Skinmed - Jan / Feb 2017

Page 1

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

COMMENTARY A New Light on the Dark DNA Damages

Micillo, Lembo, and Monfrecola

ORIGINAL CONTRIBUTIONS Carboxymethyl Cellulose, Trichloroacetic Acid, and Unna Boot for Healing Venous Ulcers: A Comparative Study of Their Efficacy and Socioeconomic Impact Carneiro, Januário, Oliveira, de Oliveira Teixeira, Maciel, Macedo, and Ramos-e-Silva

Toll-Like Receptor 2 and Its Relationship With Streptococcus in Psoriasis

Zhang, Shaver, Neidig, Jones, Cusack, and Allen

Midline Capillary Formation Nuchae and Age Klapman and Batech

REVIEW Tattoos: Very Popular, Not So Innocent

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

African Association for Dermatology

January/February 2017 • Volume 15• Issue 1

January/February 2017CURRICULUM • Volume 15• Issue 1 EDITORIAL CORE The Handheld Mirror in Leprosy: Trophic Skin Ulcers Riyaz and Sehgal Dermatology

Patel, Ring, Bhate, Schwartz, and Lambert

North American Clinical Dermatologic Society

DEPARTMENTS PERILS OF DERMATOPATHOLOGY When Immunohistochemistry Deceives Us: The Pitfalls of CD34 and Factor XIIIa Stains in Dermatofibroma and Dermatofibrosarcoma Protuberans John, Holahan, Singh, Handler, and Lambert

NEW THERAPY UPDATE Ozenoxacin Cream, 1% – Topical Treatment of Impetigo

case studies Keratoacanthoma Centrifugum Marginatum: Response to Acitretin Hawilo, Zaraa, El Euch, Mokni, Boubaker, and Ben Osman

Donovanosis With Bowen Disease Narang, Manhas, and Kumar

White Papules on the Backs of a Middle-Aged Man and His Son Fang, Larsen, and Wilson

BOOK REVIEW History of Allergy Parish

Gupta, Versteeg, and Abramovits

THE HEYMANN FILE Medical Ego Inflation and a Lesson From Mom Heymann

SOCIETY HIGHLIGHTS OF THE 57TH ANNUAL MEETING OF THE NORTH AMERICAN CLINICAL DERMATOLOGIC SOCIETY Greece! Is the Word…: May 21–27, 2016, Thessaloniki and Athens Berger

Hermida and Cabrera

Self Assessment Examination Lambert

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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 January/February 2017 • Volume 15 • Issue 1

EDITORIAL

The Handheld Mirror in Dermatology .......................................................................................................... 11

Viral M. Patel, BS; Christina Ring, BS; Chinmoy Bhate, MD; Robert A. Schwartz, MD, MPH, DSc (Hon); W. Clark Lambert, MD, PhD

COMMENTARy

A New Light on the Dark DNA Damages ...................................................................................................... 13

Raffaella Micillo, MSc; Serena Lembo, MD, PhD; Giuseppe Monfrecola, MD

ORIGINAL CONTRIBUTIONS

Carboxymethyl Cellulose, Trichloroacetic Acid, and Unna Boot for Healing Venous Ulcers: A Comparative Study of Their Efficacy and Socioeconomic Impact .............................................................. 17

Sueli Carneiro, MD, PhD; Virginia Januário, RN, PhD; Maria Leide W. Oliveira, MD, PhD; Maria Luiza de Oliveira Teixeira, RN, PhD; Solange Maciel, MD, PhD; João Carlos Macedo, MD, PhD; Marcia Ramos-e-Silva, MD, PhD

Toll-Like Receptor 2 and Its Relationship With Streptococcus in Psoriasis .................................................. 27

Jing Zhang, MD; Christine Shaver, MD; Lane Neidig, BS; Krister Jones, MD; Carrie A. Cusack, MD; Herbert B. Allen, MD

Midline Capillary Formation Nuchae and Age .............................................................................................. 31

Marvin H. Klapman, MD; Michael Batech, DrPH

REVIEW

Tattoos: Very Popular, Not So Innocent ....................................................................................................... 37

María Daniela Hermida, MD; Hugo Néstor Cabrera, MD

Self Assessment Examination ..................................................................................................................... 43

W. Clark Lambert, MD, PhD

CORE CURRICULUM Virendra N. Sehgal, MD, FNASc, FAMS, Section Editor

Leprosy: Trophic Skin Ulcers ...................................................................................................................... 45

Najeeba Riyaz, MD, FRCP (Glasgow); Virendra N. Sehgal, MD, FNASc, FAMS

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

When Immunohistochemistry Deceives Us: The Pitfalls of CD34 and Factor XIIIa Stains in Dermatofibroma and Dermatofibrosarcoma Protuberans ............................................................................ 53

Ann M. John, BA; Heather H. Holahan, MD; Parmvir Singh, BS; Marc Z. Handler, MD; W. Clark. Lambert, MD, PhD

New Therapy Update

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

Ozenoxacin Cream, 1% – Topical Treatment of Impetigo ............................................................................. 57

Aditya K. Gupta, MD, PhD, FRCPC; Sarah G. Versteeg, MSc; William Abramovits, MD

2


TABLE OF CONTENTS January/February 2017 • Volume 15 • Issue 1

The Heymann File

Warren R. Heymann, MD, Section Editor

Medical Ego Inflation and a Lesson From Mom ............................................................................................ 61

Warren R. Heymann, MD

Society Highlights of the 57th Annual Meeting of the North American Clinical Dermatologic Society

Greece! Is the Word…: May 21–27, 2016, Thessaloniki and Athens ............................................................. 63

Robert S. Berger, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Keratoacanthoma Centrifugum Marginatum: Response to Acitretin ............................................................. 69

Abdulmohti Hawilo, MD; Ines Zaraa, MD; Dalenda El Euch, MD; Mourad Mokni, MD; Samir Boubaker, MD; Amel Ben Osman, MD

Donovanosis With Bowen Disease ............................................................................................................... 73

Tarun Narang, MD; Ashwini Manhas, MD; Bhushan Kumar MD, FRCP (Edin), FRCP (London)

White Papules on the Backs of a Middle-Aged Man and His Son ................................................................. 77

Fiona Fang, MD; Dustin Larsen, BS; Barbara Wilson, MD

BOOK REVIEW

Jennifer L. Parish, MD, Section Editor

History of Allergy ........................................................................................................................................ 80

Lawrence Charles Parish, MD, MD (Hon)

3


January/February 2017

Volume 15 • Issue 1

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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Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League



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


January/February 2017

Volume 15 • Issue 1

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

Anthony A. Gaspari, MD Baltimore, MD

Brian Berman, MD, PhD Miami, FL

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 Richard L. Dobson, MD Mt Pleasant, SC

Michael H. Gold, MD Nashville, TN Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

María Daniela Hermida, MD Buenos Aires, Argentina

Art Papier, MD Rochester, NY

Warren R. Heymann, MD Camden, NJ

Johannes Ring, MD, DPhil Munich, Germany

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Roy S. Rogers III, MD Rochester, MN

Camila K. Janniger, MD Englewood, NJ

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI

SKINmed. 2017;15:9

9

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

© 2017 Pulse Marketing & Communications, LLC



January/February 2017

Volume 15 • Issue 1

Editorial

The Handheld Mirror in Dermatology Viral M. Patel, BS; Christina Ring, BS; Chinmoy Bhate, MD; Robert A. Schwartz, MD, MPH, DSc (Hon); W. Clark Lambert, MD, PhD “The doctor should be opaque to his patients and, like a mirror, should show them nothing but what is shown to him.”—Sigmund Freud

T

he most primitive mirrors were pools of still water gathered in a vessel, in which a person could view their reflection. Around 6000 BCE, mirrors were created from naturally occurring volcanic glass, a product of rapidly cooled magma.1 After 2000 BCE, handheld mirrors were inlaid with precious metals, such as copper, silver, and gold, making them a luxurious household accessory and decorative item for the wealthy. Altered manufacturing processes in the 19th century allowed for affordable handheld mirrors, which became a commonly used personal item.1 Today, the utility of the handheld mirror extends beyond personal use, with important applications in the field of medicine, especially dermatology.

Figure. Morning reflection: ‘The Sanatory Condition of the City’, Punch, London. 29 August 1846, p. 87. From 19th Century UK Periodicals Digital Database. Courtesy of Diana Garrisi, PhD, London, UK.

Purposes Handheld mirrors serve several purposes but are particularly useful as an aid for patient-physician communication and patient education. Prior to performing a skin biopsy or surgery, it may be prudent to have the patient confirm the site of the procedure with a handheld mirror, in an effort to avoid poor outcomes and potential litigation.2 Mirrors may be used to inform the patient regarding the extent of surgery, the potential size of the resulting defect, and the complexity of the repair. For patients, this practice reduces anxiety, provides an opportunity to ask questions, and sets appropriate expectations. Postoperatively, mirrors can be used to show the final result of surgery and facilitate woundcare instructions. In cosmetic and procedural dermatology, handheld mirrors have emerged as an important tool (Figure). Prior to a cosmetic procedure, patients can use the mirror as an aid to identify specific areas of concern and discuss their expectations. In addition, physicians can use the mirror throughout the procedure to receive direct feedback from patients and adjust treatment accordingly.

lesions to monitor, and changes that should prompt a follow-up visit. Many patients use a full-length or handheld mirror when conducting a skin self-examination, which is especially useful for visualization of the back.3 In addition, handheld mirrors are also helpful in demonstrating the correct application of topical medications. Conclusions Handheld mirrors are inexpensive and should be readily available in the clinic. They offer numerous benefits for both the patient and the physician, such as facilitating communication, improving patient education, and managing expectations to engage patients more fully in their care. References

Skin cancer screening represents yet another important use of handheld mirrors. Physicians may use mirrors to educate patients about the location and morphology of their moles, which

1 Melchior-Bonnet S, Jewett K. The Mirror: A History. New York: Routledge; 2002. 2 Al-Rawi H, Varma S. The use of a hand-held mirror to reduce litigation and improve communication in dermatological surgery. Br J Dermatol. 2012;167:446-447. 3 Coups EJ, Manne SL, Stapleton JL, et al. Skin self-examination behaviors among individuals diagnosed with melanoma. Melanoma Res. 2016;26:71-76.

From the Departments of Dermatology and Pathology, Rutgers – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers – New Jersey Medical School, 185 South Orange Avenue, MSB H-576, Newark, NJ 07103-2757 • E-mail: lamberwc@njms.rutgers.edu

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January/February 2017

Volume 15 • Issue 1

Commentary

A New Light on the Dark DNA Damages Raffaella Micillo, MSc;1 Serena Lembo, MD, PhD;2 Giuseppe Monfrecola, MD1

E

xcessive UV exposure may be associated with a wide range of deleterious effects, including the acceleration of photoaging, which may promote the development or exacerbation of multiple inflammatory skin diseases and cause mutations, leading to skin cancer. Both UV-A (320–400 nm) and UV-B (290–320 nm) radiation may harm DNA through multiple mechanisms, resulting in different patterns of damage.

The main injury caused by UV-B is the production of several types of lesions through formation of pyrimidines dimers, particularly cyclobutane pyrimidine dimers (CPDs): the carboncarbon double bonds of two adjacent pyrimidine react, via a photocycloadditon reaction, forming a cyclobutane ring.1 The two pyrimidine units involved in the cycloaddition are forced close to each other with consequent alteration of DNA structure. Dimers may be repaired by the nucleotide excision repair mechanism, but unrepaired dimers can accumulate and exert their mutagenic potential, ultimately leading to skin cancer initiation.2 CPDs cause pyrimidine-to-pyrimidine mutations, also referred to as “UV signature mutations” at sites of adjacent pyrimidines. Among them, cytosine (C)-to-thymine (T) substitutions are typically found in human melanomas.3 UV-A is commonly thought to damage DNA mainly by producing reactive singlet oxygen that interacts with guanine moieties, generating oxidized products such as 8-oxo-7,8-dihydroguanine. Less specific DNA damages are also promoted by UV-A through the formation of hydroxyl radicals. Interestingly, UV-A1 radiation (340–400 nm) is also able to induce a genotoxic effect generating CPDs, regarded as the typical “UV-B signature.”4 While CPD production induced by UV-B is associated with the (6-4) pyrimidone photoproducts (6-4PPs), UV-A1 induces thyminecontaining dimers, without 6-4PPs.4,5

CPDs production continues in melanocytes after UV exposure ends and requires melanin. Examination of DNA damage in murine skin shows that CPD production is induced in black and albino mice, mainly by UV-B radiation, while UV-A produces CPDs less efficiently, suggesting the existence of two different mechanisms for UV-induced melanoma.6 UV-B creates CPDs almost immediately, damaging DNA directly. This pathway is independent from melanin, which only plays a protective role by absorbing UV-B radiation. The mechanism of CPD formation by UV-A has not been fully elucidated, but the observation that UV-A–irradiated albino mice do not develop melanoma, compared with black or red mice, suggests that this mechanism depends on melanin. Of great relevance to this issue are the results of a recent study that provide evidence for a new mechanism of CPD production in the dark induced by chemiexcitation7 (Figure). Chemiexcitation is the generation of electronically excited molecules by chemical reactions, where it may have a broad importance in biology.8,9 In the past, chemiexcitation was thought to occur in bacteria and lower animals (eg, the flicker in a firefly), but the study by Premi and colleagues7 shows, for the first time, that it has great importance in mammals as well. This kind of reaction is involved in CPD generation in the dark, with melanin being an active participant in the chemical process that leads to this type of DNA lesion. Murine and human individuals with pigmented melanocytes (but not albino ones) can generate CPDs even hours after UV exposure, but this dark production is largely masked by the DNA repair mechanism. Mass spectrometry analysis shows that

From the Section of Dermatology, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy1 and Department of Medicine, Surgery and Dentistry, University of Salerno, Scuola Medica Salernitana, Baronissi, Salerno, Italy2 Address for Correspondence: Raffaella Micillo, MSc, Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples “Federico II,” Via Pansini 5, I-80131, Naples, Italy • E-mail: raffaella.micillo@unina.it

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COMMENTARY

Figure. The bright and the dark pathways of cyclobutane pyrimidine dimers (CPDs) production. ONOO– indicates peroxynitrite.

UV-A direct absorption mostly produces thymine-containing dimers, while dark CPDs include a higher number of cytosinecontaining dimers. PROPOSED MECHANISM: MELANIN, SUPEROXIDE, AND NITRIC OXIDE CREATE HIGH-ENERGY TRIPLET-STATE MOIETIES Investigating the mechanism of dimers formation, superoxide and nitric oxide were shown to play an essential role. Cellular superoxide is mainly generated by the superoxide-generating enzyme NADPH oxidase, while nitric oxide can be generated by induced nitric oxide synthase. Incubating melanocytes with the NADPH oxidase inhibitor VAS2870 or induced nitric oxide synthase inhibitor aminoguanidine, the dark CPD production after UV-A is suppressed, suggesting that these two radicals are needed for dimer formation.7 Superoxide and nitric oxide radicals can react together to give peroxynitrite (ONOO–),8–10 a powerful oxidant able to create CPDs in the absence of light. This generates a dioxetane that undergoes thermolysis, leading to two carbonyls, one of which is in the high-energy triplet state11 and is capable of transferring its energy to DNA bases with consequent photocycloadditon reaction and dimer generation. In addition, 3-nitrotyrosine assay shows that melanin-containing cells can generate ONOO–, even in the absence of UV exposure. UV exposure increases its production, while evidence for the excited triplet state comes from ultraweak blue or green luminescence measurements (400–500 nm).9 InSKINmed. 2017;15:13–15

cubating UV-A–irradiated melanized melanocytes with sodium 9,10-dibromoanthracene-2-sulfonate, a triplet energy acceptor probe, chemiluminescence is observed for several hours after irradiation, suggesting ongoing generation triplet-state species. This production is inhibited by ethyl sorbate, a triplet-state quencher. EXCITED-STATE MELANIN: A POSSIBLE MOLECULAR VECTOR Melanin reaction with ONOO– and subsequent degradation explains how melanin or its precursor monomers, located in the cytoplasm, can generate CPDs in the nucleus, acting as a triplet-state carrier. Synthetic eumelanin, the main eumelanin precursor (5,6-dihydroxyindole-2-carboxylic acid) and the main pheomelanin precursor (5-s-cysteinyldopa), generate chemiluminescence and create CPDs in the absence of UV, when oxidized by ONOO–. Through mass spectrometry, a possible triplet-carrier carbonyl has been identified: a product of oxidation of 5,6-dihydroxyindole-2-carboxylic acid, likely obtained via a muconic-type C-C cleavage or a 1,2-dioxetane–mediated C-C cleavage.12 In cells exposed to UV, differential interference contrast microscopy and three-dimensional reconstruction suggest that melanin, or its components, are able to enter the nucleus.7 Melanins, or their monomers, transfer the triplet-state energy to DNA, inducing CPDs even hours after UV exposure has ended. Dimers can be repaired. When this does not happen, they are able to induce the C→T mutation at sites of adjacent pyrimidines,3,13 as it occurs after a direct UV insult.

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A New Light on the Dark DNA Damages


January/February 2017

Commentary

Conclusions Because half or more of the CPDs in a melanocyte and in in vivo keratinocytes arises after UV exposure ends, measurement of CPDs carried out in previous studies might have underestimated the consequences of UV exposure. Without excluding the recognized role of UV radiation, the data from the study by Premi and colleagues confirm that UV-independent events play an important function in carcinogenic processes, pointing out that new forms of prevention, other than sun protection, could be necessary. Fortunately, the slowness of this dark photochemistry process allows multiple interventions, eg., the administration of antioxidants such as α-tocopherol or ethyl sorbate, the former able to reduce the dioxetanes to diols14 and the latter working as a powerful triplet quencher, to be considered. References 1 Schreier WJ, Schrader TE, Koller FO, et al. Thymine dimerization in DNA is an ultrafast photoreaction. Science. 2007;315:625–629. 2 Vink AA, Roza L. Biological consequences of cyclobutane pyrimidine dimers. J Photochem Photobiol B. 2001;65:101–104.

5 Cadet J, Douki T, Ravanat JL. Oxidatively generated damage to cellular DNA by UVB and UVA radiation. Photochem Photobiol. 2015;91:140–155. 6 Noonan FP, Zaidi MR, Wolnicka-Glubisz A, et al. Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment. Nat Commun. 2012;3:884. 7 Premi S, Wallisch S, Mano CM, et al. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science. 2015;347:842–847. 8 White EH, Miano JD, Watkins CJ, Breaux EJ. Chemically produced excited states. Angew Chem Int Ed Engl. 1974;13:229–243. 9 Waldemar A. Chemical and Biological Generation of Excited States. In: Waldermar A, Cilento G, eds. New York, NY: Academic Press; 1982:277–307. 10 Knudsen FS, Penatti CA, Royer LO, et al. Chemiluminescent aldehyde and beta-diketone reactions promoted by peroxynitrite. Chem ResToxicol. 2000;13:317–326. 11 Lamola AA. Production of pyrimidine dimers in DNA in the dark. Biochem Biophys Res Commun. 1971;43:893– 898. 12 Napolitano A, Pezzella A, Vincensi MR, Prota G. Oxidative degradation of melanins to pyrrole acids: a model study. Tetrahedron. 1995;51:5913–5920.

3 Brash DE. UV signature mutations. Photochem Photobiol. 2015;91:15–26.

13 Krauthammer M, Kong Y, Ha BH, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44:1006–1014.

4 Tewari A, Sarkany RP, Young AR. UVA1 Induces cyclobutane pyrimidine dimers but not 6-4 photoproducts in human skin in vivo. J Invest Dermatol. 2012;132:394– 400.

14 Adam W, Vargas F, Epe B, Schiffmann D, Wild D. Singleelectron-transfer in the reduction of 1,2-dioxetanes by biologically active substrates. Free Radic Res Commun. 1989;5:253–258.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:13–15

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A New Light on the Dark DNA Damages


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January/February 2017

Volume 15 • Issue 1

ORIGINAL CONTRIBUTION

Carboxymethyl Cellulose, Trichloroacetic Acid, and Unna Boot for Healing Venous Ulcers: A Comparative Study of Their Efficacy and Socioeconomic Impact Sueli Carneiro, MD, PhD;1,2 Virginia Januário, RN, PhD;2,3 Maria Leide W. Oliveira, MD, PhD;2 Maria Luiza de Oliveira Teixeira, RN, PhD;4 Solange Maciel, MD, PhD;1 João Carlos Macedo, MD, PhD;1 Marcia Ramos-e-Silva, MD, PhD2 Abstract Chronic ulcers are defined as a breakdown of the long-term cutaneous barrier or frequent recurrence of breakdowns. Dressings are a form of treatment and, in view of the variety and high cost of the products on the market, three agents were selected for this investigation, regarding their efficacy and cost/benefit ratio. The objective of the investigation was to evaluate and compare the efficacy, costs, and benefits of carboxymethylcellulose in paste at 20% (CMC 20%), trichloroacetic acid at 90% (TCA 90%), and Unna boot for treatment of chronic venous ulcers. Three groups of 30 patients each were chosen randomly for ambulatory treatment with TCA 90% (G1), CMC 20% (G2), and Unna boot (G3). The evolution of the cicatricial process of each group separately and between groups was analyzed with measurement of the lesion areas in square centimeters (cm2) and observation of the amount of exudate from observation of the photographic record, until their healing, in the maximum period of 20 weeks. A significant reduction of lesion areas in all groups was observed (P=.0001), with a median reduction of 7.6 cm2 (38.1%) for G1, 3.9 cm2 (38.8%) for G2, and 16.2 cm2 (77.8%) for G3. There was a significant difference in the absolute delta of the lesion areas (P=.0001) of the groups. The three types of treatments promoted effective improvement, with acquisition and utilization of all three products in the public health services being recommended. (SKINmed. 2017;15:17–25)

C

hronic ulcers are defined as a breakdown of the cutaneous long-term barrier (over 6 weeks) or frequent recurrence of breakdowns. In our present society, this type of disease represents one of the highest costs for public health.1,2 It is estimated that approximately 2.5 million individuals experience leg ulcers in the United States, with venous disease responsible for 72% of the lesions.1,2 The exact prevalence of venous ulcer is unknown; however, it is believed that it affects 1% to 3% of the general population, with prevalence increasing directly with the age. Risk factors for leg ulcer development include obesity, history of local trauma, deep venous thrombosis, and phlebitis.2,3

The recurrence rate can exceed 70%, especially for ulcers with evolution exceeding 1 year. Other factors associated with a worse prognosis are great extension of the lesion, presence of fibrous exudate of more than 50% of the lesion surface, ankle-brachial pressure index <0.8, and history of blood vessel ligation or removal.3 Venous ulcers are mostly secondary to venous insufficiency, with the most severe cases appearing in the postthrombotic syndrome, but occurrence of severe venous insufficiency can also occur after a long-lasting verrucous picture.4 Patients frequently complain about pain in the limbs and present edema that becomes worse at the end of the day and usually

From the University Hospital and School of Medical Sciences, State University of Rio de Janeiro;1 University Hospital and School of Medicine, Federal University of Rio de Janeiro;2 Rio das Ostras Campus/Fluminense Federal University, Rio das Ostras;3 Anna Nery Nursing School, Federal University of Rio de Janeiro;4 Brazil Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, Rua Dona Mariana 143/C 32, Botafogo 22420-020, Rio de Janeiro, Brazil • E-mail: ramos.e.silva2@dermato.med.br

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ORIGINAL CONTRIBUTION

reduces by elevating the member. Verrucous veins of variable intensity can be present, as well as stigmata of chronic venous insufficiency, as hyperpigmentation and petechiae in the skin around the ulcer, caused by accrual of hemosiderin in macrophages and red blood cells spillover. Cutaneous alterations, secondary to stasis eczema and contact eczema, can also be observed, due to the use of countless topical agents by the patients.5,6 Lipodermatosclerosis is a common finding and represents fibrosis of the subcutaneous tissue. White atrophy (livedoid vasculitis) can occur in over 40% of patients with venous ulcers.3

Patients with infected ulcers as well as those with clinical and radiologic signs of osteomyelitis, unbalanced diabetes (glucose >200 mg/dL, anemia (hemoglobin <10 g/dL), signs of arterial insufficiency, neuropathic ulcers and evidences of malignant transformation, uncompensated congestive cardiac insufficiency and deep venous thrombosis of the lower limbs, and known hypersensitivity to any of the proposed substances were excluded.

Venous ulcers can be single or multiple, are larger than ulcerations of other causes, and can affect the entire leg circumference. They are generally located in the course of the saphenous vein in the location where it becomes more superficial, which is the lower third of the leg, near the medial malleolus. These ulcers have irregular and infiltrated borders, are superficial with fibrous exudate that, when removed, reveals tissue of reddish granulation.7 Treatment of chronic cutaneous ulcers has the objective to anticipate the healing process and to prevent risks of complications. Treatment is dynamic and depends at each moment on the evolution of the cicatrization phases. The therapeutic choice and planning of care to be taken must be appropriate and based on technical-scientific knowledge acquired by the health professional in the practice of medical assistance, and is the subject of much discussion regarding which is the best therapeutic option.8–10 New technology products have been created, usually involving higher costs but without always demonstrating higher efficiency when compared with traditional methods.

