING INFORMATION [Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions For Use)] Inform patients of the following: • Instruct patients to shake before use.

• Instruct patients not to use more than 60 g every 4 days.

• Discontinue therapy when control is achieved unless directed otherwise by the physician.

• Avoid use of Enstilar ® Foam on the face, underarms, groin or eyes. If this medicine gets on face or in mouth or eyes, wash area right away.

• Wash hands after application.

• Do not occlude the treatment area with a bandage or other covering unless directed by the physician. Instruct the patients not to use other products containing calcipotriene or a corticosteroid with Enstilar ® Foam without first talking to the physician.

• Instruct patients who use Enstilar ® Foam to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.).

Physicians may wish to limit or avoid use of phototherapy in patients who use Enstilar ® Foam.

• Enstilar ® Foam is flammable; avoid heat, flame, or smoking when applying this medication.

•The foam can be sprayed holding the can in any orientation except horizontally.

Manufactured by: Colep Laupheim GmbH & Co. KG Fockestraße 12 88471 Laupheim Germany (DE)

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

LEO, the LEO Lion Design, and Enstilar are registered trademarks of LEO Pharma A/S. ©2015 LEO Pharma Inc. All rights reserved. November 2015 MAT-01533

September/October 2016

Volume 14 • Issue 5

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

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

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

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

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

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

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

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

Joseph L. Pace, MD, FRCP Naxxar, Malta

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

Art Papier, MD Rochester, NY

María Daniela Hermida, MD Buenos Aires, Argentina

Johannes Ring, MD, DPhil Munich, Germany

Warren R. Heymann, MD Camden, NJ

Roy S. Rogers III, MD Rochester, MN

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

SKINmed. 2016;14:330

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

Andrew P. Lazar, MD Washington, DC

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Editorial

Campbell de Morgan Spot, Better Known As a Cherry Angioma Ayse Serap Karadag, MD;1 Lawrence Charles Parish, MD, MD (Hon)2

I

n an era when many patients request a full-body scan, a number of benign lesions may be observed that cause concern to the patient. Among these are the cherry angioma (Figure 1), which was first described by a London surgeon, Campbell de Morgan (1811–1876), in his book on cancer in 1872.1 He considered this to be a sign of malignancy, reminiscent of the sign of Leser-Trélat. Not until 1953, when William Bennett Bean (1909–1989), the distinguished American physician, published his evaluation of 1000 patients with cherry angiomas and no associated malignancies was this concept put to rest.2 Background

Cherry angiomas, also referred to as ruby spots and even Campbell de Morgan spots, are among the most commonly developed cutaneous vascular proliferations. Because they appear with increasing frequency in older patients, they have been referred to as senile angiomas, possibly as a result of a 1970 survey, when a group observed an outbreak in several nursing homes and hospitals. They had discounted animal or insect vectors, person-toperson infection, and even other common infective or toxicologic factors. They attributed the outbreak to a recent rise in the atmospheric temperature, as the number of spots on each patient increased with temperature fluctuations.3 Another group focused solely on existing skin spots as a part of somatic overconcern. They considered cherry angiomas to develop on patients who lived in the same place as a result of psychologic interaction with each other, termed pseudo-outbreaks.4 Associations With Age and Other Conditions Without more evidence, we can only speculate about a particular genetic factor that makes patients more susceptible. There ap-

pears to be a direct correlation between cherry angiomas and age, therefore the aging process may play a role in the pathogenesis of these spots.5 These red lesions are highly unlikely to be found in patients younger than 30 years, and the frequency generally increases with age. While there is no sex distinction, it appears that 70% of seniors (those older than 70 years) have at least a few cherry angiomas.6 Some physicians have claimed that there is a rare occurrence in patients younger than 50 years, thus the term senile angiomas.7 To compound the issue, the cherry angioma has been linked with certain disease states and primary skin conditions. Patients taking cyclosporine,8 topical nitrogen mustard,9 2-butoxyethanol (ethylene glycol monobutyl ether),7 glutaraldehyde,7 and bromides10 and patients with primary biliary cirrhosis and prostatic carcinoma11 have been shown to develop the red spots.

During the Iran-Iraq conflict, civilians and military personnel suddenly developed cherry angiomas and melanocytic nevi after exposure to blister-causing agents, such as sulfur mustard.12 The abnormality of local angiogenic cytokines after epidermal damage appears to be a possible explanation for the mechanism of such eruptive cherry angiomas caused by toxic agents.9,12 Although the relationship between cherry angiomas and the sclerotic type of chronic graft-versus-host disease has been previously described,10 a recent study indicated that these are clinically and histopathologically different entities, named graft-versus-host disease-associated angiomatosis.13 Additional observations have shown cherry angiomas to be larger in diabetic patients,14 but recent studies do not support this association. Hormonal changes and pregnancy have also been implicated, as shown in a report of several pregnant women who developed lesions that involuted in the postpartum

From the Department of Dermatology, Istanbul Medeniyet University, School of Medicine, Istanbul, Turkey;1 and the Department of Dermatology and Cutaneous Biology, and the Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1845 Walnut Street, Suite 1650, Philadelphia, PA19103 • E-mail: larryderm@yahoo.com

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Editorial period.15 Two of the women with high prolactin levels reportedly developed hundreds of lesions. Human herpesvirus-8 was present in the eruptive form of cherry angiomas, specifically in the context of immunosuppression.16 Cherry angiomas are also visible in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome.15 The Facts

Figure 1. A single cherry angioma.

Cherry angiomas are bright red round-to-oval, dome-shaped papules that vary in size from being hardly visible to one millimeter to several millimeters in diameter, located predominantly on the trunk and extremities and less often on the head and extremities6,15 (Figure 2 and Figure 3). There is also an eruptive phase in the 40- to 50-year age group.16 Confusing the cherry angioma with other vascular lesions is possible but rarely occurs.

Histopathologically, cherry angiomas have dilated capillary blood vessels with variably thickened walls, located in the papillary dermis. Fully developed lesions have loss of the rete ridges with the formation of a collarette of adnexal epithelium at the periphery, which leads to a polypoid lesion.15 Treatment Treatment is by destruction, contrary to the requests some patients have for an oral panacea. Electrodestruction is effective, as well as cryosurgery, laser surgery, and cold steel surgery.6

Figure 2. Many cherry angiomas scattered on the chest of a middle-aged man.

Conclusions Cherry angiomas may amount to nuisances and occasionally a concern for the patient. They are benign and contrary to de Morgan’s concepts, are not paraneoplastic lesions. They are easily eliminated and best ignored.

References 1 De Morgan C. The Origin of Cancer. London, England: Churchill; 1872:16.

2 Bean WB. Cherry angioma: a digression on the longevity of error. Trans Assoc Am Physicians. 1952;66:240–249.

3 Honish A, Grimsrud K, Miedzinski L, Gold E, Cherry RR. Outbreak of Campbell de Morgan spots in a nursing home—Alberta. Can Dis Wkly Rep. 1988;14:211–212.

4 Poulin C, Schlech WF. A pseudo-outbreak in a nursing home. Infect Control Hosp Epidemiol. 1991;12:521–522.

5 Kim JH, Park HY, Ahn SK. Cherry angiomas on the scalp.

Case Rep Dermatol. 2009;1:82–86.

Figure 3. Congested capillaries and postcapillary venules expand the reticular dermis (hematoxylin and eosin stain, original magnification ×10).

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6 Jairath V, Dayal S, Jain VK, et al. Is sclerotherapy useful for cherry angiomas? Dermatol Surg. 2014;40:1022– 1027.

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7 Raymond LW, Williford LS, Burke WA. Eruptive cherry angiomas and irritant symptoms after one acute exposure to the glycol ether solvent 2-butoxyethanol. J Occup Environ Med. 1998;40:1059–1064.

8 De Felipe I, Redondo P. Eruptive angiomas after treatment with cyclosporine in a patient with psoriasis. Arch Dermatol. 1998;134:1487–1488.

9 Ma HJ, Zhao G, Shi F, Wang YX. Eruptive cherry angiomas associated with vitiligo: provoked by topical nitrogen mustard? J Dermatol. 2006;33:877–879.

12 Firooz A, Komeili A, Dowlati Y. Eruptive melanocytic nevi and cherry angiomas secondary to exposure to sulfur mustard gas. J Am Acad Dermatol. 1999;40:646–647.

13 Kaffenberger BH, Zuo RC, Gru A, et al. Graft-versus-host disease-associated angiomatosis: a clinicopathologically distinct entity. J Am Acad Dermatol. 2014;71:745– 753.

14 Shah K, Shah AC, Shah PC. Campbell de Morgan’s spots in diabetes mellitus. Br J Dermatol. 1966;78:493–495.

10 Cohen AD, Cagnano E, Vardy DA. Cherry angiomas associated with exposure to bromides. Dermatology.

2001;202:52–53.

15 Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol. 1997;37:887–919.

11 Mallett RB, Coulson IH, Holden CA. Acquired eruptive haemangiomata with primary biliary cirrhosis and prostatic carcinoma. Clin Exp Dermatol. 1992;17:206–207.

16 Borghi A, Benedetti S, Corazza M, et al. Detection of human herpesvirus 8 sequences in cutaneous cherry angiomas. Arch Dermatol Res. 2013;305:659–664.

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Volume 14 • Issue 5

COMMENTARY

Proximal Nail Fold Hematoma Due to Pulse Oximeter Patricia Chang, MD

T

he proximal nail fold is a component of the nail apparatus that has two important functions: (1) to act as a protective seal that protects from the external media, and (2) to be part of the formation of the nail plate.

Etiopathogenesis This fold can be affected by diverse causes of varying types including dermatologic, tumors, reactivity due to systemic disease, drug reactions, trauma, and infection, among others. The fingers can be affected by both major and minor traumas. Among such minor traumas are perionychotillomania, hangnail trimming, and, in the present case, the use of a pulse oximeter.

A pulse oximeter is used to measure continuous anesthesia saturation in patients during operations and in intensive care units. Occasionally, there can be injury to the finger induced by the pulse oximeter, as in the six reported cases, five of which were associated with the use of vasopressors and one that did not imply its use.1 The hematoma of the proximal nail fold has been subsequently studied, where it has been thought to be associated with the constant pressure exerted by the oximeter, which sometimes acts as a clip.2

Figure 1. Panoramic view of use of a pulse oximeter.

Clinical Manifestations It appears first as minimal erythema and sometimes edema (Figures 1–3) and occasionally vesicles and hematoma (Figures 4–6).

The condition can affect any finger and, in children, the first toe or the dorsum of the foot, depending on where the oximeter has been placed.3 A rare location is the pinna.4 On occasion, improper use of the oximeter can cause the condition.5 Any finger can be individually affected, or several can be affected, with the right index finger being most often afflicted. The onset of the problem varies from 3 to 15 days.

Figure 2. Proximal nail fold of the left finger.

From the Department of Dermatology, Social Security General Hospital IGSS, Guatemala City, Guatemala Address for Correspondence: Patricia Chang, MD, Social Security General Hospital IGSS, 9a Calle 7-55 Zone 9, 01009, Guatemala City, Guatemala • E-mail: pchang2622@gmail.com

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Figure 6. Dermatoscopic view of the proximal nail fold hematoma on the left annular finger.

Figure 3. Dermatoscopic view of the proximal nail fold.

Prevention of this hematoma is simple and consists of rotation of the oximeter every 2 hours.6 Conclusions Recognizing this lesion in the proximal nail fold will help in the differential diagnosis, where collagen diseases, sepsis, or some other types of trauma might be considered.

ReferenceS 1 Wille J, Braams R, van Haren WH, van der Werken C. Pulse oximeter-induced digital injury: frequency rate and possible causative factors. Crit Care Med. 2000;28:3555– 3557.

Figure 4. Proximal nail fold hematoma on the index and annular fingers.

2 Chang P, Haneke E. Hematoma del pliegue proximal.

Reporte de tres casos. Dermatología CMQ. 2008;6:189– 191.

3 Chang P. Hematoma del pliegue proximal ungueal en niños: informe de 5 casos Dermatologia CMQ. 2013;11:156–157.

4 Chang P Hematoma del lóbulo de la oreja por oxímetro.

Dermatologia CMQ. 2013;11:57.

5 Chang P, Haneke E, Rodas AC. Hematoma iatrógenico de la Uña. Dermatología CMQ. 2009;7:136–138.

6 Chang P, Rodas Diaz C. Hematoma of the proximal nail fold. Report of 41 cases. N Dermatol Online. 2011;2:65– 67.

Figure 5. Dermatoscopic view of the proximal nail fold hematoma on the left index finger.

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Volume 14 • Issue 5

Original contribution

Hair and Aging Graham A. Turner, PhD;1 Ranjit K. Bhogal, PhD2 Abstract Hair is the ultimate personal beauty tool of self-expression. It is more malleable than skin and it is more personal than clothing; however, hair does not remain constant with age. Hair is arguably in peak condition at about 30 years of age. With time, there is a gradual change in many aspects of hair: hair diameter is reduced, hair density is decreased, androgenic alopecia may develop, and pigmentation may be diminished, producing a significant psychological impact. These age-related changes can be exacerbated by blast drying, heat straightening, perming, and coloring. In this review, the changes in hair fiber and array (collection of fiber) properties that occur during aging and the impact on styling and potential interventions that consumers undergo to circumvent these issues are discussed. (SKINmed. 2016;14:338–343)

T

here is nothing more authentic than hair to express and project who a person is or who he or she wants to be. It is possible to change hair cosmetically in many more ways than skin. For example, it is possible to cut and style, change the color, straighten, curl, and bleach hair.1 Many people make such changes regularly. Because hair is a reflection of youth, health, and attractiveness, any significant changes in hair appearance and physical parameters can have a major impact on self-perception and personal well-being. Although purposeful changes to hairstyle can be made frequently, there are many changes that occur with age that prevent people from being completely satisfied with the end results obtained. These include alteration in growth patterns as a result of androgenetic alopecia and general fiber thinning,2 increased dryness perception as a result of reduction in sebum production3,4 and loss of internal lipids from the hair fiber, appearance of gray hair as a result of melanogenesis loss and decreased resistance to oxidative stress in the hair follicle, and a gradual change in natural shape (curly hair becomes somewhat straighter). In addition to these natural aging changes are those brought about by weathering (UV radiation from sun exposure) and pollution.5 This paper will review the changes that occur in hair with age and discuss the relative impact of hair care habits on hair quality and the relative importance of genetic and environmental changes on hair aging.

Hair Structure and Appearance Hair covers the whole body, with the exception of the soles of the feet, palms of the hands, mucous membranes (ie, the

eyelids), and the lips. The scalp consists of between 90,000 and 140,000 individual hair fibers.6 People with blonde hair typically have more hair (an average of 140,000 hairs) than people with brunette (105,000 hairs) or red (90,000 hairs) hair.7 Hair is made up of the protein keratin. The primary structure is a keratin coil with multiple coils forming a microfibril. The microfibrils collect together to form macrofibrils, which are arranged as cortical cells, forming the cortex of the hair fiber. The cortex makes up 80% of the hair fiber structure mass in human hair. Cortical cells are 1 to 6 mm thick and approximately 100 μm long. The cortical cells contain fibrillar and nonfibrillar protein. The remaining 20% of hair mass is composed of a thick protective covering consisting of the cuticle. The cuticle is made up of 9 to 10 sheet-like cells, 0.5 μm thick, stacked over each other and provides a protective layer to the hair fiber (Figure 1).8 Hair appearance and assessment of quality is affected by race, age, and color. It is well accepted that hair appearance has a large influence on perceived age (hair loss and the appearance of gray hair increases the perception of age). In terms of ethnicity there are some well-characterized differences in appearance and physical properties. The most apparent differences are in curl, shape, and color. Asian hair is the most circular and straight, whereas hair of African origin has the greatest ellipticity and curl. Hair of Caucasian origin has intermediate properties with a wider range of color.9

Presented at the 9th World Congress of Cosmetic Dermatology, Athens, Greece, June 27–30, 2013.

From Unilever Research & Development Port Sunlight, Bebington, Merseyside;1 and Unilever Research & Development Colworth, Sharnbrook, Bedfordshire,2 UK. Address for Correspondence: Graham A. Turner, PhD, Unilever Research & Development Port Sunlight, Quarry Road East, Bebington, Merseyside CH63 3JW, UK • E-mail: graham.turner@unilever.com

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Keratin coiled-coil Microfibril Macrofibril

Cortical

Cortex Cuticle Figure 1. Structure of the hair fiber.

As redundant as it may seem, use of styling products to refine appearance as part of the grooming process is almost globally ubiquitous. Cleansing is the most common styling process, using shampoo and, in many cases, conditioner, followed by drying (towel, blast, or natural drying) and finally combing or brushing to obtain the desired appearance.10 Beyond this basic treatment, the incidence of bleaching, coloring, blast drying, curling, straightening, and gelling is increasing. In many of these cases, the condition of the hair fiber surface can be damaged, which results in weakening of the fiber and subsequent breakage. The damage process can be seen in Figures 2A–2E. The damaging processes begin with an initial uplifting of the protective cuticle scales (Figure 2B). As the damage increases, the layers of the cuticle can be stripped away entirely, leaving the vulnerable cortex exposed (Figure 2C). The weaker exposed cortex, aggravated by further grooming, results in the development of split ends and, ultimately, breaking of fibers (Figures 2D–2E). Even without extrinsic aggressive treatment of the hair (eg, bleaching, dying), hair fibers have been demonstrated to deteriorate.11 Hair (1 m to 2.8 m long) collected from one individual has been characterized using an array of techniques. These measurements included shine, friction, diameter, lipid analysis, atomic force microscopy, and scanning and transmission electron microscopy. The results demonstrated a deterioration of the hair fiber with the newest hair being most intact and the maximum damage being apparent at the tip.11

phase reduces in duration and the number of hairs in the growing phase at any one time decreases.12 This has been demonstrated in both men and women.2,13 The number of empty follicles (kenogen follicles) increases. In men with androgenetic alopecia, this phenomenon is even greater (ie, anagen phase is reduced further and the time spent in kenogen is increased). This has the effect of decreasing the hair fiber density on the scalp. The number of hairs per follicular unit has also been shown to decrease with age, which has an impact on overall hair density.14

Physical properties Many studies have reported changes in hair diameter with increasing age. These studies have been conducted on men and women from a range of ethnic populations. The consensus appears to be that hair diameter increases to a maximum at 30 to 40 years, after which there is a gradual decrease in fiber diameter.2,13,15 Strength of hair fiber (ie, resistance to breakage) is proportional to fiber diameter.16 The average fiber diameter decreases with age. The combination of decreased fiber diameter and increased likelihood of fiber breakage with reduced diameter

Age-Related Changes

Table. Hair Growth Cycle Growth Phase

Characteristics

Anagen

Active growth phase: 3- to 6-year duration

Catagen

Regression or transition: 1–2 weeks

Hair growth cycle

Telogen

Resting phase (no active growth): 4–6 months

The hair growth cycle is summarized in the Table. The duration of elements of the hair growth cycle has been found to change with age (quite apart from androgenetic alopecia): the anagen

Exogen

Hair fall or shedding

Kenogen

Empty follicle prior to new anagen phase

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A

B

C

D

E Figure 2. The damage process of hair: healthy hair (A), cuticle starts to break down (B), cuticle dissapears and cortex is exposed, (C) split ends appear (D), and the hair breaks (E).

leads to a greater hair fiber damage with age. A further consequence of this increase in hair fiber damage is a loss of shine as a result of increased scattering of light.11 Hair in the older population looks duller and experiences increased broken fibers and split ends.17 The increased hair damage also increases the SKINmed. 2016;14:338â&#x20AC;&#x201C;343

frictional properties of the hair array (collection of fibers), which makes it more difficult to comb and brush. Consequently, the grooming process generates higher frictional forces on weaker hair and leads to further damage generation in the hair array, compounding the problems associated with hair damage.

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Sebum

Epigenetics and its implications on hair follicle

Lipids associated with hair have two origins: the sebaceous glands and hair matrix cells. The sebaceous glands are associated with hair follicles and are found all over the body in close association with hair follicles (the pilosebaceous unit).

The output of the sebaceous gland increases at puberty and remains constant for many decades. Activity of the sebaceous gland is under the control of endocrine secretions, especially androgenic hormones, and the secretion of these lipids has been shown to change with age. Such changes include sebocyte proliferation, lipid synthesis, sebum excretion rate, and rheological properties.18 The hair lipid levels appear to reach a maximum at about 45 years in Caucasian women, which corresponds with the peak sebum levels in other body sites.19,20 In all studies presented to date, the decline in sebum production is greater for women and this correlates with perimenopause and menopause changes and concomitant hormonal balance changes.3,4 Reduced sebum levels have a major impact on hair fiber characteristics as well as the relatively wellknown impact on the skin. Sebaceous secretions are readily transported from the scalp to the tips of the hair and impart shine, flexibility, and a perception of softness.10 The reduced sebum production with age can give rise to a reduction in physical properties of hair including bending modulus, dryness, and shine.

growth

Gene expression The age-related changes described have been centered on the physical changes in the hair fiber. Recent studies have utilized molecular biology techniques to investigate changes at the level of gene expression and translation. One group used microarray and qPCR techniques to investigate the impact of aging on gene expression in the hair follicle.21 Their findings showed a significant downregulation of keratin genes in participants older than 55 years and suggested that these changes may be reflected in decreased hair fiber stability and flexibility in older patients.

In a separate study, researchers used microarray and reverse transcription polymerase chain reaction (RT-PCR) techniques on plucked hairs from young and older women.22 They found a decrease in the expression levels of genes involved in the Wnt signalling pathway, which is essential for maintaining the activity of the dermal papilla and controls the transition from telogen back into anagen. A decrease in the Wnt signalling pathway with increased age would suggest that this mechanism may be responsible for the hair growth cycle changes during aging.23 SKINmed. 2016;14:338â&#x20AC;&#x201C;343

Although all cells within an organism have the same genome, it is the particular combination of genes that are switched on or off that dictates cell morphology and function. It has now become clear that epigenetic mechanisms exist which modulate gene expression altering the phenotype without changing the genotype of a cell. Recent insights from hair follicle epigenetic studies have revealed a number of differentially expressed miRNAs in dermal papillas or hair follicles.24â&#x20AC;&#x201C;26 Animal knockout studies of genes involved in DNA methylation have demonstrated changes such as high variability in the size of follicles and shorter and thinner hair fibers.27 Such epigenetic investigations are in their early days and the downstream manifestation of hair follicle miRNAs requires further understanding. Nevertheless, analysis of the hair follicle epigenome offers novel routes to target the issues associated with hair aging and loss.

