Skinmed Mar/Apr 2017 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Karadag, Parish, and Lambert

COMMENTARY Cosmetic Procedures in Pregnancy: A Reappraisal Kroumpouzos

ORIGINAL CONTRIBUTIONS The Pathergy Test as a Diagnostic Tool Kutlubay, Tüzün, and Wolf

A Retrospective Study of Multiple Sequential Light and Laser Sources to Activate Aminolevulinic Acid in the Treatment of Acne Vulgaris Friedmann, Goldman, Fabi, and Guiha

A Multicenter Clinical Study of Expected and Unexpected Side Reactions During and After Skin Cancer Treatment by Photodynamic Therapy Blanco, Inada, Silva, Stringasci, Buzzá, Ramirez, Sálvio, Moriyama, Kurachi, and Bagnato

Fixed-Combination Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam Is Well Tolerated in Patients with Psoriasis Vulgaris: Pooled Data from Three Randomized Controlled Studies

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

EDITORIAL Senile Purpura as a Stage of Dermatoporosis

Lebanese Dermatological Society

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

March/April 2017REVIEW • Volume 15• Issue 2 Vitiligo: Not Simply a Skin Disease Ahluwalia, Correa-Selm, and Rao

Self Assessment Examination Lambert

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Achieving Diagnosis: Importance of Proper Biopsy in Autoimmune Bullous Disorders

Patel, Sylvester, Baldev, John, and Lambert

NEW THERAPY UPDATES AMELUZ™ (BF-200 ALA) Gupta, Versteeg, and Abramovits

March/April 2017 • Volume 15• Issue 2

case studies Multifocal Tuberculosis Verrucosa Cutis: A Manifestation Extraordinary of Reactivation Secondary Tuberculosis Sehgal, Verma, Bhattacharya, Sharma, and Singh

Chronic Tender Ulcers on the Calf and Both Forearms Cameron, Katayama, Patel, Shenefelt, and Somboonwit

Secondary Skin Plasmacytomas

Mendes-Bastos, Brás, Amaro, and Cardoso

Grotesque Face Secondary to Immunotherapy: Cure Circumvallating to Curse Vinay, Narang, Dogra, Saikia

Targeted Treatment of Atopic Dermatitis Metin and Wallace

THE HEYMANN FILE Eosinophilic Fasciitis: A Firm Warning Heymann

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Reiter’s Syndrome Bernhardt

PHOTO CAPSULE Perianal Bacterial Disease Cohen

Menter, Stein Gold, Koo, Villumsen, Rosén, and Lebwohl

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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...

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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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FINACEAÂŽ

(azelaic acid) Foam, 15% for topical use

For Topical Use Onlyâ&#x20AC;&#x201C;Not for Oral, Ophthalmic or Intravaginal Use Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Finacea (azelaic acid) Foam, 15% is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea. 5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions There have been isolated reports of hypopigmentation after use of azelaic acid. Because azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation. 5.2 Eye and Mucous Membranes Irritation Azelaic acid has been reported to cause irritation of the eyes. Avoid contact with the eyes, mouth and other mucous membranes. If Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists. 5.3 Flammability The propellant in Finacea Foam is flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following application. Do not puncture and/or incinerate the containers. Do not expose containers to heat and/or store at temperatures above 120Â°F (49Â°C). 6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the prescribing information: t )ZQPQJHNFOUBUJPO [see Warnings and Precautions (5.1)]. t Eye and Mucous Membranes Irritation [see Warnings and Precautions (5.2)]. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Finacea Foam was evaluated for the treatment of papulopustular rosacea in two multicenter, randomized, double-blind, vehicle-controlled, 12-week clinical trials involving a total of 1362 (Finacea Foam, 15%: 681; vehicle: 681) subjects. Overall, 95.7% of subjects were White, 73.4% were female, and the mean age was 50.6 years. Table 1: Adverse Reactions Occurring in â&#x2030;Ľ 0.5% of Subjects Treated with Finacea Foam Compared with Subjects Treated with Vehicle System/Organ Class Preferred

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

Vehicle (N=681) n (%)

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

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

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

* â&#x20AC;&#x153;Application site painâ&#x20AC;? is a term used to describe disagreeable skin sensations, including burning, stinging, paraesthesia and tenderness. 6.2 Post-Marketing Experience )ZQFSTFOTJUJWJUZ SBTI BOE XPSTFOJOH PG BTUINB IBWF CFFO SFQPSUFE GSPN the postmarketing experience of azelaic acid-containing formulations. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Local Tolerability Studies In a 21-day cumulative irritation study under occlusive conditions, mildto-moderate irritation was observed for azelaic acid pre-foam emulsion. In B IVNBO SFQFBU JOTVMU QBUDI UFTU )3*15 TUVEZ OP TFOTJUJ[BUJPO QPUFOUJBM was observed for azelaic acid pre-foam emulsion. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Therefore, Finacea Foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% foam. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 UJNFT UIF NBYJNVN SFDPNNFOEFE IVNBO EPTF .3)% CBTFE PO CPEZ surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times UIF .3)% CBTFE PO #4" BOE DZOPNPMHVT NPOLFZT HJWFO NH LH EBZ UJNFT UIF .3)% CBTFE PO #4" B[FMBJD BDJE /P UFSBUPHFOJD FGGFDUT were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys. An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was PCTFSWFE JO SBUT BU BO PSBM EPTF PG NH LH EBZ UJNFT UIF .3)% based on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/ LH EBZ BOE UJNFT UIF .3)% CBTFE PO #4" /P FGGFDUT PO TFYVBM maturation of the fetuses were noted in this study. 8.3 Nursing Mothers It is not known if azelaic acid is secreted into human milk in vivo /P XFMM controlled studies of topically administered azelaic acid in nursing women BSF BWBJMBCMF /FWFSUIFMFTT UIF EFDJTJPO UP EJTDPOUJOVF OVSTJOH PS UP discontinue the drug should take into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Finacea Foam in children below the age of 18 years have not been established. 8.5 Geriatric Use Of the total number of subjects in clinical studies of Finacea Foam, 18.8 QFSDFOU XFSF BOE PWFS XIJMF QFSDFOU XFSF BOE PWFS /P PWFSBMM differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 17 PATIENT COUNSELING INFORMATION Inform patients using Finacea Foam of the following information and instructions: t 'PS FYUFSOBM VTF POMZ t $MFBOTF BGGFDUFE BSFB T XJUI B WFSZ NJME TPBQ PS B TPBQMFTT DMFBOTJOH lotion and pat dry with a soft towel. t 4IBLF XFMM CFGPSF VTF t "WPJE VTF PG BMDPIPMJD DMFBOTFST UJODUVSFT BOE BTUSJOHFOUT BCSBTJWFT BOE peeling agents. t "WPJE DPOUBDU XJUI UIF FZFT NPVUI BOE PUIFS NVDPVT NFNCSBOFT *G Finacea Foam does come in contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye irritation persists. t *G BMMFSHJD SFBDUJPOT PDDVS EJTDPOUJOVF VTF BOE DPOTVMU ZPVS QIZTJDJBO t 8BTI IBOET JNNFEJBUFMZ GPMMPXJOH BQQMJDBUJPO PG 'JOBDFB 'PBN t $PTNFUJDT NBZ CF BQQMJFE BGUFS UIF BQQMJDBUJPO PG 'JOBDFB 'PBN IBT ESJFE t "WPJE UIF VTF PG PDDMVTJWF ESFTTJOHT BOE XSBQQJOHT t 5P IFMQ NBOBHF SPTBDFB BWPJE BOZ USJHHFST UIBU NBZ QSPWPLF FSZUIFNB flushing, and blushing. These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic beverages. t 5IF QSPQFMMBOU JO 'JOBDFB 'PBN JT nBNNBCMF "WPJE mSF nBNF PS smoking during and immediately following application. t %JTDBSE QSPEVDU XFFLT BGUFS PQFOJOH ÂŠ #BZFS )FBMUI$BSF 1IBSNBDFVUJDBMT *OD "MM SJHIUT SFTFSWFE Manufactured for:

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

6798100BS

TABLE OF CONTENTS March/April 2017 • Volume 15 • Issue 2

EDITORIAL

Senile Purpura as a Stage of Dermatoporosis ............................................................................................. 91

Ayse Serap Karadag, MD; Lawrence Charles Parish, MD, MD (Hon); W. Clark Lambert, MD, PhD

COMMENTARy

Cosmetic Procedures in Pregnancy: A Reappraisal .................................................................................... 93

George Kroumpouzos, MD, PhD

ORIGINAL CONTRIBUTIONS

The Pathergy Test as a Diagnostic Tool ....................................................................................................... 97

Zekayi Kutlubay, MD; Yalçın Tüzün, MD; Ronni Wolf, MD

A Retrospective Study of Multiple Sequential Light and Laser Sources to Activate Aminolevulinic Acid in the Treatment of Acne Vulgaris ..................................................................................................... 105

Daniel P. Friedmann, MD; Mitchel P. Goldman, MD; Sabrina G. Fabi, MD; Isabella Guiha, BS

A Multicenter Clinical Study of Expected and Unexpected Side Reactions During and After Skin Cancer Treatment by Photodynamic Therapy ............................................................................................ 113

Kate C. Blanco, PhD; Natalia M. Inada, PhD; Ana. P. Silva, MS; Mirian D. Stringasci, MS; Hilde H. Buzzá, PhD; Dora P. Ramirez, MS; Ana G. Sálvio, PhD; Lilian T. Moriyama, PhD; Cristina Kurachi, PhD; Vanderlei S. Bagnato, PhD

Alan Menter, MD; Linda Stein Gold, MD; John Koo, MD; John Villumsen, MSc; Monika Rosén, PhD; Mark Lebwohl, MD

REVIEW

Vitiligo: Not Simply a Skin Disease ........................................................................................................... 125

Jusleen Ahluwalia, MD; Lilia M. Correa-Selm, MD; Babar K. Rao, MD

Self Assessment Examination ................................................................................................................... 128

W. Clark Lambert, MD, PhD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Achieving Diagnosis: Importance of Proper Biopsy in Autoimmune Bullous Disorders .............................. 129

Viral M. Patel, BS; Michael Sylvester, AB; Khushboo Baldev, BS; Ann M. John, BA; W. Clark Lambert, MD, PhD

New Therapy Updates

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

AMELUZ™ (BF-200 ALA) ........................................................................................................................... 133

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

Targeted Treatment of Atopic Dermatitis .................................................................................................. 137

Simon Arda Metin, MA (Cantab); Marc Wallace, MB ChB, BSc (Hons)

TABLE OF CONTENTS March/April 2017 • Volume 15 • Issue 2

The Heymann File

Warren R. Heymann, MD, Section Editor

Eosinophilic Fasciitis: A Firm Warning ...................................................................................................... 139

Warren R. Heymann, MD

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

Reiter’s Syndrome .................................................................................................................................... 141

Mark Bernhardt, MD

Photo Capsule

Snejina Vassileva, MD, PhD, Section Editor

Perianal Bacterial Disease ........................................................................................................................ 143

Philip R. Cohen, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Multifocal Tuberculosis Verrucosa Cutis: A Manifestation Extraordinary of Reactivation Secondary Tuberculosis ............................................................................................................................ 145

Virendra N. Sehgal, MD, FNASc, FAMS; Prashant Verma, MD; Sambit N. Bhattacharya, MD; Sonal Sharma, MD; Navjeevan Singh, MD

Chronic Tender Ulcers on the Calf and Both Forearms .............................................................................. 149

Michael C. Cameron, MD; Mitsuya Katayama, MD; Nishit S. Patel, MD; Philip D. Shenefelt, MD; Charurut Somboonwit, MD

Secondary Skin Plasmacytomas ................................................................................................................ 153

Pedro Mendes-Bastos, MD; Susana Brás, MD; Cristina Amaro, MD; Jorge Cardoso, MD

Grotesque Face Secondary to Immunotherapy: Cure Circumvallating to Curse .......................................... 157

Keshavamurthy Vinay, MD, DNB; Tarun Narang, MD; Sunil Dogra, MD, FRCP; Uma N. Saikia, MD

March/April 2017

Volume 15 • Issue 2

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.

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Chinese Society of Dermatology

Lebanese Dermatological Society

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

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

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

March/April 2017

Volume 15 • Issue 2

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc

Dallas, TX

London, Ontario, Canada

Newark, NJ

Chicago, IL

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Meridian, MS

Rio de Janeiro, Brazil

Philadelphia, PA

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

Robert L. Baran, MD Cannes, France

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

Ada Lo Schiavo, MD Naples, Italy

Virendra N. Sehgal, MD Delhi, India

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

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

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

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

Michael H. Gold, MD Nashville, TN 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 Scottsdale, AZ

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

SKINmed. 2017;15:89

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

March/April 2017

Volume 15 • Issue 2

Editorial

Senile Purpura as a Stage of Dermatoporosis Ayse Serap Karadag, MD;1 Lawrence Charles Parish, MD, MD (Hon);2 W. Clark Lambert, MD, PhD3

hat to call the purplish discolorations that are often found on the arms of mature patients? Senile purpura seems a little awkward, and not all of the patients show enough sun damage to consider calling these discolorations actinic purpura. This nonpalpable purpura is a common benign condition, representing blood that has extravasated into the dermis and is characterized by ecchymotic, purpuric patches in the older population. Background Such purpura was recognized as long ago as 1817, when Thomas Bateman (1778–1821) first described the condition as dark purple blotches of an irregular form and various magnitude that appeared on the outer surface of the arms of elderly women who were seemingly healthy.1 Bateman described the condition as “purpura senilis, scurvy of old age.”1 Fast forward to 1950, when Tattersall and Seville demonstrated degenerative collagen fibers in the affected areas and thought that individual lesions were most likely produced by minor external trauma acting on inadequately supported skin vessels,1 an explanation that is still valid. Pathogenesis There is now a movement to consider senile purpura as a part of “dermatoporosis”––a recently introduced term to include various manifestations of the chronic cutaneous insufficiency/ fragility syndrome. Morphologic markers of dermatoporosis begin to appear at 70 to 80 years of age. Beginning at 80 years, functional expression of skin fragility with the complications of dermatoporosis begin.2 With extreme aging, the loss of the protective mechanical function and viscoelastic buffering system of the skin results in extreme fragility, leading to complications such as lacerations, nonhealing ulcers, purpura, and hemato-

mas.2 A decrease in viscoelastic properties of the skin is the main cause for the intracutaneous hemorrhages that characterize senile purpura. Intrinsically, aged skin has fewer elastic fibers with a flattened dermal-epidermal junction, leading to poor skin elasticity and increased fragility, respectively. Solar exposure accelerates damage of this framework by decreased dermal collagen, affecting, in particular, precursors of collagen I and III, but this may not be the sole cause. These findings, in combination with thinning of the dermal vasculature, result in aged skin being more susceptible to mild mechanical trauma.3 Purpura represents stage I dermatoporosis along with excessive skin thinning and pseudoscars.4 Other proposed causes of skin atrophy include corticosteroid use (both topically and systemically)3 and zinc and vitamin C deficiency; however, a role of any or all of these factors in the etiopathogenesis of senile purpura is/are not proven. Clinical Findings The purpuric lesions, which have a preponderance in women and are most prevalent in the older than 70 age group, are commonly located on the extensor surfaces of the forearms and the dorsal surface of the hands. The lesions present with sharply demarcated areas of purpura that typically measure 1 to 5 cm (Figures 1 and 2). The condition may follow minor trauma, often not recalled, and is more likely to occur in patients taking aspirin or other blood thinners.5 New lesions may resolve within a few days, leaving a brownish discoloration due to deposits of hemosiderin that may clear within a few weeks.4,5 Histologically, senile purpura is characterized by extravasation of red blood cells into the dermis often found in a perivascular location. Sun-exposed skin usually displays epidermal and

From the Department of Dermatology, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey;1 the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA;2 and the Department of Dermatology and of Pathology and Laboratory Medicine, Rutgers University – New Jersey Medical School, Newark, NJ3 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 1845 Walnut Street, Suite 1650, Philadelphia, PA • E-mail: larryderm@yahoo.com

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Volume 15 • Issue 2

Figure 1. Senile purpura.

dermal thinning, marked solar elastosis and atrophy of collagen bundles,4 and a thinning of the dermal-epidermal junction with characteristically flattened rete ridges.6 Treatment Senile purpura is a benign disease, not easily confused with other types of purpura, such as hemophilia, anticoagulants, vitamin K deficiency, hepatic insufficiency, corticosteroid therapy, vitamin C deficiency (scurvy), and systemic amyloidosis. Treatment is usually unnecessary, and the extravasated blood reabsorbs within a few to several weeks.5 The most important prevention measure is the avoidance of trauma. Photoprotection refers to steps that can be taken to protect the skin from UV damage and is achieved by use of sunscreens, sun-protective clothing, and sun avoidance to prevent more damage. This may have limited benefit, however, since much of the sun damage may have occurred years previously. Various flavonoids, herbal flavonoids such as lemon, and herbal remedies containing vitamin C have been tried as treatment options with questionable results. Some other treatments including topical tretinoin, antioxidant suplements, hormones, and, surprisingly, surgical treatments, ranging from chemical peels, dermabrasion, and nonablative laser resurfacing, have also been recommended.4 SKINmed. 2017;15:91–92

Figure 2. Senile purpura.