The study complied with the determinations of resolution 196/96 of the National Health Counsel and was approved by the research ethics committee of the University Hospitals Clementino Fraga Filho (HUCFF/UFRJ) and Pedro Ernesto (HUPE/ UERJ). Treatment Protocol Initial evaluation included anamnesis, clinical examination, measurement of the ankle-brachial index and sensitivity test with monofilaments, assessment and determination of the lesion area and photographic documentation, request for laboratory examinations, simple x-ray of the affected member, and lesion border biopsy for histopathologic examination. Weekly follow-up was performed until occurrence of cicatrization, limited to a maximum of 20 weeks, along with dressing, assessment of the ulcer characteristics, and determination of the lesion area and photographic documentation.

Dressings are a form of treatment and their choice depends on intrinsic and extrinsic factors, such as the patient’s financial resources and/or those of the healthcare unit, and the requirement of long periods of ongoing healthcare.

Patients in the CMC 20% and TCA 90% groups, in addition to attendance in the hospital ward, carried out daily dressings according to previous guidance (booklet for caretakers and patients with indication of required material). The patients in the Unna boot group were instructed to change daily only the secondary dressing (gauze and crepe dressing), to reduce the accrual of exudate buildup from the lesion.

Currently, there are countless dressing options available on the market and the assessment of costs and benefits are only some aspects to be considered for decision taking. Three inexpensive and easy-to-apply agents were selected for comparison of their efficacy and cost/benefit ratio: (1) carboxymethylcellulose in paste at 20% (CMC 20%), (2) trichloroacetic acid at 90% (TCA 90%), and (3) the Unna boot.

Evaluation criteria were defined as excellent cicatrization: 100% (closing of the wound), good cicatrization: 60%–99% wound reduction, fair cicatrization: 30%–59% wound reduction, and poor cicatrization: <30% of the ulcer extension healed.

Methods

Table I shows the sample distribution of patients in relation to age and sex.

Results

Men and women older than 18 years with a clinical diagnosis of venous ulcer with evolution over 3 months and diameter ≥3 cm and length ≥20 cm were separated into three groups of 30 each to be submitted to therapeutic interventions with CMC 20%, TCA 90%, or Unna boot.

Demographics

SKINmed. 2017;15:17–25

Homogeneity of the groups Table II shows the average, standard deviation, median, minimum and maximum, and P value of the numeric clinical vari-

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Carboxymethyl Cellulose, Trichloroacetic Acid, and Unna Boot


January/February 2017

ORIGINAL CONTRIBUTION

Table I. Sample Distribution by Age and Sex Variable

Sample, No. (%)

Average

Standard Deviation

Median

Age, y

90

61.05

10.3

63.5

Men

39 (43)

Women

51 (57)

Table II. Numerical Clinical Variables per Treated Group Variable

Age, y

Ankle-brachial index

Initial lesion area, cm

2

Healing duration, wk

Group

Average

Standard Deviation

Median

Minimum

Maximum

G1

60.7

12.6

64

27

83

G2

59.9

8.7

63

40

73

G3

62.6

9.2

65.5

43

74

G1

1.14

0.22

1.1

0.80

1.65

G2

1.11

0.19

1.09

0.80

1.4

G3

1.07

0.10

1.05

0.88

1.25

G1

36.4

43.6

18.1

3

198.8

G2

19.7

24.2

10.3

3

110.5

G3

53.2

48.4

40.6

9

199.5

G1

15.6

6.6

20

3

20

G2

19.4

2.4

20

9

20

G3

17.6

4.9

20

5

20

P Valuea

Significant Differenceb

.29

.35

.0001

G3>G2

.015

G2>G1

G1: group treated with trichloroacetic acid; G2: group treated with carboxymethylcellulose; G3: group treated with the Unna boot. a Kruskal-Wallis analysis of variance median test. b Dunn’s multiple comparisons test at 5% level.

ables and the result of Dunn’s multiple comparisons test identifying the differences between the groups at a 5% level.11,12 A significant difference was observed in the initial lesion areas (P=.0001) among the groups, and it was found that group 3 (G3; Unna boot) showed initial lesion areas (cm2) significantly greater than group 2 (G2; CMC), without any noticeable difference in the initial lesion areas among the remaining pairs of groups. A significant difference in the duration of the treatment was also observed (P=.015) among the groups. G2 presented a significantly longer duration (in weeks) than group 1 (G1; TCA). There was no significant difference in duration among the remaining pairs of groups.

cation (P=.001) among the treated groups was observed. When analyzing the groups 2×2 using Fisher exact test adjusted for three multiple comparisons, it was found that: (1) G1 showed a significant greater proportion of women than G2 (P=.005) and G3 (P<.0001), (2) G3 showed a significant greater proportion of HAS than G2 (P=.009), and (3) G3 showed a significant greater proportion of claudication than G2 (P=.001). There was no significant difference among the remaining categorized clinical variables between the groups. Treatment evolution

Table III shows the frequency (number) and percentage of the categorized clinical variables according to the groups (G1, G2, and G3) and the corresponding descriptive level (P value) of χ2 or Fisher exact test.

Table IV provides the average, standard deviation, median, and minimum and maximum lesion areas at the initial and final treatment and the respective absolute variation (cm2) and relative variation (%) for the groups (G1, G2, and G3) and the corresponding descriptive level (P value) of the statistical test.

Initially, a significant difference in the proportion of women (P<.0001), systemic arterial hypertension (P=.033), and claudi-

A significant difference in the initial lesion area was observed (P=.0001) among the groups and it was identified that G3

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Table III. Categorical Clinical Variables per Treated Group G1 Variable

G2

G3

Category

No.

%

No.

%

No.

%

Male

4

13.3

14

46.7

21

70.0

Female

26

86.7

16

53.3

9

30.0

Current smoker

Yes

8

26.7

8

26.7

6

20.0

.79

SAH

Yes

16

53.3

12

40.0

22

73.3

.033

Cardiomyopathy

Yes

4

13.3

5

16.7

5

16.7

.99

Sex

P Valuea <.0001

Diabetes mellitus

Yes

6

20.0

5

16.7

5

16.7

.93

Claudication

Yes

4

13.3

1

3.3

12

40.0

.001

<1

6

20.0

5

16.7

7

23.3

1–10

13

43.3

9

30.0

11

36.7

>10

11

36.7

16

53.3

12

40.0

Time of ulcer evolution, y

.71

G1: group treated with trichloroacetic acid; G2: group treated with carboxymethylcellulose; G3: group treated with the Unna boot. Abbreviation: SAH, systemic arterial hypertension. a Fisher exact test.

Table IV. Initial and Final Lesion Areas and Deltas per Treated Group Variable

Initial lesion area, cm

2

Final lesion area, cm

2

Delta of lesion area, cm2

Delta of lesion area, %

Group

Average

SD/SE

Median

Minimum

Maximum

G1

36.4

43.6

18.1

3

198.8

G2

19.7

24.2

10.3

3

110.5

G3

53.2

48.4

40.6

9

199.5

G1

23.9

29.8

9.5

0

89.1

G2

10.1

13.7

4.9

0

49.5

G3

18.7

21.2

11

0

63.8

G1

12.5

3.8

7.6

0.9

109.7

G2

9.6

3.0

3.9

0.2

70.0

G3

34.5

7.1

16.2

0.9

139.5

G1

46.4

5.8

38.1

3

100

G2

44.7

5.0

38.8

4

100

G3

66.9

6.5

77.8

4.1

100

P Valuea

Significant Differenceb

.0001

G3>G2

.18 G3>G1 .0001

G3>G2 G3>G1

.022

G3>G2

G1: group treated with trichloroacetic acid; G2: group treated with carboxymethylcellulose; G3: group treated with the Unna boot. Abbreviations: SD, standard deviation; SE, standard error. a Kruskal-Wallis analysis of variance median test. b Dunn’s multiple comparisons test at 5% level.

showed an initial lesion area significantly greater than G2. There was no significant difference, at a 5% level, in the area of the initial lesions between the remaining pairs of groups (P=.18).

and G2 without significant absolute area reduction between G1 and G2. There was also a significant difference in the relative delta of the area (P=.022) between the groups and it was identified that G3 showed relative delta (reduction in %) significantly greater than G1 and G2, without significant relative area reduction between G1 and G2.

There was a significant difference in the absolute delta of the area (P=.0001) between the groups, and G3 showed absolute delta (reduction in cm2) significantly greater than between G1 SKINmed. 2017;15:17–25

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Table V. Degree of Improvement per Treated Group G1

Degree of Improvement

G2

G3

No.

%

No.

%

No.

%

100% (excellent)

4

13.3

2

6.7

13

43.3

60%–99% (good)

5

16.7

7

23.3

5

16.7

30%–59% (fair)

10

33.3

11

36.7

5

16.7

<30% (low)

11

36.7

10

33.3

7

23.3

G1: group treated with trichloroacetic acid; G2: group treated with carboxymethylcellulose; G3: group treated with the Unna boot. Fisher exact test.

a

Table V shows the frequency (number) and percentage of improvement from the treatment for each group. The degree of improvement corresponds to the percentage of reduction of the area lesion.

ity of the population difficult, motivated the project to evaluate cheap and efficient dressings. Women were the majority of the patients, which can be explained by the greater prevalence of the fact that women tend to see doctors more often than men and have more availability to make the weekly dressing changes.

Discussion Several theories might explain the occurrence of venous insufficiency, but its mechanism is not entirely clear.1,3,13,14 Healing is usually a fast and satisfactory process; however, its speed depends on the size and location of the wound and on whether its incisional or excisional, in addition to local factors (growth factors, edema and ischemia, low oxygen tension, and infection), regional factors (arterial insufficiency, venous insufficiency, and neuropathy), systemic factors (inadequate perfusion and metabolic disease), and other factors such as nutritional state, health or preexisting disease, types of clothing, exposure to radiation therapy, ingestion of alcohol, and smoking habit.13–20 When the process does not follow normal evolution, it results in chronic wounds, such as venous, diabetic, and hypertensive ulcers. Chronic cutaneous ulcer treatment protocols may vary from one hospital to another. Dressings are vital for wound handling, with different types at the health professional’s disposal (doctors and nurses) and the patient.10,13 Some are more expensive, others require more elaborate handling, and some have reasonable costs, including the TCA, manipulated CMC, and the Unna boot. This survey was developed in the wards of two university hospitals that receive patients for primary care of chronic venous ulcers with unsatisfactory response to different treatments using antibiotics and debriding and cicatrizing substances. The cost of biofilms and foams is high, making the attendance of the majorSKINmed. 2017;15:17–25

Arterial hypertension is prevalent in the population, and the age range of the patients may have a relation with the episodes of intermittent vascular claudication. The therapeutic response was positive in all groups (positive absolute delta), but when analyzing the response among the groups, a significant and clinically relevant difference was noted in relation to the area of the initial lesion. This showed that randomization was not perfect, which was minimized by the relative delta (percentage of regression of the lesions) and which was also positive in all groups. Patients with ulcers that lasted more than 10 years, however, required a longer treatment period. The Unna boot proved its efficacy, because seven patients experienced ulcer healing in periods of less than 20 weeks. It is supplied ready to use as a marketed product but can also be produced locally making a paste with the following materials: crepe bandage or light cotton gauze used in cheese fabrication, gelatin, glycerin, and zinc oxide, thus reducing the cost. Application of the bandage promotes an improvement in blood circulation and effectively reduces edema of the lower legs and, consequently, the diameter of the ulcers in the shortest time period. One of the positive points of the Unna boot is the possibility to keep the product for up to 7 days with the user only changing daily the secondary cover.21 The compression generated by the Unna boot and its effects generated wide acceptance of the

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ORIGINAL CONTRIBUTION

method by the patients, who referred to it, in their majority, as providing great comfort.22

tion or significant improvement of the lesions was greater than observed in the Unna boot group.

The characteristics of the lesion may determine the need to make more frequent changes (twice weekly) with reflection on the cost-benefit relationship. It was observed; however, this occurs only in the initial treatment phase. In the 16 patients who required more frequent changes, there was a rapid reduction of the lesion area (about 10 weeks), allowing the change of the boot once a week from there on.

TCA is analogous to acetic acid, whose main effect on the skin is protein denaturation, but it also suppresses keratinoid and fibroblast proliferation, protein synthesis, and metalloproteases, and activates epidermal cells with induction of growth factors and cytokines.24–30 Its direct application on the wound bed promoted, in the majority of cases, the removal of fibrin deposits, the elimination of odors, and the absence of signs of critical colonization or infection, fostering a uniform granulation and re-epithelization.31–37

The correct application depends on the professional’s training (application by a doctor or nurse) and may cause discomfort, throttling of the member, and increase of the lesion if done inadequately.21,22 The approximate expenses in this group ranged from R$330.60 to R$1322.40 for patients submitted to a single weekly change, and the expenses reached approximately R$1807.60 in those who required 2 weekly changes in the first 10 weeks.23

The main disadvantage of TCA was intense pain, noted mainly at the moment of product application, especially in patients with recent lesions or with exacerbated inflammatory characteristics. A scheme of preapplication and postapplication of analgesics was required for TCA at 90% in most of the users; however, patients with long-term lesions presented less pain sensitivity. Table VII shows the weekly cost for TCA dressings. The total cost for the patients who healed within 20 weeks was around R$951.40.

The short period of time required for cicatrization of the wound reduces the need for additional inputs and promotes an early return of the individuals to their work activities (Table VI).

CMC, a low-cost polymer, showed efficacy for the treatment of venous ulcers and was manipulated in a 20% paste concentration for this study.

TCA at 90% also showed efficacy even in patients who did not adhere to the treatment, although the time required for cicatrizaTable VI. Dressing Costs With Unna Boots

Single Change Per Week

Product

Two Changes Per Week

At the Ward

At Home

R$

At the Ward

At Home

R$

Procedure gloves (pair)

2 pairs

12 pairs

2.60

4 pairs

10 pairs

2.60

Sterilized gloves (pair)

1 pair

0.80

2 pairs

1.60

4 bottles

5.60

8 bottles

11.20

Needle 40x12

1 unit

0.04

2 units

0.08

Liquid soap (100-mL bottle)

10 mL

0.60

20 mL

1.20

Soft brush (unit)

1 unit

2.98

2 units

5.96

Sterile gauze (10-pack)

4 packs

18 packs

6.40

8 packs

15 packs

9.20

Solid Vaseline (100 g)

10 g

0.70

20 g

1.40

Unna boot (unit)

1 unit

35.00

2 units

70.00

15-cm crepe bandages (unit)

2 units

12 units

11.20

4 units

10 units

11.20

Adhesive tape (roll)

.50 cm

3.00 m

0.20

1.00 m

2.50 m

0.20

Physiologic solution 0.9% (100-mL bottle)

Total cost, R$

66.12 SKINmed. 2017;15:17–25

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Table VII. Costs of Dressings With Trichloroacetic Acid 90% Product

At the Ward

At Home

R$

Procedure gloves (pair)

2 pairs

12 pairs

2.60

Sterilized gloves (pair)

1 pair

0.80

4 bottles

12 bottles

22.40

Needle 40x12

1 unit

2 units

0.12

Liquid soap (100-mL bottle)

10 mL

60 mL

4.20

Sterile gauze (10-pack)

4 packs

18 packs

6.40

10 g

60 g

4.90

Physiologic solution 0.9% (100-mL bottle)

Solid Vaseline (100-g pot) Trichloroacetic acid 90%

1 mL

0.40

15-cm crepe bandages (unit)

1 unit

6 units

5.60

0.30 cm

1.80 m

0.15

Adhesive tape (roll) Total cost, R$

47.57

Table VIII. Dressing Costs With Carboxymethylcellulose per Week of Treatment Seven Dressings per Week

Product

At the Ward

At Home

R$

Procedure gloves (pair)

2 pairs

12 pairs

2.60

Sterilized gloves (pair)

1 pair

0.80

4 bottles

12 bottles

22.40

Needle 40x12

1 unit

2 units

0.12

Liquid soap (100-mL bottle)

10 mL

60 mL

4.20

Sterile gauze (10-pack)

4 packs

18 packs

6.40

10 g

60 g

4.90

Physiologic solution 0.9% (100-mL bottle)

Solid vaseline (100-g pot) Carboxymethylcellulose paste 20%

5g

30 g

4.00

15-cm crepe bandages (unit)

1 unit

6 units

5.60

Adhesive tape (roll)

.30 cm

1.80 m

0.15

Total cost, R$

51.17

It operates as a thickener, stabilizer, anti-adherent, lubricant, water retainer, and rheology controller,38–40 creating resistant and physiologically inert films.40–42 Its application promotes improvement of the ulcer bed aspect with reduction of the quantity of dead tissue and fosters an increase in granulation tissue. Some patients mentioned slight sensitivity (burning) with its use. It is possible that adjustments regarding product concentration may be required. The treatment costs ranged from R$463.53 to R$1023.40, depending on treatment duration. Table VIII shows the costs of weekly dressings in the CMC group. SKINmed. 2017;15:17–25

Conclusions The healing process of venous ulcers and the high occurrence of recurrences generate negative impacts, both individually and collectively, as well as for the public health system. This finding indicates the need for action in healthcare that includes new therapeutic measures or new technologies with a better cost/benefit relationship in wound healing. Considering that treatment choice and care planning should ground on technical and scientific expertise, this study presents TCA at 90%, CMC in paste at 20%, and the Unna boot as effective and lowcost therapeutic alternatives (generally less than R$1500.00 for a complete treatment). The researchers, therefore, recommend

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ORIGINAL CONTRIBUTION

the acquisition and utilization of these products by the public healthcare units. In relation to CMC, continuity of the studies is recommended in order to establish different concentrations of the product, expanding its applicability for treatment of a variety of lesions. Avoiding recurrence is the greatest challenge after ulcer cicatrization and individuals should be instructed to avoid traumata and to use elastic stockings while active. The possibility of surgical correction of venous system alterations should also be mentioned. Funding This study was financially supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (Edital Pensa Rio 2009) and was performed at the Clementino Fraga Filho (HUCFF/ UFRJ) and Pedro Ernesto (HUPE/UERJ) University Hospitals, Rio de Janeiro. References 1 Valencia IC, Falabella A, Kirsner S, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol. 2001;44:401–421. 2 Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17:763–771. 3 Phillips, T. Ulcers. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. London, England: Mosby; 2008:1597–1614. 4 Mustoe TA, O’Shaughnessy K, Kloeters O. Chronic wound pathogenesis and current treatment strategies: a nunifying hypothesis. Plast Reconstr Surg. 2006;117:35S–41S 5 Whiddon LL. The treatment of venous ulcers of the lower extremities. Proc (Bayl Univ Med Cent). 2007;20:363– 366. 6 Carr SC. Diagnosis and management of venous ulcers. Perspect Vasc Surg Endovasc Ther. 2008;20:82–85. 7 Trent JT, Falabella A, Eaglstein WH, Kirsner RS. Venous ulcers: pathophysiology and treatment options. Ostomy Wound Manage. 2005;51:38–54. 8 Clark JJ. Wound repair and factors influencing healing. Crit Care Nurs Quater. 2002;25:1–12 9 Enoch S, Grey JE, Harding KG. ABC of wound healing. Non-surgical and drug treatments. BMJ. 2006;332:900– 903 10 Franco D, Gonçalves LF. Feridas cutâneas: a escolha do curativo adequado. Ver Col Bras Cir. 2008;35:203–206. 11 Hollander M, Wolf DA. Nonparametric Statistical Methods. 2nd ed. New York, NY: Wiley-Interscience; 1999:787. 12 Dunn OJ. Multiple comparisons using ranksums. Technometrics. 1964;6:241–252.

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13 Fagundes FP, Lago EHJ, Lima BL, Carneiro SC. Cicatrização, cicatrizes e curativos In: Ramos-e-Silva M, Castro MC, eds. Fundamentos de Dermatologia. Rio de Janeiro: Atheneu; 2008:2077–2100. 14 Kirsner RS. Wound healing. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. London, England: Mosby; 2008:2147–2157. 15 Russell L. Understanding physiology of wound healing and how dressings help. Br J Nurs. 2000;9:10–16. 16 Hunt TK, Hopf H, Hussain Z. Physiology of wound healing. Adv Skin Wound Care. 2000;13:6–11. 17 Ravanti L, Toriseva M, Penttinen R, et al. Expression of human collagenase-3 (MMP-13) by fetal skin fibroblasts is induced by transforming growth factor beta via p38 mitogen-activated protein kinase. FASEB J. 2001;15:1098–1100. 18 Abbade LPF. Diagnósticos diferenciais de úlceras crônicas dos membros inferiores. In: Malagutti W, Kakihara CT. Curativos, Estomias e Dermatologia. São Paulo: Martinari; 2010:77–93. 19 Kim PJ, Evans KK, Steinberg JS, Pollard ME, Attinger CE. Critical elements to building an effective wound care center. J Vasc Surg. 2013;57:1703–1709. 20 Chaby G, Senet P, Vaneau M, et al. Dressings for acute and chronic wounds: a systematic review. Arch Dermatol. 2007;143:1297–1304. 21 Bolton L. Compression in venous ulcer management. J Wound Ostomy Continence Nurs. 2008;35:40–49. 22 Salomé GM, Ferreira LM. Qualidade de vida em pacientes com úlcera venosa em terapia compressiva por bota de Unna. Rev Bras Cir Plást. 2012;27:466–471 23 Baptista CMC, Castilho V. Levantamento do custo do procedimento com bota de Unna em pacientes com úlcera venosa. Rev Latino-Am Enfermagem. 2006;14:944– 949 24 Darwish AM, Zahran KM. Trichloroaceticacid application versus spray monopolar diathermy for treating benign cervical lesions: a randomized controlled clinical trial. J Low Genit Tract Dis. 2013;17:248–254. 25 Mradula PR, Sacchidanand S. A split-face comparative study of 70% trichloroacetic acid and 80% phenol spot peel in the treatment of freckles. J Cutan Aesthet Surg. 2012;5:261–265. 26 Pezeshkpoor F, Banihashemi M, Yazdanpanah MJ, et al. Comparative study of topical 80% trichloroacetic acid with 35% trichloroacetic acid in the treatment of the common wart. J Drugs Dermatol. 2012;11:e66–e69. 27 Barikbin B, Saadat N, Akbari Z, Yousefi M, Toossi P. Focal high-concentration trichloroacetic acid peeling for treatment of atrophic facial chickenpox scar: an openlabel study. Dermatol Surg. 2012;38:1662–1667. 28 Fox PA. Treatment options for anal intraepithelial neoplasia and evidence for their effectiveness. Sex Health. 2012;9:587–592. 29 Cha W, Cho SW, Hah JH, et al. Chemocauterization of the internal opening with trichloroacetic acid as firstline treatment for pyriform sinus fistula. Head Neck. 2013;35:431–435.

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30 Zayed A, Sobhi RM, Abdel Halim DM. Using trichloroacetic acid in the treatment of acanthosis nigricans: a pilot study. J Dermatolog Treat. 2014;25:223–225.

36 Yamamoto Y, Uede K, Ohtani T, Wakita H, Furukawa F. P-cadherin expression in skin peeled with phenol or trichloroacetic acid (TCA). J Dermatol. 2003;30:920–923.

31 Yadav KK, Mandal AK, Sen IK, et al. Flocculating property of extracellular polymeric substances produced by a biofilm-forming bacterium Acinetobacter junii BB1A. Appl Biochem Biotechnol. 2012;168:1621– 1634.

37 Boyce ST, Holder IA. Selection of topical antimicrobial agents for cultured skin for burns by combined assessment of cellular cytotoxicity and antimicrobial activity. Plast Reconstr Surg. 1993;92:493–500.

32 Li HJ, Kanazawa N, Kimura A, et al. Severe ulceration with impaired induction of growth factors and cytokines in keratinocytes after trichloroacetic acid application on TRPV1-deficient mice. Eur J Dermatol. 2012;22:614– 621. 33 Kimura A, Kanazawa N, Li HJ, et al. Influence of chemical peeling on the skin stress response system. Exp Dermatol. 2012;21:8–10. 34 Yang H, Dai Y, Dong H, et al. Trichloroethanol up-regulates matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in HaCaT cells. ToxicolIn Vitro. 2011;25:1638–1643. 35 Yonei N, Kanazawa N, Ohtani T, Furukawa F, Yamamoto Y. Induction of PDGF-B in TCA-treated epidermal keratinocytes. Arch Dermatol Res. 2007;299:433–440.

38 Lopes JJC. Metabolismo de carboidratos pelas leveduras. http://www.cca.ufscar.br/~vico/Metabolismo%20 de%20carboidratos%20pelas%20leveduras.pdf. Accessed August 4, 2013. 39 Alves M. A aplicabilidade do polímero carboximetilcelulose (CMC) [Pós-graduação]. São Paulo: Faculdade de Tecnologia do Estado de São Paulo; 2009. 40 Canevarol Jr SV. Conceito de polímero. In: Canevarol Jr SV. Ciencia dos Polímeros. 2nd ed. São Paulo: Artliber Ed Ltda; 2006:21–26. 41 Correa NM, Camargo Jr FB, Ignácio RF, Leonardi GR. Avaliação do comportamento reológico de diferentes géis hidrofílicos. Rev Bras Cienc Farm. 2005;41:73–78. 42 Leonardi GR, Maia Campos PMBG. Estabilidade de formulações cosméticas. Int J Pharm Compounding. 2001;3:154–156.