Melanogenesis Possibly the most overt sign of hair aging (with the exception of androgenetic alopecia) is loss of pigment, or graying.28 Gray hair is actually a mixture of pigmented (dark) and nonpigmented (white) hair fibers, and graying can occur from the late teenage years onwards (especially in men). Unpigmented hair fibers have different physical properties compared with pigmented fibers, eg, the torsional modulus is higher and unpigmented hair fibers have lower water content and a lower cross-sectional area. Melanogenesis in the melanocytes of the hair follicle differs from the activity of those in the skin. The melanogenic activity in hair follicles is tightly linked to the stages of the hair follicle growth cycle.29 The pigmentation process is switched on during anagen but is inactive during catagen/telogen. White hair is likely caused by a failure of melanocyte activation in early anagen as a result of one or a combination of the following: failure of the melanocytes in the outer root sheath to become activated or to proliferate in early anagen. This may be caused by a loss of activation signalling or a breakdown of the proliferation process, lack of repopulation of the bulb region by melanocytes, or failure of melanogenesis, leading to premature deactivation of melanocytes via apoptosis.

Cessation of melanogenesis via the buildup of reactive oxidative species in the hair follicle and the reduced levels of catalase in the gray hair follicle has been proposed by a number of researchers.30â&#x20AC;&#x201C;32 Oxidative stress is not the only cause of hair graying.

Studies have identified that a number of genes associated with pigmentation are downregulated in the nonpigmented follicle (endothelin-converting enzyme 1, protein kinase C, mitogenactivated protein kinase 3) and several of these changes have

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been confirmed using RT-PCR (Steven Goff, Unilever Research; Personal Communication). Currently, the relative importance of oxidative stress and other mechanisms of depigmentation/graying of hair are not fully understood.

Hair follicle stem cells The hair follicle is remarkable in that it is capable of regenerating itself and producing a new fiber after each cycle. Hair follicle stem cells (HFSCs) play a key role in hair follicle formation and renewal and also repopulate the epidermis following wounding.

They reside in the “bulge region” of the hair follicle below the sebaceous gland.33 Activated HFSCs generate proliferating progeny at the start of the anagen phase, which differentiate to form the inner root sheath and the hair shaft. A transcriptional regulator of stem cells has been shown to remain high in aged hair follicles compared with younger hair follicles, suggesting that aged HFSCs have a slower entry into anagen and therefore delayed entry into anagen and reduced hair density.34 The role of human HFSCs and signalling pathways involved in hair follicle regeneration provides a new route for tackling age-related hair concerns.

Acknowledgments David Gunn, Gail Jenkins, and Steven Goff of Unilever R&D provided insights and reviewed the manuscript. Jennifer Yates (Unilever R&D Port Sunlight) provided the photographs of damaged hair fibers used in Figure 2.

Disclosure Both authors are employees of Unilever UK Central Resources.

References

Aging Hair: Nature or Nurture The impact of genetic and environmental factors on hair aging has been investigated through monozygotic and dizygotic twins.35 The influence of genetic factors on hair graying was investigated using a genome wide analysis (GWA) approach. The data suggested that there was a very strong genetic component to the graying process. This study also investigated the relative importance of genetic and environmental factors on hair thinning and recession. Hair recession was assessed at the frontal and temporal regions of the head. Hair recession was found to be mainly influenced by genetic factors. By contrast, hair thinning had a negligible genetic component.

2 Courtois M, Loussouarn G, Hourseau C, Grollier JF. Ageing and hair cycles. Br J Dermatol. 1995;132:86–93.

3 Pierard GE, Pierard-Franchimont C, Le T, Lapiere C. Patterns of follicular sebum excretion rate during lifetime.

Arch Dermatol Res. 1987;279:S104–S107.

4 Trueb RM. Aging of hair. J Cosmet Dermatol. 2005;4:60– 72.

5 Balin AK, Pratt LA. Physiological consequences of human skin aging. Cutis. 1989;43:431–436.

6 Robbins C. Morphological, macromolecular structure and hair growth. Chemical and Physical Behaviour of Human Hair. 5th ed. Berlin, Germany: Springer-Verlag; 2012;1–104.

7 Cass C. Red hair 101 - The science behind the color.

The Redhead Handbook: A Fun and Comprehensive Guide to Red Hair and More! Boulder, CO: Blue Mountain Arts; 1983;9–12.

8 Robbins C. Chemical composition of different hair types.

Chemical and Physical Behaviour in Human Hair. Berlin, Germany: Springer-Verlag; 2012;105–176.

9 Franbourg A, Hallegot P, Baltenneck F, Toutain C, Leroy F. Current research on ethnic hair. J Am Acad Dermatol.

2003;48:S115–S119.

10 Draelos ZD. The biology of hair care. Dermatol Clin.

2000;18:651–658.

11 Thibaut S, De Becker E, Bernard BA, et al. Chronological ageing of human hair keratin fibres. Int J Cosmet Sci. 2010;32:422–434.

Conclusions Hair follicles, fibers and array properties have been shown to change with age. These changes include alteration of physical properties, which result in loss of strength and increased damage, changes in the growth cycle, and loss of pigmentation. Some of these changes may be linked to changes in the activity and behavior of the stem cell population in the hair follicle. Not all changes in hair properties are directly related to the aging process. Studies on twins have revealed that environmental and grooming factors can have an impact. The consequence of these age-related changes is that hairstyle manageability, perception of volume/body, and mechanical strength all decrease. This leads to a greater sense of dissatisfaction caused by an inability to achieve and retain the style so desired.

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1 Synnott A. Shame and glory: a sociology of hair. Br J Sociol. 1987;38:381–413.

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12 Messenger AG. Hair through the female life cycle. Br J Dermatol. 2011;165:Suppl 3:2–6.

13 Robbins C, Mirmirani P, Messenger AG, et al. What women want—quantifying the perception of hair amount: an analysis of hair diameter and density changes with age in caucasian women. Br J Dermatol. 2012;167:324–332.

14 Tajima M, Hamada C, Arai T, et al. Characteristic features of Japanese women’s hair with aging and with progressing hair loss. J Dermatol Sci. 2007;45:93–103.

15 Jeong KH, Kim KS, Lee GJ, et al. Investigation of aging effects in human hair using atomic force microscopy.

Skin Res Tech. 2011;17:63–68.

16 Erik B, Havitcioglu H, Aktan S, Karakus N. Biomechanical properties of human hair with different parameters.

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17 Nagase S, Kajiura Y, Mamada A, et al. Changes in structure and geometric properties of human hair by aging. J Cosmet Sci. 2009;60:637–648.

26 Yi R, O’Carroll D, Pasolli HA, et al. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet. 2006;38:356–362.

18 Pierard-Franchimont C, Pierard GE. Postmenopausal aging of the sebaceous follicle: A comparison between women receiving hormone replacement therapy or not.

Dermatol. 2002;204:17–22.

27 Li J, Jiang TX, Hughes MW, et al. Progressive alopecia reveals decreasing stem cell activation probability during aging of mice with epidermal deletion of DNA methyltransferase 1. J Invest Dermatol.

2012;132:2681–2690.

19 Pochi PE, Strauss JS, Downing DT. Age-related changes in sebaceous gland activity. J Invest Dermatol.

1979;73:108–111.

20 Wills T, Dolphin S, Albiston L, et al. Free internal lipids in hair from pre- and post-menopausal women. IFSCC Magazine. 2004;7:293–297.

21 Giesen M, Gruedl S, Holtkoetter O, et al. Ageing processes influence keratin and KAP expression in human hair follicles. Exp Dermatol. 2011;20:759–761.

22 Kim SN, Lee SY, Choi MH, et al. Characteristic features of ageing in Korean women’s hair and scalp. Br J Dermatol. 2013;168:1215–1223.

23 Kishimoto J, Burgeson RE, Morgan BA. Wnt signaling maintains the hair-inducing activity of the dermal papilla. Genes Dev. 2000;14:1181–1185.

24 Goodarzi HR, Abbasi A, Saffari M, et al. MicroRNAs take part in pathophysiology and pathogenesis of male pattern baldness. Mol Biol Reps. 2010;37:2959–2965.

25 Goodarzi HR, Abbasi A, Saffari M, et al. Differential expression analysis of balding and nonbalding dermal papilla microRNAs in male pattern baldness with a microRNA amplification profiling method. Br J Dermatol.

2012;166:1010–1016.

28 Westgate GE, Botchkareva NV, Tobin DJ. The biology of hair diversity. Int J Cosmet Sci. 2013;35:329–336.

29 Tobin DJ, Paus R. Graying: gerontobiology of the hair follicle pigmentary unit. Exp Gerontol. 2001;36:29–54.

30 Blume-Peytavi U. Hair, aging, and environment: fundamental aspects. Ann Dermatol Venereol. 2009;136:S25– S28.

31 Kauser S, Westgate GE, Green MR, Tobin DJ. Human hair follicle and epidermal melanocytes exhibit striking differences in their aging profile which involves catalase. J Invest Dermatol. 2011;131:979–982.

32 Seiberg M. Age-induced hair greying—The multiple effects of oxidative stress. Int J Cosmet Sci. 2013;35:532– 538.

33 Jaks V, Kasper M, Toftgard R. The hair follicle-a stem cell zoo. Exp Cell Res. 2010;316:1422–1428.

34 Keyes BE, Segal JP, Heller E, et al. Nfatc1 orchestrates aging in hair follicle stem cells. Proc Nat Acad Sci. 2013;110:E4950–E4959.

35 Gunn DA, Rexbye H, Griffiths CE, et al. Why some women look young for their age. PLoS One. 2009;4:e8021

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For more information, please contact: Natasha Mohr info@CosmeticSurgeryForum.com / 402.697.6564 / CosmeticSurgeryForum.com

September/October 2016

Volume 14 • Issue 5

Original contribution

Terra Firma-Forme Dermatosis in Singaporean Patients: The “Alcohol Wipe” Sign Choon Chiat Oh, MBBS; Hazel H. Oon, MD (Toronto); See Ket Ng, MBBS; Shang Ian Tee, MBBS; Anjali Jhingan, MBBS; Wei-Sheng Chong, MBBS Abstract The term terra firma-forme dermatosis arises from the Latin phrase terra firma, meaning dry land (dirt), thus implying dirt-like dermatosis.

The authors highlight five cases of patients with terra firma-forme dermatosis presenting to our dermatology center between 2012 and 2013. All patients presented to the dermatologist for persistent reticulated brown patches on the skin. These patients ranged in

age from 6 to 22 years. All patients had tried various cleansing soaps and agents but were unable to remove the patches. The condition was cosmetically unacceptable to the patients and parents. Clinically, these patients had reticulated brown patches.

Rubbing 70% isopropyl alcohol wipes on the affected areas demonstrated clearance of the brown pigmented patches in all cases. The diagnosis of terra firma-forme dermatosis (TFFD) was confirmed by forceful rubbing with a gauze pad immersed in 70% isopropyl alcohol or ethyl alcohol. Patients should be reassured about the benign nature of TFFD and educated about the cleaning procedure. Recognition of this condition can assist physicians in making a diagnosis and therapy with a simple alcohol wipe, preventing further unnecessary tests for patients. (SKINmed. 2016;14:345–348)

T

erra firma-forme dermatosis (TFFD) is a skin condition that presents as dirt-like, hyperpigmented plaques often affecting the neck, trunk, and umbilicus. The dermatosis cannot be removed by washing with soap and water but clears upon wiping with isopropyl alcohol. There are few published case reports to date, and it is not a well-characterized entity. TFFD can be cosmetically unacceptable for many patients, yet clinicians can provide simple, effective therapy upon recognition of the condition. We present five cases of Asian patients from the National Skin Center, a tertiary dermatological center in Singapore.

with facial scrubs without success. Clinical examination showed reticulated brown plaques on his bilateral cheeks and temples (Figure 1B).

Case 1

Case 4

A 10-year-old Chinese boy presented with asymptomatic skin darkening over his penile shaft for 1 year. His mother had tried cleaning the affected area with soap and water but it did not resolve. Clinically, there were reticulated brown plaques over the penile shaft (Figure 1A).

A 22-year-old Chinese woman presented with asymptomatic skin darkening on her face for 6 months. She had tried facial scrubs without resolution. Clinical examination showed reticulated brown plaques on her bilateral cheeks (Figure 2C).

Case 2 An 18-year-old Chinese man presented with asymptomatic skin darkening over his cheeks for 3 years. He attempted to clean

Case 3 A 6-year-old Chinese girl presented with asymptomatic skin darkening over her abdomen for 1 year. Her parents had tried cleaning the affected area with soap and water but the lesions were persistent. Clinically, there were reticulated brown plaques over her abdomen and periumbilicus (Figure 2A).

Case 5 A 12-year-old Malay girl presented with asymptomatic skin darkening over her neck for 8 years. She was treated for acanthosis nigricans in the past with topical retinoids, but the lesions

From the National Skin Center, Singapore Address for Correspondence: Wei-Sheng Chong, MD, 1 Mandalay Road, Singapore 308205 • E-mail: wschong@nsc.com.sg

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Fig Fig 1b A 2a Fig 2a

A

B Fig 2b

Fig 1a

Fig 2b

Fig 1c

Fig 1b B Fig 2a

C

Fig 2c

Fig 1b Fig 2a

Fig 2c

D

C Fig 2b

Figure 2. (A) Dirt-like brown plaques on the flank and Fig 2d abdomen of a 6-year-old Chinese girl. (B) The lesions were removed with an isopropyl alcohol wipe in the clinic.

(C) Dirt-like brown plaques on the cheek of a 22-year-old Chinese woman. (D) The lesions were removed with an Fig wipe 2d in the clinic. isopropyl alcohol

Figure 1. Figure 1. (A) Dirt-like brown plaques on the penile shaft a 10-year-old Chinese boy. (B) Dirt-like Fig of1c brown plaque on the cheek of an 18-year-old Chinese man. (C) The lesions were removed with an isopropyl alcohol Fig 2wipe b in the clinic.

Fig 1c

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persisted. Clinically, there were reticulated brown plaques over her neck (Figure 3A).

All patients presented to the dermatologist for persistent reticulated brown patches on their skin. These patients ranged in age from 6 years to 22 years. All patients had tried various cleansing soaps and agents but were unable to remove the patches. It was cosmetically unacceptable to the patients and the parents.

There was no related itch or other cutaneous symptoms. Clinically, these patients had reticulated brown patches. The distribution of the pigmented patches varied: two patients had lesions on the face, one patient on his genitalia, one patient on her trunk, and one patient on her neck.

Fig 3a

A

Rubbing 70% isopropyl alcohol wipes on the affected areas demonstrated clearance of the brown pigmented patches in all cases (Figures 1C, 2B, 2D, 3B, and 3C).

Skin biopsies were not performed in any of our cases as the patients or their parents declined further investigations. The patients were taught how to use the isopropyl alcohol wipe on the affected areas at home. They were scheduled for follow-up to monitor their progress.

Fig 3a

Discussion The term terra firma-forme dermatosis arises from the Latin phrase terra firma, meaning dry land (dirt), implying dirt-like dermatosis.

It was first described by Christopher Duncan in 1987.1

Fig 3c

B

Fig 3b

Fig 3b

This condition affects all age groups as well as both sexes, with the youngest case reported to date being a 4-month-old girl. Existing reports do not support a familial predominance or genetic susceptibility.2–5

Fig 3c

Patients are generally asymptomatic. Physical examination reveals areas of brownish to black hyperpigmentation, usually with plaques and scales. The areas involved include the face, neck, trunk, back, limbs, and umbilical and pubic areas.1,2 Because of its appearance, TFFD can be a cause for cosmetic concern for the patient as well as parents of the affected child.

The cause is unknown at present. One hypothesis suggests altered maturation of keratinocytes with retention of melanin.6

C Figure 3. (A) Dirt-like brown plaques on the neck.

(B) The lesions were removed with an isopropyl alcohol wipe in the clinic. (C) Alcohol wipe after application on the neck.

Fig 3c SKINmed. 2016;14:345–348

The diagnosis of TFFD is confirmed by forceful rubbing with a gauze pad immersed in 70% isopropyl alcohol or ethyl alcohol.

This excludes the need for unnecessary laboratory workup or biopsy. The diagnosis is often reached when the lesion is wiped off with the alcohol pad used to prep the skin for biopsy.3,4,7

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With regards to cases in the literature where biopsy was performed, the histopathological description includes prominent lamellar hyperkeratosis with focal areas of compact whorled orthokeratosis, papillomatosis, mild acanthosis, and deposition of keratotic material within the valleys between the papilla.8

a diagnosis and providing therapy with a simple alcohol wipe, thereby preventing further unnecessary tests for patients.

The differential list of dirt-like dermatosis include pityriasis versicolor, confluent and reticulated papillomatosis of Gougerot and Carteaud, acanthosis nigricans, atopic dermatitis with post inflammatory hyperpigmentation, and dermatosis neglecta. An algorithm to work up the differentials has been proposed by Tan.9

2 Browning J, Rosen T. Terra firma-forme dermatosis revisited. Dermatol Online J. 2005;11:15.

References

Reappearance is unusual once the lesion is removed by an alcohol wipe. Patients should be reassured about the benign nature of TFFD and educated about the cleaning procedure.2 Conclusions We present five cases of TFFD in Asian patients in Singapore.

Recognition of this condition can assist physicians in making

1 Duncan WC, Tschen JA, Knox JM. Terra firma-forme dermatosis. Arch Dermatol. 1987;123:567–579.

3 Berk DR. Terra firma-forme dermatosis: a retrospective review of 31 cases. Pediatr Dermatol. 2012;29:297–300.

4 Guarneri C, Cannavò SP. Is this skin diseased, or is it just dirty? JAAPA. 2009;22:17.

5 Berk DR, Bruckner AL. Terra firma-forme dermatosis in a 4-month-old girl. Pediatr Dermatol. 2011;28:79–81.

6 Raveh T, Gilead LT, Wexler MR. Terra firma forme dermatosis. Ann Plast Surg. 1997;39:542–545.

7 Guarneri C, Guarneri F, Cannavò SP. Terra firma-forme dermatosis. Int J Dermatol. 2008;47:482–484.

8 Dalton SR, Pride H. The histopathology of terra firmaforme dermatosis. J Cutan Pathol. 2011;38:537–539.

9 Tan C. Dirt-adherent dermatosis: not worth an additional name. Arch Dermatol. 2010;146:679–680.

Pogonology

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Woronoff Ring: A Novel Manifestation of Molluscum Contagiosum Vijay Zawar, MD;1 Tarang Goyal, MD;2 Dimple Doda3 Abstract Woronoff ring has been mostly discussed as a phenomenon in psoriasis, especially during therapy. It has also been reported in a few other conditions unrelated to psoriasis; however, the association of Woronoff ring has not been reported in immunocompetent, healthy, and untreated patients with molluscum contagiosum who have no apparent systemic illness. The authors report a case series of Woronoff ring seen in untreated immunocompetent patients with molluscum contagiosum involving different age groups. (SKINmed. 2016;14:349–352)

M

olluscum contagiosum is an infection caused by a DNA virus of the poxvirus group. It is frequently seen in children, sexually active adults, and immunodeficient hosts. In immunocompetent patients, infection due to molluscum contagiosum is often controlled by cellular immune response of the affected host.1

of hypopigmentation around the lesions of molluscum contagiosum. There was no history of topical application of any topical steroids or other medications. No past major illness was noted including atopic dermatitis or asthma. Results from investigations for blood cell counts, blood sugar, and HIV antibodies were normal.

Woronoff ring (WR) has been described as a pale, hypopigmented skin ring or halo around psoriatic plaques. It was first described by Dmitriy L. Woronoff (1898–1978) in 1926.2 It was proposed that an inhibitor of prostaglandin (PG) synthesis diffused outwards from the psoriatic plaques and inhibited PGE2 formation, resulting in formation of WR.3 The WR is, however, not exclusive for psoriasis and has been described in many other unrelated dermatoses. We describe a case series of healthy patients with molluscum contagiosum who demonstrated WR.

Results from punch biopsy demonstrated epidermal hyperplasia with an invagination at the site of umbilication. There were characteristic abundant intracytoplasmic large eosinophilic inclusion bodies compressing the nuclei of keratinocytes (Figure 2), confirming the diagnosis of molluscum contagiosum. She was treated with curettage of the lesions, and the condition resolved completely. There was no recurrence of molluscum contagiosum or progression of WR. The hypopigmented rim persisted at follow-up of 4 weeks but became dull at 6 weeks and later nearly completely disappeared.

Case 1 A 28-year old pregnant woman with 6-month amenorrhoea, presented with asymptomatic pearly umbilicated papules on the left side of her face and neck for 4 months showing a gradual increase. They were typical for molluscum contagiosum. As the lesions progressed in size and number, the patient presented with a pale discoloration around the mollusca (Figure 1). On examination, the lesions showed spontaneous hypopigmentary rims around almost all of the lesions. There was no history of erythematous or eczematous stage intervening before the onset

Case 2 A 30-year-old unmarried healthy woman presented with two asymptomatic dome-shaped, pearly papules of 3 months’ duration with central umbilication surrounded by a hypopigmented rim present over the anterior aspect of her right forearm that varied in size from 0.2 cm to 0.5 cm in diameter (Figure 3). They were nonprogressive and not present anywhere else on the patient’s body.

From the Department of Dermatology, Godavari Foundation Medical College, DUPMCJ, Maharashtra;1 the Department of DVL, Muzaffarnagar Medical College & Hospital, Uttar Pradesh;2 and Dr Vasantrao Pawar Medical College and Research Centre, Nashik, Maharashtra,3 India Address for Correspondence: Vijay Zawar, MD, Skin Diseases Center, Opp Hotel Panchavati, Vakilwadi, Nashik, India • E-mail: vijayzawar@yahoo.com

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Figure 3. Two asymptomatic dome-shaped, pearly papules with central umbilication surrounded by a hypopigmented rim present over the anterior aspect of the right forearm in an adult woman. (These are better appreciated while looking from a distance.)

Figure 1. Typical molluscum lesions in the neck region of an adult woman showing typical Woronoff ring.

Investigations did not suggest diabetes, HIV, or any other systemic illness. There was no history of application of topical steroids or other topical or systemic medications. Treatment involved curettage, and the clinical diagnosis of MC was confirmed histopathologically by examination of the extruded material. There was complete resolution and no recurrence at 6 months’ followup. The ring, however, had slowly faded in 4 weeks.

Case 3

Figure 2. Histopathology of the same patient as in Figure 1 showing characteristic intracytoplasmic bodies that compress the keratinocyte nucleus (hematoxylin and eosin stain, original magnification ×4). Inset: Close-up view of the same characteristic Henderson-Paterson bodies (hematoxylin and eosin stain, 10×10).

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A 5-year-old boy with a nonatopic background presented with dome-shaped, pearly papules on the face that slowly increased in number during the past 6 weeks and affected both sides of the malar areas of the face, nose, right upper scapular region of the back, and the flexor surface of the right forearm. The two earliest lesions on the left malar area of the face showed spontaneous typical WRs (Figure 4). No treatment was sought for the eruptions, including prescribed medications or over-the-counter and home remedies. He was otherwise healthy. Results from investigations for complete blood cell count, blood sugar, and HIV antibodies were in the normal range. Skin biopsy was declined by the parents. Topical cantharidin therapy was administered at the consultation, but the patient was lost to follow-up.