Conclusions Senile purpura presents as a cosmetic disturbance posing significant psychologic distress and serves as an indicator of the severity of skin thinning. It appears to be a visible marker of early-stage dysfunction of dermatoporosis; however, it has no systemic medical significance. The patient should be informed, put at ease, and advised that protection from mechanical trauma is the best prevention. References 1 Tattersall RN, Seville R. Senile purpura. Q J Med. 1950;19:151–159. 2 Kaya G. New therapeutic targets in dermatoporosis. J Nutr Health Aging. 2012;16:285–288.3 Banta MN, Kirsner RS. Modulating diseased skin with tissue engineering: actinic purpura treated with Apligraf. Dermatol Surg. 2002;28:1103–1106. 4 Kaya G, Saurat JH. Dermatoporosis: a chronic cutaneous insufficiency/fragility syndrome. Clinicopathological features, mechanisms, prevention and potential treatments. Dermatology. 2007;215:284–294. 5 Fitzpatrick JE. Geriatric dermatology. In: Fitzpatrick JE, Morelli JG, ed. Dermatology Secrets Plus. 5th ed. Philadelphia, PA: Elsevier; 2015:506–514. 6 Craig S, Kitchens CS. Purpura and other hematovascular disorders. In: Kitchens CS, Kessler CM, Konkle BA, eds. Consultative Hemostasis and Thrombosis. 3rd ed, Philadelphia, PA: Elsevier; 2013:150–173.

Senile Purpura as a Stage of Dermatoporosis

March/April 2017

Volume 15 • Issue 2

Commentary

Cosmetic Procedures in Pregnancy: A Reappraisal George Kroumpouzos, MD, PhD

valuation of the safety data regarding cosmetic procedures in pregnancy is of the utmost importance in minimizing maternal and fetal risks; however, the scarcity of data, in part due to ethical constraints on performing randomized controlled studies in gestation, makes this evaluation challenging. Physicians should be aware of existing knowledge in the field so they can provide appropriate patient counseling and minimize unnecessary stress for the patient.

likely with the volumes and concentrations used in dermatologic procedures. The amounts of lidocaine found in fillers are below the recommended maximum dose. Risks have been reported with other injectable anesthetics; mepivacaine (category C) can cause fetal bradycardia and preterm labor.2 Lidocaine and prilocaine are the preferred topical anesthetics (category B). Methemoglobinemia has been reported with very high doses of prilocaine, but this is an unlikely event with the concentrations used in dermatologic procedures.1 The safety of lidocaine 2.5%/prilocaine 2.5% cream is supported by the pediatric literature. The medication should not be applied near ocular surfaces as it can cause ocular damage. For procedures on the eyelid and periocular areas, tetracaine (category C) is preferred.2 Other topical anesthetics should be used with caution; benzocaine (category C) has been associated with methemoglobinemia in infants.1

GENERAL PRINCIPLES Patient counseling is crucial and should include discussion of safety data, risks, and benefits. Before the procedure, a detailed personal and family history needs to be taken. Recommended surgical positioning for operative procedures is the left lateral decubitus position.1 Treatment is not recommended for physiologic changes that may rebound in gestation and can diminish postpartum, such as melasma and hyperpigmentation, hypertrichosis (if associated with procedures aimed at permanent hair removal), and striae of pregnancy (striae gravidarum). Nonessential surgical procedures should be deferred until at least the second trimester.1 Use of pregnancy category B medications, such as lidocaine and penicillins, is recommended.2,3 Physicians should not pretreat with topical medications, such as retinoids and hydroquinone, that are deemed unsafe, even if the maternal/fetal risk from the medication has not been adequately established. ANESTHESIA AND HEMOSTASIS Lidocaine is the preferred injectable anesthetic, as it has a long history of uneventful use (category B). The maximum subcutaneous lidocaine dose in the United States is 4.5 mg/kg or 300 mg.2 The inadvertent arterial injection or use of high volumes of lidocaine may put the fetus at risk for cardiac or central nervous system toxicity;1 nevertheless, these adverse effects are very un-

Methods of hemostasis such as electrocoagulation and radiosurgery are considered safe. Patient exposure to smoke should be minimized during such procedures, because, based on animal studies, particles in the smoke are considered potentially mutagenic. Epinephrine (category C) is deemed safe with the dilutions and amounts used in dermatologic surgery.3 Very high epinephrine levels can cause decreased uterine blood flow or uterine artery spasm.1 MINIMALLY INVASIVE PROCEDURES Removal of skin tags, seborrheic keratoses, dermatosis papulosa nigra, and other benign soft tissue tumors with procedures such as snipping, shaving, curettage, and cryotherapy is safe in pregnancy and can be performed for cosmetic reasons. Cosmetic shave and punch removal of nevi is also safe. Removal of hemangiomas and pyogenic granulomas (granuloma gravidarum) with procedures such as electrocautery and radiosurgery is also safe during gestation.

From the Department of Dermatology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI Address for Correspondence: George Kroumpouzos, MD, PhD, Department of Dermatology, Alpert Medical School of Brown University, Rhode Island Hospital, 593 Eddy St, APC 10, Providence, RI 02903 • E-mail: gk@gkderm.com

SKINmed. 2017;15:93–96

March/April 2017

Commentary

CHEMICAL PEELS

FILLERS

Glycolic acid peels are theoretically safe because there is negligible dermal penetration. They have been considered as a safe acne procedure during pregnancy,4 but supporting safety data are lacking. Lactic acid has been anecdotally used for gestational acne and may be safe because of negligible dermal penetration. Salicylic acid peels should not be used, especially over large surface areas, because of possible dermal absorption.5

Adverse events have not been reported with fillers in pregnancy. The outcomes have not been studied, and manufacturers recommend avoidance in pregnancy; nevertheless, the injectable hyaluronic acid mimics the composition of the body’s own hyaluronic acid. Risks in the pregnant woman should be no different from those encountered in the nonpregnant patient. Of note, collagen injections for urinary stress incontinence during pregnancy have been uneventful. Potential risks may emanate from the inadvertent arterial injection of lidocaine, which is often mixed with the filler.

There is a lack of reports on the use of trichloracetic acid peels, and most authors agree that these peels should not be used in gestation owing to the risk of dermal penetration. In contrast to this prohibition, trichloracetic acid treatment of genital condylomata is considered safe.6 Maternal exposure to high doses of trichloracetic acid has been associated with intrauterine growth restriction; such doses are not used in dermatologic procedures. Systemic absorption through the ocular or oral mucosa should be avoided.2 Similarly, phenol peels should be avoided because of the risk of dermal penetration. NEUROMODULATORS Botulinum toxin (BTX) type A (BTX-A) cannot cross the placenta because its high molecular weight. BTX-A is not expected to be present in the systemic circulation after proper intramuscular or intradermal injection.7 In support of this, botulism has been reported in seven pregnant patients, contracted at 16, 23, and 36 weeks’ gestation. BTX-A injections have not been associated with fetal adverse effects,2 and no BTX-A has been detected in infant serum. High doses of onabotulinum toxin (>600 U), much higher than those used in cosmetic procedures, have been associated with systemic weakness. Reports on first-trimester onabotulinum toxin A injections are shown in the Table. BTX-A has been used for migraine prophylaxis14 and anecdotally for the treatment of Raynaud phenomenon of the nipple during gestation, without adverse effects. BTX-A may be injected unwittingly in pregnant women early in the first trimester, when they may not be aware of the pregnancy. Appropriate counseling helps alleviate patient anxiety in this case. The pregnant woman should be advised that BTX-A is not found systemically. In addition, reports on botulism in pregnancy have revealed no adverse outcomes.7 However, the safety data are insufficient, so pregnancy should be considered as a contraindication to cosmetic BTX-A treatment.15 As there are substantial legal risks, this contraindication should be included in consent forms. The foundation of a BTX pregnancy registry would be of great benefit to gather more safety data regarding its use during pregnancy.14 SKINmed. 2017;15:93–96

SCLEROTHERAPY Varicose veins that develop in pregnancy may improve postpartum. Most authors agree that they should not be treated until at least 6–12 months after pregnancy. Conservative treatment is recommended during gestation, because sclerosing solutions can cross the placenta. The German Society of Phlebology has determined that there is an absolute contraindication to sclerotherapy in the first trimester and after the 36th week of gestation,16 a period in which the hypercoagulable status is most pronounced; nevertheless, one study showed no difference in pregnancy outcomes between a group of 45 patients treated with sclerotherapy and of 56 patients treated conservatively.17 An analysis of case reports and series on intended or accidentally conducted sclerotherapy with common sclerosants and doses showed no increased risk for the mother and fetus.18 LASER THERAPIES There have been no reports of adverse pregnancy outcomes. Interestingly, laser has for decades been used successfully for fetoscopic photocoagulation without reported adverse effects. Similarly, use for other medical indications, such as the treatment of ureteral calculi, in pregnancy has been uneventful. The use of the carbon dioxide laser for the treatment of condylomata acuminata has been reviewed in six studies,2 with the largest study including 115 patients.19 There have been no maternal/fetal complications in these studies, with the exception of premature labor in one patient that resulted in a healthy neonate. Neodymium-doped yttrium aluminum garnet (Nd:YAG) laser has been also used successfully for the treatment of genital condylomata in 19 pregnant patients, without maternal/fetal complications.20 Case reports of successful treatment of severe acne and gingival pyogenic granuloma without adverse effects during gestation have been published. The above procedures require standard laser precautions, similar to those recommended for nonpregnant patients. The use of ablative fractional erbium-

Cosmetic Procedures in Pregnancy: A Reappraisal

March/April 2017

Commentary

Table. Reports on First-Trimester Use of Botulinum Toxin A Injections Report

Number of Patients

Gestational Age

Onabotulinum Toxin A Dose

Use

Outcome

de Oliveira Monteiro8

6 weeks

54 and 65 U

Cosmetic

No AEs

Li Yim et al9

5 weeks

65 U

Medical

No AEs

Every 3 months over 3 pregnancies

300 U per session

Medical

No AEs

Bodkin et al11

2 weeks 4 weeks

200 U 500 U

Medical Medical

No AEs 1 miscarriage (h/o miscarriage)

Morgan et al12

First trimester: 12 patients Second and third trimesters: 2 patients All trimesters: 1 patient Unknown trimester: 1 patient

≤300 U

Medical

1 miscarriage (h/o spontaneous abortions)

Kuczkowski13

First trimester

Not stated

Cosmetic

No AEs

Robinson and Grogan14

18 weeks

71 U

Medical

No AEs

Newman et al

Abbreviations: AEs, adverse effects; h/o, history of; U, units.

doped YAG, nonablative fractional resurfacing, and intense pulsed light treatment during gestation has not been studied.

CONCLUSIONS

EPILATION Methods of permanent hair removal, such as electrolysis and laser hair removal, are not recommended, especially with the possibility of hair regrowth during gestation. Concerns have been raised about electrolysis using galvanic current, because amniotic fluid acts as a conductor of electricity. Methods of temporary hair removal, such as depilatory products, waxing, and shaving, are safe in gestation and are preferred.

Performing cosmetic procedures on pregnant patients requires a careful approach. The lack of controlled studies makes evaluation of safety data challenging; however, many procedures are considered safe due to the proverbial test of time. Appropriate patient counseling helps alleviate patient anxiety. Creating a pregnancy registry for procedures such as BTX-A injections would be helpful in defining their safety profile. References 1 Lee KC, Dufresne R. Skin Surgery. In: Kroumpouzos G, ed. Text Atlas of Obstetric Dermatology. Philadelphia: Lippincott Williams & Wilkins; 2013:258–267.

BODY ART Although several uneventful cases of lengthy tattooing during pregnancy have been reported, no evidence-based recommendations can be made. There are no convincing data on adverse fetal effects from tattoo pigments and dyes in the first trimester.21 As the procedure may be associated with infections and hypersensitivity reactions to tattoo pigments, most authors recommend avoiding tattooing during pregnancy. Piercing does not interfere with pregnancy; however, navel and abdominal surface piercing may contribute to striae gravidarum. Avoiding the use nasal jewelry makes sense as such accoutrements can be inhaled or swallowed during orotracheal intubation.21 SKINmed. 2017;15:93–96

2 Lee KC, Korgavkar K, Dufresne RG Jr, Higgins HW 2nd. Safety of cosmetic dermatologic procedures during pregnancy. Dermatol Surg. 2013;39:1573–1584. 3 Sweeney SM, Maloney ME. Pregnancy and dermatologic surgery. Dermatol Clin. 2006;24:205–214. 4 Bayerl C. [Acne therapy in pregnancy]. Hautarzt. 2013;64:269–273. 5 Schwarb FP, Gabard B, Rufli T, et al. Percutaneous absorption of salicylic acid in man after topical administration of three different formulations. Dermatology. 1999;198:44–51. 6 Scwartz DB, Greenberg MD, Daoud Y, et al. Genital condylomas in pregnancy: Use of trichloracetic acid and laser therapy. Am J Obstet Gynecol. 1988;158:1407– 1416.

Cosmetic Procedures in Pregnancy: A Reappraisal

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Commentary

7 Tan M, Kim E, Koren G, et al. Botulinum toxin type A in pregnancy. Can Fam Physician. 2013;59:1183–1184.

15 Paul M. Controversy: Botulinum toxin in pregnancy. J Cutan Aesthet Surg. 2009;2:4–5.

8 de Oliveira Monteiro E. Botulinum toxin and pregnancy. Skinmed. 2006;5:308.

16 Rabe E, Pannier-Fischer F, Gerlach H, et al. Guidelines for sclerotherapy of leg veins. Dermatol Surg. 2004;30:687–693.

9 Li Yim JF, Weir CR. Botulinum toxin and pregnancy—a cautionary tale. Strabismus. 2010;18:65–66. 10 Newman WJ, Davis TL, Padaliya BB, et al. Botulinum toxin type A therapy during pregnancy. Mov Disord. 2004;19:1384–1385. 11 Bodkin CL, Maurer KB, Wszolek ZK. Botulinum toxin type A therapy during pregnancy. Mov Disord. 2005;20:1081–1082. 12 Morgan JC, Iyer SS, Moser ET, et al. Botulinum toxin A during pregnancy: a survey of treating physicians. Neurol Neurosurg Psychiatry. 2006;77:117–119. 13 Kuczkowski KM. Anesthetic implications of botulinum toxin type A (Botox) injections for the treatment of ‘the aging face’ in the parturient. Acta Anaesthesiol Scand. 2007;51:515–516. 14 Robinson AY, Grogan PM. OnabotulinumtoxinA successfully used a migraine prophylaxis during pregnancy: a case report. Mil Med. 2014;179:e703–e704.

17 Abramowitz I. The treatment of varicose veins in pregnancy by empty vein compressive sclerotherapy. S Afr Med J. 1973;47:607–610. 18 Reich-Schupke S, Leiste A, Moritz R, et al. Sclerotherapy in an undetected pregnancy – a catastrophe? Vasa. 2012;41:243–247. 19 Arena S, Marconi M, Frega A. Pregnancy and condyloma. Evaluation about therepeutic effectiveness and laser CO2 on 115 pregnant women. Minerva Ginecol. 2001;53:389–396. 20 Buzalov S, Khristakieva E. [Condylomata acuminata. The correlation between affecting sexual partners and the risk of developing preneoplasia of the cervix uteri. The therapeutic potentials of the Nd-Yag laser]. Akush Ginekol (Sofia). 1999;38:36–38. 21 Kluger N. Body art and pregnancy. Eur J Obstet Gynecol Reprod Biol. 2010;153:3–7.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:93–96

Cosmetic Procedures in Pregnancy: A Reappraisal

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Volume 15 • Issue 2

ORIGINAL CONTRIBUTION

The Pathergy Test as a Diagnostic Tool Zekayi Kutlubay, MD;1 Yalçın Tüzün, MD;1 Ronni Wolf, MD2 Abstract The pathergy test produces a nonspecific hyperreactive lesion in Behçet’s disease (BD), a finding that has been known since 1937. Pathergy refers to the development of new skin lesions or the aggravation of existing ones after trivial trauma. In clinical practice, the pathergy test induces a skin response by needleprick, with positive reactions manifesting as a papule or pustule developing by 48 hours. The pathergy test is one of the major features and diagnostic criteria of the disease. It is very similar to the erythematous papules or pustules that appear spontaneously in patients with BD. There is no standardized method for conducting the pathergy test. Intradermal, intravenous, and subcutaneous applications are used. There is no generally accepted opinion on which form of the test yields a higher positivity rate. The pathergy reaction is also reported in pyoderma gangrenosum, and has been noted in other neutrophilic dermatoses such as Sweet syndrome. The overall objective of this contribution is to provide a review of the available information, literature, and research relating to the pathergy test. (SKINmed. 2017;15:97–104)

n a series of publications beginning in 1937, the Turkish dermatologist Hulusi Behçet (1889–1948) described a clinical entity characterized by a triad of recurrent aphthous stomatitis, genital ulceration, and relapsing uveitis, and brought the condition to the attention of the scientific community.1–3

induration at the site of needlestick application, which has a small pustule containing sterile pus or a small papule at its centre. Blobner first described the pathergy reaction in BD in 1937, and Katzenellenbogen further investigated the phenomenon in the 1960s when he surveyed 22 cases of BD in Israel.4

Behçet’s disease (BD) is a complex multisystem inflammatory disorder of unknown etiology. It typically manifests as recurrent oral and genital ulcerations and uveitis, variably accompanied by clinical manifestations affecting the skin, large vessels, gastrointestinal system, central nervous system, and other organs. The mucocutaneous lesions include a positive pathergy reaction—the development of new skin lesions or the aggravation of existing ones following trivial trauma. It should be noted that the term pathergy is not exclusively applied to the skin. A pathergic response can also refer to a state of disease hyperreactivity in organs other than the skin after trauma, for example an exacerbation of synovitis after arthrocentesis, or uveitis after eye surgery in a patient with BD.