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Volume 15 • Issue 1

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Toll-Like Receptor 2 and Its Relationship With Streptococcus in Psoriasis Jing Zhang, MD; Christine Shaver, MD; Lane Neidig, BS; Krister Jones, MD; Carrie A. Cusack, MD; Herbert B. Allen, MD Abstract The authors present the immunopathologic findings of Toll-like receptor 2 in psoriasis. This novel work shows positive staining within the dermal capillaries in psoriatic lesions. Neither normal skin nor lesional skin in eczema showed similar staining. The authors postulate how the activation of this innate immune system reactant plays a significant role in psoriasis and show how it may be associated with a cascade of events that begins with streptococcus and ends with psoriasis. (SKINmed. 2017;15:27–30)

P

soriasis is a chronic inflammatory disease associated with significant economic, social, and emotional burdens.1,2 It has long been theorized that this condition has a genetic association predisposing individuals to a T-cell–mediated response from an unknown trigger. Recent evidence has shown activation of the innate immune system, setting off a chain of events leading to psoriasis. Specifically, toll-like receptors (TLRs) are central to this process and their stimulation leads to expression of inflammatory cytokines along with other cells of the innate immune system.3 Activation of this system then causes Tcell upregulation and keratinocyte proliferation.3,4 The inciting event for psoriasis is unknown; however, at least in the guttate form of the disease, B-hemolytic streptococcus is generally associated with its pathogenesis. Studies point to the role of streptococcus in chronic plaque psoriasis as well.4–6 Epidemiologic evidence suggests that where there is no streptococcus in the environment, there is no psoriasis.6 It has been shown that group A streptococcus can be internalized in the tonsillar epithelium, thus creating a reservoir for recurrent activation of the immune system driving psoriasis.6,7 Two trials using long-term antistreptococcal antibiotic regimens showed a psoriasis area and severity index 75 in 80% of patients.2,8

Recently, TLR2, the innate immune system molecule that responds to gram-positive and other organisms, has gained increasing scrutiny in the pathogenesis of psoriasis. TLR2 overex-

pression in psoriatic epidermis has been demonstrated, lending further credence to the theory that these receptors are central to the pathogenesis of psoriasis with gram-positive streptococcus as the inducer;9 furthermore, at least one study of patients with psoriatic arthritis has shown an elevation of soluble TLR2 in the serum.10 Multiple newer in vitro studies show that TLR2 can drive various immunologic pathways central to the pathogenesis of psoriasis. TLR2 stimulation has been shown to inhibit the function of T regulatory cells and drive the Th17 pathway towards differentiation to T-helper precursor cells with increased expression of interleukin (IL)–17.11 Human dendritic cells stimulated by TLR2 have shown increased activity and, when activated, secrete significantly more IL-12/23p40.12 These pathways are central to our current understanding of psoriasis. Our study aims to support the theory that TLR2 is indeed upregulated in psoriasis, and we show the novel finding that soluble TLR2 is preferentially increased in dermal vessels of psoriatic skin. In this study, we demonstrate immunopathologic findings in psoriatic skin lesions. Our hypothesis was that TLR2 is upregulated in the dermis (possibly by dermal dendritic cells) and this upregulation would activate the MyD88 and NFkB pathways,13 which would cause release of cytokines such as tumor necrosis factor-α (TNF-α). From TNF-α, the pathogenesis of psoriasis is well understood, namely it leads to the development of lesions.14 Finding these reactants would be an important step in the pathogenetic cascade prior to the onset of a lesion.

This paper was a Johnson Beerman prize winner at the American College of Physicians Section on Dermatology. From the Department of Dermatology, Drexel University College of Medicine, Philadelphia, PA Address for Correspondence: Herbert B. Allen, MD, Department of Dermatology, Drexel University College of Medicine, 219 N. Broad St., 4th Floor, Philadelphia, PA 19107 • E-mail: hallen@drexelmed.edu

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ORIGINAL CONTRIBUTION

Methods This study was approved by the Drexel University College of Medicine institutional review board,10 and biopsy specimens from psoriasis plaques were secured. Staining with hematoxylin and eosin (H+E) and with periodic acid Schiff (PAS) was performed. Immunoperoxidase staining with CD282 (anti-TLR2) and CD25 (dermal dendritic cells) was performed with a previously established protocol.15 Ten specimens of eczema (an inflammatory disease with a different pathogenesis) that had been previously stained with H+E, PAS, CD25, and TLR2 and 10 previously stained normal skin controls (from tips of wide excisions) served as controls. One control specimen of candidiasis was included and was stained with all of the above. Figure 1. Psoriasis lesion stained with hematoxylin and eosin 40×. Dilated vessels are seen in the upper dermis along with acanthosis of the epidermis.

Results Ten of 10 of the psoriasis specimens showed typical findings of psoriasis, such as neutrophils in the stratum corneum, hypogranulosis, regular acanthosis, thin suprapapillary plates, and dilated capillaries in the dermal papillae (Figure 1). Results from PAS were negative for fungi and yeasts and for ductal occlusion. Ten of 10 showed positive staining in the dilated dermal capillaries with TLR2 (CD282 stain) (Figure 2). Results from CD25 staining were negative, and no monocytic cells were noted in the dermal capillaries in any of the specimens. The control specimen of candidiosis showed positive staining of the yeasts with TLR2 (Figure 3). In eczema specimens, results from H+E and PAS showed typical findings such as spongiosis and exocytosis, as well as the more recent findings of occluded eccrine ducts. TLR2 staining occurred in the parakeratotic stratum corneum adjacent to the occluded sweat ducts. No staining of TLR2 was present in the dermal blood vessels and no staining of CD25 was present.

Figure 2. Psoriasis lesion stained with CD282 (Toll-like receptor 2 [TLR2]) 40×. Staining with CD282 (TLR2) is noted in the vessels in the upper dermis. It is also present in the basal layer of the epidermis (control location in the epidermis).

In the normal skin, none of the above pathologic findings were present. Staining with TLR2 was limited to the basal zone and CD25 was negative. Discussion

pathogenetic cascade, and does not rely on activation of dermal dendritic cells.

We have found what appears to be soluble TLR2 in the dermal capillaries in the lesions of 10 of 10 patients with psoriasis. Controls (10 patients with eczema and 10 normal skin samples from surgical excision tips) showed no such activation of TLR2 (P=.001). The eczema lesions showed activated TLR2 adjacent to the occluded sweat ducts in the proximal parakeratotic stratum corneum as recently described.16 No activation of CD25 was noted in either psoriasis or controls. Our observation of TLR2 in the blood vessels seems to fit well into the psoriasis SKINmed. 2017;15:27–30

A limitation of this study is the small sample size. Although our protocol has a small number of patients, it is significant statistically. Further studies that show similar findings are required to document it more fully. The cascade that we believe to be pertinent is as follows: (1) a genetically “primed” patient (PSORS genes) develops a strep-

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January/February 2017 tococcal infection.5 (2) The infection is treated appropriately. If the organism is clinically inapparent or is treated suboptimally, it will persist. (3) It has been shown to move intracellularly, stay there for up to a year, move to an extracellular location, and recolonize.7 (4) (This finding does not entirely exclude the streptococcus-making biofilms that behave in a similar fashion.17) A markedly increased level of antistreptococcal antibody (not ASO) has been found in the serum of psoriasis patients.18 (5) This antibody reacts with the blood monocytes and these monocytes display upregulated TLR2 on their cell surfaces.10 (6) TLR2 is upregulated and travels to dermal capillaries. (7) TLR2 leads directly to TNF-α and IL-17, IL-12/23 pathways leading to psoriatic lesions.11–14 Evidence is now present to support each one of these steps. Regarding the streptococcus, if these organisms are not found in the environment, there is no psoriasis present.6 If these organisms are treated over a long period, the psoriasis disappears.2,8 Regarding the immunology, the presence of an antistreptococcal antibody has been well-documented,17 and the presence of the innate immune system response has previously been shown.3 This work demonstrates the innate immune system response downstream of the prior observation and perhaps provides a “missing link” in the cascade. TLR2 has been shown to upregulate TNF-α.19 In fact, it is the primary mechanism that leads to the killing of gram-positive and other organisms for which it is intended (Figure 3).

ORIGINAL CONTRIBUTION This makes psoriasis similar to rheumatic fever and glomerulonephritis, which are known sequelae of streptococcal infections. Psoriasis, like these other disorders, is associated with many systemic findings, such as the metabolic syndrome. Conclusions Our findings help support the observations of researchers who showed dramatic improvement in two cohorts of psoriasis patients treated with long-term antibiotics.8 Our findings also help support the intracellular/extracellular movement of the organisms noted by other investigators.7 The daily administration of penicillin or pulse azithromycin thereby kills these organisms when they appear.2,8 The long-term administration would also allow the antistreptococcal antibody to decay and not trigger the innate immune system. This is our postulate why antibiotic treatment must be extended. This concept also helps the consideration that streptococcal organisms form the environmental “hit” in the double hit theory. The genetic hit has been previously mentioned. This also helps establish that both psoriasis and eczema are caused by bacteria, but neither is a classic infection. References 1 Luba MK, Stulberg DL. Chronic plaque psoriasis. Am Fam Physician. 2006;73:636–644. 2 Saxena VN, Dogra J. Long-term azithromycin in chronic plaque psoriasis: a controlled trial. Eur J Dermatol. 2010;20:329–333. 3 Sweeney CM, Tobin AM, Kirby B. Innate immunity in the pathogenesis of psoriasis. Arch Dermatol Res. 2011;303:691–705 4 Fry L, Baker BS, Powles AV, et al. Is chronic plaque psoriasis triggered by microbiota in the skin? Br J Dermatol. 2013;169:47–52. 5 Villeda-Gabriel G, Santamaría-Cogollos LC, Pérez-Lorenzo R, et al. Recognition of Streptococcus pyogenes and skin autoantigens in guttate psoriasis. Arch Med Res. 1998;29:143–148. 6 McFadden JP, Baker BS, Powles AV, et al. Psoriasis and streptococci: the natural selection of psoriasis revisited. Br J Dermatol. 2009;160:929–937. 7 Wood DN, Chaussee MA, Chaussee MS, et al. Persistence of Streptococcus pyogenes in stationary-phase cultures. J Bacteriol. 2005;187:3319–3328. 8 Saxena VN, Dogra J. Long-term use of penicillin for the treatment of chronic plaque psoriasis. Eur J Dermatol. 2005;15:359–362. 9 Begon E, Michel L, Flageul B, et al. Expression, subcellular localization and cytokinic modulation of Tolllike receptors (TLRs) in normal human keratinocytes: TLR2 up-regulation in psoriatic skin. Eur J Dermatol. 2007;17:497–506.

Figure 3. Yeasts stained with CD282 (Toll-like receptor 2 [TLR2]) 40×. TLR2 staining coats the organisms in this specimen of candidiasis. Here, the TLR2 is activated to kill yeasts. SKINmed. 2017;15:27–30

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ORIGINAL CONTRIBUTION 15 Allen HB, Vaze ND, Choi C, et al. The presence and impact of biofilm-producing staphylococci in atopic dermatitis. JAMA Dermatol. 2014;150:260–265.

10 Carrasco S, Neves, FS, Fonseca MH, et al. Toll-like receptor (TLR) 2 is upregulated on peripheral blood monocytes of patients with psoriatic arthritis: a role for a gram-positive inflammatory trigger? Clin Exp Rheumatol Supp. 2011;29:958.

16 Choi C, Hailu T, Cusack CA, et al. The earliest immunologic finding in atopic dermatitis: periductal Toll-like receptor 2 expression in response to ductal occlusion by Staphylococcus epidermidis biofilm. J Am Acad Dermatol. 2012;66:AB71.

11 Nyirenda MH, Sanvito L, Darlington PJ, et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol. 2011;187:2278–2290.

17 Ogawa T, Terao Y, Okuni H, et al. Biofilm formation or internalization into epithelial cells enable Streptococcus pyogenes to evade eradication in patients with pharyngitis. Microbial Pathogenesis 2011;51:58–68.

12 Obendorf J, Renner Viveros P, Fehlings M, et al. Increased expression of CD25, CD83, and CD86, and secretion of IL-12, IL-23, and IL-10 by human dendritic cells incubated in the presence of Toll-like receptor 2 ligands and Giardia duodenalis. Parasit Vectors. 2013;6:317.

18 El-Rachkidy RG, Hales JM, Freestone PP, et al. Increased blood levels of IgG reactive with secreted Streptococcus pyogenes proteins in chronic plaque psoriasis. J Invest Dermatol. 2007;127:1337–1342.

13 Wang Q, Dziarski R, Kirschning CJ, et al. Micrococci and peptidoglycan activate TLR2→ MyD88→ IRAK→ TRAF→ NIK→ IKK→ NF-κB signal transduction pathway that induces transcription of interleukin-8. Infect Immun. 2001;69:2270–2276.

19 Candia L, Marquez J, Hernandez C, et al. Toll-like receptor-2 expression is upregulated in antigen-presenting cells from patients with psoriatic arthritis: a pathogenic role for innate immunity? J Rheumatol. 2007;34:374– 379.

14 Ettehadi P, Greaves MW, Wallach D, et al. Elevated tumour necrosis factor-alpha (TNF-α) biological activity in psoriatic skin lesions. Clin Exp Immunol. 1994;96:146–151.

“Tuberculosis cutis verrucosa.” Moulage No. 188, made by Adolf Fleischmann in 1920 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www. moulagen.ch Courtesy of Michael Geiges, MD

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Volume 15 • Issue 1

ORIGINAL CONTRIBUTION

Midline Capillary Formation Nuchae and Age Marvin H. Klapman, MD;1 Michael Batech, DrPH2 Abstract Midline capillary formation nuchae (MCFN) consists of blanchable pink macules located around the midline of the occiput and nape. It has been implicated in the literature as a risk factor for angiosarcoma and might be related to a decrease in innervation of the involved capillaries. Although there is ample literature on its prevalence from birth through adult life, the literature in late life is sparse. The objective of this study was to determine the prevalence in late life, whether it is truly a risk factor for angiosarcoma and whether it might be an indication of a systemic neuroendocrine effect or a local reaction. In routine skin screening examinations of 411 patients, the prevalence of MCFN increased with age (P<.0001), by quartiles of age overall (P=.0001), and among men only (P=.0013). No difference in prevalence was observed across quartiles of age among women only (P=.0688). No association was found with routine parameters that might be influenced by the systemic neuroendocrine system. Prevalence increases in old age, is not a risk factor for angiosarcoma, and might represent a response of local capillaries to normal changes in the neuroendocrine system that occur with age. (SKINmed. 2017;15:31–36)

M

idline capillary formation (MCF) consists of blanchable macules on the midline, also called salmon patch or nevus simplex.1 We use the word formation rather than malformation, because we consider MCF a variation of normal. MCF nuchae (MCFN) is an MCF located on the occiput and nape (Figure 1), which can continue beyond infancy unlike the transient glabellar MCF,2 and does not develop thickening or nodules unlike lateral capillary malformations (port wine stains).3 MCFN has been suggested as a precursor to angiosarcoma.4 We addressed this issue and also whether MCFN might be related to systemic changes or local responses. Our study focused on the prevalence of MCFN in advanced age. Methods This study was approved by the institutional review board of Southern California Kaiser Permanente. All adult patients given screening examinations by one dermatologist between November 2013 and October 2014 were examined for the presence of MCFN. Patients were divided into quartiles of age and the prevalence for each group is reported by age quartile and sex. In addition, the health records of a random sample of 108 of the three oldest quartiles of patients with MCFN (57 years and older) were reviewed for their most recent systolic blood pressure, diastolic blood pressure, pulse rate, and body mass index

compared with an equal number of age-matched patients randomly selected from those without MCFN. The health records of all of the patients with and without MCFN were reviewed for history of angiosarcoma. The prevalence of MCFN in newborns (younger than 1 year), school-aged children (6 to 17 years), and adults (18 years and older) in the literature were reviewed by searching PubMed and Google for studies that showed or allowed calculation of the prevalence, number of patients with MCFN, and total number of patients examined in at least one age group. We also included studies that reported subjective language that seemed to indicate the groupings that matched our definitions. References within the contributions found in the search that met the criteria for inclusion were also examined for eligibility of inclusion into our study. Comparisons between patients with MCFN and those without MCFN were made using chi-square or Fisher exact test for categorical variables, and independent samples t test or Wilcoxon’s rank-sum test for continuous variables, where appropriate. Test of the normality assumption of parametric tests was conducted using Shapiro-Wilk and Anderson-Darling tests and non-normal data were tested using the nonparametric equivalent methods. All analyses were conducted using SAS/STAT version 12.1 (SAS Institute Inc, Cary, NC).

From the Department of Dermatology1 and the Department of Research and Evaluation,2 Southern California Permanente Medical Group, Woodland Hills, CA Address for Correspondence: Marvin H. Klapman, MD, Department of Dermatology, Southern California Permanente Medical Group, Woodland Hills Medical Center, 5601 De Soto Avenue, Woodland Hills, CA 91367 • E-mail: marvinklapman@gmail.com

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© 2017 Pulse Marketing & Communications, LLC


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ORIGINAL CONTRIBUTION

Figure 1. Midline capillary formation nuchae in a 77-yearold man.

Figure 2. Prevalence of midline capillary formation nuchae by sex and age quartiles.

There was no significant difference in systolic blood pressure, diastolic blood pressure, pulse rate, or body mass index between the 108 randomly sampled patients with MCFN and an equal number of patients without MCFN (Table I). The mean systolic blood pressure was 129.5 mm Hg in patients with MCFN and 128.3 mm Hg in those without, the mean of diastolic blood pressure was 71.6 mm Hg in patients with MCFN and 69.5 mm Hg in those without, the mean pulse rates were 73.6 in patients with MCFN and 73.1 in patients without, and the mean body mass indices were 26.7 in patients with MCFN and 26.8 in those without (P value for all comparisons >.05). No evidence of angiosarcoma was found in patients with MCFN by examination and review of the health records. One 92-year-old man without MCFN developed angiosarcoma on his ear.

Results We examined 411 patients for MCFN ranging in age from 21 to 96 years. Of these, 141 (34.3%) were identified with MCFN; 44% were women, and the median (interquartile range [IQR]) age was 70 (62–80) years. Of the 270 (65.7%) without MCFN, 47% were women, and the median (IQR) age was 64 (54–73) years. Of the 141 patients with MCFN, 18 were aware of it at the time of examination. No patients with MCFN displayed thickening, nodules, or hypertrophy. Among the 222 (54%) men in our study, 79 (35.6%) had MCFN, with a median (IQR) age of 73 (63–81) years. Of the 143 (64.4%) men without MCFN, the median (IQR) age was 64 (55–75) years. Age was statistically associated with MCFN status among men (P<.001). Among the 189 (46%) women in our study, 62 (32.8%) had MCFN, and their median (IQR) age was 68 (59–80) years. Of the 127 (67.2%) women without MCFN, median (IQR) age was 64 (53–72) years. Age was statistically associated with MCFN status among women (P=.04). Overall, the prevalence of MCFN was 35.6% in men and 32.8% in women and not statistically significantly different (P=.55). The age quartiles fell into clear cutoffs of 56, 66, and 76 years and the prevalence of MCFN increased across the quartiles. Among patients 56 years and younger, 23 (21.1%) had MCFN, while 32 (30.5%), 34 (35.4%), and 52 (51.5%) of those aged 57–66, 67–76, and 76 or older, respectively, had MCFN. Figure 2 shows the prevalence of MCFN by sex and age quartile for men, women, and combined. The prevalence of MCFN was globally significant across quartiles overall (P<.01) and for men (P=.001) but not for women (P=.07). SKINmed. 2017;15:31–36

Literature Review We identified 19 studies in the literature that reported data on MCFN prevalence in different age groups, including newborns, school-aged, adults, and various age groups (Table II). There was variation in data between studies in each age group. One report found a prevalence of 82% in the first year of life, which decreased during childhood to a low of 4.5% at 9 years of age and then progressively increased from puberty on to plateau during adulthood above 30%.5 Studying children from birth to 10 years of age, researchers demonstrated a prevalence of 38.1% in the first 3 months of life with a subsequent progressive decrease in incidence to 1.4% between 5 and 6 years and none after that.6 Another investigation focused on patients 60 years and older and demonstrated a 48% prevalence rate in that age group.7 Table III summarizes data by age group across our study and those in the literature.

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Table I. Comparison Between a Random Sample of the Top Three Quartiles of Age of MCFN Patients to a Random Sample of Patients in the Same Age Range Without MCFN MCFN Not Present n=108

MCFN Present

(50.0)

n=108

(50.0)

Total

P Value

n=216

Patient sex, No. (%)

>.99

Women

48 (44.4)

48 (44.4)

96 (44.4)

Men

60 (55.6)

60 (55.6)

120 (55.6)

Patient age, y

.34

No.

108

108

216

74.7 (9.22)

73.6 (9.40)

74.1 (9.31)

Median

74

73.5

74

Q1, Q3

67.0, 83.5

66.0, 81.0

67.0, 82.5

(59.0–94.0)

(57.0–96.0)

(57.0–96.0)

Mean (SD)

Range Systolic blood pressure, mm Hg

.51

No. Mean (SD)

108

108

216

128.3 (19.53)

129.5 (12.70)

128.9 (16.44)

129

132

130

Median Q1, Q3

116.5, 139.0

122.5, 137.0

120.5, 138.0

Range

(62.0–174.0)

(87.0–157.0)

(62.0–174.0)

Diastolic blood pressure, mm Hg

.40

No. Mean (SD)

108

108

216

69.5 (12.73)

71.6 (10.48)

70.5 (11.68)

Median

71

71

71

Q1, Q3

61.5, 78.0

64.0, 79.0

63.0, 79.0

(14.0–93.0)

(45.0–98.0)

(14.0–98.0)

108

108

216

73.1 (12.84)

73.6 (13.56)

73.4 (13.18)

71

72

72

Range Pulse rate, beats per min

.84

No. Mean (SD) Median Q1, Q3 Range

65.0, 80.5

63.5, 83.0

64.5, 82.0

(48.0–122.0)

(49.0–105.0)

(48.0–122.0)

Body mass index, mg/kg2 No. Mean (SD)

.92 108

108

216

26.8 (5.49)

26.7 (4.74)

26.7 (5.12)

Median

25.8

26.4

26

Q1, Q3

22.9, 30.1

23.3, 29.5

23.0, 29.6

(14.3–52.5)

(14.6–39.0)

(14.3–52.5)

Range

Abbreviations: MCFN, midline capillary malformation nuchae; Q1, quartile 1; Q2, quartile 2; SD, standard deviation.

Discussion This study investigated the prevalence of MCFN in adults with a focus on the elderly. The literature was reviewed to observe the SKINmed. 2017;15:31–36

33

prevalence in newborns, school age, and adults in order to put our findings into perspective. Two studies reported a decrease in prevalence following the newborn period and one showed an increase after that period.5,6 Reviewing all the studies and eliminatMidline Capillary Formation Nuchae and Age


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ORIGINAL CONTRIBUTION

Table II. Total Number of Patients Examined for Midline Capillary Formation Nuchae and Estimated Prevalence By Age Group in the Present and 19 Additional Studies Newborns Study

School Age

Total

152

30 (50.0)

60

6 (2.90)

210

10 (5.7)

175

Smith

97 (40.1)

242

Leung6

299 (37.0)

808

266 (45.5)

584

165 (50.0)

330

431

463 (42.5)

1089

Osburn

244 (29.4)

830

Mitsuhashi5

155 (82.0)

189

Boccardi

143 (23.1)

620

Pollitzer

40 (35.1)

114

Tan

679 (23.4)

Monteagudo23

226 (37.7)

Corson

14

15

Kanada

16

Bossard

17

Pratt

18 19

20

21

22

94 (61.8)

No. (%)

82 (27.0)

304

86 (20.0)

– –

No. (%)

No. (%)

Total

2079

2901

600

104 (26.0)

400

185 (14.0)

1323

Total

Older than 75

No. (%)

Bettley

Total

Older than 60

Total

2

No. (%)

All Adults

2268 (30.0)

7560

665 (32.0)

883 (40.5)

2181

25

57 (23.2)

246

Van der Werf

64 (42.1)

152

-

Zumkeller27

300 (50.0)

600

Saalfeld

228 (57.0)

400

Verbov

Present study

Oster

24

Holzammer

26

28

7

141 (34.3)

ing the study age groups with the most extreme outlying prevalence rates, the data were viewed in two ways, as a mean of the prevalence in three age groups (newborns, school-aged children, and adults) for each study regardless of the study size and as a prevalence determined by pooling the patients in all the studies by age groups. The results were comparable for both methods. In newborns, the prevalence was 36% according to a mean of studies and 32% according to pooled patients. It was 29% and 30% in school children and 38% and 32% in adults, respectively. Therefore, the literature indicates that the prevalence of MCFN in newborns is about one third and continues as such into adulthood. There was a possible small dip in school-aged children but not nearly the sharp decrease reported by some invesitgators.5,6 This study takes off where the literature becomes sparse. It agrees with the literature by demonstrating a prevalence of about 34% for adults in all patients studied. The adults with MCFN, however, were significantly older than those without MCFN and this age difference was more pronounced in men than women. In addition, there was a progressive increase in prevalence from younger SKINmed. 2017;15:31–36

91 (48.4)

188

411

86 (42.0)

205

52 (51.0)

102

adults to older adults and most significantly to adults older than 75 years. This study is consistent with another study that concentrated on patients older than 60 years and reported a prevalence of 48% but did not stratify prevalence within that age group.7 As for the suggestion that MCFN might be a precursor of angiosarcoma,4 the one patient in the study with an angiosarcoma did not have MCFN. Angiosarcoma is a rare neoplasm in the general population and is most prevalent in people older than 60 years.8,9 This study demonstrated the prevalence of MCFN to be about one third of the population older than 66 years and half of those older than 76 years. The presence of angiosarcoma in a large portion of the older patients in the study with MCFN would have been necessary to suggest a significant correlation between MCFN and angiosarcoma. Any subtle correlation would have required a much larger population, and our study was not designed to investigate it a priori. Although angiosarcoma might appear clinically similar to MCFN at its onset, a phenomenon as common as MCFN ought not to be considered a marker for a neoplasm as uncommon as angiosarcoma.