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ORIGINAL CONTRIBUTION should determine the frequency of WR in PUVA-treated patients.5 WR can develop following different forms of phototherapy for psoriasis. WR are not only caused by PG synthesis inhibition but also vasoconstriction or failure of vasodilatation.6 The development could be due to superficial edema, analogous to white dermatographism. WR are seen not only in psoriasis but in other conditions as well.

Histologically, biopsies of this perilesional pallor show a 40% increase in epidermal thickness compared with normal skin, minimal acanthosis, and a remarkable decrease in basal melanin.7 It has also been observed that local cutaneous blood flow varies remarkably from the psoriatic plaque, the WR, and nonlesional skin; however, subcutaneous blood flow is the same within the plaque and the ring.8 Furthermore, the glycoprotein endoglin, which is upregulated in psoriatic cell proliferation, is found in decreased levels in the plaque circumference. It was proposed that this may play a role in the pathogenesis of the ring.9 WR has also been noted around a variety of nontreated skin lesions as erythema multiforme, pityriasis rosea, chicken pox, leishmaniasis,10 anthralin therapy for psoriatic plaques, and recently even after adalimumab therapy11 for psoriasis.

Figure 4. Typical pearly papules on the left malar area of the face of a 5-year-old boy demonstrating classical Woronoff ring.

Case 4 A 2-year-old nonatopic girl presented with multiple asymptomatic raised lesions over the right side of the lower aspect of her abdomen and the anterior part of her right thigh for 3 months.

No lesions were present elsewhere on the body and there was no history of topical application to the lesions. Two large, older-looking papules showed an indistinct hypopigmented rim.

Treatment was performed with curettage and diagnosis of MC was confirmed histopathologically by examination of the extruded material. There was complete resolution of the lesions and no recurrence. The ring, however, faded in 6 weeks.

Discussion WR were first described by Woronoff in 19262 and have been described as perilesional pale skin rings induced by UV treatment of psoriatic plaques. Use of the Goeckerman regimen with coal tar and UV florescent light, with 80% being below the 320-nm range, has been studied by some investigators.3 They proposed that the inhibitor of prostaglandin (PG) synthesis diffused outwards from the psoriatic plaques and inhibited PGE2 formation, resulting in formation of WR. Methoxsalen and UV light at 360 nm have also been used.4 Indomethacin, a known inhibitor of PGE2 synthesis, had no effect on psoralen–UV-A (PUVA)–induced erythema, whereas it reduced erythema due to UV-B rays. There have been discrepancies in study findings and further examination SKINmed. 2016;14:349–352

The pathogenesis of WR in our patients is intriguing and is far from clear. Our patients developed WR spontaneously, without intervening inflammatory or frank eczematous stage, (although case 2 showed slight scaling around one lesion).

Thus, it seems unlikely that WR is purely a postinflammatory hypopigmentation. All patients were immunocompetent with no apparent systemic abnormalities. Case 1 and 3 showed WR on photoexposed facial areas. In case 2, WR appeared on the arm, which was partially photoexposed. In case 4, however, lesions on the lower abdomen that demonstrated WR did not seem to be related to sunlight. Cutaneous lesions of molluscum contagiosum, which were slightly larger and older were affected by WR. Larger and older but stationary lesions of a few weeks’ duration demonstrated WR. Thus, the pathogenetic and clinical significance of WR in these patients is unclear. It may be speculated that the larger, older, stationary untreated lesions of molluscum contagiosum, which failed to rapidly involute, may demonstrate a hypopigmentary rim sign of Woronoff.

Very recently, a case of molluscum contagiosum with truncal involvement with halos around the lesions was reported in a patient with stage 4 Sézary syndrome and severe atopic dermatitis while on treatment with systemic chlorambucil and prednisolone and topical steroids. Topical corticosteroids by themselves may induce perilesional hypopigmentation. Thus,

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it may be likely in this patient that the hypopigmentary rim around the molluscum lesions might be due to topical steroids.

Moreover, the background described for this patient clearly indicates an immunocompromised state.12 Conclusions To the best of our knowledge, this is the first case series to describe the sign of WR in the context of untreated molluscum contagiosum in healthy immunocompetent patients. We believe, however, that such cases may not be rare. We propose that further studies are required to ascertain the exact pathophysiology of WR and its relationship with MC.

4 Lord, JT, Ziboh VA, Poitier J, et al. The effects of photosensitizers and ultraviolet irradiation on the biosynthesis and metabolism of prostaglandins. Br J Dermatol.

1976;95:397–406.

5 Lowe NJ, Bures F. Woronoff’s rings with PUVA therapy.

Arch Dermatol. 1978;114:278–280.

6 Warin AP, Greaves MW. Woronoff’s rings with PUVA therapy. Arch Dermatol. 1979;115:105.

7 Koplon BS, Waterson KW Jr, Shapiro L. The Woronoff ring of psoriasis: study of a patient. Int J Dermatol.

1971;10:233–236.

8 Klemp P, Bojsen J. Local variation in cutaneous and subcutaneous blood flow measured by CdTe(C1) minidetectors in psoriatic and normal skin. J Invest Dermatol.

1986;86:109–114.

9 Van de Kerkhof PC. The Woronoff zone surrounding the psoriatic plaque. Br J Dermatol. 1998;139:167–168.

References 1 Nguyen HP, Franz E, Stiegel KR, et al. Treatment of molluscum contagiosum in adult, pediatric, and immunodeficient populations. J Cutan Med Surg. 2014;18:299– 306.

2 Woronoff D. Die peripheren Veraenderungen der Haut um die Effloreszenzen der Psoriasis vulgaris and Syphilis corymbosa. Dermatol Wochenschr.1926;82: 249–257.

3 Penneys NS, Ziboh V, Simon P, et al. Pathogenesis of Woronoff ring in psoriasis. Arch Dermatol. 1976;112:955– 957.

10 Yücel A, Günasti, S, Denli Y, et al. Cutaneous leishmaniasis: new dermoscopic findings. Int J Dermatol.

2013;52:831–837.

11 Park KK, Swan JW, Eilers D, et al. Woronoff ring associated with adalimumab therapy for psoriasis. Cutis.

2014;93:E1–E2.

12 Le Treut C, Granel-Brocard F, Bursztejn AC, et al. Molluscum contagiosum surrounded by a white halo and Sezary syndrome. J Eur Acad Dermatol Venereol.

2015;29:1837–1839.

“Dermatitis phytogenis,” multiple blue nevi in a child with lentiginosis. Moulage No. 42, made

by Lotte Volger in 1928 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Edward L. Keyes Resident Contest for Outstanding Case Reports 12th World Congress of the International Academy of Cosmetic Dermatology May 4-6, 2017, Bengaluru, India Abstract deadline: January 10, 2017 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017.

We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, or cosmetic (or combined) in nature.

The author, whose abstract receives the highest score during the review process, will be awarded a scholarship by the IACD to present the full paper at the 12th World Congress of the International Academy of Cosmetic Dermatology in Bengaluru, India, May 4-6, 2017.

The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend.

Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, January 10, 2017, and should be no longer than 2,500 characters including spacing.

Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thought-out, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been or is in consideration for publication elsewhere at any time prior to the meeting.

The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology.

By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31st, 2017. The applicant must be in training at the time of the Congress presentation.

All applicants will receive e-mail notice of the Resident Case Report Review Committeeâ&#x20AC;&#x2122;s decision by February 5, 2017.

Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor and Interim Chair The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

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Dermatomyositis––Part 2: Diagnosis, Association With Malignancy, and Treatment Marcia Ramos-e-Silva, MD, PhD;1 Ana Paula Frade Lima Pinto, MD;1 Rodrigo Pirmez, MD;1 Tullia Cuzzi, MD, PhD;2 Sueli Carneiro, MD, PhD1,3 Abstract In this second part of the series on dermatomyositis, the diagnosis and its criteria with review of autoantibodies, capillaroscopy, imaging exams, histopathology, muscle biopsy, electroneuromyography, and muscular enzymes will be assessed. The association with malignancy, since it is described as paraneoplasic, will be discussed. The different therapeutic options for this disease will also be reported, including for dystrophic calcification, a rare and late complication of dermatomyositis. (SKINmed. 2016;14:354–358)

A

utoantibodies associated with dermatomyositis are divided into two groups: myositis-specific and myositisassociated. Specific autoantibodies are represented by antisynthetase antibodies, anti-Mi-2, anti-signal recognition particle (anti-SRP), CADM-140, and anti-p155/p140. Each patient expresses only one type of myositis-specific antibody and its positivity is associated with certain clinical features and prognosis.1,2 Antisynthetase antibodies arise against specific tRNA-synthetase–related amino acids, are represented by the FAN cytoplasmic pattern, and five different types are described: anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, and anti-OJ, each facing a different amino acid (histidine, threonine, alanine, glycine, and isoleucine, respectively). Anti-Jo-1 was the first to be described in 1980 and is the most frequently encountered,3 with a reported rate of about 25% to 30% of patients. 4 Antisynthetase syndrome is the association of myositis, interstitial lung disease, nonerosive arthritis, fever, and hyperkeratotic lesions on the lateral surface of the fingers (“mechanic’s hands”) and is associated with the presence of these antibodies.5 Mi-2 antibody is present in 20% to 30% of patients3 and is associated with low mortality, good therapeutic response, typical

cutaneous signs (such as cuticular alterations and shawl sign), and low risk for malignancy.2,3 Anti-SRP is associated with rapidly progressive and severe muscular disease and with the finding of muscle fiber necrosis and sparse lymphocytes inflammatory infiltrate in histopathology.3 Autoantibody CADM-140 is present in the amyopathic form, but also in its classical form, and is related to severe disease progressing to pulmonary fibrosis. Its frequency is not yet determined.2 The autoantibody anti-p155/p140 marks the association between dermatomyositis and neoplasia.2 The following antibodies are classified as being associated with myositis: anti-PM/Scl, anti-Ro, and anti-Lae U1RNP.6 FAN can be positive in 5% to 20% of patients in titrations that generally do not exceed 1/320 with dotted or speckled deposit patterns. It should not be considered diagnostic.7 Periungual capillaroscopy consists of in vivo visualization of the microvascular net of the periungual region. It is a noninvasive examination that provides additional data regarding disease activity and efficiency of the treatment.8 The capillaroscopic find-

See also Ramos-e-Silva M, Pinto APFL, Rodrigo Pirmez R, et al. Dermatomyositis––part 1: definition, epidemiology, etiology and pathogenesis, and clinics. SKINmed. 2016;14:273–279.

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

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ings maintain a correlation with cutaneous disease activity, but do not relate to muscular symptoms.9 The alterations found are similar to those seen in patients with scleroderma. Capillary loops ectasia, avascular regions, reduction in capillary density, and hemorrhage may be observed.8,10 Some features may help in the specific diagnosis, such as the great prevalence of capillaries with lush ramifications (scrub capillaries), and greater definition in vessel edges.11 Imaging tests help in the early diagnosis of muscular disease, may guide the best area for muscular biopsy, and are also useful in the assessment of the response to the treatment.12 Magnetic resonance imaging is more sensitive than computer tomography and the most significant finding is muscular edema, which may be present even before the clinically established muscle weakness. It is not specific, however, and may be seen in other myopathies. The findings are generally symmetrical and occur more frequently in the proximal muscles. Fat infiltration is a sign of chronicity and lack of response to treatment. Muscular atrophy is nonspecific and is indicative of prolonged illness.4,13 Calcification between muscle fibers is rare. It is better viewed through computerized tomography and is also observed at advanced stages of the disease.13

Figure 1. Histopathology of skin—superficial perivascular lymphocytic infiltrate and vacuolar degeneration (hematoxylin and eosin stain, original magnification ×10).

Muscle Biopsy A muscle biopsy should be performed whenever possible, as it is the most specific examination.4,14 The main difficulty is obtaining an adequate sample, because the results may be normal, even with clinically established muscular weakness, and may not reflect the severity of the disease. A muscle group that presents moderate weakness should be chosen to increase the biopsy’s effectiveness.

Because the disease is symmetrical, the contralateral electroneuromyography may determine the biopsy area.4 Open biopsy is preferable to needle biopsy as it provides a larger sample.

Figure 2. Histopathology of skin—superficial perivascular lymphocytic infiltrate, vacuolar degeneration, and keratinocyte necrosis (hematoxylin and eosin stain, original magnification ×40).

Histopathologic Examination Histopathologic findings on the skin are similar or indistinguishable from those of systemic lupus erythematosus and include: (1) interface dermatitis with vacuolar degeneration of basal keratinocytes, (2) thickening of the base membrane, (3) pigmentary incontinence, (4) superficial or diffuse perivascular lymphocytic infiltrate, and (5) hyperkeratosis and destruction of interpapillary cones. There is mucin deposition in the dermis.

Initial lesions show little histologic alterations (Figures 1 and 2).

The most characteristic observations following muscular biopsy are perifascicular atrophy with necrosis of the muscular fiber.

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The presence of perivascular inflammatory infiltrate with CD4+ and B lymphocytes is another specific finding. In some cases, inflammatory infiltrate can be absent.3,15 Reduction in vascular density is also observed. Vascular injury is mediated by the membrane attack complex comprising lytic components of the complement system. This can be detected in the vessel wall at the early stages of the disease, even where the muscular fiber histopathology appears normal. It suggests that the vascular damage

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Table. Bohan and Peter Criteria for the Diagnosis of Dermatomyositis Individual criteria: 1. Symmetric proximal muscle weakness 2. Evidence of inflammatory myopathy in muscle biopsy 3. Increase in serum skeletal muscle enzymes (creatine kinase, aspartate aminotransferase, alanine aminotransferase, aldolase, and lactate dehydrogenase) 4. Characteristic electromyographic pattern 5. Typical cutaneous signs of dermatomyositis as heliotrope, Gottron papules, Gottron sign Dermatomyositis is defined as: Definite: 5 plus any 3 of criteria 1–4 Probable: 5 plus any 2 of criteria 1–4 Possible: 5 plus any 1 of criteria 1–4

Figure 3. Histopathology of panniculitis—focal inflammatory involvement of hypodermis with lymphocytes, macrophages, and few plasma cells and neutrophils without vasculitis (hematoxylin and eosin stain, original magnification ×40).

Modified from Bohan and Peter.17

Other less sensitive and specific markers are lactate dehydrogenase and transaminases.

is the cause of the muscular injury.15 In the juvenile form, the typical feature is the presence of an occlusive noninflammatory vasculopathy, especially in the capillaries.14 When panniculitis is present, histopathology is dense lobular infiltrate of lymphocytes, plasma cells and histiocytes with fat necrosis, and subsequent fibrosis. These changes may be accompanied by calcified areas, ulceration, fistulas, and membranocystic lesion.16 There are focal areas of lobular panniculitis in the subcutaneous tissue (Figure 3).

Electroneuromyography Electromyography is altered in 70 to 90% of cases. The frequent findings include: myopathic pattern and increase in insertional and spontaneous activity. The disease activity is given by the magnitude of spontaneous activity, and, as with fibrosis, insertional activity decreases. These findings are not specific and may be present in other muscular diseases.4 In addition, 10% of patients with altered biopsy present normal electroneuromyography.14 Muscular Enzymes An increase in creatine kinase (CK) is the most sensitive finding in disease activity. CK levels can rise even before muscle symptoms appear and it is the last enzyme to normalize.7 Patients with normal CK levels have worse prognosis for lung disease.14 The aldolase enzyme is a less sensitive parameter than CK; however, it may be increased in cases where CK levels are normal.

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Criteria for Diagnosis Bohan and Peter17 proposed five criteria to facilitate the diagnosis of dermatomyositis (Table).

Association With Malignancy Neoplasms are associated with dermatomyositis in a frequency ranging from 3% to 40%. The most common tumor sites are the ovary, breast, colorectal region, and lung. The cancer can be detected before, after, or at the time of dermatomyositis diagnosis. It is believed that the neoplasm is hidden when the diagnosis occurs within the first year of dermatomyositis onset.18 The risk factors for malignancy include age older than 50 years, skin disease extension and severity, and reduced responsiveness of clinical manifestations to treatment.3 It is suggested that interstitial lung disease negatively correlates with malignancy association.

The investigation must follow the guidelines established for age and sex and a careful anamnesis is necessary. The investigation must be repeated regularly every 6 to 12 months to 5 years from the diagnosis of dermatomyositis. After this period, the risk of malignancy is reduced to that of the general population.6 Treatment Patients with dermatomyositis must be advised to use sunscreen on a daily basis, and muscular rehabilitation through supervised exercises must be proposed to prevent significant loss of muscular mass.19

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Topical steroids can be applied daily on localized lesions, with an average course of 2 weeks, followed by 2 weeks without treatment.6 Pruritus can be difficult to treat; however, topical corticosteroids and antipruritic agents can be used, with variable response. Antihistamines, doxepin (10 to 50 mg at night), cimetidine (200 to 400 mg, four times a day), mirtazapine, and naltrexone are alternative options.6 Improvement of cutaneous lesions with the use of antimalarials can reach up to 80%. The use of hydroxychloroquine is preferable, in a dosage of 200 to 400 mg/d, presenting good response.

Where there is no improvement, some studies have demonstrated the benefit of chloroquine diphosphate 250 to 500 mg/d.6 Attention must be paid to the worsening of muscular strength that may be associated with the use of antimalarials by the development of the vacuolar toxic myopathy.6,14 Systemic steroids are the first line of treatment. There is a consensus that their use in the initial stages of the disease (in the first year of onset of symptoms) is associated with better prognostics.

About 60% to 70% of patients respond positively to therapy.

Older age, pulmonary interstitial illness, cardiac involvement, and malignancy associated with positivity of myositis-specific antibodies are factors that, if present, determine worse response to therapeutic steroids.19 Oral prednisone is the drug of choice. The recommended dosage is 1 to 1.5 mg/kg/d for 1 to 3 months to reach remission (ie, normalization of muscular enzymes and improvement in cutaneous inflammation and muscular strength). Drug administration must be maintained for approximately 12 to 24 months to prevent recurrences.14 Pulse therapy with methylprednisolone can be used in more acute settings (eg, myocardiopathy, esophageal involvement) at a dosage of 500 mg/d for 3 days, followed by oral prednisone, but there are no random studies that have established the effectiveness of this measure.19 Clinically amyopathic dermatomyositis can also be treated with steroids; however, there are no indications that their use prevents the development of clinically established myositis.

A quarter of patients do not respond to systemic corticosteroids.

If there is no response after 12 weeks, the drug must be discontinued and an alternative therapy should be proposed.

Immunosuppressors are used in patients who do not obtain clinical improvement, in those who present with significant adverse reactions caused by the extended use of oral steroids, or as a drug to avoid the use of corticoids. Methotrexate and azathioprine are the most commonly used drugs.

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Methotrexate is administered by intramuscular, oral, or subcutaneous means, for both systemic and muscular symptoms. The recommended dosage varies between 15 and 25 mg a week. The more frequent adverse effects are gastrointestinal. Attention must be given to interstitial pulmonary fibrosis induced by methotrexate, which can be clinically indistinguishable from pulmonary disease secondary to dermatomyositis.

Azathioprine is administered orally in a dosage of 2 to 3 mg/kg/d and some studies show that clinical improvements are observed only after extended therapy of approximately 6 to 8 months.

Immunoglobulins can be used in patients who are refractory to steroids, methotrexate, and azathioprine, or when there is a contraindication for the use of immunosuppressors. A dosage of 1 g/kg/d must be given for 2 consecutive days every month. Esophageal symptoms appear to respond well to immunoglobulins.

Cyclophosphamide must be reserved for patients with severe interstitial lung disease because of their high toxicity potential.

When there is no improvement with the proposed therapies, a revision of the diagnosis should be performed. Other muscular disorders such as myositis by inclusion corpuscles, steroid myopathy, and other inflammatory myopathies should be considered.19 Immunobiologicals, especially rituximab, may be attempted in these cases, with varying results.

Dystrophic calcification is treated with anti-inflammatory and immunosuppressive agents. Diltiazem is used at a dosage of 240 to 480 mg/d. This drug reduces influx of intracellular calcium and, thereby, the concentration of calcium in the muscular cells.20 Aluminum hydroxide reduces gastrointestinal calcium absorption and probenecid increases renal excretion.

Conclusions A proper early diagnosis is necessary for avoidance of complication and for the discovery of an eventual neoplasia, which can be associated in 3 to 40 of the patients. Many exams should be performed to elucidate this diagnosis following the criteria, and appropriate therapy must be instituted as soon as the diagnosis is confirmed.

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18 Zampieri S, Valente M, Adami N, et al. Polymyositis, dermatomyositis and malignancy: a further intriguing link. Autoimmun Rev. 2010;9:449–453.

19 Marie I, Mouthon L. Therapy of polymyositis and dermatomyositis, Autoimmun Rev. 2011;11:6–13.

20 Palmieri GM, Sebes JI, Aelion JA, et al. Treatment of calcinosis with diltiazem. Arthritis Rheum. 1995;38:1646– 1654.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2016;14:354–358

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SELF ASSESSMENT EXAMINATION

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD

1. Regarding autoantibodies associated with dermatomyositis: a. They are divided into two groups, myositis-specific and myositis-associated. b. Each patient expresses only one type of myositisspecific autoantibody. c. Expression of each separate type of myositisspecific autoantibody is associated with a different response to treatment. d. Expression of each separate type of myositisspecific autoantibody is associated with a different prognosis. e. Each of these statements is correct.

2. Which of the following is a/are myositis-specific autoantibody/autoantibodies expressed in patients with dermatomyositis? a. Antisynthetase antibodies. b. Anti-Mi-2. c. Anti-signal recognition particle (anti-SRP). d. CADM-40. e. Anti-p155/p140. f. All of the above.

3. Which of the following is a myositis-specific antisynthetase autoantibody found in some patients with dermatomyositis? a. Anti-Jo-1 (with specificity for transfer RNA (t RNA) with specificity for the amino acid histidine). b. Anti-PL-7 (with specificity for transfer RNA (t RNA) with specificity for the amino acid threonine).

c. Anti-PL-12 (with specificity for transfer RNA (t RNA) with specificity for the amino acid alanine). d. Anti-EJ (with specificity for transfer RNA (t RNA) with specificity for the amino acid glycine). e. Anti-OJ (with specificity for transfer RNA (t RNA) with specificity for the amino acid isoleucine). f. Each of the above is a myositis-specific antisynthetase autoantibody found in some patients with dermatomyositis.

4. In a patient with dermatomyositis, positivity for which of the following myositis-specific autoantibodies is most closely associated with internal malignancy? a. Antisynthetase antibodies. b. Anti-Mi-2. c. Anti-signal recognition particle (anti-SRP). d. CADM-40. e. Anti-p155/p140.