Pathergy was regarded as pathognomonic of BD, because it was absent in control groups with recurrent aphthous stomatitis and systemic lupus erythematosus. Because of its high specificity, a positive pathergy test can therefore be very supportive of a diagnosis of BD.5 Although it is not always a reproducible indicator of disease activity and has a varied prevalence rate among different ethnicities, the pathergy test remains the most diagnostically relevant finding in individuals with BD.6

The absence of a pathognomonic laboratory test means that a diagnosis of BD must be made according to clinical criteria. A positive pathergy test is characterized by erythematous

A number of different sets of clinical criteria have been proposed for the diagnosis and classification of BD. The pathergy test has been defined by the International Study Group (ISG) as one of the criteria for the diagnosis of BD. The most commonly used of these are the criteria of the ISG and the Behçet’s Disease Research Group of Japan. These were initially published as “classification criteria,” and their diagnostic

From the Department of Dermatology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey;1 and the Dermatology Unit, Kaplan Medical Center, Rechovot, Israel2 Address for Correspondence: Zekayi Kutlubay, MD, Department of Dermatology, Istanbul University, Cerrahpasa Medical Faculty, Kocamustafa Pasa Caddesi, Istanbul, Turkey 34098 • E-mail: zekayikutlubay@hotmail.com

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ORIGINAL CONTRIBUTION

Table. Classification Criteria According to the International Study Group for Behçet’s Disease (2006)51 Score

Feature

1 point

Oral aphthosis

1 point

Skin manifestations (pseudo-folliculitis, skin aphthosis)

1 point

Vascular lesions (phlebitis, superficial phlebitis, large vein thrombosis, aneurysm, arterial thrombosis)

1 point

Positive pathergy test

2 points

Genital aphthosis

2 points

Ocular lesions

Diagnosis of Behcet’s disease is made with a score of 3 points or more.

suitability, including their performance in terms of sensitivity and specificity, has been questioned; however, these criteria are the most recently revised diagnostic ones.7 A diagnosis of BD is made if there is a total of three or more points on the ISG scoring system (Table). The ISG criteria have reported values of 92% for sensitivity and 97% for specificity.

Koebner phenomenon, most well known in psoriasis. The occurrence of pathergy in other dermatoses may help to provide some insight into their etiology and pathogenesis. The pathergy test itself is characterized by the formation of a sterile papule or pustule 24–48 hours after an intradermal needleprick has been applied (Figure). In clinical practice, it is often induced by the perpendicular or oblique insertion of a sterile 20-gauge needle into the dermis at three different avascular sites on each forearm. Introduction of saline or other solutions or chemicals has been found not to be necessary. The observation of erythema alone at the needle site is considered a negative result.

Although the prevalance of a positive reaction varies among different series, a positive test has been suggested to be highly specific for BD,5,8 and has also been shown to be highly specific for BD in certain populations.9 A positive pathergy test is more often seen in patients from areas where the disease is more prevalent. Results have been shown to vary not only between the populations studied, but also between different investigators studying the same population. Genetic and disease-related factors have been proposed as explanations for these disparate findings. In addition, the test has also been used as an indicator of disease activity.9 Recently, it has been suggested that thrombomodulin may serve as a marker for BD.10 One study found a strong correlation of high blood levels of thrombomodulin with a positive pathergy test. This study suggests the measurement of thrombomodulin as an additional test for the investigation of endothelial dysfunction in BD and even as an alternative to the pathergy test.9

The histopathologic features of this reaction are considered to be identical to the spontaneous mucocutaneous lesions seen in the disease. There is controversy, however, concerning the histopathology and mechanisms underlying the pathergy test; however, a growing number of reports have implicated T-lymphocyte–mediated immune responses in the disease process. Some authors claim mixed infiltration, while others report neutrophilic infiltration with leukocytoclastic vasculitis. A possible explanation for this discrepancy may be the different methods used to induce lesions (needleprick, blunt needle, histamine injection) and variations in biopsy time and ethnic origin.12

Pathergy has now also been widely reported in other conditions, such as pyoderma gangrenosum. Similar reactions have been reported in erythema elevatum diutinum and other neutrophilic dermatoses including Sweet syndrome and the blind loop syndrome.9,11 The use of the term pathergy in these conditions usually describes the occurrence of lesions following minor trauma that exactly parallel the pathology of the primary condition. In this case, there is some similarity to the

Characteristic histopathologic findings include mononuclear cell infiltration around dermal blood vessels, with increased numbers of mast cells, polymorphonuclear leukocyte infiltration with epidermal thickening, and subcorneal pustule formation. Histologically, the pathergy test is characterized predominantly by macrophages and CD4+-T cells infiltrating the dermis, accompanied by strong human leukocyte antigen (HLA)-DR staining of epidermal keratinocytes.13

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ORIGINAL CONTRIBUTION pathergy lesions seen in BD were characterized by a superficial/superficial deep perivascular mixed inflammatory cell infiltrate containing neutrophils.12 The presence of neutrophils in pathergy lesions has led to the suggestion that altered neutrophil function is an important etiological factor.14,15 Immunohistochemical examination demonstrated a mixed inflammatory cell infiltrate around the vessels and skin appendages that extended a certain distance into the deep dermis.16 Positive segmental staining for E-selectin and P-selectin was noted in the endothelial cells of biopsies obtained from patients with a positive pathergy test. İmmunostaining for these markers was found to be negative in biopsies of normal skin from pathergy-positive patients, pathergy-negative patients, and healthy control subjects. The authors concluded that an interaction of cellular adhesion molecules, together with endothelial proliferation, might play an important role in the formation of pathergy lesions in patients with BD. A T cell–mediated immune response is not a consistent finding of the pathergy reaction. The presence of neutrophil-predominating inflammatory infiltrates, some of which exhibit the features of leukocytoclastic vasculitis,17 and an increased presence of mast cells in skin infiltrates15,18 have been reported. It is not clear whether this reflects different pathogenic mechanisms operating in tissue inflammation, or if the exact nature of the infiltrate may depend on the timing of biopsy or the way pathergy has been induced, such as by histamine; however, immunohistologic studies did not find an antibodymediated or immune complex–mediated immune response associated with pathergy reaction.17

Figure. Pathergy reactions evaluated 48 hours after on needleprick sites. (A) Negative result, (B) papule formation, and (C) sterile pustule formation.

Leukocytoclastic vasculitis with immunoglobulin and complement deposition in the walls of dermal vessels has been reported, and polymorphonuclear leukocytes have been suggested to play an important role in the pathogenesis of pathergy test and, therefore, in the lesions of BD.14 The SKINmed. 2017;15:97–104

A study revealed the responses to needleprick in BD patients and healthy volunteers. Two study groups, each consisting of 10 BD patients with a positive pathergy test and 6 controls, were evaluated using either immunohistochemistry or quantitative real-time polymerase chain reaction to measure inflammatory cell and cytokine levels in biopsy specimens obtained serially from independent sites at 0, 8, and 48 hours after needleprick. Similar cellular infiltration patterns in response to needleprick were found in BD patients and controls between 0 and 8 hours. Increases in levels of cytokines, chemokines, and adhesion molecules were noted at 48 hours in the skin of BD patients with a positive pathergy test but not in the skin of healthy controls. These results suggest that, in contrast to the self-limited inflammation associated with epithelial disruption of normal skin, BD patients experience marked cellular influxes into the injury site, leading to an exaggerated lymphoid T helper 1–type response.13 The Pathergy Test as a Diagnostic Tool

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Most of respondents participating in one study18 reported that they were performing the test using only a needleprick. Another study19 evaluated the pathergy test with only one needleprick and 0.1 mL physiologic saline, and found that there was no significant difference between sterile puncture and the use of physiological saline. Use of an intradermal injection of monosodium urate crystals has been reported to induce a pathergy reaction that has a greater sensitivity and reproducibility than the classic pathergy test.20 The test positivity in BD is characterized by sustained erythema at 48 hours that is significantly greater in diameter compared with healthy controls. When Turkish patients with BD were compared with control participants with other diseases, including familial Mediterranean fever, rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, the test was found to be 60% sensitive and 100% specific for BD; however, among a British population, the monosodium urateâ&#x20AC;&#x201C;induced pathergy reaction in BD had higher sensitivity (93%) than the classic pathergy reaction (28%) but lower specificity; positivity was reported for 18% of healthy controls and 25% of controls with other diseases, including rheumatoid arthritis and ankylosing spondylitis.21 The usefulness has been reported of the pathergy test conducted intradermally and intravenously with disposable/sharp needles compared with nondisposable/blunt needles in diagnosis of the disease and determination of disese activity.11 In addition, histopathologic evaluation of the pathergy test was compared with clinical evaluation. It was found that clinical evaluation of the pathergy test conducted intradermally with nondisposable/blunt needles was sufficient for both diagnosis of BD and determination of disease activity. Histopathologic evaluation of the test was not found to be more sensitive than clinical evaluation. In order for a pathergy reaction to occur, the needle must reach the dermis.19,20 It was concluded that the positivity rate attained using nondisposable/blunt needles was statistically higher than the rate attained using disposable/sharp needles when both needles were used on the same patients.8 This conclusion can be explained by the fact that calcium accumulates at the tip of nondisposable/blunt needles when they are sterilized in boiling water, and hence they become more traumatic than disposable/sharp needles.6 The paucity of significance of a positive pathergy test in the diagnosis of BD in developed countries may be explained by the fact that disposable/sharp needles were used for a comparatively longer period of time in underdeveloped countries before the 1980s.8,9,24 An analysis of retrospective patient series indicates decreasing rates of SKINmed. 2017;15:97â&#x20AC;&#x201C;104

positivity over the years, which seems to be accounted for by increasing use of less traumatic disposable needles (the more traumatic, the more positivity);6 moreover, an increased positivity rate of the pathergy test with the use of blunt needles has been shown.8 Use of multiple needlepricks plays an important role in increasing the likelihood of a positive pathergy test. However, it is not known how many needlepricks should be used to achieve a positive pathergy result. Many methods of testing have been used, employing between 1 and 16 needles.1 Some25 have suggested that two needlepricks are sufficient. It has been observed that the multiple needleprick approach was sustained, and 46.9% of participants reported that they were performing three injections into forearm.18 The authors of one study used two means of modifying the pathergy test.26 One was to use needles dipped in steroid solution, and in this case there still were two positive reactions. They found that changing the needle from metal to acrylic nonmetal did not produce any changes: the test was still positive. They also tried to determine whether systemic steroids had any effect on the pathergy reaction, reporting that steroids did not alter either the gross appearance or the histology of the pathergy test. A total of 74 of 84 (88%) of patients with BD in Turkey had a positive pathergy test; the same test proved positive in 9 (7%) of 122 control participants who were healthy or had other diseases. The inflammatory reaction of the pathergy test consisted mainly of polymorphonuclear white cells and mast cells. The authors concluded that the pathergy test was quite specific for BD and was unaltered by various maneuvers. Data, however, support a decline in the incidence of a positive pathergy test in BD patients over time.5 A decreased positivity rate has been reported when the reaction is induced in surgically cleaned skin.24 Some18 found a wide variation in terms of cleaning of the pathergy site: 23.5% of respondents reported never cleaning the skin for the test, and those working in special BD clinics were more likely to do so. Povidone iodine is commonly used for skin sterilization but may have immunosuppressive properties. Others24 showed that there was a suppression of the pathergy test by surgical sterilization. The effectiveness of an oral pathergy test in BD was investigated.27 Performing the pathergy test by pricking the mucosa of the lower lip was associated with lower sensitivity than an ordinary skin pathergy test. An advantage of the oral pathergy test was the fact that it resulted in a pustule or ulcer in the

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oral mucosa that resembled the primary oral lesion of BD, rather than producing a skin papule as seen in skin pathergy tests. The authors concluded that the oral pathergy test was easier to assess than the skin pathergy test as there was no need to measure the size of the lesion: a pustule or ulcer of any size was considered positive. In view of the methodologic discrepancies in ways of performing the pathergy test, one group18 carried out a study to evaluate different pathergy test techniques. They reported that all respondents were using the forearm for pathergy testing, only 13 dermatologists were using the gluteal region, and one was using the lower lip mucosa as an additional region. One study28 evaluated the pathergy test applied to different hairless sites on the different body areas. The site most frequently returning a positive result was the forearm, while the least positive was the abdomen. In 2007, it was suggested that the oral pathergy test is more sensitive than skin pathergy test.29 The sex and ethnic origin of the patients, the clinical severity of the disease, HLA-B51 status, and the method of application of the needleprick have been reported to be significant factors in gaining a positive pathergy reaction.2,8,24,30,31 In one study, the effects of the patientâ&#x20AC;&#x2122;s sex and age of disease onset on the pathergy test and its correlation with disease activity in BD were investigated by two independent observers. It was found that the pathergy test was more strongly positive among male than female patients of a similar age and disease duration.32 The age at onset did not affect the severity of the pathergy reaction.32 Pathergy test positivity in male patients was reported to be between 42% and 83% in the studies carried out in Turkey.33,34 One study35 reported that the pathergy test was positive in only eight of 100 patients with BD (8%), and in 2% of patients with recurrent aphthous stomatitis. The pathergy test appeared to have no association with disease activity36,37 or with any particular disease manifestation;6,21,37 however, one study38 reported that the pathergy test was less commonly positive in patients with milder BD, for example community- rather than hospital-based patients. Unfortunately, even though the rate of a positive reaction might be influenced by disease activity, there are few formal studies investigating this.14 One study found that the pathergy test was not associated with the clinical variables or disease severity, but that it was usually found during active phase in cases with a positive reaction. Pustule formation at the venous puncture site in patients with negative pathergy might be considered to be positive.36 SKINmed. 2017;15:97â&#x20AC;&#x201C;104

The rate of the positive pathergy test in patients with BD from Turkey, Japan, and Israel has been reported to be more than 50%, in comparison with the rate in healthy or control participants or control groups who had another disease, including some haematologic disorders, for which the rate of a positive test did not exceed 3%.2 The pathergy test is also not constant during the course of the disease; like other disease manifestations, it can appear and disappear.5 The test shows a high positivity in countries where the disease is more prevalent, notably the Mediterranean basin, Middle East, and Far East. As stated above, the high prevalence of positive pathergy tests among patients with BD and its negativity among control individuals led to inclusion of the pathergy test in the ISG criteria for diagnosis of BD.39 The frequency of test positivity ranges from 30% to 70% in endemic areas.40 In previous studies, the pathergy test was found to be positive in 44.4% of Egyptian,41 98% of Israeli,31 20% of Jordanian,19 11% of Saudi Arabian,42 5.3% of British,43 71% of Iraqi, and 82% of Turkish patients.27 In one study,30 28 of 48 (58%) of Turkish patients had a positive pathergy test, whereas all British patients and control individuals from either country had negative pathergy reactions. The absence of the pathergy phenomenon among the British patients is another major point of difference between the Turkish and British patients with BD, in addition to the already established different HLA association: the authors previously demonstrated that HLA-B5 was not associated with pathergy positivity among Turkish patients.2 Thus, the absence of a positive pathergy test among British patients cannot readily be explained by different HLA associations. In a study,36 the pathergy test was not associated with age at disease onset, sex, other clinical features, or the presence of HLA-B51. In one study,1 49 of 58 (84%) patients with BD in Turkey had a positive pathergy test; the same test proved positive in 3 of the 90 (3%) healthy control subjects or patients with other diseases. This study indicates that the sensitivity and specificity of the pathergy test for BD are quite high. Its sensitivity and specificity,8 inter- and intraobserver variations,44 and diagnostic usefulness2,45 in patients with BD from Turkey have been previously determined. As already noted, any disruption of tissue integrity is potentially associated with an exaggerated inflammatory response in BD, in either the skin or the mucus membranes. In particular, posttraumatic arterial thrombus and/or aneurysm formation after conventional angiographic interventions,46

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lesions after vascular surgery, superficial thrombophlebitis induced by venipuncture, eye inflammation after intraocular corticosteroid injections,47 and anastomotic ulcers after surgical treatment of intestinal ulcers are well-known examples of pathergy reactions triggered at different tissue sites.40 In a study of Turkish patients,48 the pathergy test was positive in 79% of those with vascular system disease and 56% of those without vascular involvement, indicating a significant association with vascular disease. One study47 described a patient with BD who developed a pathergy-like reaction after an intravitreal triamcinolone acetonide injection. The following day, the patient was noted to have erythematous swelling around the injection site, and the lesion disappeared spontaneously within 2 weeks. Investigators6,36 have also also noticed that a few patients with BD with a negative pathergy test develop pustules at the venous puncture site used for an intravenous fluid infusion or blood sampling.