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Table III. Characteristics of Studies Describing MCFN Prevalence by Age Categories

No. of studies

Newborns

SchoolAged

All Adults

Older than 60

Older than 75

13

6

8

3

1

Study prevalence, mean (range)

39 (3–82)

24 (0–42)

34 (6–57)

NA

NA

Study prevalence without EOs, mean (range)

36 (23–50)

29 (14–42)

38 (20–57)

NA

NA

Pooled patients without EOs: No. with MCFN (prevalence); total examined

2788 (32.1); 8669

1271 (30.3); 4196

3167 (31.6); 10,037

NA

NA

Abbreviations: EOs, extreme outliers (prevalence more than 20 percentage points away from the mean); MCFN, midline capillary malformation nuchae; NA, not applicable.

Although salmon patches on the glabella and nuchal area are usually classified together as nevus simplex, there are similarities and differences that call into question whether they are similar in pathogenesis. Both consist of dilated capillaries, are located around the midline, and do not develop an association with thickening, nodules, or hypertrophy, unlike lateral port wine stains; however, while the glabella salmon patch is transient, MCFN continues into adult life and increases in prevalence in old age. A decrease in sympathetic neural stimulation has been suggested as the pathogenesis of lateral capillary malformations, which is supported by the demonstration of decreased innervation of capillaries in port wine stains.10 Nevus simplex of the glabella in newborns is possibly due to a delay in full development of the sympathetic nervous system; however, that delay would not explain the presence of MCFN in newborns because MCFN continues after the newborn period. It has been suggested that the increased prevalence with old age might be related to a decrease in sympathetic nerve activity. It has been demonstrated that the elderly experience decreased outflow by the sympathetic nervous system as well as decreased responsiveness to the system by the vasculature.11 Blood pressure, pulse, and body mass index were reviewed, because these parameters have been demonstrated to be affected by the neuroendocrine system.12,13 In this study, however, these parameters were not different between the patients with or without MCFN, which suggests no systemic neuroendocrine difference. Conclusions One might suggest that in the subset including approximately one third to half of the population who experience MCFN, particularly in old age, the nuchal capillaries respond to normal changes in the neuroendocrine system to a greater extent than in the rest of the population. Perhaps, the difference is due to difference in neuroendocrine receptors in those capillaries. SKINmed. 2017;15:31–36

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References 1 Juern AM, Glick ZR, Drolet BA, Frieden IJ. Nevus simplex: a reconsideration of nomenclature, sites of involvement, and disease associations. J Am Acad Dermatol. 2010;63:805–814. 2 Bettley FR. Erythema 1940;12:363–370.

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3 Klapman MH, Yao JF. Thickening and nodules in portwine stains. J Am Acad Dermatol. 2001;44:300–302. 4 Iga N, Endo Y, Fujisawa A, et al. Possible association between cutaneous angiosarcoma of the scalp and nuchal salmon patch. J Dermatol. 2013;40:1049–1050. 5 Mitsuhashi Y. Does the salmon patch reappear? Lancet. 1998;351:1034. 6 Leung AK, Telmesani AM. Salmon patches in Caucasian children. Pediatr Dermatol. 1989;6:185–187. 7 Verbov J, Steinberg R. The persistent nuchal or occipital salmon patch. Br J Dermatol. 1974;90:586–587. 8 Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978-2001: An analysis of 26,758 cases. Int J Cancer. 2006;119:2922–2930. 9 Albores-Saavedra J, Schwartz AM, Henson DE, et al. Cutaneous angiosarcoma. Analysis of 434 cases from the surveillance, epidemiology, and end results program, 1973-2007. Ann Diagn Pathol. 2011;15:93–97. 10 Smoller BR, Rose S. Port-wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122:177–179. 11 Holowatz LA, Kenney WL. Peripheral mechanisms of thermoregulatory control of skin blood flow in aged humans. J Appl Physiol. 2010;109:1538–1544. 12 Molfino A, Fiorentini A, Tubani I, et al. Body mass index is related to autonomic nervous system activity as measured by heart rate variability. Eur J Clin Nutr. 2009;63:1263–1265. 13 Chopra S, Baby C, Jacob JJ. Neuro-endocrine regulation of blood pressure. Indian J Endocrinol Metab. 2011;15:S281–S288. 14 Corson EF. Nevus flammeus: Its occurrence and abnormalities. Am J Med Sci. 1934;187:121–124.

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ORIGINAL CONTRIBUTION

15 Smith MA, Mansfield PA. The salmon patches in the first year of life. Br J Dermatol. 1962;74:31–33. 16 Kanada KN, Merin MR, Munden A, Friedlander SF. J Pediatr. 2012;161:240–245. 17 Bossard K. Die blassen Feuermale der Kinder. Jahrb f Kinderh. 1918;88:204. 18 Pratt AG. Birthmarks in infants. Arch Dermatol Syphilol. 1953;67:302–305. 19 Osburn K, Schosser RH, Everett, MA. Congenital pigmented and vascular lesions in newborn infants. J Am Acad Dermatol. 1987;16:788–792. 20 Boccardi D, Menni S, Ferraroni M, et al. Birthmarks and transient skin lesions in newborns and their relationship to maternal factors: a preliminary report from Northern Italy. Dermatology. 2007;215:53–58. 21 Pollitzer S. Tumors and Malformations of the Blood Vessels. In: Bangs LB, Hardaway WA, eds. Syphilis and Diseases of the Skin. Philadelphia, PA: WB Saunders; 1898:1009.

22 Tan KL Nevus flammeus of the nape, glabella, and eyelids. A clinical study of frequency, racial distribution, and association with congenital anomalies. Clin Pediatr (Phila). 1972;11:112–118. 23 Monteagudo B, Labandeira J, Acevedo A, et al. Salmon patch: a descriptive study. Actas Dermosifilogr. 2011;102:24–27. 24 Oster J, Nielsen A. Nuchal naevi and interscapular telangiectases. Acta Paediat Scand. 1970;59:416–423. 25 Holzammer H. Nackenflecke. Inaug Dissert. Erlangen; 1933. 26 Van der Werf E. Een onderzuck vaar huidangiomen bij schoolkinderen. Thesis. Amsterdam; 1952. 27 Zumkeller R. A propos de la frequence et de l’heredite de “Naevus Vasculosus Nuchae” (Unna). J Genet Hum. 1957;6:1–12. 28 Saalfeld E. Ueber Naevi angiomatosi in der Hinterhauptsnackengegend. Medizinische Klinik. 1910;4:145.

SKINverse: The Healing She looks through the window And what does she see A reflection of self The shadow of Me The deep-seated pain The hollow within Where to look now Where to begin Flaws in the window Is all she can see Where am I, she weeps Why don’t I see Me A teardrop reflects The sorrow, the flight And then she sees distant A soothing, bright light As softness spreads out The healings begin The crevasses yield To beauty within She looks to the window Where one used to be A doorway she sees now And cries ’tis for Me By Vesna Petronic-Rosic, MD, MSc The University of Chicago Pritzker School of Medicine, Section of Dermatology, Chicago, IL

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Volume 15 • Issue 1

REVIEW

Tattoos: Very Popular, Not So Innocent María Daniela Hermida, MD;1 Hugo Néstor Cabrera, MD2,3 Abstract Tattooing is a popular practice worldwide. Its origin dates back to the year 5000 BCE with a frozen mummy and travels across time through diverse cultures and places until it reaches the modern occidental world. Inks and materials used for tattooing are poorly controlled and carry potential risks of skin reactions. The procedure itself is also not innocuous. In this review, different types of tattoos are mentioned and associated dermatologic conditions are discussed. Unfortunately, treatment and removal procedures are often poor in effectiveness and lead to unwanted results. Combining different lasers may be a suitable option that requires further investigation. (SKINmed. 2017;15:37–42)

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attooing has been a form of body art since ancient times. The first evidence of a human tattoo was found in 1991 on a frozen mummy known as the “Iceman” who is thought to have lived 5200 years ago on the Italian-Austrian border. Ötzi, as he was called, had several tattoos on his back and over his knees and ankles, consisting of simple lines made from rubbing powdered charcoal into small cuts.1,2 Scientists believe tattooing served medical purposes, because the marks were over joints that showed bone degeneration. Female Egyptian tattooed mummies and figurines dating between 4000 and 1300 BCE were also identified, as well as small bronze instruments used for tattooing. The significance of these marks is uncertain, although there is evidence to suspect that they served as protective amulets during pregnancy or birth, because they were located over the abdomen, breasts, and thighs and were found only on women.1

with sailors and lower class members or even criminals. Soon, it spread over Europe. Martin Hildebrandt, a German who arrived in Boston, was the first professional tattooer to practice in the United States in 1846. He tattooed soldiers on both sides of the Civil War. In 1891, a New York inventor named Samuel O’Reilly patented the first electric tattooing machine.1

Japanese used tattoos for identifying social status, criminal activities, and religious practices and casting out selected individuals from society.3

Amateur tattoos (Figure 1) are those that are performed with home or self-made instruments, usually needles, often in black, due to the application of some form of charcoal into the dermis.

Polynesians perfected the art to the point of covering their entire bodies with drawings,1,2 and the word “tattoo” derives from Tahitian “tatau,” which means tapping a mark into the body.1 It was first introduced by Captain James Cook around 1770 after his voyages to Polynesia. These overseas expeditions were the connecting bridge between ancient tribal and modern tattooing, as this practice was soon acquired by the crew.3 By the 19th century, tattooing was well recognized in Britain, mostly associated

Professional tattoos are those that are often carried out by an experienced tattooer with electric tattooing machines and special instruments. By no means does the word “professional” refer to the fact that this activity has regulatory measures. On the contrary, it presents a public health issue.

Currently, it has become a popular practice worldwide and has different meanings for each individual in accordance with religious beliefs, music affinities, personal matters, or other interests. Types of Tattoos There are several kinds of tattoos based on the skills of the performer or the elements used for the procedure.

Cosmetic tattoos (Figure 2) usually serve the purpose of enhancing or correcting facial features and act as permanent makeup.

From the Department of Dermatology, Center of Medical Education and Clinical Investigation,1 and Department of Dermatology, Hospital Nacional Prof. A. Posadas (former chairman),2 and the University of Buenos Aires,3 Buenos Aires, Argentina Address for Correspondence: María Daniela Hermida, MD, Talcahuano 1234 (C1014ADB) Ciudad de Buenos Aires, Argentina • E-mail: mdhermida@gmail.com

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Accidental tattoos (Figure 3) appear after unintentional (or not) laceration of the skin against a surface or element, such as a pencil, that can pass pigment into the dermis or gingiva in the case of amalgams. Medical tattoos are made to guide radiotherapy treatments or replace pigments in the case of vitiligo or reconstructive breast surgery. Identification tattoos deserve to be mentioned, as they represent those that were made by the Nazis during the holocaust to mark the victims of concentration camps. Today, some descendants of Jewish prisoners, such as grandchildren, acquire a similar tattoo on themselves as a tribute to their relatives. Inks, Pigments, and Potential Health Risks

Figure 1. Amateur tattoo performed by the patient with a needle and black ink.

Inks and pigments used in tattoos are impure mixtures of chemicals that contain heavy metal oxides, salts, organic molecules and dyes, or herbal extracts. Additional ingredients are added to obtain an ink suitable for tattooing; nevertheless, there is no control of the application of these products, and they are not regulated by the Food and Drug Administration.4 Examples of these compounds are shown in Table I. Modern inks are often commercialized on the internet and at tattoo conventions and mostly include azo-pigments and polycyclic compounds, which are manufactured primarily for other purposes. These are classified by their chemical constitution, around 60% being azo-pigments, and there are some well-known carcinogens on the list.4

Figure 2. Cosmetic tattoo for lip lining with lichenoid papules over the pigmented line.

Black inks, derived from soot, comprise carbon-based products that often contain polycyclic aromatic hydrocarbons. Most of these compounds are well-known carcinogens that produce free oxygen radicals when exposed to UV light, which may cause subsequent tissue damage.5 The relationship between the size of the tattoo and the amount of pigment injected to produce color is believed to be important. Metallic salts traditionally used for tattooing, such as mercury for red (cinnabar), cobalt for blue, chromium for green, and magnesium for purple, are currently less common (azo-pigments replaced these compounds), but dermatologists may see their adverse effects, because complications can appear years after these tattoos were performed.3 Of all the colorants applied, most cutaneous lesions are triggered by red ink, which often contains mercury that is responsible for many of the hypersensitivity reactions.6 Cosmetic tattoos frequently need brown, red, and pink pigments, which contain ferric oxide.7 SKINmed. 2017;15:37–42

Figure 3. Accidental gingival tattoo over amalgam (arrow).

The histopathology of tattooed skin shows free dermal pigment as well as macrophages containing pigment particles. The amount of pigment found depends on the procedure and the

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Table I. Compounds Found in Tattoo Inks8 Black Inks

Colored Inks

Used for Whitening

Residues, Impurities, and Decomposition Products

Carbon black Iron

Monoazo pigment Disazodiarylide Naphthol AS pigment Quinacridone Dioxacine Cu-phthalocyanine Cu/Al-phthalocyanine-BrxCly Mercurya Cadmiuma Cobalta Chromea

Titanium dioxide Aluminium

Naphthol AS 2-Methyl-5-nitroanilina 2-5-Dichloraniline 4-Nitrotoluene Policyclic aromatic hydrocarbons Phenol Benzophenone Dibenzofuran Methenamine Dibutyl phthalate Hexachloro-1,3-butadiene

Inorganic salts.

a

age of the tattoo. Older tattoos show less free pigment and more pigmented perivascular macrophages. It is well established that pigment metabolism occurs and is transported to lymph nodes, sometimes mimicking melanoma metastases. Dermatologic Complications From Tattooing Complications that arise from skin tattooing may vary in form and severity.8 As a first approach to classify these reactions, we can divide them into immediate or delayed. The former often occur within the first month of having performed the tattoo, and the latter can follow an immediate reaction or appear de novo even many years after the procedure. These are often very difficult to treat and leave permanent scars or unwanted aesthetic results. Clinically, three main groups of dermatologic complications can be identified: infectious reactions, allergic/hypersensitivity reactions, and coexistent findings. Infections The tattooing procedure itself represents a risk for acquiring an infection, as the skin barrier is disrupted. Asepsis regarding not only the instruments and inks but also the place where the tattooer works is not always guaranteed. The healing process also produces itching and secondary impetiginization of the wounds. Bacterial infections, such as impetigo, folliculitis, erysipelas, and cellulitis, are not uncommon and are often produced by Staphylococcus aureus or Streptococcus pyogenes. These often respond well to antibiotics, but systemic compromise and sepsis have been documented in the literature.9,10 There have been cases of community-acquired SKINmed. 2017;15:37–42

methicillin-resistant S aureus infections.11 Tinea corporis is an uncommon complication that can also arise after tattooing. Evidence of viral disease transmission, such as human papilloma virus, molluscum contagiosum, herpes virus, hepatitis B and C, and even human immunodeficiency virus, have also been reported;8,12,13 moreover, there have been reports of mycobacteriosis outbreaks due to ink contamination before the container was even opened in a group of patients tattooed in the same facility.14,15 Hypersensitivity reactions The fact that the colorant acts as a permanent intradermal foreign body gives rise to a spectrum of delayed hypersensitivity reactions (Table II). These are often lichenoid, pseudolymphomatous, and granulomatous.16 Lichenoid reactions may present as erythematous papules or plaques with a scaly surface frequently accompanied by pruritus (Figure 4). Microscopic examination shows vacuolization of junctional keratinocytes and a band-like lymphocytic infiltrate with admixed pigment. Granulomatous processes can show erosions or ulcerations on the surface (Figure 5). They may represent foreign body granulomas, in most cases, or sarcoidal granulomas, which eventually occur in patients with systemic sarcoidosis. The granulomatous process over the tattoo can precede systemic manifestations acting as a traumatic triggering factor. Ruling out mycobacteriosis is essential in these cases. Pseudolymphomatous reactions clinically show red or violaceous papules, plaques, or nodules with a smooth surface (Figure 6). These cutaneous lymphoid hyperplasias have B- or T-cell infiltrates with follicle formation or lichenoid T-cell lymphoma-like histopathology. Immunological and genetic receptor arrangement studies demonstrate that the infiltrate is composed of polyclonal cell populations.

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Table II. Types of Hypersensitivity Reactions Type of Reaction

Clinical Findings

Histopathological Findings

Lichenoid reactions

Erythematous papules and plaques, scaly surface

Basilar keratinocytic vacuolization and band-like lymphocytic infiltrate

Granulomatous processes

Erythematous lesions with ulcerated surface or erosions

Foreign body or sarcoidal granulomas

Pseudolymphomatous reactions

Smooth-surfaced red violaceous plaques or nodules

Cutaneous lymphoid hyperplasia with polyclonal cellularity

Figure 4. Lichenoid reaction over red ink. Fine white scales covering an indurated plaque.

Figure 5. Granulomatous tattoo reaction with erythematous erosive lesion.

There are also investigations reporting vasculitis (Figure 7) and psoriatic eruptions (representing a Koebner phenomenon) among others.6,17 Sometimes, there is considerable clinical overlap between these reactions, and coexistence of two pathologic findings, such as lichenoid infiltrates with underlying dermal granulomas, is not uncommon (Figure 8). Temporary henna tattoos, a well-known ritual used frequently in Indian weddings, also present risks, because the mixture to prepare the black dye often includes paraphenylenediamine, a potent skin sensitizer. Allergic contact dermatitis can occur after the sensitization has taken place. The clinical picture is a blistering eruption over the tattooed surface.18 As it is advertised as temporary without the risks of permanent tattoos, this practice is often carried out in children.19

Neoplastic-associated lesions

All of these clinical complications are difficult to treat because the pigments cannot be removed effectively. Topical high-potency or intralesional corticosteroids are often the first therapeutic measures employed, often showing poor results.

There have been multiple reports of neoplastic lesions arising from tattoos. Skin trauma appears to be a triggering factor in these cases but it is not the only postulated etiological theory. Carcinogens present in tattoo inks and their relationship with

SKINmed. 2017;15:37–42

Figure 6. Cutaneous lymphoid hyperplasia over the red ink of a bicolour tattoo.

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REVIEW for its specific treatment, especially in the case of melanoma, and its recognition can be challenging; moreover, results from sentinel lymph node biopsy may be misleading due to the presence of pigment within the lymph nodes, and clinical follow-up of patients is often difficult. Removing Tattoos

Figure 7. Leukocytoclastic vasculitis after the patient had a second tattoo. Hemorrhagic blisters are shown.

Removal procedures are not only sought for treating a medical condition but also for a patient’s desire to have a tattoo removed. A study that analyzed motivations for tattoo removal revealed that most patients were women who acquired tattoos at a younger age. For these patients, the meaning of the tattoo has changed, and they feel that it is no longer socially acceptable, as they no longer interact in the same social circle.22 Ablative procedures, such as microdermoabrasion, chemical peelings, and ablative lasers, have been used but frequently leave unwanted scars, which are cosmetically undesirable. Laser tattoo removal is currently the best option but does not prove to be successful in all cases.23 The most effective lasers for this purpose are Q-switched ruby, alexandrite, or Nd:YAG. These all work with very short pulses, in the nanosecond range, which is more suitable to destroy pigment particles without further damage to the surrounding tissue, according to the selective photothermolysis theory described by Anderson and Parrish.24,25 In a multicolor tattoo, one or two lasers can be used to achieve complete removal of the picture. The different wavelengths of these lasers can be combined to treat more than one color (Table III).7,24 Yellow and orange pigments are very difficult to remove.

Figure 8. Lichenoid subepidermal infiltrate and granulomatous reaction in the same lesion over a red tattoo.

UV light exposure could be important in the development of skin tumors,17 and there has been a case of a B-cell lymphoma presenting over a pseudolymphomatous tattoo reaction.20 Further investigation is needed to demonstrate a clear tattoo-cancer relationship. Patients presenting with melanocytic nevi in a tattooed area are especially difficult to follow up, because clinical examination tends to be hindered. Dermatofibromas, keratoacanthomas, basal cell carcinoma, squamous cell carcinoma, melanoma, and others have all been found over tattooed skin.4 Keratoacanthomas have been shown to appear over the red ink component and therefore the causative factor is more clear;21 nevertheless, the appearance of a neoplastic lesion over tattooed skin is a drawback SKINmed. 2017;15:37–42

Picosecond lasers have been recently developed and since pulse duration is so short, they are more effective for removing pigment. Currently the use of 755, 1064, and 1064/532 nm picosecond lasers are the best option available for this purpose.26,27 Several adverse effects have been reported after laser treatments for tattoos. One of the most common is residual hypopigmentation, but ink dispersion to the surrounding skin, systemic allergic reactions, and augmentation of the color being removed are well-known complications.24,28 This usually happens with titanium dioxide in white and flesh-colored inks and is due to the oxidation of ferric oxide present in brown and red pigments.24 Conclusions As dermatologists, we should consider the full spectrum of clinical reactions that arise from tattoos and, because this practice is increasing, advice against tattooing should be provided to all patients. The fact that an unregulated product is introduced into the skin is not to be disregarded and should be em-

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REVIEW 11 Centers for Disease Control and Prevention (CDC). Methicillin-resistant Staphylococcus aureus skin infections among tattoo recipients––Ohio, Kentucky, and Vermont, 2004–2005. MMWR Morb Mortal Wkly Rep. 2006;55:677– 679.

Table III. Types of Q-Switched (QS) Lasers Used for Tattoo Removal, Corresponding Wavelengths, and Ink Colors That Respond Best to Each Treatment Laser

Wavelength, nm

Ink Color

QS ruby

694

Dark blue, black

QS Nd:YAG

1064

Black

QS Nd:YAG

532

Red, brown

QS alexandrite

755

Green, black

12 Carney K, Dhalla S, Aytaman A, et al. Association of tattooing and hepatitis C virus infection: a multicenter case-control study. Hepatology. 2013;57:2117–2123. 13 Jafari S, Buxton JA, Afshar K, Copes R, Baharlou S. Tattooing and risk of hepatitis B: a systematic review and meta-analysis. Can J Public Health. 2012;103:207–212. 14 Drage LA, Ecker PM, Orenstein R, et al. An outbreak of Mycobacterium chelonae infections in tattoos. J Am Acad Dermatol. 2010;62:501–506.

phasized. Very few patients come to our offices before visiting a tattoo parlor, but those who have, leave with a clear picture of the possible consequences. If they carried out their purpose, they would have asked for black ink, as it would have minimized the risks of having an unwanted reaction. With that, the decision to get a tattoo is already made the moment a person starts enquiring about it, as it represents the need to expose a feeling or a thought that is at the time so important as to engrave it in one’s body. References

15 Le Blanc P, Hollinger K, Klontz K. Tattoo ink-related infections––awareness, diagnosis, reporting, and prevention. N Engl J Med. 2012;367:985–987. 16 Shinohara MM, Nguyen J, Gardner J, et al. The histopathologic spectrum of decorative tattoo complications. J Cutan Pathol. 2012;39:1110–1118. 17 Hermida MD, Otero M, Della Giovanna P, et al. Cutaneous vasculitis following an intradermal tattoo. J Eur Acad Dermatol Venereol. 2007;21:1268–1269. 18 Evans C, Flaming J. Images in clinical medicine. Allergic contact dermatitis from a Henna tattoo. N Engl J Med. 2008;359:627. 19 Suárez Fernandez R, García P, Chavarría E, Lázaro P. Allergic contact eczema caused by henna tattoo. Allergol Immunopathol (Madr). 2002;30:292–294.

1 Franklin-Barbajosa C. Tattoo: pigments of imagination. National Geographic Magazine Online Extra. http://ngm. nationalgeographic.com/ngm/0412/online_extra.html. Accessed November 10, 2013. 2 Lineberry C. Tattoos. The ancient and mysterious history. http://www.smithsonianmag.com/history/tattoos-144038580/. Accessed November 10, 2013.