5. Internal neoplasms more frequently found in patients with dermatomyositis are those arising in the: a. Breast. b. Colorectal region. c. Lung. d. Ovary. e. All of these.

ANSWERS TO EXAMINATION: 1. e, 2. f, 3. f, 4. e, 5. e

Instructions: For each numbered question, choose the single best lettered response.

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

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MEDIA PARTNER

September/October 2016

Volume 14 • Issue 5

Core curriculum Virendra N. Sehgal, MD, Section Editor

Alopecia Areata––Part III: Prognosis and Treatment Juliany Estefan, MD;1,2 Marcia Ribeiro, MD, PhD;2 Eliane Abad, MD;3 Simone Saintive, MD;3 Marcia Ramos-e-Silva, MD, PhD1

The prognosis of alopecia areata is better in cases with single and small lesions, and the variability of the extension of the disease is one of the criteria for the choice of treatment modality. Several medications have been described in the literature for the treatment of alopecia areata, including corticosteroids, minoxidil, and diphencyprone. The authors review treatments for alopecia areata. (SKINmed. 2016;14:361–365)

A

lthough the functional benefit of hair is minimal, it is directly related to health, well-being, and beauty.

Changes in the quality and quantity of hair can trigger depression, anxiety, and dysmorphic disorders and impact an individual’s social life. Patients with alopecia areata (AA) represent about 2% of dermatological consultations.1 The clinical picture of AA may be variable with periods of improvement and deterioration. This can trigger anxiety and worsen the underlying disease. Despite the psychologic repercussions, there is no direct impact of the disease on patient physical health, which does not justify the use of treatments that may progress with severe side effects and no scientifically proven efficacy.1 The hair follicle is not destroyed in AA; therefore, there is always potential for regrowth.2 There are a few double-blind, placebocontrolled trials on the treatment of AA.3 When choosing a therapy, the dermatologist should consider the risks and benefits, patient’s age, location, and extension of the lesion.1 The patient’s reassessment must be made after a minimum period of 3 months of treatment.4

Patients with AA should be informed about the benign nature of the course of the disease and the possibility of recurrence and regrowth even without treatment.

On the other hand, poor prognosis and poor response to treatment should also be discussed so that patients do not expect disproportionate therapeutic response to what is described in the literature and may choose not to initiate treatment.1 Prognosis The course of AA is unpredictable. Over half of patients with AA will experience clinical improvement after 1 year, even without treatment5; however, most patients will present with more than one episode in their lifetime. Factors that indicate poor prognosis include extension of the lesion (extensive AA, totalis AA, and universalis AA),6 ophiasic pattern, long duration,7 atopy,8 positive family history, presence of other autoimmune diseases, nail involvement, and onset in childhood.8,9 In children, the disease may have a tendency to increase with time, even in cases where the initial presentation was associated with a good prognosis.6 In cases of alopecia totalis and alopecia universalis, complete hair regrowth is less than 10%.10

See also Estefan J, Ribeiro M, Abad E, et al. Alopecia areata––part II: diagnosis and pathology. SKINmed. 2015;13:121–126 From the the Sector of Dermatology and Post-Graduation Course, University Hospital and School of Medicine;1 the Sector of Medical Genetics, Pediatric Institute Martagão Gesteira and School of Medicine;2 and the Sector of Derma­tology, Pediatric Institute Martagão Gesteira and School of Medicine,3 Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, University Hospital and School of Medicine, Federal University of Rio de Janeiro, Rua Dona Mariana 143/C-32, 22280-020 Rio de Janeiro • E-mail: ramos.e.silva@dermato.med.br

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core curriculum orrhea, obesity, dyslipidemia, acne, and Cushing syndrome.16 The level of evidence is 311 and the degree of recommendation for oral corticosteroids and pulse therapy is C1.12

Steroids

Topical steroids Although there are only few evidences of their success, high- and average-potency corticosteroids are often used,1 being the treatment of choice in children with AA.3 The side effects may include folliculitis, erythema, acneiform eruptions, atrophy, striae, telangiectasia, and hypertrichosis.1 The evidence level for corticosteroids is 2+11 and the degree of recommendation is C1.12

Intralesional steroids Despite being widely used by dermatologists for around 50 years, alone or in combination, to treat single or multiple lesions, there are no randomized controlled trials on the use of topical corticosteroids.13 Triamcinolone acetonide1 is the preferred treatment for adults, with involvement of less than 50% of the scalp.3 Concentrations of 2.5 mg/mL to 10 mg/mL, preferably 5 mg/ mL (maximum volume of 3 mL), can be used for scalp AA, and a concentration of 2.5 mg/mL is often used for eyebrow and facial AA. The application technique consists in dividing the AA plaque into areas of 1 cm2 and performing 0.1 mL infiltration per area every 4 to 6 weeks.1–3 Its side effects include atrophy and telangiectasia.3 After each injection, gentle massage of the treated area is recommended to help prevent corticosteroid-induced atrophy.1 The injection of small volumes is also recommended, minimizing the number of injections per area and avoiding superficial injections (intraepidermal).3 Injections in the frontoparietal region are not recommended due to the risk of thrombosis of the central retinal artery by crystal deposits.1 Therapy must be suspended, if there is no improvement after 6 months of treatment.3 The evidence level of this treatment is 311 and the degree of recommendation is B.12

Systemic steroids Systemic steroids have been used daily, weekly, and monthly in pulse therapy with variable response. Various side effects and a high risk of relapse after discontinuation have been reported.2,3 The suggested dose is of 1 mg/kg/d for adults and 0.1 to 1 mg/ kg/d for children.14 Adding 2% minoxidil, 3 times daily, can reduce relapse after discontinuation of oral corticosteroids.15 Side effects include hyperglycemia, osteoporosis, cataracts, immunosuppression, dysmenSKINmed. 2016;14:361–365

Topical immunotherapy There have been reports of patients with AA and psoriasis on the scalp where hair regrowth was observed in the affected areas.

This phenomenon has been termed Renbök phenomenon or reverse Köbner phenomenon and was first described in 1991.17 Renbök phenomenon is characterized by the normalization of hair growth in AA lesions, stimulated by the inflammatory reaction triggered by psoriasis. Köbner phenomenon involves the appearance of lesions of a given dermatosis (psoriasis, lichen, vitiligo) stimulated by trauma or other inflammatory reaction. In other words, the Renbök phenomenon describes the opposite principle: the inhibition of an inflammatory response by psoriasis .18,19 This observation supported the treatment of extensive AA with sensitizers. Efficiency was reported in 29% to 78% of patients and is related to the extent of the involvement.20 Contact immunotherapy is defined as the induction of an allergic contact dermatitis through topical application of a potent contact allergen.2 The action mechanism of topical sensitizers is little understood.2 Some proposed theories are antigenic competition,21 perifollicular lymphocyte apoptosis,22 and reduction in the proportion of peribulbar CD4/CD8 lymphocytes.23 Sensitizing contact drugs include dinitrochlorobenzene (DNCB), squaric dibutylester acid (SADBE), and diphenylcyclopropenone or diphencyprone (DPCP). DNCB is no longer used because of its mutagenic potential24 and SADBE for not being stable in acetone.2 DPCP is presently the preferred topical sensitizing drug.2 DPCP, initially used by Happle,25 is the preferred choice for adults with more than 50% of scalp involvement.3 DCPC is soluble in acetone and sensitive to light and must be protected in amber glass bottles.2 The technique involves the application of DPCP at 2% with cotton in a 4×4-cm area of scalp lesion to sensitize the patient. Two weeks thereafter, a 0.001% DPCP solution is applied to half of the scalp. The DPCP concentration is gradually increased every week until a mild eczematous reaction is achieved in the treated area (erythema and mild itching within 24 to 36 hours of application).2,26 The treatment must then be kept at this concentration in weekly applications.

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The medication should remain on the scalp for 48 hours and then washed off. The treatment of both sides is recommended only after the treated side has achieved response. If there is no improvement after 6 months of treatment, it is likely that it will not present satisfactory response and must be suspended.3 The following side effects have been observed: intense eczematous reaction with blisters and vesicles, lymphadenopathy, edema, confetti dyschromias, hypopigmentation, urticaria, and fever.2,3 The level of evidence is 2++11 and the degree of recommendation is B.12 Minoxidil Minoxidil (2,4-diamino-6-piperidine-pyrimidine-3-oxide) was made and has been used as an antihypertensive drug.3 With hypertrichosis as a side effect, it has been used in the treatment of various forms of alopecia.27 Despite numerous studies, its exact mechanism of action is unknown, but it is likely to prolong the anagen phase.1 Some proposed mechanisms of action include vasodilatation, angiogenesis,28 increase in cell proliferation,29 and potassium channels action,30 with an immunosuppressive effect.31,32 It is used at a 5% concentration twice a day.4 Studies conducted of 1% and 5% minoxidil concentrations have shown better response with the 5% solution.31,32 It has little effect on severe forms.4 It can be used alone or in combination with topical steroids, anthralin, or retinoic acid, which increases its absorption.1,4 The following side effects have been described in the literature: allergic and by primary irritant contact dermatitis and transient hypertrichosis, reversible upon discontinuation.1 One study noted minimal systemic absorption of minoxidil solution (1% and 5%) with topical application, and significant clinical alterations in blood pressure, weight, cardiovascular function, electrocardiography, electrolytes, and complete blood and urine examination results were not observed.31,32 The level of evidence is 211 and the degree of recommendation is C1.12 Anthralin There are few reports of series of cases using anthralin in AA.33 The mechanism of action is unknown. In experiments with mice, the reduced expression of tumor necrosis factor (TNF)-α and TNF-β was demonstrated.34 The lack of studies makes it difficult to determine the level of response. The effect is slow and several months of treatment may be required to achieve cosmetiSKINmed. 2016;14:361–365

cally acceptable results.1 It is used at 0.5% and 1% concentrations.33 It must not be used with corticosteroid therapy.

Anthralin cream 1% is applied and must be kept for a short time in contact (initially 20 to 30 minutes) on a daily basis. After this period, the scalp must be washed with shampoo to avoid excessive irritation. The contact time should be increased by 10 minutes every 2 weeks up to 1 hour or until the development of a mild contact dermatitis. Avoid contact with the eyes and sun exposure.

The treatment should be continued for 3 months, and must be suspended if no improvement is achieved in this period.3,4,33 Side effects include severe irritant contact dermatitis, folliculitis, regional lymphadenopathy, hyperpigmentation, change in hair coloration, infection, and itching.3,4,35 The degree of recommendation is C212 and the level of evidence is 3.11 PUVA/Phototherapy Psoralen–UV-A (PUVA)/phototherapy consists of the use of a psoralen associated with systemic or topical application of PUVA.3 This method is based on the hypothesis that PUVA reduces perifollicular inflammatory infiltrate of mononuclear and Langerhans cells, leading to improvement in AA.36 Due to the high rates of relapse, lack of studies, and increased risk of skin neoplasia by PUVA, this therapy is not recommended as a firstline treatment.3 The level of evidence is 311 and the degree of recommendation is C1.12 Cyclosporine Cyclosporine is an immunosuppressive drug used after organ transplants to prevent rejection. The drug’s mechanism of action consists of inhibiting T-helper cells activity and suppressing interferon-γ.3 A side effect is hypertrichosis, which occurs in about 80% of patients, possibly as a result of extension of the anagen stage.37 Its use can evolve with serious side effects such as nephrotoxicity, hepatotoxicity, hypertension, and immunosuppression, and the recurrence rate is high.3 The degree of recommendation is C2,12 and the level of evidence is 3.11 Antihistamines Some studies have suggested beneficial effects of antihistamine drugs in AA.38,39 Fexofenadine is a useful drug in the treatment of extensive AA in atopic patients who use contact immunotherapy, although there are no significant effects in patients with AA without atopy. Ebastine has also shown favorable results in a patient with AA and atopic dermatitis refractory to immunotherapy and in a case of progressive AA with atopic dermatitis that did not respond to the use of topical corticosteroids.40 These

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results suggest that antihistamines can be used in cases of AA and atopic dermatitis as an adjunct to other treatments. The degree of recommendation for this drug is C1.12 Calcipotriol The mechanisms of action of vitamin D3 analogs include regulation of proliferation and differentiation of epidermal cells and modulation of cytokine production. These effects could explain the efficiency of vitamin D3 derivatives for the treatment of AA.41 Methotrexate A study conducted in 200642 that assessed 22 patients with AA totalis and universalis treated with weekly 20 mg to 25 mg of methotrexate and daily 20 mg prednisone revealed improvement in 14 patients (64%). Such data, however, require confirmation by further studies. The level of evidence for this drug is 3.11 Sulfasalazine Sulfasalazine has immunomodulatory, immunosuppressive, and anti-inflammatory effects. It inhibits proliferation of T cells, natural killer activity, generation of antibodies, and release of interleukin-2 and prostaglandin E2, thus reducing the inflammatory cells chemotaxis.3,43,44 Although some studies report hair growth with doses of 500 mg to 1.5 g/d, recurrences are frequent after discontinuation of treatment.43,44 The level of evidence is 3.11

good response in animal models, its use for AA in humans has not been successful.1 A study in 2005 of 11 patients showed AA involvement of 10% to 75% of the scalp and an average disease duration of 6 years. Patients were treated with 0.1% tacrolimus ointment twice a day for 24 weeks. At the end of the study, no growth of terminal hair was observed. The authors suggest that the therapeutic failure could be due to the insufficient penetration of the ointment formula.45 Garlic gel The use of 5% garlic gel associated with 0.1% betamethasone valerate was recently described, with authors suggesting that this combination can be useful in the treatment of AA.46 Conclusions Although several therapeutic options have been described for AA, studies use different methods and analyzed samples are generally not homogeneous. In addition, the disease’s natural history makes therapeutic efficiency difficult to assess, given that AA can evolve with hair regrowth regardless of treatment. Small and localized lesions can be treated with topical and/or intralesional steroids and minoxidil or may present repilation without treatment. More extensive lesions have poorer prognosis and topical immunotherapy is the main option.

References

Prostaglandin F2a analogues (latanoprost and bimatoprost)

1 Galán-Gutiérrez M, Rodríguez-Bujaldón A, Moreno-Giménez JC. Update on the treatment of alopecia areata.

Actas Dermosifiliogr. 2009;100:266–276.

Hypertrichosis of the eyelashes is described in the literature as a side effect of the topical use of prostaglandin F2α analogs for the treatment of open-angle glaucoma. A few studies have been conducted in AA with conflicting results, requiring randomized controlled studies. The level of evidence is 2.11

2 Garg S, Messenger AG. Alopecia areata: evidence-based treatments. Semin Cutan Med Surg. 2009;28:15–18.

Topical rubefacient Rubefacient is an ancient treatment, with no controlled studies to confirm its supposed effectiveness.1,4 It could be effective for forms of AA with a single plaque or that are few in number, with natural benign course and involution to healing in a few months.4

3 Alkhalifah A, Alsantali A, Wang E, Mcelwee KJ, Shapiro J. Alopecia areata update. Part II. Treatment. J Am Acad Dermatol. 2010;62:191–202.

4 Rivitti EA. Alopecia areata: revisão e atualização. An Bras Dermatol. 2005;80:57–68.

5 Shapiro J, Madani S. Alopecia areata: diagnosis and management. Int J Dermatol. 1999;38(suppl 1):19–24 6 Tosti A, Bellavista S, Iorizzo M. Alopecia areata: a long term follow-up study of 191 patients. J Am Acad Dermatol. 2006;55:438–441.

7 Lew BL, Shin MK, Sim WY. Acute diffuse and total alopecia: a new subtype of alopecia areata with a favorable prognosis. J Am Acad Dermatol. 2009;60:85–93.

The drugs reported include chloral hydrate, acetic acid, cantharides dyes at 5%, phenol, and benzoyl peroxide.1,4

8 Muller SA, Wilkelmann RK. Alopecia areata. An evaluation of 736 patients. Arch Dermatol. 1963;88:290–297.

Tacrolimus and pimecrolimus

9 Madani S, Shapiro J. Alopecia areata update. J Am Acad Dermatol. 2000;42:549–566.

Tacrolimus and pimecrolimus are macrolides with immunosuppressive properties that act by inhibiting calcineurin. Despite the

10 Walker SA, Rothman S. A statistical study and consideration of endocrine influences. J Invest Dermatol.

1950;14:403–413.

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11 Messenger AG, Slater DN, Bleehen SS. Alopecia areata: alterations in the hair growth cycle and correlation with the follicular pathology. Br J Dermatol. 1986;114:337– 347.

29 Mori O, Uno H. The effect of topical minoxidil on hair follicular cycles of rats. J Dermatol. 1990;17:276–281.

12 Ito T. Advances in the management of alopecia areata. J Dermatol. 2012;39:11–17.

31 Fiedler-Weiss VC. Potential mechanisms of minoxidilinduced hair growth in alopecia areata. J Am Acad Dermatol. 1987;16(3 pt 2):653–656.

13 Delamere FM, Sladden MM, Dobbins HM, Leonardi-Bee J. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.

14 Tan E, Tay YK, Giam YC. A clinical study of childhood alopecia areata in Singapore. Pediatric Dermatol.

2002;19:298–301.

15 Olsen EA, Carson SC, Turkey EA. Systemic steroids with or without 2% topical minoxidil in the treatment of alopecia areata. Arch Dermatol. 1992;128:1467–1473.

16 Freitas TH, Souza DA. Corticosteroides sistêmicos na prática dermatológica. Parte II – Estratégias para minimizar os efeitos adversos. An Bras Dermatol.

2007;82:177–182.

17 Happle R, van der Steen PH, Perret CM. The Renbök phenomenon: an inverse Köbner reaction observed in alopecia areata. Eur J Dermatol. 1991;1:228–230.

18 Harris JE, Seykora JT, Lee RA. Renbök phenomenon and contact sensitization in a patient with alopecia universalis. Arch Dermatol. 2010;146:422–425.

19 Camargo CM, Brotas AM, Ramos-e-Silva M, Carneiro S. Isomorphic phenomenon of Koebner: facts and controversies. Clin Dermatol. 2013;31:741–749.

20 Freyschmidt-Paul P, Happle R, McElwee KJ, Hoffmann R. Alopecia areata: Treatment of today and tomorrow. J Investig Dermatol Symp Proc. 2003;8:12–17.

21 Happle R. Antigenic competition as a therapeutic concept for alopecia areata. Arch Dermatol Res. 1980;267:109– 114.

22 Herbst V, Zöller M, Kissling S, et al. Diphenylcyclopropenone treatment of alopecia areata induces apoptosis of perifollicular lymphocytes. Eur J Dermatol. 2006;16:537– 542.

30 Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004;150:186–194

32 Fiedler-Weiss VC. Topical minoxidil solution (1% and 5%) in the treatment of alopecia areata. J Am Acad Dermatol. 1987;16(3 pt 2):745–748.

33 Fiedler-Weiss VC, Buys CM. Evaluation of anthralin in the treatment of alopecia areata. Arch Dermatol.

1987;123:1491–1493.

34 Tang L, Cao L, Sundberg JP, Lui H, Shapiro J. Restoration of hair growth in mice with an alopecia areata-like disease using topical anthralin. Exp Dermatol. 2004;13:5– 10 35 Sasmaz S, Arican O. Comparison of azelaic acid and anthralin for the therapy of patchy alopecia areata: a pilot study. Am J Clin Dermatol. 2005;6:403–406.

36 Ree K. Reduction of Langerhans cells in human epidermis during PUVA therapy: a morphometric study. J Invest Dermatol. 1982;78:488–492.

37 Taylor M, Ashcroft AT, Messenger AG. Cyclosporin A prolongs human hair growth in vitro. J Invest Dermatol.

1993;100:237–239.

38 Yoshizawa Y, Kawana S. Efficacy of ebasitne in the treatment of alopecia areata. Jpn J Dermatol. 2005;115:1473– 1480.

39 Inui S, Nakajima T, Toda N, Itami S. Fexofenadine hydrochloride enhances the efficacy of contact immunotherapy for extensive alopecia areata: retrospective analysis of 121 cases. J Dermatol. 2009;36:323–327.

40 Ohyama M, Shimizu A, Tanaka K, Amagai M. Experimental evaluation of ebastine, a second-generation anti-histamine, as a supportive medication for alopecia areata.

J Dermatol Sci. 2010;58:154–157.

23 Happle R, Klein HM, Macher E. Topical immunotherapy changes the composition of the peribulbar infiltrate in alopecia areata. Arch Dermatol Res. 1986;278:214–218

41 Kim DH, Lee JW, Kim IS, et al. Successful treatment of alopecia areata with topical calcipotriol. Ann Dermatol.

2012;24:341–344.

24 Strobel R, Rohrborn G. Mutagenic and cell transforming activities of 1-chlor-2,4-dinitrobenzene (DNCB) and squaric acid-dibutylester (SADBE). Arch Toxicol.

1980;45:307–314.

42 Joly P. The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis. J Am Acad Dermatol.

2006;55:632–636.

25 Happle R, Hausen BM, Wiesner-Menzel L. Diphencyprone in the treatment of alopecia areata. Acta Derm Venereol. 1983;63:49–52.

43 Ellis CN, Brown MF, Voorhees JJ. Sulfasalazine for alopecia areata. J Am Acad Dermatol. 2002;46:541–544.

26 Orecchia G, Perfetti L. Alopecia areata and topical sensitizers: allergic response is necessary but irritation is not. Br J Dermatol. 1991;124:509.

27 Wasserman D, Guzman-Sanchez DA, Scott K, McMichael A. Alopecia areata. Int J Dermatol. 2007;46:121–131.

28 Lachgar S, Charveron M, Gall Y, Bonafé JL. Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells. Br J Dermatol.

1998;138:407–411.

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44 Misery L, Sannier K, Chastaing M, Le Gallic G. Treatment of alopecia areata with sulfasalazine. J Eur Acad Dermatol. 2007;21:547–548.

45 Price VH, Willey A, Chen BK. Topical tacrolimus in alopecia areata. J Am Acad Dermatol. 2005;52:138–139.

46 Hajheydari Z, Jamshidi M, Akbari J, Mohammadpour R. Combination of topical garlic gel and betamethasone valerate cream in the treatment of localized alopecia areata: a double-blind randomized controlled study. Indian J Dermatol Venereol Leprol. 2007;73:29–32.