CONCLUSIONS The pathergy test, a nonspecific hypersensitivity of the skin to a needleprick, is a curious and unique phenomenon that occurs in patients with BD and has been proposed as a useful adjunct to its diagnosis. This phenomenon has been accepted as one of ISG’s major criteria for the diagnosis of BD. The pathergy response in BD patients may be caused by immune dysregulation resulting in an increased and prolonged inflammatory response. Three simultaneous subcutaneous pricks with thick needles on each forearms should be used for the skin pathergy test. Further studies are necessary to explain the triggering factors and immunologic mechanisms causing the exaggerated inflammation determined in BD. The pathergy test yields positive results for patients with active disease but either positive or negative results for patients in remission. References

One study35 found that the positivity rate of pathergy test in patients with BD who had not previously been treated for their BD was higher (14.81%) than in those who had been treated at some time in the past but not in the previous 1 year (5.47%). This may indicate that any kind of treatment for BD might affect pathergy test results. A study showed that patients treated with interferon-α for chronic myeloid leukaemia had a high prevalance of a positive pathergy test (24%). The specificity of the test for BD was calculated to be 98% in the groups other than interferon-α– treated chronic myeloid leukaemia patients, and 92% if the latter group was included.15 A high positivity rate was not observed in BD patients receiving interferon-α treatment compared with cyclosporine A, azathioprine, colchicine, or no treatment. In a short-term controlled study of etanercept use in BD patients, it was shown that blocking tumor necrosis factor-α did not suppress the pathergy reaction, whereas it was significantly effective in controlling most of the mucocutaneous manifestations of the disease.40,49 A study aimed to investigate argon laser photocoagulation– induced cutaneous inflammation in patients with BD and control participants, as well as to compare the results with the skin pathergy test. The preliminary results of this study revealed that argon laser photocoagulation could induce a skin hyperreactivity similar to the needleprick-induced skin pathergy test in patients with BD. Argon laser photocoagulation was able to induce skin inflammation with its thermal effect and without any inoculation of antigen in BD. 50

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1 Tuzun Y, Yazici H, Pazarli H, Yalcin B, Yurdakul S, Muftuoglu A. The usefulness of the nonspecific skin hyperreactivity (the pathergy test) in Behcet’s disease in Turkey. Acta Derm Venereol. 1979;59:77–79. 2 Yazici H, Tuzun Y, Pazarli H, Yalcin B, Yurdakul S, Muftuoglu A. The combined use of HLA-B5 and the pathergy test as diagnostic markers of Behcet’s disease in Turkey. J Rheumatol. 1980;7:206–210. 3 Behçet H. Ueber rezidivierende aphtose durch ein virus verursachte geschwuere am mund, am auge und an den genitalien. Dermatol Wochenschr. 1937;105:1152. 4 Katzenellenbogen I. Survey of 22 cases of Behçet’s disease: The significance of specific skin hyperreactivity. Int Dermatol. 1968;321. 5 Davatchi F, Shahram F, Chams-Davatchi C, et al. Behcet’s disease: From East to West. Clin Rheumatol. 2010;29:823–833. 6 Ozarmagan G, Saylan T, Azizlerli G, Ovul C, Aksungur VL. Re-evaluation of the pathergy test in Behcet’s disease. Acta Derm Venereol. 1991;71:75–76. 7 Zouboulis CC. Adamantiades – Behcet disease. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: McGraw Hill; 2008:1620– 1626. 8 Dilsen N, Konice M, Aral O, Ocal L, Inanc M, Gul A. Comparative study of the skin pathergy test with blunt and sharp needles in Behcet’s disease: confirmed specificity but decreased sensitivity with sharp needles. Ann Rheum Dis. 1993;52:823–825. 9 Varol A, Seifert O, Anderson CD. The skin pathergy test: innately useful? Arch Dermatol Res. 2010;302:155– 168. 10 Menashi S, Tribout B, Dosquet C, et al. Strong association between plasma thrombomodulin and pathergy test in Behcet disease. Ann Rheum Dis. 2008;67:892–893. 11 Akmaz O, Erel A, Gurer MA. Comparison of histopath-

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ologic and clinical evaluations of pathergy test in Behcet’s disease. Int J Dermatol. 2000;39:121–125.

application of multiple needle pricks on the pathergy reaction. Int J Dermatol. 2008;47:335–338.

12 Ergun T, Gurbuz O, Harvell J, Jorizzo J, White W. The histopathology of pathergy: A chronologic study of skin hyperreactivity in Behcet’s disease. Int J Dermatol. 1998;37:929–933.

26 Tuzun Y, Altac M, Yazici H, et al. Nonspecific skin hyperreactivity in Behçet’s disease. Haematologica. 1980;65:395–398.

13 Melikoglu M, Uysal S, Krueder JG, et al. Characterization of the divergent wound-healing responses occurring in the pathergy reaction and normal healthy volunteers. J Immunol. 2006;177:6415–6421. 14 Jorizzo JL, Solomon AR, Cavallo T. Behcet’s syndrome. Immunopathologic and histopathologic assessment of pathergy lesions is useful in diagnosis and followup. Arch Pathol Lab Med. 1985;109:747–751. 15 Budak-Alpdogan T, Demircay, Alpdogan O, et al. Skin hyperreactivity of Behcet’s patients (pathergy reaction) is also positive in interferon alpha-treated chronic myeloid leukaemia patients, indicating similarly altered neutrophil functions in both disorders. Br J Rheumatol. 1998;37:1148–1151. 16 Inaloz HS, Evereklioglu C, Unal B, Kirtak N, Eralp A, Inaloz SS. The significance of immunohistochemistry in the skin pathergy reaction of patients with Behcet’s syndrome. J Eur Acad Dermatol Venereol. 2004;18:56– 61. 17 Gilhar A, Winterstein G, Turani H, Landau J, Etzioni A. Skin hyperreactivity response (pathergy) in Behcet’s disease. J Am Acad Dermatol. 1989;21(3 Pt 1):547– 552. 18 Ozden MG, Bek Y, Aydin F, Senturk N, Canturk T, Turanli AY. Different application techniques of pathergy testing among dermatologists. J Eur Acad Dermatol Venereol. 2010;24:1240–1242. 19 Askari A, Al-Aboosi M, Sawalha A. Evaluation of pathergy test in North Jordan. Clin Rheumatol. 2000;19:249– 251. 20 Fresko I, Ozsoy Y, Mat C, Melikoglu M, Tunc R, Yazici H. The response to the intradermal injection to monosodium urate in Behçet’s syndrome and its comparison to the pathergy test. Yonsei Med J. 2000;41:25. 21 Cakir N, Yazici H, Chamberlain MA, et al. Response to intradermal injection of monosodium urate crystals in Behcet’s syndrome. Ann Rheum Dis. 1991;50:634– 636. 22 Iscimen A, Tozakı S, Serdaroglu S. Paterji testinde pikür derinligi ve dermal travma derecesinin sonuç üzerindeki etkisi (intraepidermal ve dermal paterji uygulaması). Deri Hast Ve Frengi Ars. 1989;23:175– 181. 23 Serdaroglu S, Iscimen A, Tuzun Y, Yazici H. Behçet hastalıgında paterji testinin multipl pikür tarzında uygulanmasının önemi. XIII Ulusal Dermatoloji Kongresi Kitabı, Adana, 1990;339–344. 24 Fresko I, Yazici H, Bayramicli M, Yurdakul S, Mat C. Effect of surgical cleaning of the skin on the pathergy phenomenon in Behcet’s syndrome. Ann Rheum Dis. 1993;52:619–620. 25 Ozdemir M, Bodur S, Engin B, Baysal I. Evaluation of

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27 Sharquie KE, Al-Araji A, Hatem A. Oral pathergy test in Behcet’s disease. Br J Dermatol. 2002;146:168–169. 28 Ozdemir M, Balevi S, Deniz F, Mevlitoglu I. Pathergy reaction in different body areas in Behcet’s disease. Clin Exp Dermatol. 2007;32:85–87. 29 Gul U, Gonul M. Oral and genital pathergy in Behcet’s disease. Dermatology. 2007;215:80–81. 30 Yazici H, Chamberlain MA, Tuzun Y, Yurdakul S, Muftuoglu A. A comparative study of the pathergy reaction among Turkish and British patients with Behcet’s disease. Ann Rheum Dis. 1984;43:74–75. 31 Friedman-Birnbaum R, Bergman R, Aizen E. Sensitivity and specificity of pathergy test results in Israeli patients with Behcet’s disease. Cutis. 1990;45:261–264. 32 Yazici H, Tuzun Y, Tanman AB, et al. Male patients with Behçet’s syndrome have stronger pathergy reactions. Clin Exp Rheumatol. 1985;3:137–141. 33 Iscimen A, Serdaroglu S, Tuzun Y. Paterji testinde sabit pikür derinligi saglayan yeni bir yöntem. XIII Ulusal Dermatoloji Kongresi Kitabı, Adana, 1990;333–338. 34 Gurler A, Boyvat A, Tursen U. Clinical manifestations of Behçet’s disease: an analysis of 2147 patients. Yonsei Med J. 1997;38:423–427. 35 Dogan B, Taskapan O, Harmanyeri Y. Prevalance of pathergy test positivity in Behcet’s disease in Turkey. J Eur Acad Dermatol Venereol. 2003;17:228–229. 36 Chang HK, Cheon KS. The clinical significance of a pathergy reactions in patients with Behçet’s disease. J Korean Med Sci. 2002;17:371–374. 37 Krause I, Molad Y, Mitrani M, Weinberger A. Pathergy reaction in Behcet’s disease: Lack of correlation with mucocutaneous manifestations and systemic disease expression. Clin Exp Rheumatol. 2000;18:71–74. 38 Yurdakul S, Gunaydin I, Tuzun Y, et al. The prevalence of Behcet’s syndrome in a rural area in northern Turkey. J Rheumatol. 1988;15:820–822. 39 Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet. 1990;335:1078–1080. 40 Mat MC, Bang D, Melikoglu M. The mucocutaneous manifestations and pathergy reaction in Behçet’s disease. In: Yazıcı Y, Yazıcı H, eds. Behçet’s Syndrome. New York: Springer; 2010:53–72. 41 El Menyawi MM, Raslan HM, Edrees A. Clinical features of Behçet’s disease in Egypt. Rheumatol Int. 2009;29:641–646. 42 al-Dalaan AN, al Balaa SR, el Ramahi K, et al. Behcet’s disease in Saudi Arabia. J Rheumatol.1994;21:658–661. 43 Davies PG, Fordham JN, Kirwan JR, Barnes CG, Dinning WJ. The pathergy test and Behcet’s syndrome in Britain. Ann Rheum Dis. 1984;43:70–73.

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44 Altac M, Tuzun Y, Yurdakul S, Binyildiz P, Yazici H. The validity of the pathergy test (non-specific skin hyperreactivity) in Behcet’s disease: A double-blind study by independent observers. Acta Derm Venereol. 1982;62:158–159. 45 Ozyazgan Y, Pazarli H, Yazici H et al. Usefulness of HLA determination and pathergy test in the diagnosis of uveitis in Turkey. Br J Ophthalmol. 1981;65(11):798–799.

48 Koc Y, Gullu I, Akpek G, et al. Vascular involvement in Behcet’s disease. J Rheumatol. 1992;19:402–410. 49 Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behcet’s disease: A double blind, placebo controlled study. J Rheumatol. 2005;32:98– 105.

46 Alpagut U, Ugurlucan M, Dayioglu E. Major arterial involvement and review of Behçet’s disease. Ann Vasc Surg. 2007;21:232–239.

50 Sayarlioglu M, Calka O, Cinal A, et al. Comparison of argon laser photocoagulation-induced cutaneous inflammation and skin pathergy test in Behcet’s disease. Clin Rheumatol. 2010;29:59–63.

47 Yalcindag FN, Batioglu F. Pathergy-like reaction following intravitreal triamcinolone acetonide injection in a patient with Behçet’s disease. Ocul Immunol Inflamm. 2008;16:181–183.

51 International Team for the Revision of the International Criteria for Behcet’s Disease (ITR-ICBD). Revision of the International Criteria for Behcet’s Disease (ICBD). Clin Exp Rheumatol. 2006;24):14–15.

“Akne rosacea.” Moulage No. 82, made by Lotte Volger in 1929 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www. moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2017;15:97–104

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A Retrospective Study of Multiple Sequential Light and Laser Sources to Activate Aminolevulinic Acid in the Treatment of Acne Vulgaris Daniel P. Friedmann, MD;1 Mitchel P. Goldman, MD;2 Sabrina G. Fabi, MD;2 Isabella Guiha, BS2 Abstract Reports of the sequential use of multiple light and laser sources for topical 5-aminolevulinic acid (ALA) activation in photodynamic therapy (PDT) of inflammatory acne vulgaris are lacking. The authors sought to retrospectively compare field-directed ALA-PDT with blue light only, blue light + pulsed dye laser (PDL), blue light + intense pulsed light (IPL), blue light + PDL + IPL, or blue light + red light + PDL + IPL for inflammatory acne of the face or upper trunk. Results showed a trend toward greater patient-reported improvement with comparable tolerability using multiple, sequential light sources in ALA-PDT for acne vulgaris, albeit not statistically significant. The addition of red light, however, did not improve outcomes. The disparate numbers of patients between treatment arms and high potential for recall bias limit this single-center retrospective study. (SKINmed. 2017;15:105–111)

cne vulgaris is a dermatologic disease of pilosebaceous units in adolescents and young adults that often leads to significant psychological distress.1 The pathophysiology of acne within pilosebaceous units is multifactorial, including androgen-mediated excess sebum production, follicular keratinocyte hyperproliferation and plugging, Propionibacterium acnes proliferation, and inflammation and hypervascularity secondary to follicular rupture.2 Acne is also not uncommonly refractory to topical medications, requiring the long-term use of systemic antibiotics and/or retinoids. Photodynamic therapy (PDT) for acne may obviate the need for these conventional treatments and their myriad potential side effects. Given that P acnes produces photosensitive porphyrins in the form of coproporphyrin III, exogenous precursors of intracellular heme biosynthesis such as 5-aminolevulinic acid (ALA) and its more lipophilic methylated counterpart, methylaminolevulinic acid (MAL), can enhance this endogenous photodynamic reaction.3 Sebaceous glands preferentially absorb and metabolize these topical agents, producing highly photoactive protoporphy-

rin IX (PpIX).4 Excitation of PpIX with a light source of an appropriate wavelength (Figure 1) leads to reactive oxygen species that incite localized oxidative stress and cell death.1,5,6 A number of well-designed, randomized controlled clinical trials have demonstrated statistically significant reductions in inflammatory lesions of acne vulgaris using PDT, albeit with short follow-up times.7–11 Photoactivation of porphyrins with a single light source, including incoherent, continuous-wave red or blue light, pulsed dye laser (PDL), or intense pulsed light (IPL), has been the foundation of traditional PDT.12 Reports of the sequential use of multiple light sources for ALA/MAL activation in the treatment of acne are lacking, however. Combining the anti-inflammatory, epidermal turnover, and antimicrobial effects of blue light with the focused damage to sebaceous glands produced by deep penetration of red light and photothermal effects of pulsed lasers may lead to improved long-term results.1,13,14 The sequential use of different light sources may also ensure that the multiple absorption peaks of PpIX are successfully targeted.15–17

From the Westlake Dermatology Clinical Research Center, Westlake Dermatology & Cosmetic Surgery, Austin, TX;1 and Goldman, Butterwick, Fitzpatrick, Groff, and Fabi: Cosmetic Laser Dermatology, San Diego, CA2 Address for Correspondence: Daniel P. Friedmann, MD, Westlake Dermatology Clinical Research Center, 8825 Bee Cave Road, Suite 100, Austin, TX 78746 • E-mail: daniel@westlakedermatology.com

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Figure 1. In vivo absorption spectrum for protoporphyrin IX. Absorption peaks at 405 to 415 nm (Soret band) and 506 to 540 nm, 572 to 582 nm, and 628 to 635 nm (Q bands).14 Wavelengths of pertinent light sources are overlapped, including incoherent blue light (peak 417 nm), incoherent red light (peak 635 nm), pulsed dye laser (585–595 nm), and intense pulsed light (560–1200 nm).

The aim of this nonblinded, retrospective, multi-arm study was to compare the safety and efficacy of ALA-PDT for acne vulgaris using blue light combined with red light, PDL, and/or IPL. Methods A total of 78 patients treated with field-directed ALA-PDT between 2001 and 2010 for moderate to severe inflammatory facial or upper trunk acne were enrolled in this retrospective, singlecenter study. Off-label treatments were performed with either blue light only, blue light + PDL, blue light + IPL, blue light + PDL + IPL, or blue light + red light + PDL + IPL in a nonrandomized fashion by two board-certified dermatologists. All treatment areas were degreased with acetone and microdermabraded for 5 minutes (Vibraderm; Esthetica Inc., Allentown, PA) prior to application of 20% ALA (Levulan Kerastick, Dusa Pharmaceuticals Inc., Wimington, MA) with 1 hour of unoccluded incubation in a dimly lit room. The ALA was removed with a baby wipe immediately before treatment. Patients were then exposed to 417 nm blue light (BLU-U, DUSA Pharmaceuticals Inc., Wimington, MA) for 15 minutes with a 10 J/cm2 fluence dose. If 630 nm red light (Aktilite CL128, Photocure Inc., Princeton, NJ) was used in addition to blue light, irradiation was performed simultaneously or sequentially for 8 minutes with a 37 J/cm2 fluence dose. Cold-air cooling SKINmed. 2017;15:105–111

(Artek Air, Thermotek Inc., Flower Mound, TX) was used during illumination for increased patient comfort. PDL (Cynergy, Cynosure, Westford, MA, or VBeam Perfecta, Candela Corp., Wayland, MA) and IPL (Lumenis 1 or M22, Lumenis Inc., San Jose, CA), if performed, were always utilized prior to blue and red light sources. PDL spot-treatment of acne lesions used two passes with a 5- to 7-mm spot-size to deliver pulse durations of 10 to 40 ms and fluences of 5 to 12 J/cm2. IPL treatment parameters were chosen relative to patient skin type, with a 560-nm cutoff filter, mean double-pulse durations of 3 to 4 ms with a delay of 10 to 30 ms, and fluences of 15 to 20 J/cm2. In addition to the IPL’s chilled 15x35-mm sapphire tip and a 1-mm layer of optical coupling gel, cold-air cooling (Cryo 5, Cynosure, Westford, MA) was used to increase patient comfort. Patients had a physical sunscreen applied immediately post-treatment and were advised to practice strict sun protection for 24 to 36 hours. A prescripted telephone questionnaire was performed from 2 to 8 years postprocedure to collect patient-reported outcomes, including prevalence of adverse events (peeling, acne, erythema, and pain), degree of acne improvement, and improvement in overall skin quality. All criteria were graded by patients using four-point scales: 0=none, 1=mild, 2=moderate, 3=severe for adverse events and 0=none, 1=mild, 2=moderate/good, 3=excellent for improvement in acne or overall skin quality. Patient willingness to undergo repeat treatment was assessed with a three-point

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Table. Patients by Treatment Arm Group

Total Patients/Total Sessions, No.