20 Sanueza OP, Yadav S, White CR Jr, et al. Evolution of B-cell lymphoma from pseudolymphoma. A multidisciplinary approach using histology, immunohistochemistry, and Southern blot analysis. Am J Dermatopathol. 1992;14:408–413.

3 Wikipedia Web site. History of tattooing. https:// en.wikipedia.org/wiki/History_of_tattooing. Accessed April 1, 2014.

21 Vitiello M, Echeverria B, Romanelli P, et al. Multiple eruptive keratoacanthomas arising in a tattoo. J Clin Aesthet Dermatol. 2010;3:54–55.

4 Kluger N, Koljonen V. Tattoos, inks, and cancer. Lancet Oncol. 2012;13:e161–e168.

22 Armstrong M, Roberts A, Koch J, et al. Motivation for contemporary tattoo removal: a shift in identity. Arch Dermatol. 2008;144:879–884.

5 Regensburger J, Lehner K, Maisch T, et al. Tattoo inks contain polycyclic aromatic hydrocarbons that additionally generate deleterious singlet oxygen. Exp Dermatol. 2010;19:e275–e281. 6 Jacob C. Tattoo-associated dermatoses: a case report and review of the literature. Dermatol Surg. 2002;28:962–965 7 Ortiz A, Alster T. Rising concern over cosmetic tattoos. Dermatol Surg. 2012;38:424–429. 8 Wenzel S, Rittmann I, Landthaler M, et al. Adverse reactions after tattooing: review of the literature and comparison to results of a survey. Dermatology. 2013;226:138– 147 9 Tse D, Khan S, Clarke S. Bacterial endocarditis complicating body art. Int J Cardiol. 2009;133:e28–e29. 10 Korman T, Grayson M, Turnidge JD. Polymicrobial septicaemia with Pseudomona aureginosa and Streptococcus pyogenes following traditional tattooing. J Infect. 1997;35:203.

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23 Bencini P, Cazzaniga S, Tourlaki A, et al. Removal of tattoos by Q-switched laser: variables influencing outcome and sequelae in a large cohort of treated patients. Arch Dermatol. 2012;148:1364–1369. 24 Kent K, Graber E. Laser tattoo removal: a review. Dermatol Surg. 2012;38:1–13. 25 Anderson R, Parrish J. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science. 1983;220:524–547. 26 Ibrahimi OA, Sakamoto FH, Anderson RR. Picosecond laser pulses for tattoo removal: a good, old idea. JAMA Dermatol. 2013;149:241. 27 Reiter O, Atzmony L, Akerman L, et al. Picosecond lasers for tattoo removal: a systematic review. Lasers Med Sci. 2016;31:1397–1405. 28 Ortiz A, Avram M. Redistribution of ink alter laser tattoo removal. Dermatol Surg. 2012;38:1730–1731.

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SELF ASSESSMENT EXAMINATION

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD 3. Tumors associated with tattoos include: (Choose as many as apply. All, some, one, or none of the lettered responses may be correct.) a. Basal cell carcinoma. b. Dermatofibroma. c. Keratoacanthoma. d. Malignant melanoma. e. Squamous cell carcinoma.

Instructions: For each numbered question, choose the single most appropriate lettered response, unless otherwise directed. 1. Temporary henna tattoos, a well-known ritual frequently performed in association with Indian weddings: a. Are not associated with any side effect and may be safely administered to children. b. May be associated with anaphylactic shock related to the potent skin sensitizer balsam of Peru present in the tattoo. c. May be associated with allergic contact dermatitis related to the potent skin sensitizer paraphenylenediamine present in the tattoo. d. May be associated with allergic contact dermatitis related to the potent skin sensitizer tubocurare present in the tattoo. e. May be associated with renal failure related to the potent skin sensitizer balsam of Peru present in the tattoo.

4. A tattoo using which of the following color inks has the least likelihood of having an unwanted reaction? a. Black ink. b. Orange ink. c. Red ink. d. Yellow ink. e. A tattoo using any color ink is equally likely to have an unwanted reaction.

ANSWERS TO EXAMINATION: 1. c; 2. a, b, c, d, e; 3. a, b, c, d, e; 4. a; 5. e.

2. Infections associated with tattoos include those due to: (Choose as many as apply. All, some, one, or none of the lettered responses may be correct.) a. Bacteria. b. Hepatitis B virus. c. Hepatitis C virus. d. Herpes viruses. e. Human immunodeficiency virus.

5. If a patient inquires about having a tattoo done, the best advice you can give him/her is (to): a. Avoid tattoos using any color ink. b. Avoid tattoos using green ink. c. Consider the expense since it is unlikely that the patient’s health insurance will cover the cost. d. Have it done only by a certified tattooist. e. Not to do it.

VINTAGE LABEL

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

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January/February 2017

Volume 15 • Issue 1

Core curriculum Virendra N. Sehgal, MD, FNASc, FAMS, Section Editor

Leprosy: Trophic Skin Ulcers Najeeba Riyaz, MD, FRCP (Glasgow); Virendra N. Sehgal, MD, FNASc, FAMS

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Approximately 30% of patients with leprosy develop nerve damage. Trophic, or neuropathic, ulcer is a common complication of an anesthetic foot. The term plantar, trophic, or perforating ulcer was introduced in 1959. It was defined as a chronic ulceration of the anesthetic foot, situated in well-defined areas overlying bony prominences, resistant to local and/or systemic therapy, and characterized by a marked tendency to recur. It is responsible for much of the morbidity associated with leprosy. (SKINmed. 2017;15:45–51)

T

moderate degree, causing inflammation and autolysis; and (5) pressure on the infected tissue, resulting in spread of infection.4,5

he proportion of new cases presenting with World Health Organization (WHO)1 grade 2 disability ranges from 6% to 21%. Among major endemic countries, plantar ulceration is the most common disability. It occurs in about 10% to 20% of patients with leprosy,2 with the front part of the foot accounting for 71% to 90% of plantar ulcers. Its medial part is more vulnerable than the lateral part. The proximal phalanx of the large toe is the most common site for trophic ulcers.3 Pathogenesis

Ten percent of the ulcers arise from perceived or unperceived neglected injuries resulting in infection and tissue damage, and 5% arise from neglect of deep cracks in the dry, anhidrotic, and hyperkeratotic skin of the sole or from infection underneath callosities or corns through fine cracks. The majority of plantar ulcers6, however, arise from breakdown of plantar subcutaneous tissue due to the stress and strain of normal walking.

Anesthesia of the foot is the central factor in the pathogenesis of plantar ulcers. An anesthetic foot is “ulcer-liable,” and ulceration of the foot makes it “ulcer-prone,” producing a cycle of scarulcer-scar. Plantar anesthesia, unprotected walking, poor quality of scar formation resulting from previous ulceration, excessive load on the scar, and persisting foci of infection are some of the main factors for the recurrence of plantar ulcers.3 The pathogenesis of plantar trophic ulcers has been extensively investigated. Five mechanisms that produce damage to insensitive tissues include: (1) continuous pressure, causing necrosis due to lack of blood supply; (2) concentrated high pressure, causing cutting/crushing by mechanical violence; (3) heat/cold, causing burning or frost bite; (4) repetitive mechanical stress of

All plantar intrinsic muscles exert their effect in the region of the metatarsophalangeal joints. When these muscles are paralyzed, the compression and shearing forces are increased, even during normal walking. The plantar intrinsic muscles are maximally active during the “push-off” stage of walking, when the forepart of the foot pushes the ground backward in order to propel the body forward. Their contraction creates a thrust that counters the compressive, shearing, and distracting forces at the metatarsophalangeal joint region that are normally generated at this stage of walking. When the plantar intrinsic muscles are paralyzed, this protective effect is lost, and the toes get clawed during the push-off stage of walking, causing momentary increases in stress and strain in the region of the metatarsophalangeal joint at each step. Even small increases in stresses can lead to breakdown of tissue if repeated long enough, causing ulceration.6

From the Department of Dermatology Government Medical College Calicut Kerala, Dermato-Venereology (Skin/VD Centre), Sehgal Nursing Home, Delhi, India Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, Dermato-Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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core curriculum

The pathogenesis of plantar ulcers is unique and includes three stages: • Stage of threatened ulcer: This is called the preulcerative stage of aseptic inflammation. Increased stress exerted over a period gives rise to a traumatic (aseptic) inflammation in the subcutaneous layer of the sole, which is most vulnerable to mechanical stress. This usually occurs under a joint or a bony prominence just distal to the head of a metatarsal. The affected site is edematous. This is seen as a mild or obvious splaying of a toe, which stands apart from other toes. The affected site is often tender to deep digital pressure. • Stage of concealed ulcer: This is the stage of the necrotic blister. The inflamed site undergoes necrosis due to the stress of continued walking, with the subcutaneous tissue undergoing necrosis. The liquefied tissue mixed with blood is forced to the surface by continued walking to present as a blister. This usually overlies the area of necrosis, but sometimes the overlying tissue is too tough that it may track along a path of least resistance and emerge to the surface at a distance, at the side of the toe or in the interdigital web. This stage may go unnoticed. With the formation of the necrotic blister, the destruction of the subcutaneous tissue is complete, except that the “ulcer” is not seen or obvious because it is still covered with skin.

Figure 1. Leprosy, trophic skin ulcers: an initial stage depicting erythema, edema, scaling, and pigmentation on the sole of the right foot.

• Stage of overt or open ulcer: This is the stage when the skin overlying the blister breaks open and the necrotic area becomes exteriorized.6 Clinical Connotation Every ulcer passes through a set of events before becoming indolent. The first stage is acute ulceration, accompanied by pain and inguinal lymphadenopathy. With rest and antibiotics, the ulcer may improve. Due to the underlying tissue damage, however, the ulcer heals with scaring, which may frequently break down and result in chronic ulceration. An ulcer becomes complicated due to spread of infection into the deeper structures with associated paralysis of the foot muscles and fixed deformities resulting from bone and joint infection. Old healed or latent ulcers break down and fresh ones appear (Figures 1–4). These ulcers resist routine treatment, and the foot becomes the site of recurrent plantar ulceration.7

Figure 2. Leprosy, trophic skin ulcers: an initial stage displaying erythema, edema, and pigmentation affecting the soles.

edges of the ulcer become swollen, the edema being more over the dorsum even when the infected site is in the sole. There is copious discharge of pus/serosanguineous fluid. The floor of the ulcer is often covered with necrotic tissue. There may be associated inguinal adenitis, lymphangitis, and fever. Polymorphonuclear leukocytosis is common. The ulcer presenting with acute inflammation is often referred to as an “acute ulcer.” Initially, the infection and inflammation are

A trophic ulcer, which is often painless, does not typically bother the patient. It may enlarge without healing for weeks or months. When acutely infected, the area including the SKINmed. 2017;15:45–51

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core curriculum Usually this stage of acute inflammation subsides with treatment, and the ulcer may heal. After initial improvement, the ulcer may sometimes recur and persist as a small raw area, a “chronic ulcer.”6 Chronic ulcers have scanty discharge, hyperkeratotic edges, and a hard fibrosed base and floor covered with pale unhealthy granulation tissue. Differential Diagnosis The differential diagnosis of trophic ulcers8 includes other neurogenic ulcers, arterial ulcers, venous ulcers, and ulcers due to systemic causes. Other neurogenic ulcers are due to diabetic neuropathy, syringomyelia, spina bifida, and pressure sores. Vascular causes include peripheral arterial disease, microangiopathy, atherosclerosis, and stasis ulcers. Systemic causes of ulceration are vitamin B12 deficiency, severe avitaminosis, and gouty ulceration. There is a high incidence of plantar ulceration in patients with diabetes.9 Risk factors include deformed insensitive feet, high foot pressure when standing and walking, reduced blood flow in feet and calves, and uncontrolled hyperglycemia. Excessive plantar pressure from diabetic peripheral neuropathy is one of the primary risk factors for foot ulceration.10 Even in the absence of peripheral vascular disease, patients with peripheral neuropathy have a seven-fold increase in foot ulceration11 probably caused by persistent poor microcirculation and high plantar pressure.12 One study found that 40% of ulcerations were located at the first metatarsal, 40% at the second to fifth metatarsals, and 20% at the great toe.13 The incidence of heel ulceration14 was found to be 13% in a population of 314 individuals. In another study, 11% of patients with diabetes had heel ulcers, hypothesizing that the plantar surface rarely experiences pressure ulceration in individuals with diabetes.15 Heel ulcerations, however, are directly correlated with peripheral neuropathy and impaired vascular status.

Figure 3. Leprosy, trophic skin ulcers: break in the skin apparent as an ulcer with well-defined margins.

Treatment Trophic ulcers can remain for several years even after the initial infection is resolved. The most important causal factor for neuropathic foot ulcers is the presence of dynamic or static deformities leading to local areas of peak pressure on insensitive skin, well-illustrated by pressure studies.13 This repetitive overload on specific areas of the sole could partially explain why plantar ulcers are deeper and smaller than leg and ankle ulcers.

Figure 4. Leprosy, trophic skin ulcers: an explicit ulcer on the sole.

confined to the subcutaneous tissue without extending to deeper tissue or structures such as bones, joints, or tendon sheaths. This is called a “simple” or “uncomplicated ulcer.” SKINmed. 2017;15:45–51

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Treatment should aim at wound management, correction of deformity, restoration of sensation, reconstitution of normal skin, elimination of abnormal pressures, and eradication of deep-seated infections.7 Leprosy: Trophic Skin Ulcers


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core curriculum

Wound management Wound management begins with debridement. Surgical debridement should be aggressive to remove surrounding hard callus, hyperkeratotic skin, and necrotic tissue, resulting in soft, nonkeratotic wound edges with a well-vascularized tissue bed. After debridement, wound bed preparation is performed for complete healing. Deep tissue culture should be performed during debridement. Systemic antibiotics, oral and/ or parenteral, are required in the acute infective phase, in the presence of cellulitis or failure of a properly treated wound to heal. Topical antimicrobials help to eliminate bacteria in the ulcer. Osteomyelitis is ruled out by probing the ulcer. If bone can be reached during probing, the patient most likely has developed osteomyelitis. Bone probing has a positive predictive value of 89%. Radiography should be performed in all cases. Magnetic resonance imaging and bone biopsy are the best tools for confirming osteomyelitis when probing findings are negative. A moist wound environment facilitates rapid migration of keratinocytes into the wound bed; hence, wounds should be kept as moist as possible, while avoiding maceration of the surrounding tissues, by constant irrigation or by using an intermittent spray. The recent advent of phenytoin sodium fine powder zinc paste16 has added an innovative dimension in the management of leprosy trophic skin ulcers, purported to recommend the formation of granulation tissue and/or re-epithelialization as a vital parameter in wound healing. Advanced moist wound therapy Advanced moist wound therapy8 can be given with hydrogels and alginates. The silver barrier dressings destroy bacteria in the wound. The antimicrobial barrier is effective for up to 3 days. Exudative wounds are dressed with hydrocolloid dressings, which can absorb the exudate. Dressing selection should be reassessed at regular intervals. Off-loading pressure Off-loading pressure is the key to successful management of a trophic ulcer. It can be achieved by strict bed rest and use of crutches, wheel chairs, or walkers. Pressure-reducing measures such as air cushions, waterbeds, plaster boots, total contact casting, removable contact casting, half shoes, or specialized footwear are also useful. Off-loading devices are not that useful if they are not used consistently or if compliance is poor. Uncomplicated plantar ulcers can heal in approximately 6 to 8 weeks with strict off-loading. The best off-loading device is a total contact cast (TCC)/plaster boot. TCCs should be applied only after SKINmed. 2017;15:45–51

debridement and removal of all dead tissue. Its greatest advantage is that it is a nonremovable device and thus eliminates the problem of unreliability. The drawbacks of TCCs are that they are technically demanding and, if wrongly applied, can lead to more ulcers. They do not allow for daily inspection and cannot be used in ischemic ulcers. The problem of a removable plaster cast is that patients tend to remove it more often, and the offloading becomes unreliable. A new technique for the management of plantar ulcers has been described.17 In this technique, plaster casing with a window and a walking iron for weight bearing is used. The advantage is that dressing can be accomplished through the window, and the patient can be ambulatory with the walking iron. This helps in early mobilization and prevents secondary complications such as foul-smelling discharge, decalcification of bone, and other complications. Bioengineered tissue and growth factors have been used to enhance healing. Examples include artificial skin made from fibroblasts cultured from newborn foreskin and woven poligalacticacid mesh.18,19 Growth factors are proteins secreted by a variety of cell types during the different phases of wound healing such as basic fibroblast growth factor,20 epidermal growth factor,21 and platelet-derived growth factor.22 Becaplermin is the first recombinant formulation containing platelet-derived growth factor. Surgical options8 for reconstruction should be considered for complicated ulcers with exposed bone or tendons and for nonhealing ulcers even after conservative management for 2 months. They can range from skin grafts to local regional or free flaps depending on the available donor tissue and the requirements of the defects. For smaller defects, however, the best method of resurfacing plantar ulcers is by using local tissue. While for medium-sized defects, plantar artery skin fascia flap by Eiffel, a medial plantar flap with a lateral plantar pedicle by Martin, and reverse medial plantar artery flap by Gravem,2 are useful adjuncts. Advancement flaps, including both approximation and V-Y advancement flap, rotation flap, or a first toe web flap can be used for revision of scar in the forefoot. Island and rotation flaps are helpful in heel scar revision. Availability of a large nonweight-bearing area facilitates rising of transposition and island flaps for scar revision in the midfoot.3 Low-level laser therapy (LLLT)23 has been used to accelerate wound healing since the late 1960s, but its results are controversial. One study24 evaluated the use of LLLT in the treatment of leprosy ulcers with 66% cure; however, a systematic A Cochrane review25 did not find evidence of improvement in wound heal-

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core curriculum Patients should also be advised regarding safe limits of walking and the distance in which the patient can walk without damaging the foot. After walking for some known distance, the patient should rest for about 20 minutes and examine the feet for signs of internal damage, persistent warmth, swelling or blistering, burning sensation, or tenderness. The presence of some or all of these signs indicates that the foot has been damaged and that the distance walked has exceeded the safe limit for that foot. Patients should be advised not to walk beyond a safe limit.31

ing related to LLLT. In one study,26 LLLT did not demonstrate any additional benefit to ulcer healing when compared with the control group. Prevention of trophic ulceration Delayed diagnosis, lack of appropriate treatment, and failure in control of leprosy reactions contribute to the occurrence of nerve damage and neuropathic ulcers in patients with leprosy. The prevention of trophic ulceration in anesthetic feet largely depends on the even distribution of pressure over the sole of the foot. The purpose of molding the sole of the shoe to the curvature of the foot is to distribute pressure over more of the plantar surface of the foot. Accurate molding to all contours of the foot is not advisable, because the foot moves inside the shoe. An arch support provides a simple and generally applicable approach to molding. A metatarsal bar provides another practical approach to better pressure distribution. A shoe with a rigid sole pivoting on a rocker near the center of the foot most effectively reduces pressures under the forefoot of shortened, deformed feet. The use of insoles made of microcellular rubber is recommended. It is important to fit each shoe to the patient with a pressureindicating footprint for guidance.27

Daily foot checks should be part of the patient’s routine from a preventive aspect. Fungal and bacterial infections of the toenails should be looked for and treated accordingly. Routine grooming of the nails and feet should be performed in all cases of neuropathic feet. This includes regular trimming of nails, treatment of ingrown toenails, and application of skin creams to keep the skin and nails soft. Regular chiropodist care is effective in preventing ulcers in high-risk individuals.8

Protective footwear including sports shoes have a definite role in the protection of feet with sensation loss.28 A total of 506 patients received footwear in a prevention of disability project, of which 122 patients with plantar ulcers achieved healing within 1 year of the project and 75% had reduction within the 3-year period.

Cigarette smoking reduces the rate of oxygen intake and delivery to the wound site and retards wound repair. Nicotine, carbon monoxide, and hydrogen cyanide in the smoke also have a toxic effect on platelets and inhibit normal cellular metabolism, which may affect healing. Smoking may cause vasoconstriction and accelerate the development of atherosclerosis.8

Self-care in the presence or absence of medical supervision is important for prevention of trophic ulcers. Self-care can be defined as “the range of behavior undertaken by the individuals to promote or restore health,” or “the process of enabling people to increase control over, and to improve, their health.” In selfcare, the affected persons take control of the management of their condition. They are supported by a team of health and social care facilitators who empower individuals to solve problems themselves.

Record keeping is an essential part of management as it keeps the treating surgeon and the patient aware of the progress. It should be performed by photographic record of the ulcers and documenting the length, breadth, and depth of the ulcer at weekly intervals. If the patient is on a home care regimen, the caregivers at home can record measurements. It helps to objectively analyze healing and motivates patients towards self-care.8

Self-care in the prevention of disability in leprosy is one of the prime components in the WHO Global Strategy29 for reducing the leprosy burden and sustaining quality leprosy services. Self-care measures should include care of dry, denervated skin of the palms and soles in order to prevent wounds, ulcers, and skin cracks. Prevention of occupational30 injuries, such as burns caused by handling hot objects, should be an important aspect of the counseling of individuals with sensory loss in the limbs.

Patient education empowers the patient and their caregivers toward preventive measures. All high-risk individuals should have the benefit of disease-specific education by the primary physician, books, pamphlets, videos, and/or disease support groups. Hence, it is worthwhile to summarize the instructions to prevent trophic ulcer:

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• Explanation in simple terms about their specific pathology • Lifestyle changes to prevent progression of disease and its consequences • Cessation of smoking • Regular podiatric care • Strict glycemic control in patients with diabetes Leprosy: Trophic Skin Ulcers


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• Compression treatment for varicosities • Daily end-of-day check of hands and feet for signs of breakdown • Self-monitoring of sole/fingertip temperature

9 Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293:217– 228. 10 Bild DE, Selby JV, Sinnock P, et al. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care. 1989;12:24–31. 11 Litzelman DK, Marriott DJ, Vinicor F. Independent physiological predictors of foot lesions in patients with NIDDM. Diabetes Care. 1997;20:1273–1278.

• Specialized footwear for off-loading pressure • Regular follow-up even if there are no ulcers Anesthetic feet are at risk for developing ulcers, and once ulceration has occurred, recurrence is likely. This cycle of events may ultimately result in mutilation of the foot but can be arrested at any stage provided that prompt and adequate treatment is given and suitable measures are taken to prevent recurrence of ulcers. In such patients, even the denervated foot can serve the patient for a long time.32

12 Young MJ, Cavanagh PR, Thomas G, et al. The effect of callus removal on dynamic plantar foot pressures in diabetic patients. Diabet Med. 1992;9:55–57. 13 Lavery LA, Vela SA, Lavery DC, Quebedeaux TL. Reducing dynamic foot pressures in high-risk diabetic subject with foot ulcerations. A comparison of treatments. Diabetes Care. 1996;19:818–821. 14 Apelqvist J, Castenfors J, Larsson J, Stenström A, Agardh CD. Wound classification is more important than site of ulceration in the outcome of diabetic foot ulcers. Diabet Med. 1989;6:526–530.

Malignant transformation33 is a late complication of plantar ulcers in leprosy. In a retrospective study conducted at the National Center of Leprosy in Casablanca, malignancy was found in 10 patients, with an average duration of chronic trophic ulcers of 34.4 years. Clinical appearance at diagnosis was ulcerative and vegetative tumors. Six patients had metastatic spread. They were treated by radical amputation. Prevention of such complications should be part of the national fight against leprosy.

16 Sehgal VN, Prasad PVS, Kaviarasan PK, Rajan D. Trophic skin ulceration of leprosy: evaluation of efficacy of topical phenytoin sodium zinc paste. Int J Dermatol. 2014;53:873–878.

References

17 Chaudhury AR. Chronic planter ulcer: a new technique of management. IJPMR. 2004;15:45–47.

15 Perell KL, Merrill V, Nouvong A. Location of plantar ulcerations in diabetic patients referred to a Department of Veterans Affairs podiatry clinic. J Rehabil Res Dev. 2006;43:421–426.

1 Disability prevention and rehabilitation: report of the WHO Expert Committee on Disability Prevention and Rehabilitation. Technical report series No. 668. Geneva: World Health Organization; 1981.

18 Badiavas EV, Paquette D, Carson P, Falanga V. Human chronic wounds treated with bioengineered skin: histologic evidence of host-graft interactions. J Am Acad Dermatol. 2002;46:524–530.

2 Bhatt YC, Panse NS, Vyas KA, Patel GA. Free tissue transfer for trophic ulcer complicating leprosy. Indian J Plast Surg. 2009;42:115–117.

19 Strait M, Braathen LR. Apligraf—a living human skin equivalent for the treatment of chronic wounds. Int J Artif Organs. 2000;23:831–833.

3 Gahalaut P, Pinto J, Pai G, et al. A novel treatment of plantar ulcers in leprosy: local superficial flaps. Lepr Rev. 2005;76:220–231.

20 Fu XB, Guo ZR, Sheng ZY. Effects of basic fibroblast growth factor on the healing of cutaneous chronic wounds. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 1999;13:270–272.