Alopecia Areata––Part III: Prognosis and Treatment

Volume 14 • Issue 5

September/October 2016

HISTORICAL VIGNETTE Charles Steffen, MD, Section Editor

Early Description of Diet-Induced Blistering Skin Diseases in Medieval Persia: Avicenna’s Point of View Fatemeh Atarzadeh, MD, PhD;1,4,5 Babak Daneshfard, MD, PhDc;4,5 Ladan Dastgheib, MD;6,7 Amir-Mohammad Jaladat, MD, PhD;5,8 Gholamreza Amin, PhD2,3

Pemphigus is an autoimmune blistering skin disease that is strongly associated with different environmental factors. Among these, nutritional factors are considered to trigger pemphigus; however, their role may be underestimated. Investigated more recently in conventional medicine, this causative bond between dietary factors and blistering skin diseases was mentioned by Persian scholars such as Avicenna a thousand years ago. Avicenna, a well-known Persian physician and philosopher, who could be considered a pioneer in dermatology, discussed skin diseases in a chapter in The Canon of Medicine. He accounted for some nutritional triggers for skin blisters (mentioned as “hot swellings”), such as onion, garlic, leek, pepper, and wine. His precise description of causative factors based on principles of traditional Persian medicine (TPM) is appreciable and might well lead us to find more efficient ways for the prevention and treatment of blistering skin diseases. (SKINmed.

2016;14:367–370)

P

emphigus, which is rooted from the Greek word pemphix (blister), is a life-threatening autoimmune bullous disease.

The disease, involving skin and mucous membranes with widespread blistering, is divided into two major subtypes of vulgaris and foliaceus.1,2

An interaction between genetic and environmental parameters is considered to play an important role in pemphigus. These environmental factors comprise infection, occupational exposure, drugs, and even food.3 Nutritional factors are usually underestimated as triggers of pemphigus or other bullous diseases.4,5 According to TPM literature, diet plays an important role in the development of diseases. This would lead to diet modification or food therapy as one of the main steps for both prevention and treatment prior to herbal and/or manual therapy.6

Traditional Persian Medicine TPM, which is also known as Arabic/Unani medicine, is a holistic medical system including theory and practice. It is based on humoral medicine, which tries to maintain the balance between the four humors (ie, bile, sanguine, phlegm, and black bile), while emphasizing both the spiritual and physical aspects of human health.7,8 TPM has evolved since ancient times, continuing through the middle ages with Persian physicians, such as Rhazes (865–925 CE), Haly Abbas (949–982 CE), and Avicenna (980–1037 CE).9–11 It has survived with the establishment of traditional medicine faculty in Iran’s medical universities.

TPM literature continues in India by Persian language scientists such as Aqili Alavi Shirazi (1670–1747 CE),12 Mohammad Akbar Arzani (?–1772 CE),12 and Mohammad Azam Khan (1814–

From the Department of Traditional Persian Medicine, School of Traditional Medicine,1 and the Departments of Pharmacognosy2 and Traditional Pharmacy,3 Tehran University of Medical Sciences, Tehran, Iran; and the Research Center for Traditional Medicine and History of Medicine,4 the Essence of Parsiyan Wisdom Institute, Traditional Medicine and Medicinal Plant Incubator,5 the Shiraz Molecular Dermatology Research Center,6 the Department of Dermatology,7 and the Department of Traditional Persian Medicine,8 School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran Address for Correspondence: Babak Daneshfard, MD, PhDc in Traditional Persian Medicine, Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Imam Hossein Square, School of Medicine, Shiraz, Iran • E-mails: babakdaneshfard@gmail.com, daneshfard@sums.ac.ir

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HISTORICAL VIGNETTE tection. These transferred toxins can give rise to different skin diseases including color changes and swellings.6 The cause of these problems could be the process of bad humors, warding them off from the internal organs to the skin. There is a theory in TPM where the nature of the body as a particular system removes the hazardous materials from vital organs—ie, brain, heart, liver, and gonads, which are called “A’zay-e- Raise” in TPM—to weaker and less important organs (such as skin) in order to protect them.18 Skin is a complex organ that has a dynamic intercommunication with psychoneuroimmune and endocrine systems.19 Recent studies have shown that the skin, nervous system, and immune system are related to each other and speak the same language (by means of different neurotransmitters and cytokines), acting as a “unique neuroimmunocutaneous system.” Accordingly, the function of such an interconnected system could lead to initiation of autoimmune skin diseases such as pemphigus vulgaris following emotional stress.5

Figure 1. Painting of Hakim Mohammad Azam Khan (1814–1902 CE). (Courtesy of Dr Naseri.)

Skin blisters in TPM

1902 CE)13 (Figure 1), who is the author of Eksir-e-Azam (The Greatest Elixir) in which the relationship between dietary factors and skin blisters is expressed as follows.14 Food categorization in TPM The relationship between the makeup of medical plants and their major chemical compounds, in addition to the different effects of hot- and cold-temperament herbs, have all been the subject of several investigations in recent years.16 For instance, hot and spicy foods can cause bodily imbalance and adverse effects such as dysuria.17 Skin association with internal organs The ancient sages considered the skin to have a protective role for internal organs. From the TPM point of view, skin has a neural origin with a strong association with internal organs, especially the nervous system. Intrinsic waste materials are shed into the skin surface by the natural body defense for internal organ pro-

In TPM, any increase in abnormal material in an organ or tissue that hurts the body is defined as Varam (swelling),20 which is divided into “hot” and “cold” swelling based on its characteristics.

Hot skin swellings such as pemphigus blisters are accompanied by redness, itching, burning sensation, and clear contents and early tear of (possible) blisters, whereas cold swellings are painless and do not show inflammatory signs.6,14 Hot blisters can be induced either by external causes such as heat shock or by internal inducers such as foods that produce hot temperament (Mosakhenāt). Such swellings are caused by the accumulation of hot temperament materials among separated skin layers.6 The accumulation of harmful substances in the body may be secondary to gluttony, junk food consumption, sedentary lifestyle, lack of sweating, and impaired digestion.6 Nutritional factors in pemphigus In recent years, increasing evidence has shown the role of special dietary nutrients as triggers of pemphigus.21 This phenomenon is

Table. Temperament of Different Tastes Not Hot or Cold Temperament

Cold Temperament

Hot Temperament

Fatty food

Sour food

Spicy food

Sweet food

Astringent food

Bitter food

Tasteless food

Salty food SKINmed. 2016;14:367–370

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Figure 2. Bust of Avicenna (980–1037 CE), Martyr Faghihi Hospital, Shiraz, Iran. (Photograph by Dr Daneshfard.)

Figure 3. First page of lithography of The Canon of Medicine, National Library of Iran (book ID: 1181397).

thought to be caused by the similarity of the molecular structure of these nutrients, which may have an acantholytic potential.5 Many studies have mentioned the genus Allium, which is comprised of thiol-rich plants such as onion, garlic, and leek. Tannins of some foodstuffs such as tea, black pepper, cherry, blackberry, and red wine are introduced as other inducers of pemphigus in genetically predisposed individuals.5,22 Avicenna’s citing of diet-induced blistering skin diseases Ibn Sina (980–1037 CE), who is best known as Avicenna in the West (Figure 2), was a genius medieval Persian physician and one of the greatest scientists of the Islamic Golden Age (9th–12th century CE).23 His masterpiece, Al-Qanunfi-al-Tibb (The Canon of Medicine) (Figure 3), is one of the most renowned books in the history of medicine, which was used as the main medical source in the West until the 16th century.24 Avicenna dedicated a chapter of his book to dermatologic conditions, including skin diseases25 such as leprosy, vitiligo, and pemphigus,26,27 and referred to this causative bond between diet and skin blisters. Sina mentions onion, garlic, varieties of leeks, and wine as hot-temperament foods that could lead to “torrid [warmth-inducer] blood” in the body.

“These hot-temperament foods are among the causes of hot swelling…” (Figure 4).6 SKINmed. 2016;14:367–370

Figure 4. Chapter of swellings and postulates in the 4th volume of The Canon of Medicine, Saab Medical Library, American University of Beirut. http://ddc.aub.edu.lb/ projects/saab/avicenna/640/html/S2_062.html.

Conclusions Blistering skin diseases could be considered as hot swelling (Varam-e-Hār) due to hot-temperament–making agents (Mosakhenāt) including some foods (such as pepper, garlic, and

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wine), which produce “torrid blood.”14 Consequently, patients should avoid these hot-temperament foods before using any therapeutic regimen.

Avicenna’s citing of the role of dietary factors involved in the formation of hot swelling could be considered as one of the first descriptions of diet-related blistering skin diseases. It would naturally clarify the importance of evaluating remedies suggested

by TPM for prevention and treatment of this category of skin diseases. An integrative approach is recommended in any therapeutic regimen for blistering skin diseases.

Acknowledgment This paper has been adapted from the PhD thesis written by Fatemeh Atarzadeh at the School of Traditional Medicine, Tehran University of Medical Sciences. The authors thank Eng. Reza Sanayiæ for linguistic editing.

References 1 Ljubojevic S, Lipozencic J, Brenner S, Budimcic D. Pemphigus vulgaris: a review of treatment over a 19-year period. J Eur Acad Dermatol Venereol. 2002;16:599–603.

2 Martin LK, Werth VP, Villaneuva EV, Murrell DF. A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. 2011;64:903–908.

3 Brenner S, Tur E, Shapiro J, et al. Pemphigus vulgaris: environmental factors. Occupational, behavioral, medical, and qualitative food frequency questionnaire. Int J Dermatol. 2001;40:562–569.

4 Caldarola G, Feliciani C. A glass of red wine to keep vascular disease at bay, but what about pemphigus vulgaris? Expert Rev Clin Immunol. 2011;7:187–191.

5 Ruocco V, Ruocco E, Lo Schiavo A, et al. Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clin Dermatol. 2013;31:374–381.

6 Avicenna. Canon of Medicine (Qanun fi al-Teb). Beirut, Lebanon: Al-Elmi Lel-Matbuat; 2005.

7 Nimrouzi M, Zare M. Principles of nutrition in Islamic and traditional Persian medicine. J Evid Based Complementary Altern Med. 2014;19:267–270.

8 Nimrouzi M, Mahbodi A, Jaladat AM, Sadeghfard A, Zarshenas MM. Hijamat in traditional Persian medicine risks and benefits. J Evid Based Complementary Altern Med. 2014:19:128–136.

9 Kordafshari G, Kenari HM, Esfahani MM, et al. Nutritional aspects to prevent heart diseases in traditional persian medicine. J Evid Based Complementary Altern Med. 2015:20;57–64.

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10 Daneshfard B, Dalfardi B. Medieval roots of modern knowledge regarding carotid sinus syncope. Int J Cardiol.

2014;173:342–343.

11 Zargaran A, Zarshenas MM, Ahmadi SA, Vessal K. Haly Abbas (949–982 AD). J Neurol. 2013;260:2196–2197.

12 Derakhshan AR, Choopani R, Dehghan S. A new look at epicardial adipose tissue from the perspective of Iranian traditional medicine. J Integr Med. 2014;12:529–530.

13 Zargaran A, Zarshenas MM, Borhani-Haghighi A, Mohagheghzadeh A. A short introduction to a 19th century persian book on pulsology: Naiier Azam. J Res Hist Med. 2014;3.

14 Azam-Kkan M. Great Elixir (Exir-e-Azam). Tehran, Iran: Alma’a; 2014.

15 Alavi S. Makhzan-al-Adviyah (The Storehouse of Medicaments). Tehran, Iran: Intisharat va Amoozesh Enghelab Press; 2009.

16 Ardekani MR, Rahimi R, Javadi B, Abdi L, Khanavi M. Relationship between temperaments of medicinal plants and their major chemical compounds. J Tradit Chin Med. 2011;31:27–31.

17 Jaladat AM, Atarzadeh F, Rezaiezadeh H, Amin G. Avicenna’s dietary and herbal recipe for urethral syndrome.

Infect Dis Clin Pract. 2015;23:168.

18 Nazem E. Tabiat dar pezeshki Irani (Nature in Persian Medecine). 1st ed. Tehran, Iran: Andisheh Avar; 2010.

19 Hochman B, Isoldi FC, Furtado F, Ferreira LM. New approach to the understanding of keloid: psychoneuroimmune-endocrine aspects. Clin Cosmet Investig Dermatol.

2015;8:67.

20 Arzani MA. Akbar’s Medicine (Teb-e-Akbari). Vol 2. Qom: Jalaleddin; 2008.

21 Fedeles F, Murphy M, Rothe MJ, Grant-Kels JM. Nutrition and bullous skin diseases. Clin Dermatol. 2010;28:627– 643.

22 Brenner S, Srebrnik A, Goldberg I. Pemphigus can be induced by topical phenol as well as by foods and drugs that contain phenols or thiols. J Cosmet Dermatol.

2003;2:161–165.

23 Daneshfard B, Yarmohammadi H, Dalfardi B. The origins of the theory of capillary circulation. Int J Cardiol.

2014;172:491–492.

24 Zargaran A, Mehdizadeh A, Zarshenas MM, Mohagheghzadeh A. Avicenna (980-1037 AD). J Neurol.

2012;259:389–390.

25 Atarzadeh F, Heydari M, Sanaye MR, Amin G. Avicenna: a pioneer in Dermatology. JAMA Dermatol. In press.

26 Gorouhi F, Firooz A, Davari P. History of dermatology in Persian territory. J Am Acad Dermatol. 2009;60:30.

27 Mortazavi H, Dowlati Y, Dowlati B. A brief history of dermatology in Iran. Arch Dermatol. 2001;137:936–937.

Early Description of Diet-Induced Blistering Skin Diseases

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Volume 14 • Issue 5

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

The Skin: A Time Capsule Parmvir Singh, BS;1 Ann M. John, BA;1 Yi C. Lai, MPH;1 Marc Z. Handler, MD;2 W. Clark Lambert, MD, PhD2 “Time flies over us, but leaves its shadow behind.”––Nathaniel Hawthorne

T

he skin is a dynamic organ, in a constant state of turnover.1 This proliferation plays a role in the normal protective function of the skin; however, when aberrant, it is also responsible for certain disease states, such as psoriasis.

Early methods of estimating skin renewal involved labeling with C14 and H3 or fluorescent dyes,2,3 such as dansyl chloride, have been used to estimate the transit time in the stratum corneum.4,5 More recently, labeling the with 2H20 (heavy water) has been employed.1 With knowledge of the turnover time of the skin, histologic examination can be used to estimate when certain insults occurred.

2

H20 Labeling

Psoriatic and nonpsoriatic lesions in four men were sampled.6 Proteins were labeled with 2H20 (given twice daily for 16–38 days), and tape stripping was used to remove two affected and two nonaffected sites in each patient. Tape stripping, which is a simple and noninvasive method of obtaining a skin sample, did not cause the Koebner effect in any patient. Turnover times through the stratum corneum were determined using gas chromatography/mass spectrometry. In psoriatic skin, 2H20-labeled protein appeared at the surface in 3 to 8 days. In nonpsoriatic skin, it took 10 to 20 days for 2H20-labeled protein to appear at the surface. In a study of three women who had received 2H20 twice daily for 7 days followed by skin stripping,1 it took 18 days before labeled keratin appeared on the surface.

epidermal proliferation rate.5 In this study, dansyl chloride was applied occlusively and dispersed in white soft paraffin. Fluorescence intensity was measured using a comparator and a fluorometer. The rate of turnover was 23.7 days in sites protected with gauze and 14.5 days in control sites. The turnover rate was twice as fast during the day as the night. When a keratolytic agent such as salicylic acid was used, measured turnover time was 2.9 days. In another study detecting the disappearance of dansyl chloride fluorescence, the stratum corneum turnover time was 20 days.5 Older Techniques Tritium labeling has been used to calculate the duration of the cell cycle in psoriatic and nonpsoriatic lesions.7 The estimated duration was 311 hours in normal skin and 36 hours in psoriatic skin.

The long intervals were later interpreted to be caused by failure to account for the fact that only a small subset of cells in the epidermis (stratum malpighii) were actually proliferating. Using tritium labeling, Epstein and Maibach3 showed an epidermal renewal time of 13 to 18 days. Tritium is minimally toxic and mutagenic; hence, it is no longer used for studies of skin proliferation.6 The epidermal transit time has been calculated using glycine labeled proteins. The proteins reached the top of the stratum corneum on the back of unaffected patients after 13 to 14 days, eight times slower than in lesional skin of psoriatic patients.2

Dansyl Chloride Fluorescence

Using Skin Turnover to Estimate Lesion Timing

In an analysis of eight men aged 21 to 28 years and six men aged 33 to 46 years, turnover times through the stratus corneum were 12.9 days and 15.1 days, respectively.4 Transit time is hypothesized to increase with age as a result of decreased

We recently observed two very interesting cases. The first case was of suspected irritant contact dermatitis in a child with exfoliative dermatitis. We used the location of the lesion in the stratum corneum on biopsy to estimate that the insult had occurred

From Rutgers-New Jersey Medical School, Newark, NJ,1 and the Departments of Pathology and Laboratory Medicine and of Dermatology, Rutgers-New Jersey Medical School, Newark, NJ2 Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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PERILS OF DERMATOPATHOLOGY about 7 days prior to biopsy (Figure 1). The elongated nuclei observed were interpreted to be a result of DNA denaturation from high temperature. We suspected that the patient experienced dermatitis from heat exposure. This was subsequently verified. The patient, an 8-year-old boy, had been subjected to an overly hot bath several days prior to biopsy.

Figure 1. Previous irritant contact dermatitis detected in the stratum corneum (arrow). Note the elongated nuclei indicative of thermal injury. The patient, an 8-year-old boy, had been exposed to overly heated bath water 7 days prior to biopsy (hematoxylin and eosin stain, original magnification ×540).

The second case was of a patient who presented with scabies.8 The diagnosis was made based on the presence of a dead mite in the stratum corneum (Figure 2). Due to of its location in the upper part of the stratum corneum, we estimated that the organism had died about 10 days prior to biopsy. Were it not for the presence of the dead organism in the stratum corneum, the diagnosis would have been missed altogether in this case, because the live organism had migrated beyond the site of the lesion. This has been discussed in another paper.8 Conclusions Turnover time in the skin has been studied extensively. Stratum corneum transit times between 14 and 20 days have been reported in normal skin.2,5,7 This knowledge, coupled with the depth of damage in the stratum corneum seen on histology, can be used to estimate when an injury occurred. Using this technique can be beneficial in correlating clinical observations with the histopathology.

References 1 Lindwall G, Hsieh EA, Misell LM, et al. Heavy water labeling of keratin as a non-invasive biomarker of skin turnover in vivo in rodents and humans. J Invest Dermatol.

2006;126:841–848.

2 Rothberg S, Crounse RG, Lee JL. Glycine-C-14-incorporation into the proteins of normal stratum corneum and the abnormal straum corneum of psoriasis. J Invest Dermatol. 1961;37:497–505.

3 Epstein WL, Maibach HI. Cell renewal in human epidermis. Arch Deramtol. 1965;92:462–468.

4 Takahashi M, Machida Y, Marks R. Measurement of turnover time of stratum corneum using dansyl chloride fluorescence. J Soc Cosmet Chem. 1987;38:321–331.

5 Grove GL, Kligman AM. Age-associated changes in human epidermal cell renewal. J Gerontol. 1983;38:137– 142.

Figure 2. Due to the organism’s ability to suppress inflammation, the characteristic tract-like lesions associated with scabies should be biopsied approximately 2 mm proximal to where inflammation is visible, which was not done in this case; however, this particular organism (arrow) was nevertheless identified, because it had died and been transported to the upper stratum corneum during the several days prior to biopsy (hematoxylin and eosin stain, original magnification ×540).

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6 Emson CL, Fitzmaurice S, Lindwall G, et al. A pilot study demonstrating a non-invasive method for the measurement of protein turnover in skin disorders: application to psoriasis. Clin Transl Med. 2013;2:12.

7 Weinstein GD, McCullough JL, Ross PA. Cell kinetic basis for pathophysiology of psoriasis. J Invest Dermatol.

1985;85:579–583.

8 Kim HJ, Lambert WC. Scabies: too late? No, checkmate.

Skinmed. 2015;13:127–129.

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September/October 2016

Volume 14 • Issue 5

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

What Is New in the Management of Alopecia Areata Aditya Gupta, MD, PhD, FRCPC;1,2 Jessie Carviel, PhD;2 William Abramovits, MD3,4,5

A

lopecia areata (AA) manifests as nonscarring, autoimmune-driven, hair loss that may result in patchy hair loss in its mild form or progress to more severe forms of hair loss including alopecia totalis (AT), loss of all scalp hair, or loss of both scalp and body hair (alopecia universalis [AU]). Prognosis is good for patients with mild patchy hair loss, as spontaneous remission can occur in up to 80% of patients, although recurrences are common.1 Treatment is less effective in cases of childhood onset, more severe forms of AA, or development of AT/ AU where full recovery is estimated at closer to 10%.1 There are currently no approved treatments as efficacy rates of traditional off-label therapy have varied widely.2 Biologics, such as tumor necrosis factor α blockers, were previously explored as innovative therapy options and were found to be ineffective for AA.3 As a result, new options are being investigated, which include the immunomodulators discussed below.

Ruxolitinib Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor (Figure) that is approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis.4

of treatment, scalp hair had increased from 63% to 85% and was maintained at 12 weeks post-ruxolitinib discontinuation.

Treatment with systemic ruxolitinib (20 mg twice daily) resulted in near-complete hair regrowth within 3 to 5 months of treatment in three additional patients with moderate to severe AA.5 In a third study, after 10 months of receiving ruxolitinib for the treatment of thrombocythemia, a woman with AU displayed almost complete regrowth, which was reported as lasting over 4 years posttreatment with no side effects.7 Although serious adverse effects were not reported in the cases described above, previously reported side effects of ruxolitinib include moderate to severe thrombocytopenia and anemia, as well as “ruxolitinib withdrawal syndrome.”8 There is currently an open-label pilot study in progress that may confirm these results.9 Tofacitinib

Animal models

Tofacitinib is a JAK 1/3 inhibitor (Figure) that is FDA-approved for treatment of rheumatoid arthritis.10

Treatment with systemic ruxolitinib prevented AA onset while topical applications induced complete hair regrowth in murine models.5

Animal models

Case Studies Ruxolitinib (20 mg twice daily for 20 weeks) was used to treat a 35-year-old-man with concurrent vitiligo and AA.6 By 12 weeks

Systemic tofacitinib prevented development of AA as well as reversed established disease in murine models.5 Treatment results persisted 2 to 3 months posttreatment. Complete hair regrowth was also observed with topical tofacitinib application.

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, Houston, TX;3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School, Dallas, TX;4 and the Dermatology Treatment and Research Center, Dallas, TX5 Address for Correspondence: Aditya K. Gupta, MD, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Figure. Hypothesized mechanisms of new alopecia areata treatments. Janus kinase (JAK) inhibitors interrupt a proinflammatory positive feedback loop between T cells and endothelial cells. Tofacitinib blocks JAK 1/3-mediated interferon Îł upregulation in T cells while ruxolitinib blocks JAK 1/2-mediated interleukin (IL) 15 upregulation in endothelial cells. Simvastatin is believed to have multiple mechanisms of action including blocking expression of major histocompatibility class II as well as adhesion molecules such as intracellular adhesion molecule 1 and vascular cell adhesion molecule 1, thus inhibiting lymphocyte activation and release of proinflammatory cytokines. IL-2 is believed to attract regulatory T cells, which suppress the activities of effector T cells.