Blue light

17/25

Blue light + PDL

31/46

Blue light + IPL

19/22

Blue light + IPL + PDL

4/6

Blue light + red light + IPL + PDL

7/7

Abbreviations: IPL, intense pulsed light; PDL, pulsed dye laser.

scale (0=no, 1=yes, 2=undecided). Two-sample t tests were used to compare parallel-group data.

Figure 2. Mean acne improvement following photodynamic therapy.

Results A total of 106 procedures were performed, with a mean of 1.4±0.6 (1–3) sessions per patient (Table). The mean age of patients treated was 39.1 years, and 70% of patients were women. No standardized assessment of acne grade, severity, or lesion count was utilized. Forty-two percent of patients stated that they would repeat the procedure, 41% stated that they would not, and 17% were undecided. The majority of patients who would not undergo repeat treatment reported costs and distance issues as reasons. The mean degree of acne improvement was 1.7 (mild to moderate improvement) among all patients. Despite the lack of a statistically significant difference between patient groups, there was a trend toward greater acne improvement with blue light + IPL + PDL (2.17) than with blue light only (1.76), blue light + IPL (1.91), or blue light + PDL (1.67; Figures 2–4). The mean reported improvement in overall skin quality, which was 1.6 among all treated patients, followed a similar trend (Figure 5). The addition of red light to the combination of blue light + IPL + PDL did not add further benefit in either case.

Figure 3. Inflammatory acne vulgaris. Full face (left) before treatment and (right) 6 months following one session of pulsed dye laser with blue light, red light, pulsed dye laser, and intense pulsed light.

Seventy-five percent of patients reported some degree of peeling postprocedure, 34% reported acne outbreaks, 92% reported erythema, and 74% reported pain. No statistically significant differences in postprocedure peeling, erythema, or pain were found between groups (Figure 6). Patients with blue light + IPL reported a lower rate of acne flares posttreatment than those treated with blue light + IPL + PDL (P=.019) and blue light + red light + IPL + PDL (P=.028). Discussion Phototherapy with blue and red light has been widely studied for the management of acne vulgaris. Although short-wavelength SKINmed. 2017;15:105–111

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Figure 4. Inflammatory acne vulgaris. Full face (left) before treatment and (right) 2 months following one session of pulsed dye laser with blue light, red light, and pulsed dye laser. A Retrospective Study

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ORIGINAL CONTRIBUTION with blue light PDT in 22 patients led to marginally greater improvement in overall acne severity and reduction in papules and pustules after two sessions spaced a week apart.24

Figure 5. Mean improvement in overall skin quality following photodynamic therapy.

(417 nm) blue light has limited in vivo dermal penetration, it corresponds to the maximal absorption peak of PpIX. Blue light may improve acne by decreasing proinflammatory cytokines and exerting a bactericidal effect against P acnes.18 Despite in vivo clinical studies19,20 failing to show significant reductions in P acnes colonization posttreatment, an in vitro study21 confirmed the bactericidal effects of blue and red light illumination of cultured P acnes, with the pretreatment addition of ALA improving the efficacy of red light in reducing bacterial counts. The reduction in P acnes within pilosebaceous units following PDT is likely mediated by cytotoxic reactive oxygen species resulting from ALA activation.22 An uncontrolled pilot study of blue light PDT for moderate to severe acne demonstrated improvement in two thirds of patients, with a mean acne grade reduction of 1.75 on a four-point scale after two to four sessions.23 A nonrandomized, nonblinded study of full-face blue light compared

Red light, on the other hand, has a longer wavelength, with a peak at 635 nm, targeting deeper dermal structures such as sebaceous glands.11 A single-blinded, randomized, split-face trial of 28 patients found that at-home use of a red light device (635–670 nm) twice a day for 8 weeks led to greater reductions in inflammatory lesions, total lesion count, and visual analogue scale compared with no treatment.25 One study26 demonstrated excellent improvement in 22% and 34% of patients with severe facial acne, after one and two treatments with 10% ALA-PDT using red light, respectively. Red light PDT may produce greater sebaceous gland injury and further decrease sebum production, leading to superior clinical results. Moreover, another study27 demonstrated dramatic increases in apoptotic sebocytes on histopathologic examination after three sessions of ALA-PDT with red light. Given the moderate success of pulsed light sources in reducing inflammatory acne lesions, with rates of 23% to 74% with IPL and 49% and 67% with PDL, these devices have more recently been investigated for the photodynamic treatment of acne.28,29 The available studies, however, are marred by short follow-up schedules, lack of clinical controls, nonblinded assessments, and/or the absence of statistically significant results.30–35 Nevertheless, comparative studies have demonstrated greater reductions in inflammatory lesion counts with their photodynamic use, up to 83% to 89.5% with ALA-PDT-IPL, 65% with MAL-PDT-IPL, and 80% with MAL-PDT-PDL.30–32,36 A split-face, randomized, evaluator-blinded study of inflam-

Figure 6. Postprocedure adverse events. Peeling, erythema, and pain were not significantly different between groups. Acne flares were significantly less common postprocedure in patients with blue light + intense pulsed light. SKINmed. 2017;15:105–111

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matory acne37 found no significant differences in acne grade or inflammatory and noninflammatory lesion reduction after three sessions of red light- or IPL-mediated MAL-PDT. Three sessions of ALA-IPL were also found to be superior to ALAblue light in a randomized parallel-group study of facial inflammatory acne.29

(2–8 years) between patients are also major flaws of our study design. While patients who could not recall or had difficulty in recalling having had PDT were excluded, recall bias may still be a substantial factor.

Well-controlled clinical studies have illustrated the ability of pulsed lasers to successfully target cutaneous sebaceous glands and associated microvascular supply via photodynamic and photothermal effects.38,39 Although an in vivo study of mild to moderate acne treated with PDL found no decrease in sebum production, IPL and IPL-mediated PDT have both been shown to diminish sebaceous gland function.31,40 IPL and broad-spectrum, incoherent light sources also have the potential to photoactivate the degradation products of porphyrins, potentiating their photodynamic effects.13,41

PDT with multiple, sequential laser and light sources demonstrated a trend towards greater patient-graded improvement in acne vulgaris than that with a single light source (blue light), without significant differences in post-treatment adverse events. The addition of red light to combination blue light, IPL, and PDL did not lead to any further acne improvement nor did it enhance the overall appearance of treated areas. It is possible that porphyrin photobleaching may have reached a maximal state, given that the red light is used last in our treatment paradigm. Nevertheless, the small number of patients in the multiple modality treatment arms and prolonged, variable follow-up times between patients substantially limit the significance of our results. A larger, prospective, multicenter, randomized-controlled study is warranted.

The sequential use of different light and laser sources in a single session thereby takes advantage of their distinct mechanisms of action, mitigates their individual weaknesses, and allows for the targeting of multiple porphyrin absorption peaks concurrently, likely leading to improved overall efficacy. The synergy of blue and red light sources, for example, pairs superior porphyrin absorption at 417 nm with greater depth of penetration at 635 nm, respectively.42,43 Their interaction may further reduce the follicular obstruction underlying acne development, with red light acting on pilosebaceous units directly and blue light promoting superficial keratinocyte shedding.1 One study44 reported a marked reduction in acne severity and lesion count in a single patient with facial cystic acne following four PDT sessions (ALA-IPL, then ALA-blue light x3) at 3-week intervals. A split-face and back clinical study in 10 patients with inflammatory acne also found that 970-nm irradiation prior to ALA-red light (630 nm) led to improvement in acne severity and lesion counts compared with control sides without pretreatment.45 Nevertheless, no prospective study has yet investigated the sequential use of multiple laser or light sources for the photodynamic management of acne.

Conclusions

Disclosures Work was performed at Goldman, Butterwick, Fitzpatrick, Groff, and Fabi: Cosmetic Laser Dermatology, San Diego, CA. Dr Goldman is a consultant and speaker and has received payments for performing clinical research for Lumenis Ltd. Drs Friedmann and Fabi are speakers and have performed clinical research for Lumenis Ltd. Isabella Guiha has no conflicts of interest to disclose. References

Study Limitations Although our single-center, parallel-group study has revealed a trend towards greater efficacy with comparable tolerability using multiple, sequential modalities for ALA-PDT of acne, the relatively small number of patients in the blue light + PDL + IPL ± red light groups and the overall disparate patient numbers between groups limits the statistical significance of our retrospective data (Table). The lack of internal clinical controls or randomization and widely variable, inconsistent follow-up times SKINmed. 2017;15:105–111

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1 Sakamoto FH, Lopes JD, Anderson RR. Photodynamic therapy for acne vulgaris: a critical review from basics to clinical practice: part I. Acne vulgaris: when and why consider photodynamic therapy? J Am Acad Dermatol. 2010;63:183–193. 2 Riddle CC, Terrell SN, Menser MB, et al. A review of photodynamic therapy (PDT) for the treatment of acne vulgaris. J Drugs Dermatol. 2009;8:1010–1019. 3 Gold MH, Goldman MP. 5-aminolevulinic acid photodynamic therapy: where we have been and where we are going. Dermatol Surg. 2004;30:1077–1083. 4 Divaris DX, Kennedy JC, Pottier RH. Phototoxic damage to sebaceous glands and hair follicles of mice after systemic administration of 5-aminolevulinic acid correlates with localized protoporphyrin IX fluorescence. Am J Pathol. 1990;136:891–897. 5 Touma DJ, Gilchrest BA. Topical photodynamic therapy: a new tool in cosmetic dermatology. Semin Cutan Med Surg. 2003;22:124–130. 6 Pottier RH, Chow YF, LaPlante JP, et al. Non-invasive technique for obtaining fluorescence excitation and emission spectra in vivo. Photochem Photobiol. 1986;44:679–687.

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7 Horfelt C, Funk J, Frohm-Nilsson M, et al. Topical methyl aminolaevulinate photodynamic therapy for treatment of facial acne vulgaris: results of a randomized, controlled study. Br J Dermatol. 2006;155:608–613. 8 Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminolevulinate. J Am Acad Dermatol. 2006;54:647–651. 9 Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, controlled trial. Br J Dermatol. 2006;154:969–976. 10 Pollock B, Turner D, Stringer MR, et al. Topical aminolaevulinic acid-photodynamic therapy for the treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br J Dermatol. 2004;151:616–622. 11 Hongcharu W, Taylor CR, Chang Y, et al. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol. 2000;115:183–192. 12 Sakamoto FH, Torezan L, Anderson RR. Photodynamic therapy for acne vulgaris: a critical review from basics to clinical practice. J Am Acad Dermatol. 2010;63:195–211. 13 Yung A, Stables GI, Fernandez C, et al. Microbiological effect of photodynamic therapy (PDT) in healthy volunteers: a comparative study using methyl aminolaevulinate and hexyl aminolaevulinate cream. Clin Exp Dermatol. 2007;32:716–721. 14 Taylor MN, Gonzalez ML. The practicalities of photodynamic therapy in acne vulgaris. Br J Dermatol. 2009;160:1140–1148. 15 Alexiades-Armenakas M. Intense pulsed light-mediated photodynamic therapy. J Drugs Dermatol. 2005;4:657– 658. 16 Ashkenazi H, Malik Z, Harth Y, et al. Eradication of Propionibacterium acnes by its endogenic porphyrins after illumination with high intensity blue light. FEMS Immunol Med Microbiol. 2003;35:17–24. 17 Togsverd-Bo K, Idorn LW, Philipsen PA, et al. Protoporphyrin IX formation and photobleaching in different layers of normal human skin: methyl- and hexylaminolevulinate and different light sources. Exp Dermatol. 2012;21:745–750. 18 Shnitkind E, Yaping E, Geen S, et al. Anti-inflammatory properties of narrow-band blue light. J Drugs Dermatol. 2006;5:605–610. 19 Ammad S, Gonzales M, Edwards C, et al. An assessment of the efficacy of blue light phototherapy in the treatment of acne vulgaris. J Cosmet Dermatol. 2008;7:180– 188. 20 Omi T, Bjerring P, Sato S, et al. 420 nm intense continuous light therapy for acne. J Cosmet Laser Ther. 2004;6:156–162. 21 Choi MS, Yun SJ, Beom HJ, et al. Comparative study of the bactericidal effects of 5-aminolevulinic acid with blue and red light on Propionibacterium acnes. J Dermatol. 2010;38:661–666. 22 Jori G, Fabris C, Soncin M, et al. Photodynamic therapy in the treatment of microbial infections: basic principles and perspective applications. Lasers Surg Med. 2006;38:468–481.

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23 Taub AF. Photodynamic therapy for the treatment of acne: a pilot study. J Drugs Dermatol. 2004;3:S10–S14. 24 Goldman MP, Boyce SM. A single-center study of aminolevulinic acid and 417 nm photodynamic therapy in the treatment of moderate to severe acne vulgaris. J Drugs Dermatol. 2003;2:393–396. 25 Na JI, Suh DH. Red light phototherapy alone is effective for acne vulgaris: randomized, single-blinded clinical trial. Dermatol Surg. 2007;33:1228–1233. 26 Wang XL, Wang HW, Zhang LL, et al. Topical ALA PDT for the treatment of severe acne vulgaris. Photodiagnosis Photodyn Ther. 2010;7:33–38. 27 Jeong E, Hong JW, Min JA, et al. Topical ALA-photodynamic therapy for acne can induce apoptosis of sebocytes and down-regulate their TLR-2 and TLR-4 expression. Ann Dermatol. 2011;23:23–32. 28 Seaton ED, Charakida A, Mouser PE, et al. Pulsed-dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet. 2003;362:1347–1352. 29 Taub AF. A comparison of intense pulsed light, combination radiofrequency and intense pulsed light, and blue light in photodynamic therapy for acne vulgaris. J Drugs Dermatol. 2007;6:1010–1016. 30 Yeung CK, Shek SY, Bjerring P, et al. A comparative study of intense pulsed light alone and its combination with photodynamic therapy for the treatment of facial acne in Asian skin. Lasers Surg Med. 2007;39:1–6. 31 Oh SH, Ryu DJ, Han EC, et al. A comparative study of topical 5-aminolevulinic acid incubation times in photodynamic therapy with intense pulsed light for the treatment of inflammatory acne. Dermatol Surg. 2009;35:1918–1926. 32 Hædersdal M, Togsverd-Bo K, Wiegell SR, et al. Longpulsed dye laser versus long-pulsed dye laser-assisted photodynamic therapy for acne vulgaris: a randomized controlled trial. J Am Acad Dermatol. 2008;58:387–394. 33 Orringer JS, Sachs DL, Bailey E, et al. Photodynamic therapy for acne vulgaris: a randomized, controlled, split-face clinical trial of topical aminolevulinic acid and pulsed dye laser therapy. J Cosmet Dermatol. 2010;9:28–34. 34 Gold MH, Bradshaw VL, Boring MM, et al. The use of a novel intense pulsed light and heat source and ALA-PDT in the treatment of moderate to severe inflammatory acne vulgaris. J Drugs Dermatol. 2004;3:S15–S19. 35 Alexiades-Armenakas M. Long-pulsed dye laser-mediated photodynamic therapy combined with topical therapy for mild to severe comedonal, inflammatory, or cystic acne. J Drugs Dermatol. 2006;5:45–55. 36 Rojanamatin J, Choawawanich P. Treatment of inflammatory facial acne vulgaris with intense pulsed light and short contact of topical 5-aminolevulinic acid: a pilot study. Dermatol Surg. 2006;32:991–997. 37 Hong JS, Jung JY, Yoon JY, et al. Acne treatment by methyl aminolevulinate photodynamic therapy with red light vs. intense pulsed light. Int J Dermatol. 2012;52:614–619. 38 Alster TS, Tanzi EL. Photodynamic therapy with topical aminolevulinic acid and pulsed dye laser irradiation for sebaceous hyperplasia. J Drugs Dermatol. 2003;2:501–504.

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39 Gold MH, Bradshaw VL, Boring MM, et al. Treatment of sebaceous gland hyperplasia by photodynamic therapy with 5-aminolevulinic acid and a blue light source or intense pulsed light source. J Drugs Dermatol. 2004;3:S6–S9. 40 Seaton ED, Mouser PE, Charakida A, et al. Investigation of the mechanism of action of nonablative pulsed-dye laser therapy in photorejuvenation and inflammatory acne vulgaris. Br J Dermatol. 2006;155:748–755. 41 Brancaleon L, Moseley H. Laser and non-laser light sources for photodynamic therapy. Lasers Med Sci. 2002;17:173–186. 42 Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol. 2000;142:973–978.

43 Alexiades-Armenakas M. Aminolevulinic acid photodynamic therapy for actinic keratoses/actinic cheilitis/acne: vascular lasers. Dermatol Clin. 2007;25:25– 33. 44 Melnick S. Cystic acne improved by photodynamic therapy with short-contact 5-aminolevulinic acid and sequential combination of intense pulsed light and blue light activation. J Drugs Dermatol. 2005;4:742–745. 45 Barolet D, Boucher A. Radiant near infrared light emitting Diode exposure as skin preparation to enhance photodynamic therapy inflammatory type acne treatment outcome. Lasers Surg Med. 2010;42:171– 178.