4 Bauman JH, Girling JP, Brand PW. Plantar pressures and trophic ulceration. An evaluation of footwear. J Bone Joint Surg Br. 1963;45:652–673.

21 Zhu JX, Zhang YM. Application of recombinant human epidermal growth factor on chronic ulcer wound. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2002;16:42–43.

5 Sabato S, Yosipovitch Z, Simkin A, Sheskin J. Plantar trophic ulcers in patients with leprosy. A correlative study of sensation, pressure and mobility. Int Orthop. 1982;6:203–208.

22 Tarroni G, Tessarin C, De Silvestro L, et al. Local therapy with platelet-derived growth factors for chronic diabetic ulcers in haemodialysis patients. G Ital Nefrol. 2002;19:630–633.

6 Srinivasan H. Management of ulcers in neurologically impaired feet in leprosy affected persons. In: Schwarz R, Brandsma W, eds. Surgical Reconstruction and Rehabilitation in Leprosy and Others Neuropathies. Kathmandu: Ekta Books; 2004:193–226.

23 Tunér J, Hode L. The Laser Therapy Handbook. Gränsgesberg, Sweden: Prima Books AB; 2004. 24 Gonçalves G, Gonçalves A, Padovani CR, Parizotto NA. Promovendo a cicatrização de úlceras hansênicas e não hansênicas com laserterapia: ensaio clínico em unidades ambulatoriais do Sistema Único de Saúde. Hansenol Int. 2000;25:133–142.

7 Rao PT, Jena SK. Surgical treatment of plantar ulcers in leprosy. Int Orthop. 1986;10:75–78. 8 Puri V, Venkateshwaran N, Khare N. Trophic ulcersPractical management guidelines. Indian J Plastic Surg. 2012;45:340–351.

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25 Flemming K, Cullum NA. Laser therapy for venous leg ulcers. Cochrane Database Syst Rev. 2000(2):CD001182.

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26 Barreto JG, Salgado CG. Clinic-epidemiological evaluation of ulcers in patients with leprosy sequelae and the effect of low level laser therapy on wound healing: a randomized clinical trial. BMC Infect Dis. 2010;10:237. 27 Bauman JH, Girling JP, Brand PW. Plantar pressures and trophic ulceration. An evaluation of footwear. J Bone Joint Surg Br. 1963;45:652–673.

30 WHO Expert Committee on Leprosy: eighth report. Technical report series No. 968. Geneva: World Health Organization; 2010. 31 Srinivasan H. Prevention of disabilities in patients with leprosy: a practical guide. Geneva: World Health Organization; 1993. 32 Dharmendra, Srinivasan H. Treatment of ulcers in leprosy patients. In: Dharmendra, ed. Leprosy. 1st ed. Bombay: Kothari; 1978:599–616.

28 Chen S, Zhang L, Wang Z, et al. Experiences from a collaborative project on the prevention of disability in leprosy patients in Shandong Province, the People’s Republic of China. Lepr Rev. 2001;72:330–336.

33 Hali F, Latifi A, Sbai M. Malignant transformation of plantar ulcers in leprosy: experience of National Leprosy Center in Casablanca. Bull Soc Pathol Exot. 2011;104: 6–9.

29 Ebenso J, Muyiwa LT, Ebenso BE. Self care groups and ulcer prevention in Okegbala, Nigeria. Lepr Rev. 2009;80:187–196.

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January/February 2017

Volume 15 • Issue 1

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

When Immunohistochemistry Deceives Us: The Pitfalls of CD34 and Factor XIIIa Stains in Dermatofibroma and Dermatofibrosarcoma Protuberans Ann M. John, BA; Heather H. Holahan, MD; Parmvir Singh, BS; Marc Z. Handler, MD; W. Clark. Lambert, MD, PhD “Fool me once, shame on you. Fool me twice, shame on me.”––Randall Terry

I

t is sometimes difficult to make a clinical and histologic distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP). While DF usually has a benign course and a low risk of local recurrence, DFSP commonly recurs and may be extremely destructive. Differentiating between the two tumors is important for determining excision margins and prognosis.1

shows no extension into the subcutaneous fat, thus resembling DF. In addition, the deep penetrating variant of DF is composed of intersecting fascicles of fibroblastic cells with subcutaneous extension and almost no nuclear pleomorphism, similar to DFSP. When a superficial biopsy specimen is examined, dermal and subcutaneous extension of DFSP may be missed.4 In these cases, immunohistochemistry with factor XIIIa and CD34 usually provides an easy tool to make a clear differentiation. Factor XIIIa is a fibrin-stabilizing protein that functions in the coagulation cascade. Factor XIIIa also stains dendritic cells in the upper papillary dermis. CD34 is a glycosylated transmembrane protein, usually found in the vascular endothelial cells and certain tumors. CD34 immunostaining usually highlights dendritic interstitial cells in the reticular dermis, spindle cells around eccrine glands, and spindle cells in the midportion of the hair follicle.4

Clinical Findings Clinically, DFSP presents as an irregular, tan or brown multilobular lesion. It is classically described as having a “mountain-like” appearance and generally occurs on the trunk or shoulders of middle-aged adults. DF usually occurs on the lower extremities of middle-aged adults and presents as a tan, firm, flat to elevated papule with scaling and a positive dimpling sign.2 Histologically, DFSP is composed of spindle cells arranged in a repetitive, storiform pattern with little nuclear pleomorphism. Giant cells, siderophages, and chronic inflammatory cells are rarely found. Dermal and subcutaneous extension may occur in an infiltrative pattern or as parallel arrays. In contrast, classic DF is composed of fibroblastlike spindle cells arranged within a collagenous stroma.3 Histologic Findings

DF stains positively for factor XIIIa, while DFSP does not5; however, DFSP stains positively for CD34.6 It is well accepted that DF demonstrates a positive factor XIIIa and negative CD34 stain, while DFSP demonstrates a positive CD34 stain and a negative factor XIIIa stain. On occasion, the opposite is true—ie, DF stains positively for CD34 and less so for factor XIIIa and DFSP stains positively for factor XIIIa and less so for CD34.

Variants of both forms of conditions may make distinguishing histologic patterns difficult. The plaque stage of DFSP usually

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

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PERILS OF DERMATOPATHOLOGY

Figure 1. Dermatofibroma in case 1 (hematoxylin and eosin stain, original magnification ×90).

Figure 3. Dermatofibroma in case 1 (factor XIIIa immunostain, ×220).

Figure 2. Dermatofibroma in case 1 (CD34 immunostain, ×90).

Two Patients Figure 4. Dermatofibrosarcoma protuberans in case 2 (hematoxylin and eosin stain, original magnification ×480).

We present two cases: one of CD34 staining in DF, with weaker staining for factor XIIIa and one of factor XIIIa staining in DFSP, with weaker staining for CD34.

Case 1

Case 2

A 47-year-old Caucasian man developed an asymptomatic firm nodular lesion in the right groin area. The biopsy findings are shown in Figures 1, 2, and 3. Despite the clear identity of the lesion as a DF (Figure 1), results from CD34 staining were clearly positive (Figure 2) and results from factor XIIIa staining were only more weakly positive (Figure 3).

A 54-year-old man developed a firm, asymptomatic lesion in the right groin area. The biopsy findings are shown in Figures 4, 5, and 6. The highly storiform lesion was unquestionably a DFSP (Figure 4); however, results from factor XIIIa immunostaining were clearly positive (Figure 5), whereas results from CD34 staining showed only blood vessels (Figure 6).

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PERILS OF DERMATOPATHOLOGY more accurately differentiate DF from DFSP. Stains of CD44s, CD44v5, CD44v10, HMGA1, HMGA2, stromelysin 3, and tenascin have only shown positive staining in DF.7–10 In contrast, hyaluronate has shown only positive staining in DFSP.8 Dermatopathologists should consider using confirmatory staining for the uncommon cases of ambiguous histology in DF and DFSP, especially if the clinical examination points toward a diagnosis that is not confirmed with immunostaining. References 1 West KL, Cardona DM, Su Z, Puri PK. Immunohistochemical markers in fibrohistiocytic lesions: factor XIIIa, CD34, S-100 and p75. Am J Dermatopathol. 2014;36:414–419.

Figure 5. Dermatofibrosarcoma protuberans in case 2 (factor XIIIa immunostain, ×480).

2 Abenoza P, Lillemoe T. CD34 and factor XIIIa in the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans. Am J Dermatopathol. 1993;15:429–434. 3 Altman DA, Nickoloff BJ, Fivenson DP. Differential expression of factor XIIIa and CD34 in cutaneous mesenchymal tumors. J Cutan Pathol. 1993;20:154–158. 4 Goldblum JR, Tuthill RJ. CD34 and factor-XIIIa immunoreactivity in dermatofibrosarcoma protuberans and dermatofibroma. Am J Dermatopathol. 1997;19:147–153. 5 Cerio R, Spaull J, Jones EW. Histiocytoma cutis: a tumour of dermal dendrocytes (dermal dendrocytoma). Br J Dermatol. 1989;120:197–206. 6 Ramani P, Bradley NJ, Fletcher CD. QBEND/10, a new monoclonal antibody to endothelium: assessment of its diagnostic utility in paraffin sections. Histopathology. 1990;17:237–242. 7 Kahn HJ, Fekete E, From L. Tenascin differentiates dermatofibroma from dermatofibrosarcoma protuberans: comparison with CD34 and factor XIIIa. Human Pathol. 2001;32:50–56.

Figure 6. Dermatofibrosarcoma protuberans in case 2 (factor CD34 immunostain, ×480).

8 Calikoglu E, Augsburger E, Chavaz P, Saurat JH, Kaya G. CD44 and hyaluronate in the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans. J Cutan Pathol. 2003;30:185–189.

Conclusions

9 Kim HJ, Lee JY, Kim SH, et al. Stromelysin-3 expression in the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans: comparison with factor XIIIa and CD34. Br J Dermatol. 2007;157:319–324.

Cases in which DF stains with CD34 and DFSP stains with factor XIIIa have been previously reported.2–4,7 While these cases are rare, it is important to be aware of the occasional deceitful immunohistochemistry because of the drastic difference in recurrence rates and prognosis between DF and DFSP and consequent distinction in required excision margins. Fortunately, there are other immunostains that are currently being used to

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10 Li N, McNiff J, Hui P, Manfioletti G, Tallini G. Differential expression of HMGA1 and HMGA2 in dermatofibroma and dermatofibrosarcoma protuberans: potential diagnostic applications, and comparison with histologic findings, CD34, and factor XIIIa immunoreactivity. Am J Dermatopathol. 2004;26:267–272.

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The Pitfalls of CD34 and Factor XIIIa Stains


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January/February 2017

Volume 15 • Issue 1

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

Ozenoxacin Cream, 1% – Topical Treatment of Impetigo Aditya K. Gupta, MD, PhD, FRCPC;1,2 Sarah G. Versteeg, MSc;2 William Abramovits, MD3,4,5

I

mpetigo is a highly contagious bacterial skin infection that frequently begins with papules that form vesicles. These vesicles rupture, resulting in superficial yellow (honey) crustcovered erosions, and can present in two forms: nonbullous and bullous.1 The majority of impetigo cases (70%) are considered nonbullous and are caused by direct bacterial infection through skin disruption (eg, trauma, scabies, etc.).2 Impetigo is more prevalent in children than adults, with a higher prevalence in tropical countries.3 Treatments for impetigo include topical therapies (eg, mupirocin, retapamulin) and oral therapies (eg, erythromycin, cephalosporin). Topical treatments are recommended for small localized impetigo patches, and oral therapies are suggested for systemic infections, extensive infections, or infections recalcitrant to topical treatments.4,5 Ozenoxacin is a new topical nonfluorinated quinolone, whose New Drug Application was recently accepted by the Food and Drug Administration. MECHANISM OF ACTION Horizontal and plasmid-mediated spreading leading to gram-positive (eg, Staphylococcus aureus) resistance to current impetigo treatments (eg, mupirocin, fusidic acid, methicillin) has created the need for novel antibacterial agents.6–8 Quinolones elicit bactericidal effects by disrupting bacterial DNA replication, inhibiting topoisomerases DNA gyrase (topoisomerase II) and topoisomerase IV.9 Ozenoxacin retains its bactericidal effect even in mutated quinolone-resistant strains (eg, mutated grlA locus, mutated gyrA locus).10 SAFETY AND TOLERABILITY Across several phase I studies, no systemic absorption (concentrations occurring above the limit of quantification, <0.49 ng/

mL) has been reported in healthy adults.11 Detection of ozenoxacin in plasma arrays has been noted in children (<12 years old) in a study with 1% ozenoxacin cream (twice a day application for 5 days).12 No serious adverse effects have been described, with only mild or moderate treatment-related adverse effects (eg, site pruritus, edema, erythema) reported.11,12 Due to the possibility of cumulative irritation, sensitizing potential, phototoxicity, and photoallergy, testing has been evaluated with 1% and 2% ozenoxacin cream in randomized, controlled, comparative, healthy participant studies.13 No irritation on intact or abraded skin was found with 1% ozenoxacin, yielding a mean cumulative irritation score of 0, when 2% ozenoxacin cream was used daily for 21 days. Dermal sensitization was not found with either 1% or 2% ozenoxacin-treated patients, and in phototoxicity studies none of the patients met phototoxic reaction criteria, after the application had been irradiated with ultraviolet light (290 to 320 nm). During photoallergy testing, seven applications of 20 mg of ozenoxacin 1% or 2% cream were applied, with mild erythema occurring in irradiated and nonirradiated application sites. Across all studies, this topical agent was deemed to be safe and well tolerated. OZENOXACIN AS A TREATMENT FOR IMPETIGO The efficacy of ozenoxacin was evaluated in a randomized, investigator-blinded, controlled trial, involving patients with clinically diagnosed nonbullous and bullous impetigo (Table).8 Patients were instructed to apply the test cream/ointment (ozenoxacin 1% cream, placebo cream, or retapamulin 1% ointment) twice daily to all infected areas for 5 days. Ozenoxacin had a signifi-

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

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Table. Efficacy rates of ozenoxacin (1%) treated patients Endpoints

Definition

Gropper et al.8

Gropper et al.12

Clinical cure

• A SIRS of 0 for exudates, pus, crusting, tissue warmth, and pain • A score of ≤1 for erythema/inflammation, tissue edema, and itching • No additional antimicrobial therapy was required in baseline affected area

Ozenoxacin: 54/155=34.8%* Placebo: 30/156=19.2% Retapamulin: 58/154=37.7%*

• A SIRS of 0 for exudates, pus, crusting, tissue warmth, and pain • A score of ≤1 for erythema/inflammation, tissue edema and itching • A >10% total SIRS decrease • No additional antimicrobial therapy was required in baseline affected area

Ozenoxacin: 22/45=48.9%

• • • •

Ozenoxacin: 132/153=86.3%* Placebo: 115/151=76.2% Retapamulin: 128/152=84.2%

Ozenoxacin: 147/155=94.8%a Placebo: 146/156=93.6%a

Ozenoxacin: 23/45=51.1%

Absence of treated lesions Improvement in lesions Reduction in affected areas No further antimicrobial therapy was required

Clinical improvement

• A >10% decrease in total SIRS • Did not fulfill cure criteria

Clinical failure

• No change in total SIRS Ozenoxacin: 98/155=63.2% • A <10% increase or decrease in total SIRS Placebo:120/156=76.9% • Additional antimicrobial therapy was required in baseline Retapamulin: 91/154=59.1% affected area

Microbiologic success

• Bacterial eradication

Ozenoxacin: 122/154=79.2%b,* Placebo: 86/152=56.6%b Retapamulin: 125/153=81.7%b,*

Ozenoxacin: 0/45=0%

Abbreviation: SIRS, skin infection rating score. a At visit 2 (day 3 to 4). b At visit 3 (day 6 to 7). *Significantly higher than placebo (P<.05).

cantly higher clinical success (skin infection rating score of 0 for exudates/pus, crusting, tissue warmth, and pain, and a score of ≤1 for erythema/inflammation, tissue edema, and itching) compared to placebo (34.8% and 19.2%, respectively) (P=.003). Ozenoxacin had a greater effect in patients with nonbullous impetigo (compared to placebo P<.001), in patients with fewer affected areas (two to four sites, compared to placebo P=.006) and those with a skin infection rating score ranging between 15 and 28 (score of <15, compared to placebo P=.047; scores between 15 and 28, compared to placebo P=.025). Clinical improvement (≥10% reduction in skin infection rating score) was not significantly different between patients treated with ozenoxacin (94.8%) or placebo (93.6%). Microbiologic success (bacterial eradication) was found in 70.8% of ozenoxacin patients by their second examination (day 3 to 4) and 79.2% by end of treatment (day 6 to 7) (compared to placebo P<.0001 and P<.0001, respectively). The success rate of ozenoxacin was significantly higher SKINmed. 2017;15:57–59

compared to retapamulin on days 3 and 4 (60.0% and 74.7%, respectively, P=.0087) with both treatments equally effective by the end of treatment. In 35 patients (35/464=7.5%), at least one treatment-emergent adverse effect was found; however, none were deemed to be related to the study treatment (ozenoxacin). Application site events (pain and irritation) occurred in two retapamulin-treated patients. Ozenoxacin has shown similar efficacy in children. In a phase I study, the clinical success of ozenoxacin (1% cream) was evaluated using a twice-daily application for a 5-day period (Table).12 The surface area of the skin lesions across all treated patients (2 months to 65 years old) decreased by the end of treatment, with the largest improvement occurring in patients below the age of 2 years. The mean severity index scores (based on seven signs and clinical manifestations of impetigo) also decreased, with 48.9% (22/45) of treated patients clinically cured (>10% decrease, score

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of 0 for exudates, pus, crusting, tissue warmth, and pain, and a score of <1 for erythema, inflammation, tissue edema, and itching). The highest clinical cure rate (66.7%) was found in patients between the ages of 12 and 18 years, with the lowest clinical cure rate (22%) found in patients between the ages of 2 and 12 years. OZENOXACIN COMPARED TO OTHER THERAPIES Ozenoxacin may have higher antibacterial activity than other agents used for impetigo. Ozenoxacin had the highest antibacterial activity against gram-positive quinolone-susceptible and quinolone-resistant strains compared to moxifloxacin, levofloxacin, and ciprofloxacin, with MIC values ranging from 0.008 to 4 mg/L.14 Additionally, when tested against gram-positive strains known be associated with skin infections, ozenoxacin (MIC50 0.004 to 0.016 mg/L) displayed higher antibacterial activity than ciprofloxacin (MIC50 0.5 mg/L) and levofloxacin (MIC50 0.25 mg/L to 1 mg/L).15 CONCLUSIONS Resistance has limited the efficacy of available treatments and, as such, research into alternative topical antibacterial agents has occurred. Ozenoxacin has shown clinical success in patients with impetigo with limited adverse effects, and has shown higher antibacterial activity than other antibacterial agents (eg, ciprofloxacin, moxifloxacin). More pediatric studies should be done, with only one trial having focused on children, in which systemic absorption of ozenoxacin was above the lower limit of quantification (0.5 ng/mL) in four plasma assays in patients under the age of 12 years.12 As impetigo is most likely to occur in children, alterations in dosages or regimens should be evaluated with a focus on longterm responses. In vitro research suggests ozenoxacin could also be used in treating acne vulgaris, as it shows high antibacterial activity against Propionibacterium and Staphylococcus strains.16 References 1 Cole C, Gazewood J. Diagnosis and treatment of impetigo. Am Fam Physician. 2007;75:859–864. 2 Hartman-Adams H, Banvard C, Juckett G. Impetigo: Diagnosis and treatment. Am Fam Physician. 2014;90:229– 235.

5 Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2005;41:1373–1406. 6 Deshpande LM, Fix AM, Pfaller MA, Jones RN, SENTRY Antimicrobial Surveillance Program Participants Group. Emerging elevated mupirocin resistance rates among staphylococcal isolates in the SENTRY Antimicrobial Surveillance Program (2000): Correlations of results from disk diffusion, Etest and reference dilution methods. Diagn Microbiol Infect Dis. 2002;42:283–290. 7 Howden BP, Grayson ML. Dumb and dumber—the potential waste of a useful antistaphylococcal agent: Emerging fusidic acid resistance in Staphylococcus aureus. Clin Infect Dis Off Publ Infect Dis Soc Am. 2006;42:394–400. 8 Gropper S, Albareda N, Chelius K, et al. Ozenoxacin 1% cream in the treatment of impetigo: A multicenter, randomized, placebo- and retapamulin-controlled clinical trial. Future Microbiol. 2014;9:1013–1023. 9 Wiles JA, Bradbury BJ, Pucci MJ. New quinolone antibiotics: A survey of the literature from 2005 to 2010. Expert Opin Ther Pat. 2010;20:1295–1319. 10 Yamakawa T, Mitsuyama J, Hayashi K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J Antimicrob Chemother. 2002;49:455–465. 11 Gropper S, Albareda N, Santos B, Febbraro S. Systemic bioavailability, safety and tolerability of topical ozenoxacin in healthy adult volunteers. Future Microbiol. 2014;9:S11–S16. 12 Gropper S, Cepero AL, Santos B, Kruger D. Systemic bioavailability and safety of twice-daily topical ozenoxacin 1% cream in adults and children with impetigo. Future Microbiol. 2014;9:S33–S40. 13 Gropper S, Cepero AL, Dosik JS, LaStella P, Siemetzki H, Wigger-Alberti W. Cumulative irritation, sensitizing potential, phototoxicity and photoallergy of ozenoxacin in healthy adult volunteers. Future Microbiol. 2014;9:S23– S31. 14 López Y, Tato M, Espinal P, et al. In vitro activity of ozenoxacin against quinolone-susceptible and quinoloneresistant gram-positive bacteria. Antimicrob Agents Chemother. 2013;57:6389–6392. 15 Tato M, López Y, Morosini MI, et al. Characterization of variables that may influence ozenoxacin in susceptibility testing, including MIC and MBC values. Diagn Microbiol Infect Dis. 2014;78:263–267. 16 Nakajima A, Ikeda F, Kanayama S, et al. Antimicrobial activities of ozenoxacin against isolates of propionibacteria and staphylococci from Japanese patients with acne vulgaris. J Med Microbiol. 2016;65:745–750.

3 Romani L, Steer AC, Whitfeld MJ, Kaldor JM. Prevalence of scabies and impetigo worldwide: A systematic review. Lancet Infect Dis. 2015;15:960–967.

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4 Koning S, van der Sande R, Verhagen AP, et al. Interventions for impetigo. Cochrane Database Syst Rev. 2012;1:CD003261.

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THE INTERSECTION OF DISEASE AND DESIRE DERMATOLOGY

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January/February 2017

Volume 15 • Issue 1

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

Medical Ego Inflation and a Lesson From Mom Warren R. Heymann, MD

L

ast week, my 95-year-old mother literally returned from the deceased. In classic Hollywood motif, my cousin Elysa, who was at her bedside at the time she was moribund, was pleading for me to desperately get there, demanding that the attending do something, as he was asking her about her DNR status. “Can’t you at least give her oxygen?,” Elysa asked. He complied, while I was frantically trying to find a parking spot. Finally, jumping out of the car, running through the hospital in lunatic mode, I made it to the bedside, where I thought this was the end. My mother had had yet another syncopal episode the day before (her repeated very thorough workups had been nonrevealing); she bruised herself falling in the bathroom and could not get up. When I had left the hospital room late the night before, she seemed stable. “What’s going on?” I asked hurriedly. “We think she has pneumonia, so we put her on antibiotics. We don’t think she has a PE [pulmonary embolus], but we anticoagulated her. There’s really not much else we can do.” “Excuse me, but 24 hours ago she was ranting about Hillary and commenting on the latest issue of Scientific American. We don’t want to sustain her life artificially. If you told me she had a massive stroke or MI, that’s one thing, but pneumonia??? She’s not DNR—please pull out the stops—perhaps this is reversible— she deserves that chance,” I declared assertively. Off to the ICU, with a pH of 7.04, a lactic acid of 8, intubated, and sedated. A gathering of her loved ones congregated, with an overarching disbelief that this was the passing of the matriarch. I went home, exhausted and somewhat guilt-ridden that my decision prolonged the inevitable, and at what cost? The following

Mrs. Ruth Heymann

morning, she woke up, able to write questions, including “What happened?” She alertly absorbed what transpired. When I asked her if I made the right decision, my mind eased when she wrote “yes.” Within 48 hours, she amazed all by being extubated, her shock numbers normalized, smiling, conversing in her usual manner, and out of the ICU. My resilient mom escaped her demise again.

From the Division of Dermatology, Departments of Medicine and Pediatrics, 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, 100 Brick Road, Suite 306, Marlton, NJ 08053 • E-mail: wrheymann@gmail.com

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Her pulmonologist and cardiologist think they may have an explanation—possibly worsening aortic stenosis with small-volume left ventricular outflow obstruction.

Presidential Medal of Freedom, and a World Series ring (Cleveland or Chicago) all bestow singular and esteemed achievements.