Case studies When treated with systemic tofacitinib (5 mg twice daily), a 42-year-old man with AU displayed modest and significant hair growth on the scalp and beard, respectively, with 3 months of treatment.11 By 6 months, hair growth was apparent throughout the body, while eyebrows and eyelashes were established by 8 months. The patient reported no serious adverse effects with tofacitinib treatment at 2 years. In a second patient with AU, also treated with tofacitinib 5 mg twice daily, scalp hair started to noticeably increase in density, while eyebrow and leg hair began regrowth at a moderate pace by the first month. By 4 months, significant scalp regrowth was observed in the Hamilton 5A pattern, as well as eyelash, eyebrow, and beard regrowth. Axillary hair regrowth and isolated leg hair were noted by 8 months. Treatment SKINmed. 2016;14:375â&#x20AC;&#x201C;378

was paused for 1 month because of viral infections and complaints of fatigue.

In a second study, a patient diagnosed with concurrent psoriasis and AU treated with tofacitinib 5 mg twice daily displayed partial scalp and face hair regrowth by 2 months.12 The dosage was then increased to tofacitinib 10 mg in the morning, which resulted in complete scalp regrowth and significant additional growth including eyebrows and eyelashes. Full hair regrowth was achieved by 8 months.

Although serious adverse effects were not observed in the AU case studies mentioned above, previously noted concerns with use of tofacitinib include an increase in infection,13 anemia, neutropenia, headache, and mild nausea.14 There is currently an

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open-label pilot study in progress that may confirm these results.15 Low-dose IL-2 Interleukin (IL) 2 is a cytokine (Figure) that has been approved for cancer treatment and investigated for autoimmune disease.

Prospective pilot study

A similar study that recruited patients with more severe disease (AT, AU, or greater than 70% scalp involvement) reported different results.20 Simvastatin/ezetimibe given at 40 mg/10 mg daily for 6 months led to no cosmetically acceptable hair regrowth in the 17 participants who completed the study. No hair regrowth was observed in 82% of patients. Side effects included mild headache and muscle cramps.

Conclusions

In a prospective open pilot study (N=5), women with severe AA for a mean duration of 10 years and recalcitrant to previous systemic treatments were administered subcutaneous IL-2 at 1.5 million IU/d for 5 days followed by three 5-day courses of IL-2 (3 million IU/d) at 3, 6, and 9 weeks.16 The baseline Severity of Alopecia Tool (SALT) score improved from 82 at baseline to 69 by 6 months as a result of partial hair regrowth in 80% of participants, but no complete hair regrowth was observed. Regrowth was reportedly highest at 6 months after treatment with no serious adverse events. Mild to moderate symptoms included asthenia, arthralgia, urticarial, and local reactions at the injection sites.

Statins: Simvastatin/Ezetimibe A combination of simvastatin and ezetimibe has been previously approved for the treatment of high cholesterol.

Currently, there is no approved therapy for AA, although investigations into new biologics are hopeful. Use of JAK inhibitors, low-dose IL-2, and simvastatin/ezetimibe is still preliminary, with some mixed results, considering anything less than complete or almost complete recovery is most likely not helpful to patients. Of all, tofacitinib appears to be the most promising. The data reported here come from a patient subset composed of the most difficult cases including patients with severe AA, AT, or AU, highlighting the potential for the majority of patients who are more mildly affected. Ongoing and future randomized controlled trials are required to determine whether these new treatments have a place in AA therapy.

References

Case studies A report of two patients with previously unresponsive AT displayed improvement after treatment with a combination of simvastatin/ezetimibe and intralesional corticosteroid injections.17 A 54-year-old man with longstanding AU prescribed simvastatin/ezetimibe (40 mg/10 mg daily) for the treatment of hyperlipidemia displayed dense scalp hair growth and patchy growth in additional body areas after 1 month of treatment.18 Previous use of simvastatin alone did not induce any similar results.

Prospective pilot studies AA patients (N=19) with 40% to 70% scalp involvement were treated with simvastatin/ezetimibe at 40 mg/10 mg daily.19 By 24 weeks, 14 patients displayed more than 20% hair regrowth and treatment was either terminated or continued for an additional 24 weeks. Of the seven who continued treatment, five remained stable or continued to improve, one displayed new hair loss, and one was lost to follow-up. Of the seven who stopped treatment, five relapsed, one remained stable, and one was lost to follow-up. Using the Fisher exact test (one-tailed), stable remission as a result of continued treatment was considered significant (P=.04). No side effects were observed.

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1 MacDonald Hull SP, Wood ML, Hutchinson PE, Sladden M, Messenger AG; British Association of Dermatologists.

Guidelines for the management of alopecia areata. Br J Dermatol. 2003;149:692–699.

2 Delamere FM, Sladden MM, Dobbins HM, Leonardi-Bee J. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.

3 Abramovits W, Losornio M. Failure of two TNF-alpha blockers to influence the course of alopecia areata.

Skinmed. 2006;5:177–181.

4 Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;11:3109– 3117.

5 Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20:1043–1049.

6 Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol.

2016;74:370–371.

7 Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. Am J Hematol. 2015;90:82–83.

8 Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86:1188– 1191.

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9 Pilot study to evaluate the efficacy of ruxolitinib in alopecia areata. https://clinicaltrials.gov/show/ NCT01950780. Accessed July 25, 2016.

Tofacitinib in Moderate to Severe Alopecia Areata, Totalis and Universalis. 2014. https://clinicaltrials.gov/ct2/ show/NCT02299297. Accessed July 25, 2016.

10 Yamaoka K, Tanaka Y. Targeting the Janus kinases in rheumatoid arthritis: focus on tofacitinib. Expert Opin Pharmacother. 2014;15:103–113.

16 Castela E, Le Duff F, Butori C, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 2014;150:748–751.

11 Gupta A, Carviel J, Abramovits W. Efficacy of tofacitinib in treatment of alopecia universalis in two patients. J Eur Acad Dermatol Venereol. 2016;30:1373–1378.

17 Ali A, Martin JM. Hair growth in patients alopecia areata totalis after treatment with simvastatin and ezetimibe. J Drugs Dermatol. 2010 ;9:62–64.

12 Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134:2988– 2990.

18 Robins DN. Case reports: alopecia universalis: hair growth following initiation of simvastatin and ezetimibe therapy. J Drugs Dermatol. 2007;6:946–947.

13 Ortiz-Ibáñez K, Alsina MM, Muñoz-Santos C. Tofacitinib and other kinase inhibitors in the treatment of psoriasis.

Actas Dermosifiliogr. 2013;104:304–310.

14 Tofacitinib. Drugs R D. 2010;10:271–284 15 An Open-Label Pilot Study to Evaluate the Efficacy of

19 Lattouf C, Jimenez JJ, Tosti A, et al. Treatment of alopecia areata with simvastatin/ezetimibe. J Am Acad Dermatol. 2015;72:359–361.

20 Loi C, Starace M, Piraccini BM. Alopecia areata (AA) and treatment with simvastatin/ezetimibe: experience of 20 patients. J Am Acad Dermatol. 2016;74:e99–e100.

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

(Continued on page 400)

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Volume 14 • Issue 5

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

Becoming Wiser About the Wiesner Nevus Warren R. Heymann, MD

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an you pass the nevus eponym quiz? Perhaps you’ll recognize the following variants: Miescher (dome-shaped with dermal nevus cells), Unna (exophytic and papillomatous), Myerson (nevus with eczema), Sutton (halo nevus), Nanta (nevus with osteoma), Duperrat (nevus with an associated cyst), and Clark (dysplastic nevus). A new variant, the Wiesner nevus, is the focus of this commentary. While recognition of the other nevi variants may qualify you as an erudite dermatologist, diagnosing a Wiesner nevus may allow you to save a life.

A Novel Familial Cancer Syndrome In 2011, Wiesner described two families with an autosomal dominant syndrome, characterized by multiple skin-colored melanocytic lesions (initially described as “reminiscent of Spitz nevi”), and an increased risk of uveal melanoma and cutaneous melanoma, associated with inactivating mutations of the BAP1 gene.1 Subsequently, other tumors such as mesothelioma, clear cell renal carcinoma, lung adenocarcinoma, neuroendocrine carcinoma, and abdominal (suspected ovarian) carcinoma have been identified, although the complete tumor spectrum of this mutation is unknown. BRCA1-associated protein-1 (BAP1) is a protein that binds to BRCA1. It is a tumor suppressor that presumably mediates its effects by chromatin modulation, transcriptional regulation, and possibly via the ubiquitin-proteasome system and the DNA damage response pathway.2 The nonlysosomal degradation of nuclear and cytosol proteins is targeted by the ubiquitin proteasome machinery utilizing adenosine triphosphate and other mechanisms. Proteins that regulate the cell cycle are controlled by ubiquitin. Dysregulation of the components of the ubiquitin system have been linked to inflammatory disorders and malignancies. The ubiquitin-proteasome pathway is currently targeted for potential cancer therapies.3

The Wiesner Nevus In the initial familial cases, affected patients developed lesions in their second decade. The number of lesions ranged from five to greater than 50, being described as “skin-colored to reddishbrown, dome-shaped to pedunculated, well-circumscribed papules with an average size of 5 mm.” Histopathologically, the lesions were primarily dermal, being composed of epithelioid melanocytes with abundant amphophilic cytoplasm and prominent nucleoli. The loss of BAP1 expression was accompanied by BRAF mutations in 88% of the lesions tested.1 In a subsequent study of 32 sporadic atypical Spitz nevi, nine (28%) showed loss of BAP1 expression, of which eight (89%) had concomitant BRAF mutations. Only one (4%) of the BAP1-positive atypical Spitz nevi exhibited a BRAF mutation, a highly statistically significant difference. The combination of the loss of expression of BAP1 and BRAF mutation correlated with the histologic features described above, allowing for the accurate diagnosis of the Wiesner nevus as a unique subset of atypical Spitz nevi.4 The Wiesner nevus may be differentiated from a classic Spitz nevus in that the Wiesner nevus is entirely dermal, lacking epidermal hyperplasia, Kamino bodies, or an intraepidermal or junctional component. It has a clonal “sheet-like” pattern, does not demonstrate significant mitotic activity, and does not display maturation to the base of the lesion. Classic Spitz nevus cells stain positively for BAP1 and negatively with VE1 antibody (for the BRAF V600E mutation) in contrast to the epithelioid melanocytes of Wiesner nevi, which are BAP1-negative and predominantly VE1-positive.5,6 Not surprisingly, variants of Wiesner nevi have also been reported, such as the case of a 44-year-old woman who presented with a solitary pink papule with brown “dots” at the periphery on the posterior aspect of her right extremity.

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

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The lesion had been present for only 6 months, and there was no personal or family history of cancer. Results from routine biopsy demonstrated features of a Wiesner nevus; findings from immunohistochemical stains were negative for BAP1 and VE1.

The lesion was re-excised because the authors acknowledged that the precise malignant risk of this variant of Wiesner nevus is unknown.

Wiesner nevi have previously been described in the literature as BAPoma and melanocytic BAP1-associated intradermal tumor.6 These latter terms are confusing, because they imply that these nevi express BAP1, which they do not. Given the potential immunohistochemical variability of the lesions, until further analysis solidifies the diagnostic criteria, I contend that using the eponym Wiesner nevus be utilized.

Conclusions The Wiesner nevus appears to be a unique variant of an atypical Spitz nevus that may present as a solitary lesion or as multiple lesions. The dermal histology, confirmed by being BAP1-negative in all and BRAF-positive in the majority of cases, defines this lesion. Lesions are clinically indolent, although malignant potential exists—solitary lesions should be conservatively excised, and multiple lesions followed carefully, with any changing lesion subsequently excised. A careful family history should be obtained, focusing on uveal or cutaneous melanoma, mesothelioma, and clear cell renal carcinoma. Further research is warranted so that dermatologists and dermatopathologists become wiser about Wiesner nevi.

References

Solitary Wiesner Nevus vs Multiple Wiesner Nevi The practical issue of how to address Wiesner nevi was recently addressed in a case report of a 21-year-old man who presented with multiple enlarging nodules on his scalp, right cheek, right antihelix, and right fifth toe that were present since childhood.

His family history was remarkable for gastric cancer. Results from histologic examination, both routine and immunohistochemical, confirmed the diagnosis of Wiesner nevi. The authors assert that in most cases BAP1 loss is somatically acquired, but multiple tumors tend to be associated with a germline mutation of BAP1.

As long-term follow-up is lacking in many cases, the authors suggest a prudent approach. Preliminary evidence suggests that most lesions are clinically indolent.7 To date, only one case of melanoma within areas of a Wiesner nevus has been reported.6 For patients with solitary lesions, a conservative complete excision of the lesion is recommended. For patients with multiple lesions, genetic counseling (including testing for germline mutations) and careful clinical follow-up are advised, with surgical excision of changing lesions.7

1 Wiesner T, Obenauf AC, Murali R, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43:1018–1021.

2 Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology. 2013;45:116–126.

3 Jain CK, Arora S, Khanna A, et al. The ubiquitin-proteasome pathway and emerging anticancer strategy for therapeutics: a patent analysis. Recent Pat Anticancer Drug Discov. 2015;10:201–213.

4 Wiesner T, Murali, Fried, et al. A distinct subset of atypical Spitz tumors is characterized by BRAF mutation and loss of BAP1 expression. Am J Surg Pathol. 2012;36:818– 830.

5 Llamas-Velasco M, Pérez-Gónzalez, Requena L, Kutzner H. Histopathologic clues for the diagnosis of Wiesner nevus. J Am Acad Dermatol. 2014;70:549–554.

6 Requena C, Sanz V, Nagore E, et al. BAP1-deficient and VE1-negative atypical Spitz tumor. J Cutan Pathol.

2015;42:564–567.

7 Busam KJ, Wanna M, Wiesner T. Multiple epithelioid Spitz nevi or tumors with loss of BAP1 expression: a clue to a hereditary tumor syndrome. JAMA Dermatol.

2013;149:335–339.

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Volume 14 • Issue 5

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

Trench Foot Mark Bernhardt, MD

I

n the first winter of the Great War, a baffling disease appeared among British soldiers. Medical authorities quickly recognized this was a new entity as well as its unique predilection for soldiers fighting in the frigid muddy trenches of the Western Front. There were intriguing clues that weather had to be a significant fact in its causation; yet, there were puzzling inconsistencies to cold being the single responsible factor. The number of new cases dramatically fell as spring arrived, but the disease affected only the lower extremities, never the exposed face.

Not all soldiers were at equal risk. British soldiers fared the worst, while their Belgian colleagues were relatively unscathed.

Some authorities considered the condition a constitutional disturbance caused by the unsanitary state of the trenches, while others thought poor nutrition was the cause. French doctors favored an infectious element, claiming the pathogen was a mold, Scopulariopsis koningii.

Trench Foot and the War Effort

Defeating trench foot was crucial to winning the War. The number of men who had to be removed from active duty due to their condition not only reduced the fighting force, but also added a huge monetary cost to the war effort with their hospitalization, treatment, forced early discharge, or permanent disability. Those who recovered were more susceptible to recurrence with the return of wintry conditions. Even in the context of the drudgery, carnage, and filth of the trenches, this disease seemed to have an especially demoralizing effect on the troops.

Defeating Trench Foot It is a testament to the brilliant deductive reasoning of both military and medical leaders that such rapid progress was made in the

elucidation of the cause and the institution of effective prophylaxis against trench foot. It was soon recognized that there was not a sole etiologic agent at work, but rather a combination of factors unique to trench warfare. There were hours, if not days, of standing motionless in frigid muddy water. The immobility deprived the legs of the muscular assist to prevent venous stasis. The worse the swelling, the more peripheral circulation was choked off by tight, ill-fitting boots. The immunity of the Belgian troops was due to the fact that they did not wear the woolen puttees that were a part of the British uniform. In the waterlogged trenches, these leg wrappings quickly became soaked and swollen, further compromising peripheral circulation.

Even the structural design of the trenches worked against the soldiers. When they were at rest with their legs dangling below, the dependent position of their feet confounded venous return.

The British Army redesigned their uniforms to make them less constrictive. It encouraged soldiers to use protective ointments on their feet and to change to dry socks daily. It instructed its troops to elevate their legs whenever possible.

The incidence of trench foot fell dramatically by the end of the War, although it is unclear whether this was the result of the preventive measures or the decline in trench warfare itself. In hindsight, Napoleon’s troops in Russia had trench foot, as did soldiers in both World War II and the Vietnam War. As late as 1982, British troops in the Falklands still suffered from what is now more prosaically called nonfreezing cold injury or immersion foot syndrome. But to any of its victims, the grim imagery brought up by the term, trench foot, is far more hauntingly vivid.

I have followed in the footsteps of Atenstaedt RL. Trench foot: the medical response in the first world war 1914–1918. Wilderness Environ Med. 2006;17:282–289.

From Private Practice, Fort Lauderdale, FL Address for Correspondence: Mark Bernhardt, MD, Private Practice, 1601 East Broward Boulevard, Fort Lauderdale, FL 33301 • E-mail: cheesedb@aol.com

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THE INTERSECTION OF DISEASE AND DESIRE DERMATOLOGY

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September/October 2016

Volume 14 • Issue 5

PHOTO CAPSULE

Desquamative Dermatitis Caused by Erlotinib: An Underreported Cutaneous Adverse Event Miriam L. Vega, MD, MPH;1 Natalie C. Yin, BS;2 Matthew Keller, MD1

W

e present a case of a 52-year-old woman with metastatic small cell lung cancer treated with 150 mg erlotinib daily, lobectomy with gamma knife, and electron beam radiation therapy for brain metastases in 2009. The patient presented to our clinic complaining of a 2-year history of persistent asymptomatic sloughing of her skin starting several months after initiation of erlotinib therapy. Physical examination revealed a thin superficial desquamation in sheets, with cigarette paper–like appearance of the skin, without a background of erythema, on her neck, shoulders, abdomen, back, and proximal thighs (Figures 1 and 2). Other associated findings were fine, brittle hair and a thick adherent yellowish scale on the scalp (Figure 3). There was no other evidence of an underlying dermatosis that would otherwise explain the patient’s skin findings.

Discussion

Figure 1. Superficial desquamation with a cigarette paper–like appearance of the skin, without a background of erythema.

Erlotinib is a reversible tyrosine kinase epidermal growth factor receptor (EGFR) inhibitor used to treat non–small cell lung cancer, among other solid tumors. EGFR knockout mouse models have established that EGFR is an important regulator of epidermal growth and differentiation1; therefore, its inhibition is associated with a number of cutaneous side effects. The exact pathophysiology of EGFR inhibitor skin toxicity is not well understood, but it is believed to be dose-dependent and result from direct receptor inhibition in the skin.2 Although dermatologic side effects are usually mild or moderate, in many cases they can impact the patient’s quality of life and hinder lifesaving treatments, as certain medications may need to be discontinued in the setting of severe cutaneous complications.3 The most common cutaneous side effects include acneiform eruptions, xeroderma, pruritus, and paronychia.3 In contrast to the typical xerodermic features of skin dryness and rough-

Figure 2. Thin desquamation in sheets, with a cigarette paper–like appearance on the trunk.

From the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA;1 and the Leonard M. Miller School of Medicine, University of Miami, Miami, FL2 Address for Correspondence: Matthew Keller, MD, Department of Dermatology and Cutaenous Biology, Thomas Jefferson University Hospital, 833 Chestnut Street, Suite 740, Philadelphia, PA 19106 • E-mail: matthew.keller@jefferson.edu

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PHOTO CAPSULE lotinib to be the etiologic agent of her active condition and we believe these findings are indicative of concurrent cicatricial alopecia and EPDS. Recent evidence suggests that a skin reaction following EGFR inhibitor treatment may predict a better response to the medication and a more favorable prognosis.6 These patients have been shown to have longer progression-free survival and overall survival.7 Consistent with these data, our patient’s primary and metastatic cancer have been stable since her diagnosis in 2009.

Conclusions We present the first case of a chronic, diffuse, superficial skin sloughing following the use of erlotinib and the rare associated findings of scarring alopecia and pustular dermatosis.

References 1 Tran QT, Kennedy LH, Leon Carrion S, et al. EGFR regulation of epidermal barrier function. Physiol Genomics.

2012;44:455–469.

2 Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290:2149–2158.

3 Kiyohara Y, Yamazaki N, Kishi A. Erlotinib-related skin toxicities: treatment strategies in patients with metastatic non-small cell lung cancer. J Am Acad Dermatol.

2013;69:463–472.

Figure 3. Thick adherent yellowish scale and scarring alopecia.

ness with mild scaling and progression to fissuring, our patient’s skin condition was characterized by chronic fine desquamation and very superficial epidermal sloughing in sheets.

Our patient’s case was also unique in that it was complicated by extensive scarring alopecia and erythematous plaques with yellow crusting on the scalp. Hair abnormalities can occur following EGFR inhibitor treatment, including eyelash trichomegaly and/or thinning of the face or scalp hair.4 Although extremely rare, scarring alopecia and erosive pustular dermatosis of the scalp (EPDS) have been described following erlotinib and gefitinib treatment.5 It is possible that the patient’s prior radiation treatment contributed to the scarring alopecia, although the persistent inflamed plaques suggest er-

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4 Costa DB, Kobayashi S, Schumer ST. Erlotinib-associated alopecia in a lung cancer patient. J Thorac Oncol.

2007;2:1136–1138.

5 Toda N, Fujimoto N, Kato T, et al. Erosive pustular dermatosis of the scalp-like eruption due to gefitinib: case report and review of the literature of alopecia associated with EGFR inhibitors. Dermatology. 2012;225:18–21.

6 Mita AC, Papadopoulos K, de Jonge MJ, et al. Erlotinib ‘dosing-to-rash’: a phase II intrapatient dose escalation and pharmacologic study of erlotinib in previously treated advanced non-small cell lung cancer. Br J Cancer.

2011;105:938–944.

7 Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2013;8:e55128.

Desquamative Dermatitis Caused By Erlotinib

September/October 2016

Volume 14 • Issue 5

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

A Pigmented Subcutaneous Nodule on the Scalp Shuwei Wang, BS;1 Jeff D. Harvell, MD;2 Kenneth J. Friedman, MD;2 A. Yasmine Kirkorian, MD;1 Sandy Milgraum, MD1 A 52-year-old man presented to his primary doctor with a slow-growing cystic lesion on his occipital scalp. His primary care doctor diagnosed the lesion as a pilar cyst and recommended observation because the lesion was asymptomatic at that time. The patient had no significant medical or surgical history. There was no family history of skin cancer or other malignancies. (SKINmed. 2016;14:385–388)

O

ne year later, the patient presented to the dermatologist because his lesion continued to grow and became progressively painful. Physical examination demonstrated a 3.5-cm skin-colored fluctuant subcutaneous nodule. Excision was planned because the lesion was painful. During the excision, a dark brown viscous discharge was extruded from the specimen, which, along with a biopsy of the skin and subcutis, was submitted for histopathologic examination.