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Volume 15 • Issue 2

ORIGINAL CONTRIBUTION

A Multicenter Clinical Study of Expected and Unexpected Side Reactions During and After Skin Cancer Treatment by Photodynamic Therapy Kate C. Blanco, PhD;1 Natalia M. Inada, PhD;1 Ana. P. Silva, MS;1 Mirian D. Stringasci, MS;1 Hilde H. Buzzá, PhD;1 Dora P. Ramirez, MS;2 Ana G. Sálvio, PhD;3 Lilian T. Moriyama, PhD;1 Cristina Kurachi, PhD;1 Vanderlei S. Bagnato, PhD1 Abstract Photodynamic therapy (PDT) has been widely used for oncologic indications, especially nonmelanoma skin cancer such as superficial and nodular basal cell carcinoma (BCC). We present a multicenter clinical study conducted between 2012 and 2014 analyzing the adverse reactions during and after PDT with a standardized protocol in 866 lesions. A total of 728 patients with positive clinical and histopathological diagnosis for BCC with up to 2 cm diameter were treated. The procedure consisted of curettage and topical application of cream containing 20% methyl 5-aminolevulinate. The illumination (630 nm and 150 J/cm2) was performed 3 hours after the cream application. The expected and unexpected effects observed were pain, healing, and inflammatory reactions. The pain intensity was correlated with the anatomical localization of the lesion. The patients reported a higher intensity of pain in lesions located on the head and neck rather than on the trunk and limbs. The number of sessions also influenced the pain response. A total of 83% of patients showed perfect healing and the other 17% presented abnormal healing. PDT plays an important role in BCC because of its low cost, ease of use, and low rate of side effects. (SKINmed. 2017;15:113–118)

hotodynamic therapy (PDT) has been used for the treatment of skin cancer for over 30 years.1 It is a noninvasive technique that has yielded excellent esthetic results when used in the early stage of skin cancer. PDT has also shown high cure rates, especially in cases of basal cell carcinoma (BCC), and it is often used as the first treatment option for thin lesions with skin cancer.2

The inflammatory response is an essential face to healing, characterized by increased vascular permeability, release of cytokines,6 and restoration of tissue. The reactive oxygen species assists in repairing the damaged tissue. The molecules involved in the cellular repair process conducted by receptors on the membrane surface may cause local changes in both the cell metabolism and the phenotype and effects, such as redness and pain.7

The procedure involves the application of topical agents, such as aminolevulinic acid (ALA) or methyl aminolevulinate (MAL), to the lesion to be treated. Following occlusion for approximately 3 hours, it is absorbed and metabolized in protoporphyrin IX (PpIX), an endogenous photosensitizer (PS) generated into mitochondria through the heme cycle.3 Red light irradiation is carried out after the cream has been removed. The PS generates oxygen radicals in the therapeutic response of the target cell.4 Because the procedure involves illumination at the skin and interaction with a PS, many reactions, including pain during treatment, might occur.5

Adverse reactions of PDT include edema and pain. Pain may be caused by sensitivity to the drug or photosensitivity.8 According to the International Association for the Study of Pain, as defined in 1986, pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.”9 Untreated pain may increase oxygen consumption and hinder the patient’s recovery.10 The pain score is important for an appropriate study of its minimization and for obtaining better results in PDT. Researchers for the Brazilian Photodynamic Therapy project have considered ways to minimize pain and other adverse effects, including lesion size and skin pigmentation,11 which may account for approxi-

From the University of São Paulo, São Carlos Institute of Physics, São Carlos,1 the Federal University of São Carlos, PPGBiotec, São Carlos,2 and Hospital Amaral Carvalho, Jaú,3 São Paulo, Brazil Address for Correspondence: Kate Cristina Blanco, PhD, CEPOF, Av. Trabalhador São-carlense, 400, São Carlos, São Paulo, Brazil, 13566-590 • E-mail: blancokate@gmail.com

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mately 1% of all adverse reactions, including atrophic, hypertrophic, hypochromic, and hyperchromic scars following PDT.1 This research included a total of 728 patients with 866 lesions from clinical centers in Brazil and other countries of Latin America. The objective was to analyze the adverse reactions during and after PDT with our clinical protocol. Materials and Methods

A verbal numeric scale was used for analysis of the pain intensity during the time of illumination (20 minutes) and the most common terms used were painless or medium, moderate, severe, and intense pain. The pain scale included painless (0), average pain (intensity 1 to 3), moderate pain (intensity 4 to 6), and severe pain (intensity 7 to 10).

Analysis of Scarring, Keloids, and Pigmentary Changes

We performed a multicenter prospective study that included 80 dermatology centers in Brazil, plus Mexico, Chile, Colombia, Ecuador, Venezuela, El Salvador, Bolivia, Peru, and Cuba. In total, there were 728 patients and 866 lesions. The approval of the ethical committee was obtained as required (73th Ethical Committee Meeting on October 28, 2011) by the Amaral Carvalho Foundation Hospital, Jahu City, São Paulo, Brazil, and the study was conducted in compliance with current Brazilian regulations.

Participants The observational study involved 728 patients with a total of 866 BCC lesions according to the International Classification of Diseases, 10th Revision, code D04. The 866 lesions had histopathologic confirmation of BCC, measuring up to 2 cm in diameter. All patients provided written informed consent before enrollment into the study.

Study procedures Superficial BCC lesions were prepared by surface debridement to remove scales and crusts and to facilitate penetration of the MAL cream. For nodular BCC, curettage without local anesthesia was performed to reduce the tumor thickness, resulting in a flatter surface.12 In the first and second sessions, the lesions were first cleaned with chlorhexidine prior to curettage. The medicine was applied in all extension of lesion and immediately sealed with film and aluminum foil. After 7 days, the patients were evaluated and received a second treatment. LINCE (MMOptics, São Carlos-SP, Brazil) was used as the source of light. This equipment used a light-emitting diode at 630 nm (125 mW/cm2), with a total dose of 150 J/cm2. In previous studies, we found that fluorescence from PpIX, an endogenous photosensitizer, disappeared after 20 minutes of illumination, resulting in a dose of 150 J/cm2. After 7 days, the patients were reassessed and underwent a second treatment that followed the same protocol of the first session. After 30 days, they returned for a clinical evaluation and histopathology examination. SKINmed. 2017;15:113–118

Pain Score

Analysis of scarring, keloids, and pigmentary changes were performed with clinical evaluation 30 days following the first session with the assistance of the Celestron digital microscope (Torrance, CA), coupled with one of the LINCE tips for fluorescence wide-field imaging acquisition. A digital camera (SONY model H50; Tokyo, Japan) was used to record the resolution of the white light images.

Statistical Analysis The Wilcoxon test for nonparametric data was used for the comparison of the results of the two PDT sessions. A P<.05 level was considered significant. Results The main adverse reaction observed was pain, although other side effects included scarring, increase in the lesion size, and pigmentation changes of the surrounding tissue. Although all of the centers received the same training, with the increase in professional experience, there was an increase in the success of treatment. Expected Reactions

Pain A variation in the pain scale was observed according to the anatomical region of the body, time of illumination, and number of sessions during PDT. Figure 1 highlights the severe pain rate reported by 632 patients over the time period whose 410 lesions were located on the head and neck and 222 on the trunk and extremities. Patient withdrawal due to pain accounted for 96 lesions. The patients were questioned about pain intensity during 20 minutes of illumination. Severe intensity was reported at 5, 10, 15, and 20 minutes in the first session for 25%, 27.5%, 21.5%, and 17% of 632 patients, respectively; however, at 5, 10, 15, and 20 minutes, 30%, 32.5%, 22.5%, and 20% of patients, respectively, reported severe pain in the second session. The percentage with severe pain decreased after 10 minutes of treatment for both sessions and was higher in the second than in the first session.

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All 728 patients reported average pain intensity during 20 minutes of PDT in the first and second sessions. The verbal numerical scale was painless (0), average pain (intensity 1 to 3), moderate pain (intensity 4 to 6) and severe pain (intensity 7 to 10). Figure 2 shows the average of pain intensity during PDT on a 0 to 10 scale over the time period. The patients reported pain at intervals of 5 minutes during 20 minutes. Figure 2A illustrates the pain scales of lesions of the head and neck and Figure 2B shows those of the trunk and extremities.

Both show an increase in pain intensity from 0 (the beginning of application of light) to 10 minutes and a reduction after 10 minutes in the first and second session, the same results as those found in Figure 1. Increased pain in the first 15 minutes may be related to high PS concentrations which is consumed with the increase of lesion lighting. Figure 2A shows averages of 6.30 (0 minutes), 6.47 (10 minutes), 6.12 (15 minutes), and 5.64 (20 minutes) in the first session. The highest intensity of pain occurred in the second session, regardless of the lesion site, with averages of 6.8 (0 minutes), 6.8 (10 minutes), 6.4 (15 minutes), and 5.9 (20 minutes). The pain is greater in the second session due to the occurrence of an inflammatory process in lesions 7 days after the first session. Patients whose lesions were located on the trunk and extremities (65%) reported less pain than patients with involvement on the head and neck (35%), as can be observed with the comparison between Figure 2A and 2B (the highest average of the last treatment is not more than 4.5).

Scarring and keloid

Figure 1. Percentage of severe pain reports during the first and second sessions of photodynamic therapy over time.

In this study, among the lesions treated with PDT, 83% showed perfect skin regeneration and 17% were related to abnormal lesions. Figure 3 shows cases of abnormal regeneration, as the case of hypertrophic (before and after in Figure 3A and 3E) and atrophic (Figure 3B and 3F) types. Despite such scars, 85.7% of these BCC lesions were completely cured. The lesions treated with PDT that resulted in abnormal scars presented with a prevalence rate of 69.05% of atrophic scarring. Hy-

Figure 2. Average pain intensity reported by patients with lesions on the head and neck (A) and on the trunk and limbs (B) during all 20 minutes of photodynamic therapy. SKINmed. 2017;15:113â&#x20AC;&#x201C;118

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pertrophic scarring that presents high texture in the surrounding skin occurred in 9.52% of the cases of abnormal scarring, among which 75% were BCC nodules and may be due to a different genetic origin of fibroblasts and abnormal amounts of collagen.13

Pigmentation changes Lesions with abnormal pigmentation were observed in 21.4% of all lesions after PDT and were subdivided into hyperchromic and hypochromic. Among the lesions with pigmentation changes, 50% were of phototype IV in the skin color scale. Figure 3 also shows cases of pigmentation changes in hypochromic (C and G, before and after, respectively) and hyperchromic (D and H) lesions. Pigmentation alterations were on the face in 86% of cases, a region more exposed to the sun. Exceptional cases Conventional treatment is not indicated for some clinical cases; however, the clinician may indicate PDT for a specific protocol. Two cases are reported below. Figure 4A shows case A before treatment. After the first session, the clinician reported significant improvements in the lesion and authorized the second session; however, 1 month after the second application, an increase in the lesion was observed (Figure 4B). In case B (Figure 5), a significant improvement was observed in the lesion just after the first PDT procedure; however, 4 months after the second PDT session (Figure 5B), an increase in the lesion was observed compared with before PDT (Figure 5A).

Both cases illustrate that unexpected results may be related to several factors, such as treatment of high thickness lesions, which hampers the penetration of the drug and light into the lesion. Thickness is confirmed by a preoperative biopsy, a criterion for the classification of histological types of BCC. A biopsy after PDT was also performed, confirming that the lesion remained BCC. Most of the patients presented with the expected reactions. Thickness, curettage mode, and application of cream on the lesions of the nodular BCC are essential factors to be analyzed for successful treatment with PDT. Discussion In this study, PDT caused pain associated with tissue injury and inflammatory process. The pain is characterized as sharp and burning due to cutaneous nociceptors present in the skin and subcutaneous tissue.14 Psychologic factors such as stress and anxiety may also contribute to the pain due to environmental changes.15 The painful feeling may decrease when the patient becomes accustomed to the pain and the PS is consumed. According to some researchers,16 the pain is dependent on the anatomical location and size of the lesion, as well as the accumulation of PS (PpIX) at nerve endings. The pain perception in different anatomical locations may vary. This is probably related to the irrigation area of blood vessels in these areas with the characteristics of the skin in those parts of the body.17 Considering that the pain during PDT is one of the few expected adverse effects of the treatment of skin cancer, some studies

Figure 3. Examples of abnormal regeneration. A and E correspond with hypertrophic, B and F with atrophic, C and G with hypochromic, and D and H with hyperchromic lesions, shown before and after treatment, respectively. SKINmed. 2017;15:113â&#x20AC;&#x201C;118

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Figure 4. Increase in lesion size in case A. Lesion before treatment with photodynamic therapy (A). Lesion 30 days after the second treatment with photodynamic therapy (B).

Figure 5. Increase in lesion size in case B. Lesion before treatment with photodynamic therapy (A). Lesion 4 months after the second treatment with photodynamic therapy (B).

suggested the following: ALA ester is less painful than ALA18; the pain scores did not correlate with the intensity of PpIX fluorescence16; the histamine may be responsible for pain during acute inflammatory reactions using ALA-PDT19; ALA induced the pain because this drug is transported via carriers across the plasma membrane, with are present in peripheral nerves18; and age, phototype, and total dose of irradiation does not interfere with the painful sensation during ALA-PDT.1

aesthetic results, however. PDT has shown low risk for abnormal scarring such as keloids, and treatment is most appropriate when healing is the main concern.

PDT is a procedure also indicated for patients with advanced age who are taking anticoagulant medications, and who cannot undergo surgical procedures. It is also helpful in the treatment of subclinical skin lesions.20 Benefits of PDT have surpassed the

Hyperchromic pigmentation is common in patients of high phototype and may occur as a result of melanocyte formation.23 The use of ALA and MAL in PDT may also induce the increase in pigmentation in healthy skin.1,24 In one study,24 the frequency

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The tissue repair undergoes several stages after PDT, from inflammation to skin wound healing.21 An atrophic scar results from the destruction of the connective tissue and probably appears during an inflammation process.22

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of hyperpigmentation after 28 days of treatment was higher for patients undergoing ALA-PDT than MAL-PDT. On the other hand, hypopigmentation may occur as a result of either phototoxic damage to melanocytes or nonreplenishing of skin melanin. Conclusions PDT has been shown to be a good option for the treatment of BCC because of its low cost, ease of application, and low rate of side effects. Regarding the reactions during and after PDT procedures, the pain seems to be one of the main obstacles for the technique, and most patients decline a second round of treatment because of this discomfort. This obstacle is a significant barrier for the full adaptation of topical PDT. Action should be taken to minimize such effects. Acknowledgments Several Brazilian Funding Agencies provided support for this study: BNDES (09.2.1458.1); FINEP; Capes; CNPq (INOF – INCT grant: 573587/2008-6); and grant 2013/07276-1 (CEPOF), São Paulo Research Foundation (FAPESP). References 1 Ibbotson SH. Adverse effects of topical photodynamic therapy. Photodermatol Photoimmunol Photomed. 2011;27:116–130. 2 Sidoroff A, Thaler P. Taking treatment decisions in nonmelanoma skin cancer—the place for topical photodynamic therapy (PDT). Photodiagnosis Photodyn Ther. 2010;7:24–32. 3 Gerritsen MJ, Smits T, Kleinpenning MM, Van De Kerkhof PC, van Erp PE. Pretreatment to enhance protoporphyrin IX accumulation in photodynamic therapy. Dermatology. 2009;218:193–202. 4 Ashur I, Goldschmidt R, Pinkas I, et al. Photocatalytic generation of oxygen radicals by the water-soluble bacteriochlorophyll derivative WST1l, noncovalently bound to serum albumin. J Phys Chem A. 2009;113:8027–8037. 5 Attili SK, Dawe R, Ibbotson S. A review of pain experienced during topical photodynamic therapy—our experience in Dundee. Photodiagnosis Photodyn Ther. 2011;8:53–57. 6 Witte MB, Barbul A. General principles of wound healing. Surg Clin North Am. 1997;77:509–528. 7 Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res. 2009;37:1528–1542. 8 Allison RR, Downie GH, Cuenca R, et al. Photosensitizers in clinical PDT. Photodiagnosis Photodyn Ther. 2004;1:27–42. 9 Merskey H, Bogduk N. Part III. Pain terms: a current list with definitions and notes on usage. Classification of Chronic Pain. 2nd ed. IASP Task Force on Taxonomy. IASP Press: Seattle, WA; 1994:209–214.

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10 Fuchs J, Thiele J. The role of oxygen in cutaneous photodynamic therapy. Free Radic Biol Med. 1998;24:835– 847. 11 Bagnato VS, Kurachi C, Ferreira J, et al. PDT experience in Brazil: a regional profile. Photodiagnosis Photodyn Ther. 2005;2:107–118. 12 Ramirez DP, Kurachi C, Inada NM, et al. Experience and BCC subtypes as determinants of MAL-PDT response: preliminary results of a national Brazilian project. Photodiagnosis Photodyn Ther. 2014;11:22– 26. 13 Verhaegen PD, van Zuijlen PP, Pennings NM, et al. Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: an objective histopathological analysis. Wound Repair Regen. 2009;17:649–656. 14 Ringkamp M, Meyer RA. Physiology of nociceptors. The Senses: A Comprehensive Reference. Elsevier: Amsterdam, Netherlands; 2010:5:97–114. 15 Linton SJ. Occupational psychological factors increase the risk for back pain: a systematic review. J Occup Rehabil. 2001;11:53–66. 16 Wiegell SR, Skiveren J, Philipsen PA, Wulf HC. Pain during photodynamic therapy is associated with protoporphyrin IX fluorescence and fluence rate. Br J Dermatol. 2008;158:727–733. 17 Gondim E Jr, Setzer FC, Dos Carmo CB, Kim S. Postoperative pain after the application of two different irrigation devices in a prospective randomized clinical trial. J Endod. 2010;36:1295–1301. 18 Rud E, Gederaas O, Høgset A, Berg K. 5-aminolevulinic acid, but not 5-aminolevulinic acid esters, is transported into adenocarcinoma cells by system BETA transporters. Photochem Photobiol. 2000;71:640– 647. 19 Brooke RC, Sinha A, Sidhu MK, et al. Histamine is released following aminolevulinic acid-photodynamic therapy of human skin and mediates an aminolevulinic acid dose-related immediate inflammatory response. J Invest Dermatol. 2006;126:2296–2301. 20 Armbrecht AM, Aspinall PA, Dhillon B. A prospective study of visual function and quality of life following PDT in patients with wet age related macular degeneration. Br J Ophthalmol. 2004;88:1270–1273. 21 Morton CA. The emerging role of 5-ALA-PDT in dermatology: is PDT superior to standard treatments? J Dermatolog Treat. 2002;13:25–29. 22 Zhu X, Zhuo S, Zheng L, et al. Quantification of scar margin in keloid different from atrophic scar by multiphoton microscopic imaging. Scanning. 2011;33:195–200. 23 Cestari TF, Dantas LP, Boza JC. Acquired hyperpigmentations. An Bras Dermatol. 2014;89:11–25. 24 Steinbauer J, Schreml S, Karrer S, et al. Phototoxic reactions in healthy volunteers following photodynamic therapy with methylaminolevulinate cream or with cream containing 5-aminolevulinic acid: a phase II, randomized study. Photodermatol Photoimmunol Photomed. 2009;25:270–275.