“If she were 52, we’d do a procedure,” the pulmonologist stated, “but for now we’ll monitor it.” “Monitor it for what? To only happen again? Let me ask my mother, but I already know what the answer will be,” I responded. “Tell him to treat me like I’m 52. My body may be 95, but my mind is 52,” mom opined. I would have been stunned by any other response. I thought everything was going in the right direction until her attending advised me to stay close, because her pulmonary status had worsened. I asked him outright if I should cancel my visiting professorship to Bob Brodell’s Department of Dermatology at the University of Mississippi, and his answer was an unequivocal yes. (I cannot thank Bob enough for his gracious support and understanding this week, as I have been dealing with this. His ability as a dermatologist is exceeded only by his warmth and understanding.) CREDENTIAL PROLIFERATION As I sit here with mom, holding her hand, there is not much else I can do other than go through e-mails, and delete, delete, delete. I cannot believe how many requests I get for yet another “Top Doctor” plaque and requests to write a paper for another open access online journal (with a hefty publication fee and deadline!), or join their editorial board.

Publications matter. Despite the challenges, peer-reviewed papers in prestigious journals such as The New England Journal of Medicine, JAMA Dermatology, and the JAAD are essential for advancing knowledge and academic promotion. The proliferation of awards and online access journals has diminished the meaning of excellence. I am not being cynical in stating that each has become big business by taking advantage of a professional’s ego. The ethics of “Top Doctor” awards has been thoughtfully discussed,1 and the undermining of academic integrity of “predatory” journals has been justifiably detailed.2 MOTHERLY ADVICE One of the greatest lessons my mother has taught me is to look in the mirror and “always do your very best—if any less than that, you’re only fooling yourself. There will always be someone richer, but many poorer; someone brighter, but many less so; and someone more generous, but many less caring. Be grateful and keep your ego in check.” She also encouraged me go into medicine rather than journalism—“be a doctor first, you can always write.” Mom, I may be approaching Medicare age, but I pray you pull through. I still need your love and advice. References

Don’t get me wrong—I am truly honored and humbled by legitimate accolades; however, I do not wish to be taken advantage of by the process.

1 Kirsch B, Grant-Kels JM, Bercovitch L. The ethics of “Top Doctor” awards: A tangled web. J Am Acad Dermatol. 2013;69:792–794.

Awards count. Even Bob Dylan finally acknowledged the importance of his Nobel Prize for literature. The Academy Awards, the

2 Eriksson S, Helgesson G. The false academy: Predatory publishing in science and bioethics. Med Health Care Philos. 2016 October 7 [Epub ahead of print]

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Volume 15 • Issue 1

Society Highlights of the 57th Annual Meeting of the North American Clinical Dermatologic Society

Greece! Is the Word…: May 21–27, 2016, Thessaloniki and Athens Robert S. Berger, MD THESSALONIKI, MAY 21 At the Thessaloniki meeting, I discussed how branded medication prices have increased more than 300% over the past 3 years (eg, tetracycline at $10 per pill and Targretin® at $30,000 per tube). Ignore zero or little cost to the patient—ask your pharmacist the insurance cost. Smaller specialty pharmacies are, however, cheaper, as are companies that make generic formulations. Richard L. Spielvogel, MD (Philadelphia, PA), reviewed hepatitis C virus, a major cause of hepatitis in the United States, with higher rates in impoverished areas. The highest risk comes from unscreened transfusions, followed by unprotected sex, and sharing personal items such as needles, toothbrushes, and razors. There are multiple acute-stage clinical manifestations including lichen planus (especially oral involvement). Porphyria cutanea tarda is common in southern Europe. In 70% of patients, the infection becomes chronic, and 20% develop cirrhosis. Initially, interferon is used, then pegylated interferon and ribavirin, and then protease inhibitors (all costing many dollars). Hepatitis C virus is also associated with acral necrolytic erythema (similar to psoriasis), Sjögren’s syndrome, Mooren syndrome (corneal ulcer), and antiphospholipid syndrome. Adam Rubin, MD (Philadelphia, PA), discussed erythronychia. Polydactylous disease is seen in inflammatory disease, and the longitudinal pattern is the most common. Tinea causes v notching distally, and glomus tumors are tender and sensitive to cold. A biopsy (preferably excisional) should be taken at the origin of the streak, including the nail bed, and longitudinal processing used. Amelanotic melanoma shows single cells in the nail plate. In contrast, squamous cell carcinoma (SCC) shows diffuse erythema, involves the lunula, and demonstrates onycholysis.

Darius Mehregan, MD (Detroit, MI), presented invisible dermatoses with normal-appearing skin but histopathologic findings (Grover disease, pretibial myxedema), as well as normal histopathology in the setting of clinical dermatoses (seborrhea, asteatotic eczema, vitiligo).

THESSALONIKI, MAY 22 Robert Hamill, MD (Tampa, FL), emphasized communication between providers, elderly patients, and patients’ families to achieve the best outcomes. Most patients are not concerned with scarring or cosmesis, but with function, ease of care and downtime. Mark Valentine, MD (Seattle, WA), presented eruptive disseminated porokeratoses caused by topical steroids, resolving after discontinuation. Of the nine types of porokeratoses (disseminated being the most common), five are genetic syndromes. Coronoid lamella is a constant histopathologic finding but is also seen in warts, actinic keratoses, ichthyoses, and nevoid hyperkeratosis. It has a variable presentation, can occur with immunosuppression, and is difficult to treat. Anthony Benedetto, DO (Philadelphia), presented surgical pearls related to skin conditions in pregnant and lactating women. The second trimester is the best for surgery, except for melanoma and atypical (severe) nevi. If sentinel node biopsy needs to be carried out, technetium rather than blue dye should be used. Ideally, the woman should be placed in the left lateral decubitus or tilt position (with a pillow between the knees), with the second choice being the right lateral decubitus position; she should NEVER be placed supine. The skin should be cleaned with alcohol or Hibiclens®, not povidone iodine. Topical anes-

From Department of Dermatology, Johns Hopkins University, Baltimore, MD, and Charles County Dermatology Associates, White Plains, MD. Address for Correspondence: Robert S. Berger, MD, Charles County Dermatology Associates, 4225 Altamont Place, Unit 3, White Plains, MD 20695 • E-mail: rsbcsb@aol.com

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thetics can be used, and esters are preferred for local anesthesia; mepivocaine and bupivacaine should not be used. Saline or diphenhydramine can be used for lidocaine allergy. Epinephrine is safe for skin surgery. Use handheld electrocautery, and a mask if smoke is anticipated. There are no suture contraindications. Delayed healing, post-inflammatory hyperpigmentation, and keloid formation should be anticipated. Antibiotics that can be used in pregnancy for any infection include mupirocin (topical), penicillin, cephalosporins, and erythromycins. Cephalosporins are the first choice if there is penicillin resistance, and erythromycins are preferred with penicillin allergy. Tetracyclines should not be used. Acetaminophen is recommended for pain, rather than nonsteroidal anti-inflammatory agents or aspirin. Codeine should be used only when absolutely necessary in FDA pregnancy category C. Suzanne Connolly, MD (Phoenix, AZ), reminded us that contact dermatitis mimics a range of diseases (impetigo, lupus erythematosus, herpes, lymphoma, dermatomyositis). Think photosensitizing agents could be culprits when encountering difficult cases. Benzophenones are the most common sunscreen allergen. Compositae are a common cause (sesquiterpine alcohol most common), followed by fragrances (balsam of Peru). Chamomile is found in many moisturizers, and bisabolol is becoming more common as a cause of dermatitis. Nail products (acrylates) cause eyelid dermatitis; however, super glue (which contains methyl acrylate) does not cross react with nail products (which contains ethyl acrylates). In cases of perianal eruption, ginkgo, nickel, and balsam of Peru should be considered. Desoximetasone ointment is the only nonsensitizing topical steroid. Patch testing can be carried out during methotrexate therapy, but mycophenolate mofetil, azathioprine, and systemic steroids interfere with the

results, reactions being much stronger than readings indicate. http://contactderm.org is a good source of information.

THESSALONIKI, DEPARTMENT OF DERMATOLOGY, MAY 23 At the Department of Dermatology meeting in Thessaloniki (Figures 1 and 2), Assistant Professor Elena Sotiriou, MD (Thessaloniki), presented topical photodynamic therapy (PDT) use in actinic keratosis, SCC in situ, and superficial and nodular basal cell carcinoma (BCC); it cannot, however, be used for invasive SCC. Red light is used with 16% methyl a levalonic acid for actinic keratosis, Bowen’s disease, and BCC. 5-Amiolevulinic acid and keratostick are only used for actinic keratosis. The lesion is prepared with a keratolytic agent for 3–7 days or under occlusion for one night, and hyperkeratotic lesions and nodular BCC must be debulked. Treatment is more painful with actinic keratosis, and is associated with hair loss with BCCs. Rarely, there is scarring. Use of daylight instead of PDT does not require application of amiolevulinic acid under occlusion and is less painful. Off-label uses of PDT include photorejuvenation, mycoses fungoides, extramammary Paget’s disease, and the prevention of new skin cancers (eg, in transplant patients). Michael Arabatzls, MD (Thessaloniki), discussed a case of cryptococcosis after exposure to olive tree branches. Around 10% of cases are related to olive trees, and 35% to eucalyptus trees. Increased dandruff fuels speculation regarding an etiology of seborrheic dermatitis may be caused by cryptococcosis. Sporotrichosis organisms are found concentrated on thorns. Outbreaks of sporotrichosis are more common as temperature and humidity rise. Organisms are also found in hay and corn crops,

Figure 2. Dr Spielvogel and Dr Benedetto present membership in NACDS to Dr Ioannnides.

Figure 1. Thessaloniki meeting with NACDS and Greek physicians. SKINmed. 2017;15:63–67

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and have been reported in cats in Brazil. A newly identified organism, Toxicladisporium irritans, may be associated with atopic dermatitis. Elizabeth Lazaridou, MD (Thessaloniki), presented pearls of wisdom for detecting melanoma. The risk increases with age and with a history of nonmelanoma skin cancer (NMSC). Risk is highest if there are ≥20 nevi, patients are less than 50 years old, or actinic damage is present. Patients more than 12 years of age have a higher risk of malignant melanoma (MM) in spitzoid tumors. Dermatoscopic clues include a blue-black color over 10% of surface, milky/red areas, and polymorphic vessels. Amelanotic MM shows polymorphic vessels with white lines and ulcerations. Grey to blue colors are seen in lentigos or seborrheic keratoses. Polymorphic vessels are identified in pyogenic granulomas or Spitz nevi.

can be seen in seborrheic hyperplasia. Psoriasis is associated with many dotted vessels and white scale. In dermatitis, dotted vessels and yellowish scales or crusts (spongiosis) can be identified. Amelanotic MM can be featureless. Gray color is a most useful clue for lentigo maligna.

KALEMBUKA, MAY 24

Zoe Appalla, MD (Thessaloniki), presented trends in NMSC in Greece. Coastal areas and higher elevations are associated with higher rates. Many cancer registries do not include NMSC, so its incidence is unknown. It is more common in individuals who are male, are more than 50 years of age, have received high levels of ultraviolet (UV) exposure, have genetic factors, have undergone organ transplantation (calcineurin inhibitors are more likely to be associated than antimetabolites and mechanistic target of rapamycin [mTOR] inhibitors), and have been exposed to viruses (human papillomavirus [HPV]). An increased incidence of BCC/SCC is seen with trauma (burns/scars), skin irradiation, chronic diseases (lichen sclerosis et atrophicus, tuberculosis, porokeratosis), and arsenic exposure. More than 1 Gy of exposure to radiation increases the risk of BCC. When discussing prevention, female patients tend to be more responsive to the threat of wrinkles, aging, and scarring, and male patients to avoiding painful sunburn, than all are to cancer prevention. It has been calculated that 47 patients need to be screened to detect one skin cancer (MM, NMSC), and the yield increases with age, male sex, skin type, and history of previous NMSC.

Adam Rubin, MD (Philadelphia, PA), presented bullous disease of infancy. Its differential diagnosis includes chronic bullous disease of infancy, bullous pemphigoid, scabies, herpes, incontinentia pigmenti, Langerhans histiocytosis, epidermolysis bullosa, and bullous impetigo. Bullous pemphigoid tends to be more acral/genital in infants than it is in adults, and disease progression is not related to bullous pemphigoid antigen titer. In severe combined immunodeficiency syndrome, BCG immunization heals very slowly. Stephen Stone, MD (Springfield, IL), divided penile conditions into medical and nonmedical, the latter often seen in prisoners inserting foreign objects (beads, parts of dominos, rosaries). Medical issues include psoriasis, lichen planus, contact dermatitis, fixed drug eruptions, and pearly penile papules or hairy penis (angiofibromas). Penile melanotic macules are benign, and 95% of penile cancer is SCC. Plasma cell balanitis is cured by circumcision. The most common sexually transmitted disease is HPV. Imiquimod and liquid nitrogen therapy (with a 5 mm border) are the most commonly used therapies, and a single Picato® treatment may be effective. Gardasil should be given to all boys and girls more than 12 years of age. Topical therapy is ineffective against herpes simplex virus (HSV). The initial treatment should be valacyclovir 2 g twice daily for 7 to 10 days; subsequent outbreaks are treated with 2 g twice daily for 1 day. Suppression can be obtained with a daily dose of valacyclovir of 500 mg to 1 g (which is preferred); Famvir® can be used but is not as effective.

Amilios Lallas, MD (Thessaloniki), discussed dermatoscopy pearls. Benign vascular lesions demonstrate perfectly circumscribed globules/lacunas. Benign nevi have a regular pigment network pattern and commalike vessels; in darker skin, there can be a central increase in pigment with lighter peripheral pigmentation. Spitz nevi have linear peripheral pigment patterns. Seborrheic keratosis shows multiple shiny “stars” and round openings. Scabies mites and burrows can be seen. Granulomas have an orange-yellow color. BCCs have linear arborizing vessels, as well as blue-gray ovoid nests and globules, leaflike areas, spoke-wheel areas, and concentric structures. Invasive SCCs show white circles around hair follicles. Crown vessels and white globules

Anthony Benedetto, MD (Philadelphia, PA), presented complications of fillers. The most common immediate complications are edema and erythema, related to rapid injection and needle motion. Angioedemalike swelling can occur 1 hour after injection; this is immunoglobin E mediated and should be treated with systemic steroids. Consider giving intralesional kenalog 3 mg/mL injection before hyaluronidase. Only use hyaluronic acid fillers around eyes. Paresthesias and dysesthesias are usually located infraorbitally and are caused by nerve trauma from the needle or product. Hyaluronic acid or calcium hydroxyapatite nodules resulting from the injection of too much product or too superficial a placement may need excision. Biofilm formation can be prevented by removing the patient’s makeup, using chlorhexidine scrubs, advising against use of makeup for 24 hours after

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the filler has been given, and treatment with antibiotics. All procedures can reactivate herpes simplex virus. Temporal injections can cause pressure necrosis as too much product can be given; there is no pain, and necrosis is slow to appear. Emboli can cause loss of vision, hemiplegia, and stroke (which can be fatal). In this situation, massage the eye, blot 3 to 4 seconds, and get the patient to rebreathe into a paper bag. It should be remembered that there are only 90 minutes in which to save the eye. Christine Burns, MD (Tampa, FL), revealed that cyclosporine drops are more effective than doxycycline drops for ocular rosacea; although cyclosporine costs more, there are fewer long-term effects. There is no increase in cancer mortality in patients with inflammatory eye disease who are receiving immunosuppression without a family history of cancer, increased age, smoking or sun exposure. PROSE (prosthetic replacement of ocular surface ecosystem) devices are new options in patients with chronic symblepharon (ie, Stevens–Johnson syndrome, toxic epidermolysis). If hydroxychloroquine therapy is being given, the dose should be less than 6.5 mg/kg, based upon ideal, rather than actual, body weight. For most patients, this gives a maximum dose of 200 to 400 mg/day. A baseline examination should be made, remembering that the risk of toxicity increases in patients more than 60 years of age. For the first 5 years of therapy, the risk is very low; after this, examinations using a multifocal electro-retinogram are needed. Central vision testing not helpful, but peripheral vison should be tested using visual field tests. Retinal thickness is assessed by optical coherence tomography.

clear margins; however, they will excise these if they are recurrent, and all dermatologists excise severe atypia. The current controversy relates to what should be done with a single melanocyte in the epidermis; there is no clear consensus on this, other than recommending excision for unusual lesions.

ATHENS ANDREAS SYGROS HOSPITAL, MAY 27 Andreas Katsambis, MD (Athens), presented vitiligo as a disease with focal autoimmune destruction (by CD8 cells) of melanocytes. There is a three- to fourfold reduced incidence of melanoma/NMSC in patients with vitiligo, even those exposed to high levels of UV radiation. Narrow-band UV B and PUVA therapy has been shown not to increase the risk of MM or NMSC in

MAY 26, ATHENS At the Athens meeting (Figure 3), Robert Bryg, MD (Los Angeles, CA), reminded us that appropriate sample size coupled with appropriate statistics will lessen errors. Errors also seem to be compounded by a pressure of publication bias.

Figure 3. Athens meeting with NACDS and Greek physicians at the Athens moulage museum.

James B. Stewart, MD (Oklahoma City, OK), presented unusual skin cancers: Merkle cell carcinoma (which is increasing in incidence), fibrosarcoma, sebaceous carcinoma (Muir-Torre syndrome), adnexal cystic carcinoma, angiosarcoma, atypical fibroxanthoma, and metastasis to the skin. All of these can appear non-descript. An evolutionary history is critical, and increasing age raises more suspicion. Richard L. Spielvogel, MD (Philadelphia, PA) (Figure 4), discussed atypical nevi and the controversy surrounding observation/excision/grade of atypia. The focus has changed from the Clark level and dysplastic nevus to atypical cells and degree of atypia. Most clinicians excise areas of moderate atypia with positive margins, and observe mild atypia and moderate atypia with SKINmed. 2017;15:63–67

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Figure 4. Drs Stratigos, Benedetto, Antoniou, Spielvogel, and Berger in Athens. Greece! Is the Word…


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vitiligo patients. The low incidence of NMSC associated with vitiligo may be due to the protective function of regulated wildtype p53 expression. Melanoma patients with vitiligolike depigmentation, whether or not associated with therapy, can have a higher survival rate and better prognosis. Marita Kosmadakj, MD, PHD (Athens), discussed the biology of aging via DNA damage from oxidative insults, errors in replication, mitosis, and environmental insults (UV radiation). Mutations arise from failure to repair DNA damage. Repair genes (p53) guide the cell to die (apoptosis)or stop proliferating (senescence); a failure of repair can therefore lead to uncontrolled proliferation (cancer). Low levels of physical, chemical, or biologic stress may allow the cells to adapt and improve resistance. Broad-band light therapy has led to rejuvenated genes with an unknown duration of effects, and a decreased rate of age-associated diseases. A topical application of siloxane polymer material may be the next topical rejuvenation product. Electra Nicolaidou, MD (Athens), presented HPV infection as the most common urogenital infection seen in the United States, followed by herpes simplex virus type 2, trichomoniasis, and chlamydiosis. Around 90% of HPV infections spontaneously clear. Persistent infection and progression to cancer are associated with immunosuppression, tobacco use, oral contraceptive use, and coinfection with other sexually transmitted diseases (especially Chlamydia and herpes simplex virus type 2). Cervical cancer is the second most common cancer in women worldwide from age 15 to 44 years. The highest cancer risk is seen in women who do not attend regular cervical screening; in contrast, women who do attend screening have almost no risk. Infection is primarily from skin-to-skin contact, and condoms do not protect against transmission. The presence of clinical lesions is not necessary for infection to occur, and the virus may be latent for years. Penetrative intercourse is not necessary, and self-inoculation is possible. Oral/hand-to-genital transmission is rare. Vertical transmission from mother to newborn is also rare; this can lead to respiratory papillomatosis. Children are usually infected nonsexually. Vaccination is effective, and HPV vaccines do not cause complex regional pain syndrome or postural orthostatic tachycardia syndrome. Ioanna Panoutsopoulou, MD (Athens), reviewed the adverse effects of targeted oncologic therapy. The most common malignancies treated in Athens are breast cancer, melanoma, and colon cancer. Epidermal growth factor receptor inhibitors have cutaneous side effects in 50% to 90% of patients. The most common of these are papulopustular lesions. Around 75% occur within 1 to 2 weeks, they are dose dependent, worse with sun exposure, and not seen in irradiated areas; they primarily occur on the head, neck, trunk, SKINmed. 2017;15:63–67

and proximal aspect of the extremities. They are aseptic, and are not associated with milia. Severity may correlate with creatinine kinase levels and better prognosis. Other side effects of epidermal growth factor receptor inhibitors include photoderm, telangiectasias, xerosis, skin fragility, secondary infections, paradoxical trichomegaly of the eyelashes, and glabellar, lip, or chin hypertrichosis. Nail changes include paronychia, pyogenic granulomalike lesions, dyschromia, and onycholysis. Multikinase inhibitors are used in renal cell, liver/thyroid cancers, sarcomas, and gastrointestinal stromal tumors. Side effects include tender hyperkeratosic palms and soles and areas of pressure, alopecia, and depigmentation of the hair. Psoriasiform lichenoid desquamative erythematous lesions can occur in the genital area, with penile phimosis. Antiangiogenesis therapies can result in skin/mucosa bleeding, delayed wound healing, and fistula formation (so surgery should be undertaken with caution). BRAF/MEK inhibitors and immunomodulators (anti-CTLA-4/PD-1) are used in melanoma therapy. BRAF inhibitors cause folliculocentric smooth papules in 70% of patients; they can be extensive and turn into plaques on the trunk and extremities, although not on the head and neck. There is an increased incidence of SCC and verrucal keratoses (HPV negative), and palmoplantar hyperkeratosis, caused by friction, in 60% of patients. Dose-dependent maculopapular erythematous lesions occur in 50% to 75% of patients taking MEK inhibitors. In addition, papulopustular lesions can occur on the head, neck, and trunk, and become colonized with Staphylococcus aureus. AntiCTLA-4 causes dose-dependent maculopapular eruptions, alopecia, pruritus, and vitiligo. Panagiotis Stavropoulos, MD (Athens), reviewed the current therapies for lupus erythematosus, with sun avoidance and topical corticosteroids (with or without calcineurin inhibitors) as the initial therapy. The initial systemic therapy is hydroxychloroquine with or without nonsteroidal anti-inflammatory agents; next-line therapies are prednisone, azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil. Belimumab (a B-cell activating factor inhibitor) is a new promising therapeutic agent that may usher in a new series of treatment choices. Alexander Stratigos, MD (Athens), discussed the limited availability of Moh’s surgery in Greece, where dermatologists rely on excision and electrodessication and curettage. PDT, cryotherapy, imiquimod, and hedgehog pathway inhibitors are also in use. NACDS meeting April 20–30, 2017 Join the NACDS meeting April 20–30, 2017, beginning in Buenos Aires at the International Congress of Dermatology meeting, then onto Patagonia, and ending with a trip to the Galapagos Islands May 1–May 4 or May 8. The program is posted on www. nacds.com.

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January/February 2017

Volume 15 • Issue 1

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

Keratoacanthoma Centrifugum Marginatum: Response to Acitretin Abdulmohti Hawilo, MD;1 Ines Zaraa, MD;1,2 Dalenda El Euch, MD;1 Mourad Mokni, MD;1,2 Samir Boubaker, MD;2,3 Amel Ben Osman, MD1,2

A previously healthy 70-year-old woman presented with a 5-month history of an asymptomatic keratotic, papulonodular plaque on her right forearm. The lesion started as a follicular papule followed by progressive peripheral proliferation. No record of trauma, contact with any chemicals, use of immunosuppressive drugs, or history of neoplasm was noted. Clinical examination showed an arciform plaque of 10×5 cm, with infiltrated raised borders and central atrophy (Figure 1). Drops of yellowish material exuded from the coalescent nodules constituting an elevated and indurate border. Results from physical and laboratory examinations revealed no internal organ malignancy. The remainder of the physical examination (x-ray of the forearm and serologies for HIV, hepatitis, and syphilis) was normal. (SKINmed. 2017;15:69–71)

K

eratoacanthoma centrifugum marginatum (KCM) is an uncommon and distinct variant of keratoacanthoma, initially described in 1962.1 It is characterized by progressive peripheral expansion despite concomitant central healing and atrophy.2 Few cases of KCM have been documented in the literature. Controversy persists about the nature of keratoacanthoma, and whether active therapy is warranted. The present report describes a new case of KCM successfully treated with oral acitretin.

Considering the clinical and histopathologic evidence, a diagnosis of KCM was established. Oral acitretin (20 mg daily for 12 months) was started. After 6 months, the plaque had flattened and was no longer infiltrated; 1 year later, the patient showed no relapse and has remained without symptoms.

Histopathologic examination from the center and peripheral nodules revealed an irregularly hyperkeratotic and acanthotic epidermis with a prominent lymphocytic infiltrate producing a lichenoid reaction around dilated follicular canals that were hyperplastic but lacked atypia (Figure 2A and 2B). The dermis contained a dense lymphohistiocytic inflammatory cell infiltrate, with no abscesses or suppurative granulomas (Figure 2C). The subcutis was free of tumor. As seen in the typical keratoacanthoma, a crateriform architecture was noted, but with no loss of the granular cell layer. Results from Ziehl-Neelsen, periodic acid-Schiff, and Grocott staining revealed no acid-fast bacilli or fungal elements in the dermis or epidermal tumors.