Histopathologic examination demonstrated a spindle cell population extending into the reticular dermis and subcutaneous fat.

The majority of the spindle cells stained strongly positive with CD34 but negative with Factor XIIIa, epithelial membrane antigen, and cytokeratin. A subpopulation of spindle cells stained positively with S100 and melan-A. Discussion A previous diagnosis of benign cyst does not preclude the possibility of a subsequent malignant lesion. This was an extraordinary case of a Bednar tumor, a melanin-pigmented subtype of dermatofibrosarcoma protuberans (DFSP), masquerading as a pilar cyst.

Bednar tumor was named for Dr Blahoslav Bednar who originally described it in 1957 as “pigmented storiform neurofibroma.”

Bednar was a well-known Czechoslovakian pathologist who lived from 1916 to 1998. He spent his entire life in Prague and received his medical degree from Charles University. He was responsible for stimulating a renewed interest and respect for aca-

demic pathology in his homeland of Czechoslovakia. Among his many contributions, he was professor and chairman of the Hlava Institute of Pathology in Prague from 1955 to 1983, founded the official journal Czecho-Solvak Pathology, and published 409 papers and 25 monographs.16 Bednar tumors are a pigmented variant of DFSP, representing only 5% of all DFSP cases.2 DFSPs are rare, locally aggressive cutaneous soft tissue sarcomas composed of monomorphic, benign-appearing spindle cells arranged in an irregularly whorled or storiform pattern that resembles a straw mat.15 Bednar tumors are distinguished by melanin-pigmented dermal dendritic cells with long cytoplasmic processes scattered throughout the nonpigmented spindle cell population.7 They behave similarly to DFSPs as locally aggressive tumors of intermediate malignancy with local recurrence rates of 10% to 15% and rare reports of metastases.4 The likelihood of metastasis increases when the tumor cells acquire fibrosarcomatous features or lose melanin pigmentation.5 Reported sites of metastases include lungs, liver, brain, colon, retroperitoneum, and skin.4,5 Bednar tumors usually present as elevated, erythematous nodules or plaques, most commonly affecting the trunk and proximal parts of the limbs of young adults. Depending on the number of pigmented cells, the tumors may vary in color, usually gray, red, or brown.1 They are often associated with purulent exudates or with ulcerations and have a tendency to become painful as they grow larger.12 Under the dermatoscope, Bednar tumors display network and dotted vessels and may resemble dermatofibromas.

From the Department of Dermatology, UMDNJ Robert Wood Johnson Medical School, Piscataway Township, NJ;1 and the Bethesda Dermatopathology Laboratory, Silver Spring, MD2 Address for Correspondence: Shuwei Wang, BS, 833 Chestnut Street, Suite 220, Philadelphia, PA 19107 • E-mail: shuweiwang87@gmail.com

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Figure 1. Cystic lesion on occipital scalp after initial incision and drainage.

Figure 3. Dense spindle cell proliferation with a storiform architectural growth pattern. Hematoxylin and eosin stain, magnification ×200.

Figure 2. Scalp lesion after 5 Mohs sessions.

Figure 4. Spindle cells infiltrate the subcutaneous fat, encircling and entrapping individual adipocytes. Hematoxylin and eosin stain, magnification ×200.

This case represents the first documented case of a Bednar tumor masquerading as a fluctuant pilar cyst. There was a previous case of a DFSP misdiagnosed as a cyst. A 38-year-old woman with no significant medical history presented with a well-circumscribed subcutaneous nodule that was found to be a DFSP located deep within the hypodermis.13 Subcutaneous DFSPs are rare and were first described by Diaz-Cascajo and colleagues as “deep dermatofibrosarcoma protuberans” with little histopathological difference from the usual cutaneous form of DFSP.14 The deep DFSP may have originated from CD34+ deep dermal dendrocytes SKINmed. 2016;14:385–388

present within the connective tissue septa of the subcutis.14 This current case of Bednar tumor was not entirely subcutaneous, but its similar presentation made diagnosis more challenging.

Bednar tumors share immunohistochemical and genetic properties with DFSP, further confirming them as variants of DFSP. The spindle cells stain positively for CD34 and vimentin, and variably positive for smooth muscle actin. The pigmented dendritic cells stain positively with markers of melanocytic differentiation, including S100, melan-A, and HMB-45. The pigment is Fon-

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Figure 5. The neoplastic cells were strongly positive with CD34. CD34 stain; magnification ×200.

Figure 7. Melan-A highlighted the subpopulation of pigmented spindle and dendritic cells.Melan-A stain; magnification ×400.

shared chromosome instability causing comorbidity of a congenital Bednar tumor and Fanconi anemia.3 The differential diagnosis of Bednar tumor includes pigmented dermatofibroma, pigmented neurofibroma, myxoid malignant fibrous histiocytoma, and schwannoma.8 Although pigmented dermatofibromas can sometimes exhibit storiform growth, they typically display epidermal acanthosis and basal layer hyperpigmentation and lack significant involvement of the subcutaneous fat. Pigmented dermatofibromas are factor XIIIa positive and CD34 negative, whereas the converse is true of Bednar tumor.9 The treatment of choice is Mohs micrographic surgery.11 Recently, imatinib mesylate was approved as a molecular treatment for unresectable, recurrent, and/or metastatic DFSP. Imatinib mesylate interferes with tyrosine kinase receptors, especially PDGFB receptors that are overexpressed in DFSP with COL1A1-PDGFB fusion.6

Figure 6. An intimately admixed subpopulation of pigmented spindle and dendritic cells was evident. Hematoxylin and eosin stain; magnification ×400.

Conclusions tana-Masson positive and Perls stain negative, confirming that it is melanin rather than hemosiderin.7 Cytogenetically, Bednar tumors share the same reciprocal translocation t(17;22)(q22;q13) as DFSP. The translocation causes a fusion between the gene for collagen-type I alpha 1 (COL1A1) on chromosome 17q and the gene for platelet-derived growth factor β polypeptide (PDGFB) on chromosome 22q. This leads to upregulation of PDGF and stimulation of tumor proliferation.6 COL1A1-PDGFB fusion gene has been used for molecular biological confirmation of a Bednar tumor metastasis10 and as a possible explanation for the SKINmed. 2016;14:385–388

Bednar tumors are DFSPs with melanin-containing dendritic cells. Similar to conventional DFSPs, Bednar tumors exhibit an t(17;22)(q22;q13) translocation, and their nonpigmented cells stain with CD34. The subpopulation of pigmented spindle and dendritic cells stain with markers of melanocytic differentiation, such as S100, melan-A, and HMB-45.This is the first reported case of a Bednar tumor presenting as a pilar cyst. It is important for clinicians to be aware of this presentation since lack of recognition can lead to a delay in diagnosis. Cystic lesions that are changing or otherwise symptomatic should prompt biopsy and submission for histopathologic diagnosis.

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References 1 Bednar B. Storiform neurofibromas of the skin, pigmented and nonpigmented. Cancer. 1957;10:368–376.

2 Criscione VD, Weinstock MA. Descriptive epidemiology of dermatofibroscarcoma protuberans in the United States, 1973 to 2002. J Am Acad Dermatol. 2007;56:968– 973.

3 Lee DW, Yang JH, Won CH, et al. A case of congenital pigmented dermatofibrosarcoma protuberans (Bednar tumor) in a patient with fanconi Anemia. Pediatr Dermatol. 2011;28:583–585 4 Mentzel T, Beham A, Katenkamp D, Dei Tos AP, Fletcher CD. Fibrosarcomatous (“high-grade”) dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic significance. Am J Surg Pathol. 1998;22:576– 587.

5 Suehara Y, Yazawa Y, Hitachi K. Metastatic Bednar tumor (pigmented dermatofibrosarcoma protuberans) with fibrosarcomatous change: a case report. J Orthop Sci. 2004;9:662–665.

6 Llombart B, Sanmartin O, Lopez-Guerrero JA, et al. Dermatofibrosarcoma protuberans: clinical, pathological, and genetic (COL1A1-PDGFB) study with therapeutic implications. Histopathology. 2009;54:860–872.

9 McAllister JC, Recht B, Hoffman TE, Sundram UN. CD 34+ pigmented fibrous proliferations: the morphologic overlap between pigmented dermatofibromas and bednar tumors. Am J Dermatopathol. 2008;30:484–487.

10 Kabumoto T, Fujiwara H, Kariya N, et al. Skin metastasis of dermatofibrosarcoma protuberans with distinct morphological features, confirmed by COL1A1-PDGFB fusion gene analysis. J Am Acad Dermatol. 2009;61:130– 132.

11 Snow SN, Gordon EM, Larson PO, et al. Dermatofibrosarcoma protuberans: a report on 29 patients treated

by Mohs micrographic surgery with long-term followup and review of the literature. Cancer. 2004;101:28– 38.

12 James WD, Berger T, Elston D. Andrew’s Disease of the Skin: Clinical Dermatology. 10th ed. Philadelphia, PA: Saunders; 2005.

13 Bathelier E, Ly A, Kanitakis J, et al. Subcutaneous dermatofibrosarcoma protuberans masquerading as a cyst.

J Eur Acad Dermatol Venereol. 2007;21:1127–1128.

14 Diaz-Cascajo C, Weyers W, Rey-Lopez A, Borghi S. Deep dermatofibrosarcoma protuberans: a subcutaneous variant. Histopathology. 1998;32:552–555.

7 Zardawi IM, Kattampallil J, Rode J. An unusual pigmented skin tumour Part 1. Pathology. 2008;34:358–361.

15 Haycox CL, Odland PB, Olbricht SM, Piepkorn M. Immunohistochemical characterization of dermatofibrosarcoma protuberans with practical applications for diagnosis and treatment. J Am Acad Dermatol. 1997;37:438.

8 Wang J, Yang W. Pigmented dermatofibrosarcoma protuberans with prominent meningothelial-like whorls. J Cutan Pathol. 2008;35:65–69.

16 Whonamedit? A dictionary of medical eponyms. 1994– 2012 Ole Daniel Enersen. April 22, 2012. http://www. whonamedit.com/doctor.cfm/3270.html.

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Contact Urticaria With Paraphenylene Diamine, Rare or Underreported?

Muthu Sendhil Kumaran, MD; Tarun Narang, MD; Davinder Parsad, MD

A 45-year old woman presented with a 2-day history of intensely itchy, erythematous wheals over her scalp and around her eyes, ears, and front of the chest. She had applied hair color and immediately developed hives on the scalp, face, and chest with rhinitis and redness in the eyes. The lesions recovered within a half hour of taking a cetirizine 10-mg tablet. She gave a similar history around three times in the past 6 months. She used a different brand of hair color every time but all were associated with the same symptoms. In the first and second episodes, the itchy wheals were localized to the scalp, but in the present episode it was most severe with eye and nasal mucosal involvement and lesions spreading to involve the face, ears, and chest. There was no oozing or eczematization present. All episodes responded well to oral cetrizine. (SKINmed. 2016;14:389–390)

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linical examination revealed erythematous wheals over the scalp, ears, and eyes (Figure 1 and Figure 2) and blanchable erythema over the front of the chest.

On studying the labels of the hair dyes the patient had used, we suspected that paraphenylenediamine (PPD) might have been responsible for the reactions. To test this theory, we conducted an open test on the volar aspect of the forearm with all of the hair colors she used and PPD 0.1% in petrolatum, which showed immediate positivity in the form of a wheal >10 mm within 15 minutes with all dyes and PPD. With a clinical diagnosis of contact urticaria to PPD, the patient was treated with cetrizine tablets and prednisolone tablets of 40 mg for 1 week and asked to avoid using hair colors.

Contact urticaria is a common but under-reported diagnosis. It is categorized into two subtypes: immunologic contact urticaria (ICU) and nonimmunologic contact urticaria (NICU). ICU is a type I hypersensitivity reaction mediated by allergen-specific IgE in a previously sensitized individual. The respiratory or gastrointestinal tract may also be involved and, if severe, can cause anaphylactic shock and death. NICU on the other hand is mild and presents as localized urticaria.1

Contact urticaria (CU) syndrome was described by Maibach and Johnson2,3 and has four stages: stage 1 includes localized urticaria; stage 2, generalized urticaria; stage 3, urticaria with extracutaneous reactions (eg, oral, nasal, ocular, upper respiratory/lower respiratory or gastrointestinal symptoms); and stage 4, urticaria with shock. CU can be life-threatening, with certain substances, such as latex protein and dyes, causing anaphylaxis and even death.3 Hair care products such as ammonium persulfate, Basic Blue 99 (amino ketone dye), henna, panthenol, protein hydrolysate, and PPD have been identified as allergens that can cause ICU.4,5 There are reports of anaphylaxis after hair color application.6 Many drugs have cross-reactivity with PPD (Table),7,8 and whether a patient with CU should avoid these drugs is yet to be established. Our patient was not taking any of these drugs, but there is always a risk of the patient presenting with stage 3 or 4 of CU syndrome if exposure to the antigen continues. Patients with a history of burning sensation, stinging, itching, redness or urticaria within an hour of exposure should be immediately tested. Epidermal application of the agents (open and occlusive tests), followed by prick test if the results are negative, is recommended. Agents should not be applied at high doses if hypersensitivity type II and IV reactions are suspected, and resuscitation facilities should be available at the time of testing.1

From the Department of Dermatology, Venereology and Leprology, Post-Graduate Institute of Medical Sciences and Research, Chandigarh, India Address for Correspondence: Tarun Narang, MD, Department of Dermatology, Venereology and Leprology, Post-Graduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India • E-mail: narangtarun@yahoo.co.in

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Table. Drugs Shown to Cross-React With Paraphenylenediamine Azo and aniline dyes Benzocaine Procaine Para-aminobenzoic acid Para-aminosalicylic acid Sulfonamides Carbutamide Hydrochlorothiazide

Conclusions

Figure 1. Wheals measuring 0.5×0.5 to 1×1 cm over the left temporal area close to the hair line and right upper eyelid.

CU is underdiagnosed and more awareness is needed. Appropriate protection guidelines can be helpful to reduce the incidence of CU in high-risk groups, such as hairdressers and hair color users. Moreover, the fact that components of the hair color can cause CU and even anaphylaxis should be mentioned on the carton/box of hair color so that the user is aware of the possible complication.

References 1 Davari P, Maibach HI. Contact urticaria to cosmetic and industrial dyes. Clin Exp Dermatol. 2010;36:1–5.

2 Maibach HI, Johnson HL. Contact urticaria syndrome.

Contact urticaria to diethyltoluamide (immediate-type hypersensitivity). Arch Dermatol. 1975;111:726–730.

3 Von Krogh G, Maibach HI. The contact urticaria syndrome––an updated review. J Am Acad Dermatol.

1981;5:328–342.

4 Gimenez-Arnau A, Maurer M, De La Cuadra J, Maibach H. Immediate contact skin reactions, an update of Contact Urticaria, Contact Urticaria Syndrome and Protein Contact Dermatitis––”A Never Ending Story”. Eur J Dermatol. 2010;20:552–562.

5 Dogra A, Minocha YC, Kaur S. Adverse reactions to cosmetics. Indian J Dermatol Venereol Leprol. 2003;69:165–167.

6 Mavroleon G, Begishvili B, Frew AJ. Anaphylaxis to hair dye: a case report. Clin Exp Allergy. 1998;28:121–122.

7 Rietschel RL, Fowler JF. Appendix. In: Rietschel RL, Fowler JF, eds. Fisher’s Contact Dermatitis. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:87.

8 Rietschel RL, Fowler JF. Specific instructions for patients with common contact allergens. In: Rietschel RL, Fowler JF, eds. Fisher’s Contact Dermatitis. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:723–733.

Figure 2. Erythematous wheals over the left temporal area and left upper eyelid.

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Volume 14 • Issue 5

CASE STUDY

Unna Nevus: Early Presentation in a 10-Year-Old Girl Kingshuk Chatterjee, MNAMS, MRCPS (Glasgow);1 Sankha Koley, MD;2 Bhushan Madke, MD3 A 10-year-old girl presented with three asymptomatic raised lesions over the dorsal aspect of her left index finger present for the past 7 years. On examination, there were three skin-colored nodules overlying the middle and distal phalanx of her left index finger, without any attachment to the underlying structures (Figure 1) The nodule over the distal phalanx was the largest with a cobblestone-like surface. All the nodules were firm to touch. Cutaneous, mucosa, hair, nails, and systemic examinations were within normal limits. The two smaller nodules were excised under local anesthesia and sent for histopathologic examination. Histologic study from one of the representative lesion showed type B nevus cells (lymphocytoid), located in the expanded papillary dermis (Figures 2 and 3). (SKINmed. 2016;14:392–393)

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istogenesis of melanocytic nevi has always been difficult to understand. The classic concept classifies melanocytic nevi into junctional, compound, and dermal types, representing different stages of a pathogenic sequence (“Abtropfung”). It has been quashed under the view that such nomenclature is often misleading, as most junctional nevi show a few dermal melanocytic cells, and complete lack of melanocytic proliferation is only encountered in a few dermal nevi.1 A simple classification was suggested in 1990 by Ackerman and Magana-García to commemorate “those who first recognized or popularized them.”2 This concept classifies nevi into four types: Unna, Miescher, Spitz, and Clark.2 This classification describes the overall histologic pattern (“silhouette”) of melanocytic nevi to allow an easier clinical correlation, compared with the pseudoaccurate distinction between junctional, compound, and dermal nevi. The flat nevi (Clark type) mainly shows nevus cells at the dermoepidermal junction and in the papillary dermis. In exophytic nevi (Unna type), aggregates of melanocytic cells occupy the papillary dermis, whereas nevus cells extending to the deep reticular dermis characterizes endophytic nevi (Miescher type). The terms “exophytic” and “endophytic” describe the histologic arrangement of the melanocytic cell aggregates rather than the clinical appearance. Spitz nevi forms a separate category.3 Ackerman and Magna-García described Unna nevus as an ‘‘exophytic soft nevus, usually confined to a markedly thickened

papillary dermis. As a rule, the reticular dermis is unaffected.

The sine qua non for diagnosis of Unna nevus is exophytic character.” It is most commonly located over the trunk, neck, scalp, and extremities. A study showed the peak incidence of Unna nevus in the eighth decade of life, with no sexual preponderance3; however, our case presented in the early part of life. Clinically, the lesion was exophytic and histopathologically conformed to the diagnosis of Unna nevus. Histopathologic configurations of Unna nevus have been classified as papillomatous, horizontal, semispherical, and verrucous.2,4 Unna nevi appear as exophytic,

Figure 1. Skin-colored exophytic nodules over the left index finger.

From the Department of Dermatology, Calcutta School of Tropical Medicine, West Bengal, India;1 the Department of Dermatology, Bankura Sammilani Medical College, West Bengal, India;2 and the Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and ABVR Hospital, Sawangi (Meghe), Wardha, Maharashtra, India3 Address for Correspondence: Kingshuk Chatterjee, DNB, MNAMS, FAAD, MRCPS (Glasgow), Parnasi, Tikorhat, Ambagan, Lakurdi, Burdwan 713102, West Bengal, India • E-mail: klose2kingonly@gmail.com

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Figure 2. Hyperkeratosis, papillomatosis, and clusters of nevus cells in the papillary dermis (hematoxylin and eosin stain, original magnification ×10).

Figure 3. Type B (lymphocytoid) nevus cells (hematoxylin and eosin stain, original magnification ×40).

pedunculated, or sessile dark brown lesions, measuring a few millimeters, with soft texture and smooth surface.5

References

The true incidence of the Unna nevus has not been adequately studied, as the lesions are innocuous in appearance and are not frequently biopsied. In most cases, the diagnosis of the Unna nevus is made on a histologic basis. One must be aware that the term exophytic describes the histologic arrangement of the melanocytic cell aggregates rather than the clinical appearance.

Some dermatopatholgists have considered the Unna nevus to be a tardive congenital melanocytic nevus.6 On dermatoscopic examination, the Unna nevus shows a “globular-cobblestone structure less brown” pattern.7 Conclusions Due to its innocuous nature, the Unna nevus is an infrequently reported entity. Until the present, this disorder has been mostly reported in adults. This is a novel case of this uncommon entity in a young girl.

1 Unna PG. Naevi und Naevocarcinome. Berliner Klin Wochenschr. 1893;30:14–16.

2 Ackerman AB, Magana-García M. Naming acquired melanocytic nevi. Unna’s, Miecher’s, Spitz’s, Clark’s. Am J Dematopathol. 1990;12:193–209.

3 Witt C, Krengel S. Clinical and epidemiological aspects of subtypes of melanocytic nevi (Flat nevi, Miescher nevi, Unna nevi). Dermatol Online J. 2010;16:1–6.

4 Yus ES, Cerro MD, Simón RS, Herrera M, Rueda M. Unna’s and Miescher’s nevi: two different types of intradermal nevus: hypothesis concerning their histogenesis.

Am J Dermatopathol. 2007;29:141–151.

5 Noto G. On the clinical significance of cutaneous melanoma’s precursors. Indian Dermatol Online J. 2012;3:83– 88.

6 Sowa J, Kobayashi H, Ishii M, Kimura T. Histopathologic findings in Unna’s nevus suggest it is a tardive congenital nevus. Am J Dermatopathol. 2008;30:561–566.

7 Zalaudek I, Catricalà C, Moscarella E, Argenziano G. What dermoscopy tells us about nevogenesis. J Dermatol. 2011;38:16–24.

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September/October 2016

Volume 14 • Issue 5

CASE STUDY

Focal Epithelial Hyperplasia in Adult Patients With HIV Infection: Clearance With Topical Imiquimod Silvia Méndez-Flores, MD;1 Lilly Esquivel-Pedraza, DDS, MSc;1 Amparo Hernández-Salazar, MD;1 Yann Charli-Joseph, MD;1 Marcela Saeb-Lima, MD2

Case 1 A 41-year-old man with human immunodeficiency virus (HIV) 1 diagnosed 16 years prior to his consultation was referred for an 8-month history of multiple painless lumps in his mouth. He had A2 status (CD4 cell count of 273 cells/mm3 and viral load of 43,000 copies/μL) and was taking treatment with lamivudine/zidovudine (combivir) and efavirenz. Physical examination showed multiple small mucosal-colored and lobulated papulonodules located in the palate and lower gingiva and a whitish verrucous plaque on the lower labial mucosa (Figure 1a). The lesions were diagnosed clinically as focal epithelial hyperplasia (FEH) and further confirmed by classical histopathological findings (Figure 1b). He had previously received unspecified treatment; thus, topical 5% imiquimod cream was initiated every night. Mild erosion and ulceration developed in the upper labial mucosa, which were managed with lubrication (petrolatum ointment).