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Fixed-Combination Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam Is Well Tolerated in Patients with Psoriasis Vulgaris: Pooled Data from Three Randomized Controlled Studies Alan Menter, MD;1 Linda Stein Gold, MD;2 John Koo, MD;3 John Villumsen, MSc;4 Monika Rosén, PhD;4 Mark Lebwohl, MD5 Abstract The authors performed a pooled analysis of three randomized, 4-week, phase II/III studies in adult patients with mild to severe psoriasis and assessed the safety/tolerability of aerosol foam fixed-combination calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) versus different comparators. Overall, 1104 patients were randomized to Cal/BD aerosol foam (n=564), Cal aerosol foam (n=101), BD aerosol foam (n=101), aerosol foam vehicle (n=152), Cal/BD ointment (n=135), or ointment vehicle (n=51). A total of 543 Cal/BD patients in the aerosol foam group (96.3%) completed the studies, with only two patients (0.4%) withdrawing as a result of adverse events (AEs). Ninety-five AEs were reported in 78 patients (13.8%) receiving Cal/BD aerosol foam; similar event rates were observed in other groups. The most common AEs with Cal/BD aerosol foam were nasopharyngitis (n=6, 1.1%) and application-site pain (n=4, 0.7%); most AEs were mild (n=71/95; 74.7%). Adverse drug reactions (ADRs) experienced by two or more patients receiving Cal/BD aerosol foam were application-site pain (n=4; 0.7%) and application-site pruritus (n=2; 0.4%). There were no clinically relevant changes in calcium homeostasis. Cal/BD aerosol foam has a positive benefit–risk profile for the treatment of psoriasis vulgaris; the superior efficacy versus Cal/ BD ointment and the individual active ingredients is not associated with poorer tolerability. (SKINmed. 2017;15:119–124)

soriasis has a profound negative effect on patients’ physical, psychologic, and social well-being1–3 and has major quality of life issues comparable to those of other serious chronic diseases, including cancer.4 Topical therapy with vitamin D3 analogs and corticosteroids remains the cornerstone of psoriasis treatment;5 however, the prolonged use of high-dose corticosteroid monotherapy may be associated with safety concerns, such as skin atrophy and hypothalamic–pituitary–adrenal axis suppression, as well as tachyphylaxis. Monotherapy with vitamin D3 analogs may be associated with skin irritation and, in high doses, alteration of calcium homeostasis.6,7 Along with other contributing factors, including lack of efficacy, time consumption and poor cosmetic characteristics, safety concerns can lead to poor treatment adherence.8,9 Fixed-combination vitamin D3 analogs and corticoste-

roids attenuate some of the side effects associated with monotherapy use, and may offer the opportunity for steroid-sparing benefits by reducing the quantity of corticosteroid used.10 Fixed-combination Cal 0.005% and BD 0.064% in an aerosol foam formulation is a new treatment option for psoriasis. Cal/ BD aerosol foam has greater in vitro drug penetration11 and superior efficacy (eg, significantly greater treatment success rates and improvements in psoriasis area and severity index scores) compared with the individual active ingredients and Cal/BD ointment.12–14 Cal/BD aerosol foam combines two compounds with well-understood tolerability profiles, and there is extensive experience with Cal/BD in ointment and topical suspension formulations.15,16 It is important to establish that any new formula-

From the Division of Dermatology, Baylor University Medical Center, Dallas, TX;1 Dermatology Clinical Research, Henry Ford Health System, Detroit, MI;2 the Department of Dermatology, University of California, San Francisco, CA;3 LEO Pharma A/S, Ballerup, Denmark;4 and the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY5 Address for Correspondence: Alan Menter, MD, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246 • E-mail: amderm@gmail.com

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tion is not associated with new safety concerns, and to ensure that the superior efficacy of the aerosol foam is not achieved at the expense of a poorer safety profile. Pooling data from multiple studies increases the sample size, thereby improving the precision of safety assessments and increasing the sensitivity to rare events. This pooled analysis of three phase II/III clinical studies assessed the safety and tolerability of Cal/BD aerosol foam over a 4-week treatment period. METHODS

Study design Each study ran for 4 weeks and was randomized, multicenter, parallel-group and blinded. Study 1 was a phase II, double-blind study, where patients were randomized (1:1:1) to Cal/BD aerosol foam (n=100), Cal aerosol foam (n=101), or BD aerosol foam (n=101) (ClinicalTrials.gov identifier NCT01536938).12 Study 2 was a phase II, investigator-blind study in which patients were randomized (3:3:1:1) to Cal/BD aerosol foam (n=141), Cal/BD ointment (n=135), aerosol foam vehicle (n=49), or ointment vehicle (n=51) (ClinicalTrials.gov identifier NCT01536886).13 Study 3 was a phase III, double-blind study in which patients were randomized (3:1) to Cal/BD aerosol foam (n=323) or aerosol foam vehicle (n=103) (ClinicalTrials.gov identifier NCT01866163).14 Further information on individual study designs and full inclusion/exclusion criteria are detailed in Lebwohl et al (2015), Koo et al (2015), and Leonardi et al (2015), respectively.12–14

Patients Eligible patients were aged 18 years or above, and had psoriasis vulgaris of the body (of 6 or more months’ duration), of mild to severe disease severity (according to the Physician Global Assessment [PGA] of disease severity), involving 2–30% of body surface area, and a modified (excluding the head, which was not treated) Psoriasis Area and Severity Index (mPASI) score of 2 or more. All patients provided written informed consent.

Objective, end points, and assessments The objective of this analysis was to evaluate the safety and tolerability of Cal/BD aerosol foam in a pooled patient population, to assess the benefit–risk profile and support dosing recommendations. Safety was assessed by monitoring AEs and ADRs (AEs with a possible or probable causal relationship [ie, that were not specifically described as ‘not related’ to study treatment by investigators]), and by evaluating changes in vital signs. Blood and spot urine samples were collected for laboratory analyses at baseline and week 4. Albumin-corrected serum calcium and urinary calcium/creatinine ratio parameters were calculated. SKINmed. 2017;15:119–124

Statistical analysis The full analysis set comprised all randomized patients. The safety analysis set comprised all randomized patients who applied study medication at least once and who had a presence or confirmed absence of AEs. Safety data were summarized descriptively. All AEs were recoded according to the Medical Dictionary for Regulatory Activities version 15.1. AEs reported under different preferred terms according to the Medical Dictionary for Regulatory Activities, but representing the same phenomenon, were grouped to prevent an underestimation of that particular event. RESULTS

Patients A total of 1104 patients were enrolled, with 1099 included in the safety analysis set (Table I); five patients were excluded as they were lost to follow-up after randomization (n=4) or returned all medication unopened (n=1). Overall, 1050 patients (95.5%) completed 4 weeks of treatment. The most common reason for discontinuation was loss to follow-up (n=24). Seven patients experienced 10 AEs that led to withdrawal from study treatment: three patients receiving Cal/BD aerosol foam (substance-induced psychotic disorder; irregular menstruation; hypersensitivity; n=1 for each), three receiving Cal aerosol foam (medication residue, n=2; contact dermatitis, n=1), and one receiving Cal/BD ointment (dizziness, dyspnea, swollen face, increased heart rate). Patient demographics and baseline characteristics were generally similar across treatment groups (Table II). The mean±standard deviation weekly amount of study medication used was 30.9±22.0 g for Cal/BD aerosol foam, 35.8±22.3 g for BD aerosol foam, 35.4±21.7 g for Cal aerosol foam, 32.4±24.0 g for aerosol foam vehicle, 31.8±22.2 g for Cal/BD ointment, and 29.3±22.5 g for ointment vehicle.

Adverse events Overall, all treatments were generally well tolerated. Ninety-five AEs were reported in 78 patients (13.8%) receiving Cal/BD aerosol foam; event rates in the other active treatment groups were: BD aerosol foam, 13.1% (19 events in 13 patients); Cal aerosol foam, 10.1% (16 events in 10 patients); and Cal/BD ointment, 10.4% (22 events in 14 patients). Event rates were lower in the vehicle groups (8.6% and 3.9% with foam and ointment vehicles, respectively). There was no indication that AE frequency was dose related. The most common AEs with Cal/BD aerosol foam were nasopharyngitis and application-site pain (Table III). Overall, pru-

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Table I. Patient Disposition by Pooled Treatment Group (Safety Analysis Set) Cal/BD Aerosol Foam (n=564)

BD Aerosol Foam (n=99)

Cal Aerosol Foam (n=99)

Aerosol Foam Vehicle (n=152)

Cal/BD Ointment (n=134)

Ointment Vehicle (n=51)

21 (3.7)

5 (5.1)

6 (6.1)

6 (3.9)

8 (6.0)

3 (5.9)

1 (2.0)

Unacceptable adverse effects

2 (0.4)

2 (2.0)

1 (0.7)

Loss to follow-up

12 (2.1)

3 (3.0)

2 (1.3)

4 (3.0)

Other

7 (1.2)

2 (2.0)

1 (1.0)

4 (2.6)

3 (2.2)

2 (3.9)

543 (96.3)

94 (94.9)

93 (93.9)

146 (96.1)

126 (94.0)

48 (94.1)

Cal/BD Ointment (n=134)

Ointment Vehicle (n=51)

Discontinuation from study, n (%) Unacceptable efficacy

Patients completing, n

Abbreviations: BD, betamethasone dipropionate; Cal, calcipotriene.

Table II. Patient Demographics and Baseline Characteristics (Safety Analysis Set) Cal/BD Aerosol Foam (n=564)

BD Aerosol Foam (n=99)

Cal Aerosol Foam (n=99)

Aerosol Foam Vehicle (n=152)

Median age (range), years

51.0 (18–87)

51.0 (20–85)

51.0 (21–85)

46.0 (19–79)

52.0 (21–88)

55.0 (30–73)

Male:female, n

344:220

55:44

60:39

79:73

87:47

30:21

491 (87.1)

81 (81.8)

91 (91.9)

135 (88.8)

117 (87.3)

44 (86.3)

Black or African-American

42 (7.4)

8 (8.1)

3 (3.0)

9 (5.9)

4 (3.0)

5 (9.8)

Other

31 (5.5)

10 (10.1)

5 (5.1)

8 (5.3)

13 (9.7)

2 (3.9)

Mean BMI±SD, kg/m2

31.7±7.5

31.3±7.5

30.2±5.3

32.1±8.5

30.2±6.0

30.9±6.7

Mean body surface area affected±SD, %

7.9±6.6

10.7±7.6

10.2±7.3

7.8±7.0

7.4±6.3

6.9±6.5

Mild

81 (14.4)

10 (10.1)

12 (12.1)

24 (15.8)

22 (16.3)

10 (19.6)

Moderate

433 (76.8)

79 (79.8)

74 (74.7)

110 (72.4)

105 (78.4)

39 (76.5)

50 (8.9)

10 (10.1)

13 (13.1)

18 (11.8)

7 (5.2)

2 (3.9)

7.5 (2–37)

8.1 (3–21)

8.7 (3–28)

7.5 (2–47)

6.7 (2–23)

6.6 (3–18)

Race, n (%) White

PGA, n (%)

Severe Mean mPASI score (range)

Abbreviations: BD, betamethasone dipropionate; BMI, body mass index; Cal, calcipotriene; mPASI, modified Psoriasis Area and Severity Index; PGA, Physician Global Assessment; SD, standard deviation.

ritus/application-site pruritus (itch) was reported as an AE in two patients (0.4%) in the Cal/BD aerosol foam group, in one patient receiving BD aerosol foam (1.0%), and in two patients receiving Cal/BD ointment (1.5%). Skin irritation/applicationsite irritation was reported in two patients in the Cal/BD aeroSKINmed. 2017;15:119–124

sol foam group (0.4%) and no patients in the other treatment groups. Most AEs with Cal/BD aerosol foam were mild (71/95; 74.7%). Severe AEs were reported with Cal/BD aerosol foam (n=6; cellulitis, hypersensitivity, substance-induced psychotic disorder, bipolar disorder, psoriasis, peripheral edema) and Cal/

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Table III. Most Common Adverse Effects by Medical Dictionary for Regulatory Activities Primary System Organ Class and Preferred Term (Occurring in Two or More Patients in the Calcipotriene/Betamethasone Dipropionate [Cal/BD] Aerosol Foam Group) (Safety Analysis Set) Cal/BD Aerosol Foam (n=564)

BD Aerosol Foam (n=99)

Cal Aerosol Foam (n=99)

Aerosol Foam Vehicle (n=152)

Cal/BD Ointment (n=134)

Ointment Vehicle (n=51)

Nasopharyngitis

6 (1.1)

1 (1.0)

2 (1.5)

Application-site pain

4 (0.7)

1 (1.0)

2 (1.3)

1 (0.7)

Blood pressure increased

3 (0.5)

Nausea

3 (0.5)

1 (1.0)

1 (2.0)

BD ointment (n=2; hypertension, bronchitis); all were single events. The overall proportion of patients with one or more lesional or perilesional AEs (located 2 cm or less from the border of lesions treated with the trial medication) was 2.5% with Cal/ BD aerosol foam (n=14) and 3.7% to 5.1% with the other active treatments. No single lesional or perilesional AE was reported in 1% or more of patients receiving Cal/BD aerosol foam. All AEs were reviewed to identify those potentially related to corticosteroid use. In the Cal/BD aerosol foam group, application site discoloration (n=1), psoriatic flare (n=1; considered a rebound event as it occurred 1 week or more after discontinuation), folliculitis (n=1), and impetigo (n=1) were reported. Four patients receiving Cal/BD aerosol foam had hypertension (n=1) or increased blood pressure (n=3), one of whom experienced two separate episodes; all four patients had elevated/borderline elevated blood pressure at baseline, with none experiencing a substantial increase during treatment. Exacerbation of psoriasis (n=1; not considered a rebound event as it occurred during treatment), staphylococcal infection (n=1), and abscess (n=1) were reported in the Cal/BD ointment group. Staphylococcal infection (n=1 in the BD aerosol foam group), tinea infection (n=1 in the Cal aerosol foam group), and hypertension/increased blood pressure (n=1 each in the BD aerosol foam and Cal/BD ointment groups) were also reported. AEs potentially related to the use of Cal were increased blood calcium levels (n=1 in the Cal/BD aerosol foam group), increased urine calcium/creatinine ratio (n=1 in the Cal aerosol foam group), and nephrolithiasis (n=1 in the BD aerosol foam group). Three patients receiving Cal/BD aerosol foam had a serious AE (hypersensitivity, bipolar disorder, substance-induced psychotic disorder). Only the case of hypersensitivity was considered possibly related to treatment. It occurred in a 40-year-old man, 13 days after initiation of Cal/BD aerosol foam, and led to study SKINmed. 2017;15:119â&#x20AC;&#x201C;124

withdrawal; it resolved upon discontinuation. Three serious AEs were reported in two patients receiving Cal/BD ointment (bronchitis and hypertension, and bile duct stone); none was considered to be related to treatment. No deaths occurred.

Adverse drug reactions The proportion of patients experiencing one or more ADR was 2.7% with Cal/BD aerosol foam (n=15), 7.1% with BD aerosol foam (n=7), 6.1% with Cal aerosol foam (n=6), and 3.0% with Cal/BD ointment (n=4). No single ADR was reported in 1% or more of patients receiving Cal/BD aerosol foam. ADRs experienced by two or more patients receiving Cal/BD aerosol foam were application-site pain (n=3, 0.5%) and application-site pruritus (n=2, 0.4%). There was no indication that the frequency of ADRs was dose related.

Albumin-corrected serum calcium Mean and median albumin-corrected serum calcium values were within the normal range (2.15 to 2.55 mmol/L) at baseline and week 4 in all treatment groups; mean changes were small and similar across all groups (â&#x20AC;&#x201C;0.02 to 0.01 mmol/L; Figure). There was no apparent association between treatment group or mean weekly amount of study medication used and changes in albumin-corrected serum calcium. A shift from normal to high values at week 4 was reported for three patients in the Cal/BD aerosol foam group and one in the Cal/BD ointment group; all values returned to normal or low levels at follow-up.