Figure 1. A 10×5-cm arciform plaque with a papulonodular hyperkeratotic border and cicatricial center.

From the Department of Dermatology, La Rabta Hospital Tunis;1 the Faculté de médicine de Tunis, Université El Manar;2 and the Department of Pathology, Pasteur Institute of Tunis,3 Tunis, Tunisia Address for Correspondence: Ines Zaraa, MD, Dermatology Department, La Rabta, Hospital, Jabbari, Bab Saadoun, Tunis, 1007 Tunisia • E-mail: inesrania@myway.com

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B

Figure 2. Histopathologic findings of a hyperkeratotic, crateriform nodule, demonstrating pseudoepitheliomatous hyperplasia (A). The deepest portions of the specimen demonstrate glassy pink cytoplasm with absent to mild cellular atypia and rare mitoses (B). Hematoxylin and eosin stain; original magnification ×40 (A) and ×100 (B).

Discussion We report the successful treatment of KCM, an extremely rare form of keratoacanthoma, with acitretin. KCM presents a diagnostic challenge.1–3 It is considered by some to be benign, while others believe that the keratoacanthoma is unequivocally a subtype of squamous cell carcinoma.4 This debate is difficult to resolve, particularly as KCM may resemble various neoplastic and nonneoplastic entities both clinically and pathologically. The pathologic findings in our case resembled lichen planopilaris or verrucous carcinoma with lichenoid inflammation, but the patient had no other lesions or history of lichen planus.

lite and the pharmacologically active compound of etretinate. As in our patient, a previous report describes the successful use of acitretin.10,11 Although the exact mechanism of action is unknown, modulation of terminal differentiation of epidermal cells has been suggested to induce inhibition of keratinization or to have an antikeratin effect. References 1 Miedzinski F, Kosakiewicz J. Das Keratoakanthoma centrifugum: eine besandera Varieät des Keratoakanthoms. Hautarzt. 1962;13:348–352. 2 Hackel H, Burg G, Lechner W, et al. Keratoacanthoma centrifugum marginatum. Hautarzt. 1989;40:763–766 3 Divers AK, Correale D, Lee JB. Keratoacanthoma centrifugum marginatum: a diagnostic and therapeutic challenge. Cutis. 2004;73:257–262.

While surgical excision is most desirable for solitary keratoacanthoma, nonsurgical therapies are preferred for KCM. None of the recommended conservative treatment options have proved to be totally effective. Various treatment modalities such as Mohs micrographic surgery, oral methotrexate, and topical and intralesional treatments (5-fluorouracil, bleomycin, and interferon α) have been reported to be effective in individual cases.5–12

4 Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology. 1999;199:208–212. 5 Chaffai M, Houman MH, Haouet S, et al. Keratoacanthoma centrifugum marginatum. Ann Dermatol Venereol. 1994;120:731–733. 6 Ogasawara Y, Kinoshita E, Ishida T, et al. A case of multiple keratoacanthoma centrifugum marginatum: response to oral etretinate. J Am Acad Dermatol. 2003;48:282–285.

Conclusions Oral retinoids have been successfully used for the treatment of KCM in eight cases (etretinate in four cases, isotretinoin in two cases, and acitretin in two case).5–14 Since investigators5 reported the marked effectiveness of etretinate in KCM, its usefulness has been noted in several subsequent cases. Isotretinoin seemed ineffective in one previous case.12 Acitretin is the major metaboSKINmed. 2017;15:69–71

7 Schaller M, Korting HC, Wolff H, Schirren CG, Burgdorf W. Multiple keratoacanthomas, giant keratoacanthoma and keratoacanthoma centrifugum marginatum: development in a single patient and treatment with oral isotretinoin. Ann Dermatol Venereol (Stockh). 1996;76:40–42.

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8 Lo Schiavo A, Pinto F, Degener A, Bucci M, Ruocco V. Keratoacanthoma centrifugum marginatum. Possible etiological role of human papillomavirus and therapeutic response to etretinate. Ann Dermatol Venereol. 1996;123:660–663. 9 Kato N, Ito K, Kimura K, Shibata M. Ferguson Smith type multiple keratoacanthomas and a keratoacanthoma centrifugum marginatum in a woman from Japan. J Am Acad Dermatol. 2003;49:741–746. 10 Cherif F, Mebazaa A, Kort R, et al. Multiple keratoacanthoma centrifugum marginatum. Ann Dermatol Venereol. 2002;129:413–415. 11 Aydin F, Senturk N, Sabanciler E, Canturk MT, Turanli AY. A case of Ferguson-Smith type multiple keratoacantho-

mas associated with keratoacanthoma centrifugum marginatum: response to oral acitretin. Clin Exp Dermatol. 2007;32:683–686. 12 Mangas C, Bielsa I, Ribera M, Fernandez-Figueras MT, Ferrandiz C. A case of multiple keratoacanthoma centrifugum marginatum. Dermatol Surg. 2004;30:803– 806. 13 Lu L, Su J, Chen X, Chen M. A giant mass on the left shin: report of a case. Int J Clin Exp Pathol. 2015;8(2):2180–2182. 14 Das K, Das NK, Rathore VS, Kundu S, Choudhury S, Gharami RC, Datta PK. Keratoacanthoma centrifugum marginatum: unresponsive to oral retinoid and successfully treated with wide local excision. Dermatol Reports. 2010;18;2(1):e1.

“Acrodermatitis chronica atrophicans with fibrinoid nodules.” Moulage No. 181, made by Lotte Volger in 1925 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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MEDIA PARTNER


January/February 2017

Volume 15 • Issue 1

CASE STUDY

Donovanosis With Bowen Disease Tarun Narang, MD;1 Ashwini Manhas, MD;2 Bhushan Kumar MD, FRCP (Edin), FRCP (London)3

A 45-year-old farmer presented with ulcers and plaques over his scrotum for the past 4 to 5 years. The condition started as a small lesion on the shaft of the penis, which improved with treatment; however, after 2 to 3 months, papulonodular lesions developed on the scrotum, which increased in size and subsequently broke down to form ulcers. He denied drug abuse but had a history of multiple unprotected sexual exposures. He was prescribed oral antibiotics, which improved the lesions, but he failed to take the antibiotics for more than a week. He also used powders, lotions, and salves (exact nature not known), which did not help and sometimes even burned the skin. After stopping the medicine, he developed new lesions that followed a similar course. Examination revealed nontender ulcers on the scrotum with raised, rolled-out margins and pale red, granulation tissue that bled on touch (Figure 1). In addition, there were nodules with a pinkish red granular surface and scaly erythematous plaques on the scrotum. Regional lymph nodes were not enlarged. (SKINmed. 2017;15:73–75)

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esults from skin biopsy of a noduloulcerative lesion showed irregular acanthosis with pseudocarcinomatous hyperplasia and dense collection of polymorphs, lymphocytes, histiocytes, and plasma cells. Findings from skin smear revealed Donovan bodies (Figure 2a). Human immunodeficiency virus and venereal disease research laboratory testing was negative. He was started on doxycycline 100 mg twice a day and azithromycin 1 g/wk but after 3 weeks the response was inadequate; therefore, intramuscular gentamicin 1 mg/kg was started, which was continued for 4 weeks. The ulcers improved but the plaques persisted and were increasing in size; therefore, repeat biopsies were performed from the plaques and the findings were consistent with Bowen disease (Figure 2b). The treatment options were explained to the patient and he was referred to surgery for excision of the lesions.

Donovanosis had a fairly wide geographical distribution in the preantibiotic era, including Papua New Guinea, southern Africa, Zimbabwe, parts of India, French Guyana, and aboriginal communities in Australia.1–3 In India, the disease was mainly reported from southern parts, especially Tamil Nadu, Pondicherry, Andhra Pradesh, and Orissa.2,4 The prevalence of donovanosis has declined in many parts of the world over the past 10 years and it is rarely reported today, especially in North India.5,6 There is a possibility of it being missed, misdiagnosed, and underreported, especially in the mobile population. The debilitating or disfiguring stage of the condition is often not seen because of the use of antibiotics and the syndromic management of sexually transmitted infections, but physicians must be vigilant in its identification, as it may present in unusual forms.

Discussion

Clinically, the disease shows polymorphous features. In early stages, donovanosis is difficult to differentiate from chancroid; however, chancroid ulcers are painful, whereas those of donovanosis are painless. In later stages, donovanosis is difficult to differentiate from lymphogranuloma venereum and anogenital cutaneous amebiasis.2,3 Lesions are usually described as “beefy red,” painless ulcers that bleed readily on

Donovanosis is a chronic and progressive disease caused by Klebsiella granulomatis, involving the genital, anal, and inguinal areas. If left untreated it exhibits no tendency to go into spontaneous remission and in later stages may be severely debilitating, causing genital mutilation, disfigurement, pseudoelephantiasis, and malignancy.

From the Department of Dermatology, Venereology & Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India;1 the Department of Microbiology, Gian Sagar Medical College and Hospital, Ram Nagar, Banur, Patiala, India;2 and Silver Oaks Multispecialty Hospital, Mohali, Punjab, India3 Address for Correspondence: Tarun Narang, MD, Department of Dermatology, Venereology & Leprology, Post Graduate Institute of Medical Education and Research, Chandigarh, India • E-mail: narangtarun@yahoo.co.in

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Figure 1. Ulcers with raised, rolled-out margins and scaly plaques on the scrotum.

touch. They may also be hypertrophic, necrotic, or dry and fibrous. Self-inoculation may occur, leading to multiple ulcers that may appear to be mirror images. They are commonly located in the folds of the skin and can become extensive and secondarily infected, emitting a rank odor.3 If untreated, the affected area gradually spreads subcutaneously to involve the inguinal region, producing fluctuant pseudobuboes. Lymphadenopathy is absent unless there is extensive secondary infection. Occasionally the disease may progress by hematogenous dissemination and can involve the lungs, liver, spleen, and bones. It may be fatal under these circumstances.1–3 The diagnosis of donovanosis is made clinically and needs confirmation by direct microscopy and histopathological examination. The pathognomonic cell in tissue scrapings is a large (25–90 mm) monocyte containing typical intracellular bodies (Donovan bodies), which were detected in our case. Biopsy is recommended for lesions in which organisms are likely to be scarce, such as in very early or very sclerotic lesions and those with heavy superinfection. Culture and polymerase chain reaction methods are not routinely available and serologic tests are not reliable. Laboratory investigations may help in determining the diagnosis, but, in endemic areas, diagnosis largely depends on clinical findings and tissue smear.1–3 SKINmed. 2017;15:73–75

B Figure 2. (A) Findings from tissue smear showing Donovan bodies. (B) Biopsy findings from the plaques showing numerous dyskeratotic keratinocytes, and atypical cells in the upper layers of the epidermis. (Hematoxylin and eosin stain, original magnification ×200.)

X-ray, heavy metals, and arsenicals; nitric, carbolic, and boric acid; ointments, salves, surgical excision, and tartar emetics; charms, patent medicines and seawater baths, rubbing with soft sandstone, and cauterizing by sulfate of copper and firesticks; various antimony preparations; and antibiotics including penicillin and chloramphenicol, alone and in combination, have all been used for the treatment of donovanosis with varying rates of success, from swift and complete cure in many cases, to death from radiation, surgery, or chemical shock.6,7 Treatment with antibiotics is effective if started early, but if there has been significant spread, scarring and lymphatic obstruction may remain, producing elephantiasis and stenosis. The Centers for Disease Control and Prevention recommends azithromycin 1 g orally once per week or 500 mg daily for at least 3 weeks and until all lesions

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have completely healed. Alternative regimens include doxycycline 100 mg orally twice a day, ciprofloxacin 750 mg orally twice a day, erythromycin base 500 mg orally 4 times a day, or one doublestrength (160 mg/800 mg) tablet of trimethoprim-sulfamethoxazole orally twice a day for at least 3 weeks and until all lesions have completely healed; an aminoglycoside (eg, intravenous gentamicin 1 mg/kg every 8 hours) can be added to these regimens if improvement is not evident within the first few days of therapy.9 Some cases can be treated with commonly available antibiotics, but, in the absence of treatment, ulcers in donovanosis are known to persist for years together, leading to complications such as pseudoelephantiasis of the genitalia; stenosis of urethral, vaginal, and anal orifices; adhesion and/or incarceration of the penis into the skin of the scrotum; partial or total amputation of the penis; and squamous cell carcinoma.7,10 Carcinoma is the most serious complication of donovanosis but is relatively rare (0.25% in one series).7 To our knowledge, Bowen disease has never been reported with donovanosis.

Conclusions Donovanosis has been referred to as a disease that is “easily forgotten and poorly pursued.” The prevalence of donovanosis has been declining in many parts of the world, which could indicate that physicians/dermatologists may not be confident in diagnosing it or that the disease is frequently misdiagnosed or underdiagnosed—this delay in diagnosis leads to complications such as malignant change and elephantiasis. These complications further obfuscate the picture, and at times multiple biopsies must be performed from different sites to confirm the diagnosis and rule out malignancy.

Predisposing factors for Bowen disease include ultraviolet or other types of ionizing radiation, exposure to hydrocarbons, arsenic intake, and human papillomavirus infection.11,12 Chronic infections and different treatments such as arsenic or acids that the patient might have applied during the course of illness may also play an important role in the pathogenesis of Bowen disease,11 as seen in our case. In 1987, a new clinical classification with eight major clinical varieties was proposed: ulcerous; ulcerative lesions with hypertrophic edges; ulcerative lesions with plane edges; ulcerovegetative lesions, which are the most common pattern of the disease; vegetating lesions; elephantine manifestations; extragenital disease; and systemic infection.13 Often, when there are many clinical variants of a disease, physicians try to group all of the lesions under the same diagnosis. As in our case, we did not perform biopsies on the multiple scaly plaques on the scrotum, only the ulcerative lesion was biopsied; therefore, we missed the diagnosis of coexisting Bowen disease. Moreover, histological distinction between donovanosis and Bowen disease may be difficult where the organisms are not demonstrable. In such cases, with lesions of different morphologies and less satisfactory response than expected, multiple biopsies may need to be performed from different lesions to rule out malignant change.

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References 1 O’Farrell N. Donovanosis. In: Gupta S, Kumar B, eds. Sexually Transmitted Infections. 2nd ed. New Delhi, India: Elsevier India; 2011:533–541. 2 Sehgal VN. Epidemiological features and clinical overtones. In: Donovanosis (Granuloma Inguinale). 2nd ed. New Delhi, India: Jaypee Brothers Medical Publishers; 2013:11–40. 3 Velho PE, Souza EM, Belda Junior W. Donovanosis. Braz J Infect Dis. 2008;12:521–525. 4 Veeranna S, Raghu TY. A clinical and investigational study of donovanosis. Indian J Dermatol Venereol Leprol. 2003;69:159–162. 5 Gupta S, Kumar B. Donovanosis in India: declining fast? Int J STD AIDS. 2002;13:277. 6 Morrone A, Toma L, Franco G, Latini O. Donovanosis in developing countries: neglected or misdiagnosed disease? Int J STD AIDS. 2003;14:288–289. 7 Rajam RV, Rangiah PN. Donovanosis. World Health Organization: Monograph series No. 24. Geneva: WHO; 1954:1–72. 8 Hammar L. The dark side to donovanosis: color, climate, race and racism in American South venereology. J Med Humanit. 1997;18:29–57. 9 Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015;64(No. RR-3): 32–33. 10 Thappa DM, Senthilkumar M, Laxmisha C. Malignant transformation of donovanosis. Indian J Sex Transm Dis. 2004;25:77. 11 Arlette JP, Trotter MJ. Squamous cell carcinoma in situ of the skin: history, presentation, biology and treatment. Australas J Dermatol. 2004;45:1–9. 12 Pfister H, Ter Schegget J. Role of HPV in cutaneous premalignant and malignant tumors. Clin Dermatol. 1997;15:335–347. 13 Jardim ML. Donovanose: proposta de classificacao clinica. An Bras Dermatol. 1987;62:169–172.

Donovanosis With Bowen Disease


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January/February 2017

Volume 15 • Issue 1

CASE STUDY

White Papules on the Backs of a Middle-Aged Man and His Son Fiona Fang, MD;1 Dustin Larsen, BS;2 Barbara Wilson, MD1

A middle-aged man came in for evaluation of “white spots” on his upper body. The number of lesions had increased progressively over the past 20 years but were asymptomatic. The patient expressed concern that his young son had recently developed similar lesions on the upper part of his back. Physical examination revealed numerous, slightly elevated, flat-topped papules scattered over the back, chest, and upper extremities (Figure 1). Each 4- to 6-mm papule was oval or round, ivory white, with a cobblestone surface. The patient’s son was also examined and found to have six papules scattered across the upper part of his back and legs, identical in morphology to those of our patient. A shave biopsy was taken from of one of the papules. Results from routine hematoxylin-eosin, as well as Melan-A sections, are shown (Figure 2). The diagnosis was familial keratosis alba or familial hypochromic seborrheic keratosis. (SKINmed. 2017;15:77–78)

M

icroscopic examination revealed subtle acanthosis and orthokeratosis at the site of the lesion, flanked by areas of normal skin (Figure 2). Fontana-Masson staining (not shown) highlighted a clear lack of melanin pigmentation within the lesion. Results from Melan-A stain revealed a slightly decreased number of lesional epidermal melanocytes (Figure 2). The underlying collagen was normal, and there was no disturbance of the elastic tissue on Verhoeff-van Gieson staining (not shown). A diagnosis of keratosis alba was made based on physical examination and histopathologic findings. Given the benign nature of these skin growths, the patient decided against any treatment. Discussion Figure 1. Multiple white flat-topped papules scattered across the upper part of his back. The picture shows the typical appearance of keratosis alba. Lesions consist of white, flat-topped papules that have a velvety surface and a predilection for the upper part of the back and arms, plus the chest and abdomen.

Keratosis alba is thought to be a hypopigmented variant of seborrheic keratosis. It was described in 1971 by Cornelison and colleagues1 and again by Smith and colleagues2 that same year. Since then, there have been no cases in the literature. The paucity of reports on this entity is possibly a result of its benign appearance, lack of symptoms, and misdiagnosis, as Cornelison and Smith both suggest that, if searched for, the skin lesions are quite prevalent.

use of side lighting that the slight elevation is appreciated. Lesions are usually oval or round, but some may have scalloped borders forming clover-leaf or flower-shaped papules. These have a predilection for the upper part of the back and arms, plus the chest and

The typical lesion of keratosis alba is a small (2–8 mm) ivory white, slightly raised, flat-topped papule with a velvety surface. Lesions may appear macular, and often it is only after careful palpation and

From the Department of Dermatology, University of Virginia School of Medicine, Charlottesville, VA;1 and Virginia Commonwealth University, School of Medicine, Richmond, VA2 Address for Correspondence: Fiona Fang, MD, 20 East 46th Street, Suite 1101, New York, NY 10017 • E-mail: FionaH.Fang@gmail.com

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January/February 2017

CASE STUDY admixture of squamous and basaloid cells is observed, similar to what is seen in an early seborrheic keratosis. Findings from Melan-A staining reveal a slight decrease in melanocytes within lesional skin, and a significant decrease in melanin is seen with Fontana-Masson.1,2 The differential diagnosis for keratosis alba consists of idiopathic guttate hypomelanosis, postinflammatory hypopigmentation, vitiligo, stucco keratosis, and verruca plana. In idiopathic guttate hypomelanosis, postinflammatory hypopigmentation, and vitiligo, the lesions are macular and have different sites of predilection.4–6 In addition, results from biopsy of vitiligo show complete absence of melanocytes. Stucco keratoses are more hyperkeratotic, favor the lower extremities, and can be scraped off the skin without leaving behind points of bleeding.7 The papules of verrucae planae are often arranged in linear configurations and have distinctive koilocytic changes in the epidermis on histopathology.

A

Conclusions This is an interesting case study that further describes the clinical and histopathologic features of keratosis alba, a previously poorly defined but likely common dermatologic entity. To the authors’ knowledge this is the first study to suggest a familial association of keratosis alba, with the patient’s son presenting at a younger age than any previously described case.

B Figure 2. Shave biopsy specimen (hematoxylin-eosin, original magnification ×10) (A). This biopsy shows mild hyperorthokeratosis and acanthosis characteristic of a keratosis alba lesion flanked by normal epidermis. Shave biopsy stained for Melan-A (original magnification ×10) (B). Results from Melan-A stain reveal a slightly decreased number of lesional epidermal melanocytes.

References 1 Cornelison RL, Dosser GP, Everett MA. Hypochromic seborrheic keratosis. Cutis. 1971;8:255–258. 2 Smith JD, Dickson JE, Knox JM. Keratosis Alba. Br J Dermatol. 1971;85:418–420. 3 Cornelison RL. Hypochromic seborrheic keratosis. In: Demis J. Clinical Dermatology. Philadelphia, PA: Lippincott-Raven Publishers; 1998:21-1A:1–2. 4 Shin MK, Jeong KH, Oh IH, Choe BK, Lee MH. Clinical features of idiopathic guttate hypomelanosis in 646 subjects and association with other aspects of photoaging. Int J Dermatol. 2011;50:798–805.

abdomen. The number of papules ranges from 1 to more than 50. Age of diagnosis is usually middle age or older, and there does not appear to be a predilection for race or sex.1,2 The lesions of keratosis alba are benign and do not change color or darken over time.3

5 Vachiramon, V, Thadanipon, K. Postinflammatory hypopigmentation. Clin Exp Dermatol. 2011:36:708–714. 6 Kovacs SO. Vitiligo. J Am Acad Dermatol. 1998;38:647– 668.

On histopathology, the lesions of keratosis alba demonstrate hyperkeratosis with little or no parakeratosis. The epidermis is mild to moderately acanthotic with mild digitate papillomatosis. An

SKINmed. 2017;15:77–78

7 Willoughby C, Soter NA. Stucco keratosis. Arch Dermatol. 1972;105:859–861.

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White Papules on the Backs of a Middle-Aged Man and His Son



January/February 2017

Volume 15 • Issue 1

Book Review Jennifer L. Parish, MD, Section Editor

History of Allergy Lawrence Charles Parish, MD, MD (Hon)

born. The disease had not been fully delineated from a variety of dermatitides, including neurodermatitis, lichen simplex chronicus, and the exudative eczematoids. Sulzberger and Wise initially had thought food played a role but soon dismissed this idea.

Bergmann K–C, Ring J. History of Allergy. Basel, Switzerland, Karger, 2014: 426 pp, $135.00 Imagine modern medicine without the idea of allergy. When Clemens von Pirquet (1874–1929), a Viennese pediatrician, coined the word allergy in 1906 to indicate “altered responsiveness,” the concept permitted the development of the subspecialty of medicine known today as allergy and immunology. The exhaustive multiauthored text does credit to the physicians and scientists who have furthered the discipline of allergy and immunology. The well-written book is both extensive and wellillustrated with photographs of the famous pioneers and leaders of the field. There are even pictures of wax models that illustrate some allergic responses. The contributors, like the editors, represent the luminaries in this subspecialty of medicine and are pictured in the opening pages.

Angioedema has been known since the 16th century, when a patient was described whose lips swelled on eating eggs. Heinrich Quincke (1842–1922) and his student, Eugen Dinkelacker, published on urticaria in 1882, and some of the cases also had hereditary angioedema. At the time, angioedema was thought to occur as a result of neurogenic influences.

Highlights

Several chapters delve into the laboratory science behind allergy and immunology, ranging from the observations of what we would call eosinophiles in 1846 to the synthesis of histamine in 1907. The role of dust mites in causing asthma was elucidated as early as 1922 by Robert Cooke (1880–1960). Although we may think of corticosteroids as a wonder drug of the late 20th century, Solomon Solis-Cohen (1857–1948) recognized as early as 1900 that adrenal gland extract could be used in the treatment of asthma.

In the chapter on “Milestones in the 20th Century,” accounts of the pioneers in allergy are detailed. Robert Langerhans (1859– 1904) injected diphtheria antitoxin (Behring’s antiserum) into his 2-year-old and watched his child die within 7 minutes. The concept of serum sickness would evolve. Nicolas Maurice Arthus (1862–1945) developed the idea of “local anaphylaxis,” now known as the Arthus reaction. The idea of atopy had its origin in 1921, when Arthur Coca (1875–1959) and Robert Cooke (1880–1960) chose the word to refer to hay fever and asthma and their hereditary tendencies.

There is a concluding chapter on the development of several allergy societies and some fascinating pictures of early instruments, plus containers of early lay remedies. It is curious that no mention is made of the American College of Allergy, Asthma, and Immunology. Recommendation This is a fascinating volume that should appeal to the practicing dermatologist, as the concepts of allergy and immunology play such a significant role in the understanding of the development of many cutaneous entities. The well-done book represents a pioneering effort in this field and is a credit to the two distinguished editors.

The chapter on “Atopic Dermatitis/Atopic Eczema” proves to be of much interest to dermatologists, for it is here that the concept of atopic dermatitis, promulgated by Marian Sulzberger (1895–1983) and Fred Wise (1881–1950) in 1933, was

Reviewed by Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia PA Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), 1845 Walnut Street, Suite 1650, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

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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


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...

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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.

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© 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


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