After 2 weeks, all of the small lesions disappeared and the largest plaque resolved 1 week later (Figure 1c). A small residual mass in the area of biopsy, suggesting a scar, remained on the lower lip. The area was removed surgically and corresponded to fibrosis histologically, with no evidence of human papillomavirus (HPV) infection. CD4 cell count (694 cells/mm3) and viral load (<40 copies/μL) did not show remarkable changes after imiquimod administration. No serious side effects were observed and the patient has remained free of disease after 1 year of follow-up. (SKINmed. 2016;14:395–397)

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ase 2 A 72-year-old man was referred for an oral medicine consultation. An HIV diagnosis was established a year prior to the valuation and the following were noted: C3 stage (history of cryptococcosis, salmonellosis, and cytomegalovirus infection; last viral load values <40 copies/μL; CD4 cell count: 153 cells/mm3) and taking lamivudine, efavirenz, and abacavir antiretroviral treatment. On oral examination, multiple small papules affecting the upper labial mucosa, tongue, and left buccal mucosa (Figure 2a) were detected and clinically diagnosed as FEH. A biopsy was performed on the largest lesion in the labial mucosa, which microscopically confirmed the diagnosis. Topical 5% imiquimod was administered by night and resolution of the lesions was observed after 2 months (Figure 2b).

Discussion FEH, or Heck’s disease, is an infrequent and benign disorder characterized by the presence of multiple oral papular lesions

due to secondary infection mainly by serotypes 13 and 32 of HPV.1 It occurs primarily in children where lesions tend to be widely distributed through the labial, lingual, and buccal mucosae. In immunocompetent hosts, lesions may resolve spontaneously without treatment after a variable period of time, recur on numerous occasions, or persist indefinitely.2 FEH lesions are frequently asymptomatic, but may occasionally cause interference with function of the mouth and produce a significant reduction in quality of life. Its incidence and biological behavior in immunocompromised hosts and particularly those affected by HIV have not been fully clarified.3 Immune status has been proposed in the susceptibility of FEH acquisition. While immunosuppression secondary to HIV infection creates a suitable environment for viral opportunism, the occurrence of FEH in HIV-seropositive patients has rarely been published and objective findings regarding such an association are lacking. Some authors, however, favor the interpretation of

From the Departments of Dermatology1 and Pathology,2 Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico City, Mexico Address for Correspondence: Silvia Méndez-Flores, MD, Vasco de Quiroga No. 15, Col. Secc. XVI, Tlalpan 14000, México D.F. • E-mail: silvia_mendezflores@live.com.mx

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A

A

B

B Figure 2. Multiple small papules scattered on the left buccal mucosa, corresponding to focal epithelial hyperplasia (A). Clinical image of left buccal mucosa after imiquimod therapy (B).

C Figure 1. Multiple papules affecting the mucosa and vermilion border of the lower lip (A). The section shows parakeratosis and epithelial hyperplasia accompanied by superficial koilocytes and occasional keratinocytes with clear cytoplasm (arrow) (B). Complete remission of the whitish plaque on the lower lip (C).

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FEH as an oral manifestation of HIV-related opportunistic infections, report a higher recurrence rate and even a greater risk of malignant transformation of HPV-related lesions in this subset of patients, and therefore propose the mandatory treatment of FEH lesions.3 Paradoxically, others have reported that the introduction of highly active antiretroviral therapy is associated with increased frequency of FEH.4

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Various therapeutic modalities, all with limited success and several potential adverse effects, have been used in the treatment of FEH. Consequently, there is no gold standard for treatment and current options include ablative techniques (surgery, cryotherapy, laser, electrocautery), toxins (podophyllum resins), systemic and intralesional interferon, and retinoic acid. Results are inconsistent, however, and multiple side effects preclude their utility.2 Imiquimod, a topic nucleoside analogue of the imidazoquinolone family, has considerable efficacy on viral lesions as well as superficial skin tumors, albeit lacking direct antiviral activity. Its biological effects are mediated primarily through agonism on toll-like receptors and consequently by the induction of proinflammatory cytokines that upregulate T-helper cellular immune response. In addition, pro-apoptotic properties have been demonstrated.5 Imiquimod was approved by the Food and Drug Administration for the treatment of external genital and perianal warts in immunocompetent individuals.6 Only six cases of immunocompetent children with FEH responsive to imiquimod have been published.7–9 No reports on the use of imiquimod for the treatment of confirmed FEH involving adults, particularly those who are HIV-seropositive, exist in the medical literature.

Conclusions We present two cases to contribute to the scant literature on the association of FEH and HIV and demonstrate the clinical value of topical 5% imiquimod for the simple, effective, and nontraumatic treatment of FEH in HIV-seropositive patients. Further studies with a larger number of patients will be necessary to address the true clearance rate and possibility of recurrences with topical 5% imiquimod treatment.

References

Valuable information from our report was the clinical and histological confirmation of the disappearance of the chronic recalcitrant FEH lesions in our patients and that no significant changes were observed in CD4 lymphocyte or viral load values after topical imiquimod therapy.

Patients with HIV have unpredictable local immune responses even in the setting of profound systemic immunosuppression, and, because of the biological effects of imiquimod, it would be assumed that a partially functioning immune system would be required to have a clinical benefit when using this treatment for viral or tumoral lesions.5 Recent studies suggest, however, that the ability to produce tumor necrosis factor α and interleukin 6 following stimulation with imiquimod in HIV-seropositive patients with impaired lymphocytic reconstitution is not affected.3 Similarly, in a recent open-label clinical trial,10 clearance of anogenital warts treated with imiquimod in HIV-infected patients was not influenced by CD4 cell counts or HIV viral load.

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1 Cohen PR, Hebert AA, Adler-Storthz K. Focal epithelial hyperplasia: Heck disease. Pediatr Dermatol.

1993;10:245–251.

2 Bassioukas K, Danielides V, Georgiou I, et al. Oral focal epithelial hyperplasia. Eur J Dermatol. 2000;10:395– 397.

3 Viraben R, Aquilina C, Brousset P, Bazex J. Focal epithelial hyperplasia (Heck disease) associated with AIDS. Dermatology. 1996;193:261–262.

4 Feller L, Khammissa RA, Wood NH, Malema V, Meyerov R, Lemmer J. Focal epithelial hyperplasia (Heck disease) related to highly active antiretroviral therapy in an HIVseropositive child. A report of a case, and a review of the literature. SADJ. 2010;65:172–175.

5 Dockrell DH, Kinghorn GR. Imiquimod and resiquimod as novel immunomodulators. J Antimicrob Chemother.

2001;48:751–755.

6 Oster-Schmidt C. [Imiquimod—a substance with a broad working spectrum]. J Dtsch Dermatol Ges. 2004;2:821– 822.

7 Maschke J, Brauns TC, Goos M. Imiquimod for the topical treatment of focal epithelial hyperplasia (Heck disease) in a child. J Dtsch Dermatol Ges. 2004;2:848–850.

8 Yasar S, Mansur AT, Serdar ZA, Goktay F, Aslan C. Treatment of focal epithelial hyperplasia with topical imiquimod: report of three cases. Pediatr Dermatol.

2009;26:465–468.

9 Ponte P, Serrão V, Fiadeiro T. Focal epithelial hyperplasia (Heck’s Disease) in two siblings: response to treatment with imiquimod 5% cream. Eur J Dermatol. 2010;20:248– 249.

10 Harwood CA, Perrett CM, Brown VL, et al. Imiquimod cream 5% for recalcitrant cutaneous warts in immunosuppressed individuals. Br J Dermatol. 2005;152:122– 129.

Focal Epithelial Hyperplasia in Adult Patients

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IMPORTANT INFORMATION ABOUT September/October 2016

SOOLANTRA®

Volume 14 • Issue 5

(ivermectin) Cream, 1% correspondence Snejina Vassileva, MD, PhD, SectionCream Editor SOOLANTRA is supplied in a child-resistant capped tube.

BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert.

• To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing.

Consequences

• To MD close, gently press down on the child resistant cap and twist Alan S. Boyd, clockwise.

WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea.

To the Editor:

WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM?

SOOLANTRA I WHO sit onISthe board ofCREAM HealthFOR? Talents International (HTI), a faithSOOLANTRA Cream isheadquartered indicated for people inflammatory lesions based organization in with Searcy, Arkansas.

HTI deof rosacea. It is not known if SOOLANTRA Cream is safe and effective livers health care to underserved areas in Central America, prifor children. Advise your patients to not use SOOLANTRA Cream for a marily through a hospital it constructed in western Guatemala. condition for which it was not prescribed and remind them to not give ItSOOLANTRA also sends Cream out medical/dental during to other people, teams even if they havethe the year, same including symptoms the attend annually in Nicaragua. The clinics are held in as itone mayIharm them. churches, one day per individual congregation. The one most WHAT SHOULD I ASK PRESCRIBING frequently visited is MY in aPATIENTS barrio ofBEFORE Managua, Nicaragua’s capital, SOOLANTRA CREAM? named Rene Polanco. Since the inception of this annual trip in Before you prescribe SOOLANTRA Cream, ask your patients if they: the mid 1990s, a clinic day has been held there nearly every year.

• have that any other medical conditions.

Given most of the core group of physicians, nurses, and • are pregnant or planning to become is not known pharmacists making this trip havepregnant. done soIt for over 15 ifyears, we SOOLANTRA Cream can harm an unborn baby. have become a known entity in Rene Polanco, typically treating • are breastfeeding or plan to breastfeed.

It is not known if patients we have seen several times previously.

SOOLANTRA Cream passes into breast milk and if it can harm a baby.

CASE PRESENTATION

WHAT ARE THE MOST COMMON SIDE EFFECTS OF

About 8 yearsCREAM? ago, a young couple from the countryside 3 hours SOOLANTRA The most commonly side daughter, effects when using SOOLANTRA away brought their reported 7-year-old “Mary,” to be seen.Cream How include skin burning sensation and skin irritation.

Remind your patients to they had come to learn of our visit was unclear, but this family tell you if they have any side effect that bothers them or that does not go unit caught our attention as it deviated from the norm. Men rarely away. These are not all of the possible side effects of SOOLANTRA Cream. accompany their wives children to the clinic. In addition, we For more information, see and the full Prescribing Information. almost never see patients from further away than a mile or two at Youmost. are encouraged to report side around effects ofManagua prescriptionisdrugs to the Travel from the negative rural areas neither the FDA at www.fda.gov/medwatch You may also cheap and convenient, nor safe,orsocall we1-800-FDA-1088. knew there was something contact GALDERMA LABORATORIES, L.P. AT 1-866-735-4137. going on that was out of the ordinary. We were correct. Watching the little girl playing in the courtyard with the other children, she HOW SHOULD PATIENTS USE SOOLANTRA CREAM? looked like every other 7-year-old, but only when pediatrician • SOOLANTRA Cream is for use on the face andthe should not be usedbein ganthetoeyes, examine her, it became clear why this family had made the mouth, or vagina. effort to have her evaluated; she had the genitalia of a 25-year-old • SOOLANTRA Cream should be applied to the affected areas of the face man.

Evaluations later would disclose oncePseudohermaphroditism. a day. that she had 21-hydroxylase deficiency.

APPLYING SOOLANTRA CREAM:

There was nothing we could Cream be do should for herbeinapplied our clinic.

• A pea-sized amountthat of SOOLANTRA to eachWe the face (forehead, chin, cheek) is affected. toldarea theof parents we would seenose, whateach could bethat done and contact Avoid contact with the lips and eyes.

them when a plan was in place. Sex reassignment surgery was Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer and is unavailable inacid Nicaragua, anddimethicone, rather thanedetate spend time typestill B, cetyl alcohol, citric monohydrate, pursuing in anyisopropyl surrounding country, the powers that be at disodium,itglycerin, palmitate, methylparaben, oleyl alcohol, phenoxyethanol, cetostearyl propyleneStates glycol,and have HTI decided it polyoxyl best to 20 bring her toether, the United propylparaben, purified water, sodium hydroxide, her sorbitan her treated here.

In first world countries, casemonostearate, would have and stearyl alcohol. been unlikely to progress to the degree it had, and there would have been sufficient time to line up the specialists required to WHERE SHOULD I GO FOR MORE INFORMATION ABOUT address this situation.

SOOLANTRA CREAM? After all, it would not be considered an • This Brief Summary summarizes the most important information emergent condition. about SOOLANTRA Cream. For full Prescribing Information and PatientNicaragua, Information please see the package insert. bit an emergency. rural however, this was every

In Go to www.soolantra.com or call had 1-866-735-4137 To• date, the mother and father been able to keep the presence of this problem from everyone in their village, including their relatives. Were word to leak out, the girl would almost cerTrademarks are the property of their respective owners. tainly have been killed, likely along with her parents under the GALDERMA LABORATORIES, L.P.,orFort Worth, Texasequally 76177 USA assumption that witchcraft something diabolical was taking place. This girl needed her surgery as quickly as we could Revised: December 2014 humanly make it happen.

Recommendations HTI sends about 14 teams annually to Guatemala, El Salvador, and Nicaragua, and it is not unheard of for one of those teams to encounter a patient who cannot be cared for appropriately in Central America and needs to be brought to the United States, usually for some sort of surgical procedure. When these cases arise, the typical response is for the board members to pool their money and make it happen. Because most of the board memReferences: 1. Stein Gold L, Kircik L, Fowler J, et al; bers are physicians, dentists, and lawyers, procuring sufficient Ivermectin Phase III Study Group. Efficacy and safety cash, donated supplies and gratis surgery usually is not an insurof ivermectin 1% cream in treatment of papulopustular mountable thisrandomized, girl’s case, she double-blind, and her mother would rosacea: problem. results ofIntwo vehicle-controlled studies.

J Drugs have to be brought topivotal the United States, housedDermatol. and cared for, 2014;13(3):316-323.

2.

Data on file.

Galderma and her mother educated about what she would need long term Laboratories, L.P. 3. Taieb A, Ortonne JP, Ruzicka T, toetensure the healthPhase and safety of herGroup. daughter and husband. al; Ivermectin III Study Superiority of Not a small undertaking but metronidazole one that proceeded with all due ivermectin 1% cream over 0.75% cream in treating inflammatory lesions of rosacea: a randomized, speed nonetheless. investigator-blinded trial. Br J Dermatol. In press.

From the Departments of Medicine (Dermatology) and Pathology, Vanderbilt University School of Medicine, Nashville, TN Address for Correspondence: Alanof S. their Boyd,respective MD, 719 Thompson All trademarks are the property owners. Lane, Suite 26300, Nashville, TN 3724 ©2015 Galderma Laboratories, L.P. • E-mail: alan.boyd@Vanderbilt.edu Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 IVM-143 Printed in USA 02/15

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September/October 2016

Correspondence

A HAPPY ENDING This story has a happy ending. Things went off without a hitch, and the last word I received was that this young family was back in their village and doing well. The girl is receiving donated hormone replacement medication, growing up as the female she was reared as from birth.

When the presidential election of 2012 was over, I, and the other members of HTI’s board, realized changes were going to take place. The Bush tax reductions would be allowed to expire, and additional taxation to fund the Affordable Care Act would be implemented. To wit, we would be sending more money into Washington than had previously been the case. It has been said that “elections have consequences,” and this one was no different.

Although the societal benefits of this increased taxation can be debated, what is unassailable is that the board members of HTI now have less discretionary income and, with it, our ability to fund efforts such as the one for “Mary” has been jeopardized.

There is little doubt that those of us working with HTI will continue to encounter patients in Central America needing the specialized health care resources of the United States, and if tax relief is not forthcoming or if additional taxation is levied, we face the inevitability of having to tell someone in the near or distant future that we’re sorry. We can’t help them. In the final analysis, the people working with HTI and other groups like them are their only real hope. Nothing can or will be done for them in their own countries.

Much has been said and written about high-income families, but little of it has focused on the consequences of this group of citizens having less disposable income to fund charitable works both here and abroad. As our nation gears up for the elections this coming fall and you decide who will get your vote and/or money, I would ask you to keep in mind “Mary’s” story. Fiscal policy as set forth in Washington, DC, has real consequences that impact human lives, not all of whom happen to live in the United States.

Historical Diagnosis and treatment

SKINmed. 2016;14:399–400

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(Continued from page 378)

Consequences

FINACEAÂŽ

(azelaic acid) Foam, 15% for topical use

For Topical Use Onlyâ&#x20AC;&#x201C;Not for Oral, Ophthalmic or Intravaginal Use Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Finacea (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea.

5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

5.2 Eye and Mucous Membranes Irritation Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists.

5.3 Flammability The propellant in Finacea Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the prescribing information: t )ZQPQJHNFOUBUJPO [see Warnings and Precautions (5.1)]. t Eye and Mucous Membranes Irritation [see Warnings and Precautions (5.2)].

6.1 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.

Finacea Foam was evaluated for the treatment of papulopustular rosacea in two multicenter, randomized, double-blind, vehicle-controlled, 12-week clinical trials involving a total of 1362 (Finacea Foam, 15%: 681; vehicle: 681) subjects. Overall, 95.7% of subjects were White, 73.4% were female, and the mean age was 50.6 years.

Table 1: Adverse Reactions Occurring in â&#x2030;Ľ 0.5% of Subjects Treated with Finacea Foam Compared with Subjects Treated with Vehicle System/Organ Class Preferred

Finacea Foam, 15% (N=681) n (%)

Vehicle (N=681) n (%)

General disorders and application site conditions Application site pain* Application site pruritus Application site dryness Application site erythema

42 (6.2%) 17 (2.5%) 5 (0.7%) 5 (0.7%)

10 (1.5%) 2 (0.3%) 5 (0.7%) 6 (0.9%)

* â&#x20AC;&#x153;Application site painâ&#x20AC;? is a term used to describe disagreeable skin sensations, including burning, stinging, paraesthesia and tenderness.

6.2 Post-Marketing Experience )ZQFSTFOTJUJWJUZ SBTI BOE XPSTFOJOH PG BTUINB IBWF CFFO SFQPSUFE GSPN the postmarketing experience of azelaic acid-containing formulations.

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.

Local Tolerability Studies In a 21-day cumulative irritation study under occlusive conditions, mildto-moderate irritation was observed for azelaic acid pre-foam emulsion. In B IVNBO SFQFBU JOTVMU QBUDI UFTU )3*15 TUVEZ OP TFOTJUJ[BUJPO QPUFOUJBM was observed for azelaic acid pre-foam emulsion.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women.

Therefore, Finacea Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% foam. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 UJNFT UIF NBYJNVN SFDPNNFOEFE IVNBO EPTF .3)% CBTFE PO CPEZ surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times UIF .3)% CBTFE PO #4" BOE DZOPNPMHVT NPOLFZT HJWFO NH LH EBZ UJNFT UIF .3)% CBTFE PO #4" B[FMBJD BDJE /P UFSBUPHFOJD FGGFDUT were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys.

An oral peri- and post-natal developmental study was conducted in rats.

Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was PCTFSWFE JO SBUT BU BO PSBM EPTF PG NH LH EBZ UJNFT UIF .3)% based on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/ LH EBZ BOE UJNFT UIF .3)% CBTFE PO #4" /P FGGFDUT PO TFYVBM maturation of the fetuses were noted in this study.

8.3 Nursing Mothers It is not known if azelaic acid is secreted into human milk in vivo /P XFMM controlled studies of topically administered azelaic acid in nursing women BSF BWBJMBCMF /FWFSUIFMFTT UIF EFDJTJPO UP EJTDPOUJOVF OVSTJOH PS UP discontinue the drug should take into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and efficacy of Finacea Foam in children below the age of 18 years have not been established.

8.5 Geriatric Use Of the total number of subjects in clinical studies of Finacea Foam, 18.8 QFSDFOU XFSF BOE PWFS XIJMF QFSDFOU XFSF BOE PWFS /P PWFSBMM 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.

17 PATIENT COUNSELING INFORMATION Inform patients using Finacea Foam of the following information and instructions: t 'PS FYUFSOBM VTF POMZ t $MFBOTF BGGFDUFE BSFB T XJUI B WFSZ NJME TPBQ PS B TPBQMFTT DMFBOTJOH lotion and pat dry with a soft towel. t 4IBLF XFMM CFGPSF VTF t "WPJE VTF PG BMDPIPMJD DMFBOTFST UJODUVSFT BOE BTUSJOHFOUT BCSBTJWFT BOE peeling agents. t "WPJE DPOUBDU XJUI UIF FZFT NPVUI BOE PUIFS NVDPVT NFNCSBOFT *G Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye irritation persists. t *G BMMFSHJD SFBDUJPOT PDDVS EJTDPOUJOVF VTF BOE DPOTVMU ZPVS QIZTJDJBO t 8BTI IBOET JNNFEJBUFMZ GPMMPXJOH BQQMJDBUJPO PG 'JOBDFB 'PBN t $PTNFUJDT NBZ CF BQQMJFE BGUFS UIF BQQMJDBUJPO PG 'JOBDFB 'PBN IBT ESJFE t "WPJE UIF VTF PG PDDMVTJWF ESFTTJOHT BOE XSBQQJOHT t 5P IFMQ NBOBHF SPTBDFB BWPJE BOZ USJHHFST UIBU NBZ QSPWPLF FSZUIFNB flushing, and blushing. These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic beverages. t 5IF QSPQFMMBOU JO 'JOBDFB 'PBN JT nBNNBCMF "WPJE mSF nBNF PS smoking during and immediately following application. t %JTDBSE QSPEVDU XFFLT BGUFS PQFOJOH Š #BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD "MM SJHIUT SFTFSWFE Manufactured for:

#BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD 8IJQQBOZ /+ Manufactured in Switzerland

6798100BS

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

The first and only prescription foam approved by the FDA for the treatment of rosacea In the art of rosacea therapy...

Proven efficacy has another profile with Finacea Foam ®

IMPORTANT SAFETY INFORMATION Warnings and Precautions Skin Reactions: There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Eye and Mucous Membranes Irritation: Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea® Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a healthcare professional if eye irritation persists.

Flammability: The propellant in Finacea® Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120°F (49°C).

Most Common Adverse Reactions In clinical studies, the most frequently observed adverse reactions in ≥ 0.5% of subjects treated with Finacea® Foam included local site pain (6.2%), pruritus (2.5%), dryness (0.7%), and erythema (0.7%).

For Topical Use Only Finacea® Foam is not for oral, ophthalmic or intravaginal use.

Avoid the use of occlusive dressings or wrappings at the application site.

Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents.

Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

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.

For important risk and use information, see the full Prescribing Information at www.finaceafoam.com.

For important risk and use information, see the Brief Summary on the following page.

Discover The Foamulation www.finaceafoam.com

© 2016 Bayer. Whippany, NJ 07981.

Bayer, the Bayer Cross, and Finacea are registered trademarks of Bayer.

All rights reserved. PP-825-US-0518 January 2016