Spot urinary calcium/creatinine ratio Mean and median urinary calcium/creatinine ratios were within the normal ranges (men 0.30 to 6.10 mmol/g; women 0.22 to 8.20 mmol/g) at baseline and week 4 in all treatment groups; mean changes from baseline to week 4 were low and similar across

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ORIGINAL CONTRIBUTION ents in adults with psoriasis vulgaris. Superior efficacy of the foam12–14 was not achieved at the expense of poorer tolerability. In contrast to superpotent corticosteroids, applied twice daily for 2 to 4 weeks to reduce possible side effects,5,17,18 Cal/BD aerosol foam is well tolerated with once-daily application for 4 weeks. The prolonged or high-dose use of topical vitamin D3 analogs and corticosteroids may be associated with systemic safety concerns, such as disruption of calcium homeostasis and suppression of the hypothalamic–pituitary–adrenal axis.6,7 In this analysis, there were minimal changes in albumin-corrected serum calcium and urinary calcium/creatinine ratio with Cal/ BD aerosol foam; this is worth noting because Cal/BD aerosol foam provides enhanced skin penetration11 and a significantly greater antipsoriatic effect19 than prior formulations. No cases of adrenal suppression were reported as an AE in this analysis. Published data on patients with moderate/severe psoriasis found that 4-week, maximal-dose systemic exposure to Cal/BD aerosol foam (62 g per week versus 31 g per week in this analysis) had no clinically relevant impact on the hypothalamic–pituitary–adrenal axis or on calcium homeostasis.20 Fixed-combination therapy with Cal/BD is generally associated with fewer Cal- or corticosteroid-related AEs compared with monotherapies because (1) the anti-inflammatory action of BD reduces the incidence of skin irritation that is sometimes experienced with vitamin D3 analogs10—this may explain the relatively low incidence of skin irritation observed; and (2) Cal may offer steroid-sparing benefits by reducing the quantity of BD used, thereby decreasing the risk of steroid-associated AEs.5

Figure. Mean baseline and week 4 (a) albumin-corrected serum calcium values and (b) urinary calcium/creatinine ratio for each treatment group (safety analysis set). Normal levels: albumin-corrected serum calcium, 2.15 to 2.55 mmol/L; urinary calcium/creatinine ratio, 0.3 to 6.1 mmol/g (men), 0.22 to 8.20 mmol/g (women).

all groups (–0.19 to 0.05 mmol/g; Figure). There was no apparent association between treatment group and changes in urinary calcium/creatinine ratio. The proportion of patients with ratios shifting from normal to high at week 4 was broadly comparable across treatment groups (n=17, 3.0% with Cal/BD aerosol foam; n=1, 1.0% with BD aerosol foam; n=3, 3.0% with Cal aerosol foam; n=3, 2.0% with aerosol foam vehicle; n=3, 2.2% with Cal/ BD ointment; n=1, 2.0% with ointment vehicle); levels in patients assessed at follow-up were normal or low.

Vital signs Changes in vital signs from baseline to week 4 were minor, similar across treatment groups, and of no clinical concern. DISCUSSION This pooled analysis of three phase II/III studies demonstrated that Cal/BD aerosol foam has a comparable safety/tolerability profile to Cal/BD ointment and the individual active ingrediSKINmed. 2017;15:119–124

One limitation of this analysis is that only safety/tolerability data over 4 weeks were assessed. Longer term assessment would provide a more accurate reflection of the safety/tolerability of Cal/ BD aerosol foam with prolonged use; however, the safety/tolerability of Cal/BD ointment over 52 weeks has previously been demonstrated.21 CONCLUSIONS Cal/BD aerosol foam (n=564) was well tolerated for the treatment of psoriasis vulgaris in this patient population (n=1099). Cal/BD aerosol foam is more efficacious than the ointment13 and its individual active ingredients.12 This 4-week analysis of patients, who were highly adherent to treatment, shows that this greater efficacy has not been achieved at the expense of poorer tolerability. The combination of efficacy, tolerability, and ease of use of Cal/BD aerosol foam has significant potential to improve patient adherence to treatment, thereby increasing real-world effectiveness and patient quality of life.

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ACKNOWLEDGMENTS AND DISCLOSURE This analysis was sponsored by LEO Pharma. Medical writing support was provided by Andrew Jones PhD, from Mudskipper Business Ltd, funded by LEO Pharma. Dr Menter reports grants and honoraria from AbbVie, Allergan, Amgen, Boehringer Ingelheim, Genentech, Janssen Biotech, LEO Pharma, Novartis, Pfizer and Syntrix, honoraria from Convoy Therapeutics, Eli Lilly, Vitae, Wyeth, and Xenoport, and grants from Celgene, Merck and Symbio/Maruho; Dr Stein Gold reports grants and other conflicts of interest relating to LEO Pharma during the conduct of the study, grants from Valeant, other conflicts of interest relating to Taro, grants from Novartis, other conflicts of interest related to Pfizer, and other conflicts of interest related to Lilly, outside the submitted work; Dr Koo reports personal fees from LEO Pharma, outside of the submitted work; Ms Rosen and Mr Villumsen are employees of LEO Pharma; Dr Lebwohl is an employee of Mount Sinai Medical Center, which receives research funds from Amgen, Anacor, Aqua, Can-Fite Biopharma, Celgene, Clinuvel, Coronado Biosciences, Ferndale, Lilly, Janssen Biotech, LEO Pharma, Merz, Novartis, Pfizer, Sandoz, and Valeant. References 1 Bhosle MJ, Kulkarni A, Feldman SR, Balkrishnan R. Quality of life in patients with psoriasis. Health Qual Life Outcomes. 2006;4:35. 2 Hayes J, Koo J. Psoriasis: Depression, anxiety, smoking, and drinking habits. Dermatol Ther. 2010;23:174–180. 3 Bewley A, Burrage DM, Ersser SJ, Hansen M, Ward C. Identifying individual psychosocial and adherence support needs in patients with psoriasis: A multinational two-stage qualitative and quantitative study. J Eur Acad Dermatol Venereol. 2014;28:763–770. 4 Møller AH, Erntoft S, Vinding GR, Jemec GB. A systematic literature review to compare quality of life in psoriasis with other chronic diseases using EQ-5D-derived utility values. Patient Relat Outcome Meas. 2015;6:167– 177. 5 Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60:643–659. 6 Castela E, Archier E, Devaux S, et al. Topical corticosteroids in plaque psoriasis: A systematic review of risk of adrenal axis suppression and skin atrophy. J Eur Acad Dermatol Venereol. 2012;26 suppl 3:47–51. 7 Kragballe K, Iversen L. Calcipotriol. A new topical antipsoriatic. Dermatol Clin. 1993;11:137–141. 8 Devaux S, Castela A, Archier E, et al. Adherence to topical treatment in psoriasis: A systematic literature review. J Eur Acad Dermatol Venereol. 2012;26 suppl 3:61–67.

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9 Zschocke I, Mrowietz U, Karakasili E, Reich K. Non-adherence and measures to improve adherence in the topical treatment of psoriasis. J Eur Acad Dermatol Venereol. 2014;28 suppl 2:4–9. 10 Segaert S, Røpke M. The biological rationale for use of vitamin D analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Dermatol. 2013;12:e129–e137. 11 Hollesen Basse L, Olesen M, Lacour JP, Queille-Roussel C. Enhanced in vitro skin penetration and antipsoriatic effect of fixed combination calcipotriol plus betamethasone dipropionate in an innovative foam vehicle. J Invest Dermatol. 2014;134:S33, abst 192. 12 Lebwohl M, Tyring S, Bukhalo M, et al. Fixed combination aerosol foam calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) is more efficacious than Cal or BD aerosol foam alone for psoriasis vulgaris: a randomized, double-blind, multicenter, three-arm, Phase 2 study. J Clin Aesthet Dermatol. 2016;9:34–41. 13 Koo J, Tyring S, Werschler WP, et al. Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris-a randomized phase II study. J Dermatolog Treat. 2016;27:120–127. 14 Leonardi C, Bagel J, Yamauchi P, et al. Efficacy and safety of calcipotriene plus betamethasone dipropionate aerosol foam in patients with psoriasis vulgaris-a randomized Phase III Study (PSO-FAST). J Drugs Dermatol. 2015;14:1468–1477. 15 Kragballe K, van de Kerkhof P. Pooled safety analysis of calcipotriol plus betamethasone dipropionate gel for the treatment of psoriasis on the body and scalp. J Eur Acad Dermatol Venereol. 2014;28 suppl 2:10–21. 16 McCormack PL. Calcipotriol/betamethasone dipropionate: A review of its use in the treatment of psoriasis vulgaris of the trunk, limbs and scalp. Drugs. 2011;71:709–730. 17 Lebwohl M, Ting PT, Koo JY. Psoriasis treatment: traditional therapy. Ann Rheum Dis. 2005;64 suppl 2:ii83– ii86. 18 Uva L, Miguel D, Pinheiro C, et al. Mechanisms of action of topical corticosteroids in psoriasis. Int J Endocrinol. 2012;2012:561018. 19 Queille-Roussel C, Olesen M, Villumsen J, Lacour JP. Efficacy of an innovative aerosol foam formulation of fixed combination calcipotriol plus betamethasone dipropionate in patients with psoriasis vulgaris. Clin Drug Investig. 2015;35:239–245. 20 Taraska V, Tuppal R, Olesen M, Bang Pedersen C, Papp K. A novel aerosol foam formulation of calcipotriol and betamethasone has no impact on HPA axis and calcium homeostasis in patients with extensive psoriasis vulgaris. J Cutan Med Surg. 2015;20:44–51. 21 Kragballe K, Austad J, Barnes L, et al. A 52-week randomized safety study of a calcipotriol/betamethasone dipropionate two-compound product (Dovobet®/Daivobet®/Taclonex®) in the treatment of psoriasis vulgaris. Br J Dermatol. 2006;154:1155–1160.

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REVIEW

Vitiligo: Not Simply a Skin Disease Jusleen Ahluwalia, MD; Lilia M. Correa-Selm, MD; Babar K. Rao, MD Abstract Melanocytes, the cells responsible for skin pigmentation, are present in other parts of the body, such as the ocular, auditory, nervous, and cardiac systems. Within these systems, their roles serve a different purpose than their classical counterparts in skin as pigment cells. Such roles include cell turnover in retinal pigment epithelium, maintenance of balance and prevention of environmental damage in the auditory neuroepithelium, role-playing as dendritic cells within the leptomeninges, and prevention of oxidative damage in adipose tissue. Vitiligo, commonly known as a skin pigmentation disorder, has also been associated with several systemic disorders, such as Vogt-Koyanagi-Harada disease and Alezzandrini, Kabuki, and MELAS syndromes. Therefore, since these conditions involve compromise of systems in which melanocytes reside, it is not surprising that vitiligo has other systemic associations. The authors present a detailed review of systemic associations of vitiligo and melanocytes’ roles in other organ systems with a focus on systemic disease. (SKINmed. 2017;15:125–127)

riginating from the neural crest, melanoblasts develop and migrate to their designated locations, where they differentiate to melanocytes under certain transcribed messages from numerous genes, of which more than 25 have been identified.1 Key signaling molecules that influence melanoblast migration and differentiation include Wnt, endothelin3, bone morphogenetic proteins, steel factor, and hepatocyte growth factor.2 Several diseases have been associated with genetic defects in these signaling molecules. For example, defects in endothelins have been implicated in Waardenburg syndrome and Hirschsprung disease, while defects in c-kit ligand and steel factor have been incriminated in piebaldism.2

It is common practice to associate melanocytes with their famous location in the basal membrane of the epidermis and with their archetypal purpose of secreting melanin under a concoction of growth factors signaled by neighboring keratinocytes.1 This melanogenic cascade involves activation of the melanocortin 1 receptor by melanocyte-stimulating hormone and adrenocorticotropic hormone, which subsequently produces eumelanin. This process is regulated by the antagonist agouti signaling protein, which also produces pheomelanin.3 The resultant melanin is subsequently transported via dendritic webs to form supranuclear caps overlying keratinocytes that serve as a protective barrier against the harsh environment.1,2 Disruption of any of the above processes results in a defect of pigmentation, such as vitiligo. Many hypotheses regarding the

pathophysiology of vitiligo have been proposed, some of which include an underlying autoimmune phenomenon, viral infection, free radical damage, and neurohumoral dysfunction.4 In addition, up to 20% of patients with vitiligo report an affected relative, indicating a multifactorial, polygenic inheritance.4 Consistent with the notion that vitiligo represents a group of heterogeneous disorders, each of these potential etiologies most likely contributes in various portions to the pathogenesis of vitiligo. The pathogenic etiology is also dependent on the class (segmental vs nonsegmental) and surface area involved.4 The Melanocytic Habitat Within the System Melanocytes have long been known to reside in the epidermis; however, for the purposes of pigmentation by melanin production, a large population of melanocytes is found in the eyes and hair follicles.5 Melanocytes have also been reported to be present in the stria vascularis of the cochlea, specific cranial structures, and cardiac and adipose tissue.3 These nonclassical melanocytes located in areas that lack sun exposure serve a different purpose than their classical counterparts. In addition, they differ from classical melanocytes as their melanin is maintained within the cell and is not transferred to surrounding cytoplasm.6 This notion that melanocytes can be found in regions other than skin and hair may provide a plausible explanation for the appearance of several comorbidities associated with vitiligo.

From the Department of Dermatology, Robert Wood Johnson Medical School, Rutgers University, Somerset, NJ Address for Correspondence: Jusleen Ahluwalia, MD, Department of Dermatology, Robert Wood Johnson Medical School, Rutgers University, 1 World’s Fair Drive, Suite 2400, Somerset, NJ 08873 • E-mail: ahluwaju@rwjms.rutgers.edu

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Ocular findings, such as uveitis and retinal pigment epithelial atrophy, have been associated with vitiligo. Based on a study of patients with vitiligo, the majority experienced at least a single episode of concomitant uveitis, while a significant number demonstrated evidence of old chorioretinal scars, hypopigmentation or atrophy of the retinal pigment epithelium, or both.7 Interestingly, it is also known that the uveal tract and retinal pigment epithelium comprise two distinct populations of pigment-bearing cells: uveal melanocytes that function similarly to dermal melanocytes, and pigment epithelial cells that play a role in cell turnover, respectively.3,8 Several observational studies have suggested that depigmentation of the eyelids and poliosis of the eyebrows and eyelashes carry an increased risk of ocular findings.7,8 It is therefore essential for the clinician to recognize such comorbidities with vitiligo for the purposes of diagnosis and treatment. In addition to ocular manifestations, vitiligo has also been reported to be associated with conditions that affect the vestibulocochlear apparatus. Melanocytes are known to be present in the stria vascularis, modulus of the cochlea, and dark cells of the vestibular organ. These inner ear melanocytes have been implicated to produce melanin for the purposes of maintaining balance and preventing environmental damage to the neuroepithelium.3,9 In several reports, patients with vitiligo have also experienced concurrent sensorineural or conductive hypoacusis.10–13 Reports have estimated a prevalence of 10% to 16% of hypoacusis in the vitiligo patient population.10,11 Vertigo and tinnitus have also been associated with vitiligo as seen in the multiorgan disorder Vogt-Koyanagi-Harada (VKH) disease. Although hypoacusis has been associated with vitiligo, the defect that has been most commonly reported is a mild sensorineural deficit for which preventive treatment is lacking. Thus, screening for audiologic defects is warranted in symptomatic patients or in those who have a family history of such an involvement.4 Vitiligo with neurologic involvement has been exclusively reported as the systemic autoimmune disorder VKH disease. Patients with this multiorgan disorder that affects pigmented structures present with neurologic signs and symptoms, including headache, photophobia, hemiparesis, cerebellar ataxia, transverse myelitis, dysarthria, aphasia, altered mental status, and meningismus. Cerebrospinal fluid analysis shows evidence of pleocytosis and hypergammaglobulinemia, and radiological studies demonstrate increased signal intensity in subcortical regions.14–16 In congruence with the syndrome’s pathogenesis, melanocytes have been found in the leptomeninges as melanin-containing dendritic cells.17 On a cellular basis, the disease has been linked to a T-cell–mediated cytotoxic response against tyrosinase, which is the key enzyme in melanin production.18 It therefore seems SKINmed. 2017;15:125–127

plausible that a loss of melanocytes or destruction of melanin in the central nervous system may contribute to the neurologic disturbances in VKH disease. Reports of cardiac findings in association with vitiligo are sparse. Few case reports describe the occurrence of myocarditis, cardiomyopathy, and heart block; however, these manifestations are usually present in the setting of other autoimmune disorders.19–21 Kabuki syndrome, a disease in which vitiligo presents as a phenotype, can also manifest with a spectrum of congenital heart defects, such as septal defects and aortic coarctation.22 Interestingly, recent research suggests that melanocytes are found in the valves and septa of the heart.3 Certain studies have demonstrated evidence of excitable cells in pulmonary veins and atria that express markers of melanocytes. Furthermore, in mice models, deletion of the melanin synthesis enzyme, dopachrome tautomerase, in murine cardiac melanocytes predisposes to arrhythmias.23 Moreover, mice with hypopigmented skin showed decreased heart pigmentation.24 Although the reported cardiac manifestations in context of vitiligo may have an autoimmune rationale, exploration of the role of melanocytes with electric potential may lead to an association of arrhythmias with vitiligo. Serving as anti-inflammatory factors during adipocyte turnover and increased fat deposition, melanocytes are also found in adipose tissue reducing oxidative damage.3 In concordance with this finding, individuals who are obese tend to have increased production of melanin as a result of the increased levels of melanocyte-stimulating hormone. Loss of functional melanocytes in adipose tissue and the subsequent induction of oxygen radicals have been proposed to contribute to the metabolic syndrome.25 Yet, current associations between metabolic syndrome and vitiligo remain to be further elucidated.25 Association With Systemic Conditions Only few case reports describe Alezzandrini syndrome, which is characterized by unilateral retinal pigment epithelial degeneration, ipsilateral appearance of facial vitiligo and poliosis, and hypoacusis.4,26 VKH disease, described earlier, is a similar syndrome with uveitis, aseptic meningitis, dysacusis, alopecia, poliosis, tinnitus, and vitiligo.4,14–16,27 Following a distinctive pathogenic mechanism than VKH disease, Kabuki syndrome is characterized by multiple anomalies, including congenital heart defects, idiopathic thrombocytopenic purpura, thyroiditis, hemolytic anemia, and vitiligo.4,28 The mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) is a mitochondrial disorder with a reported prevalence of vitiligo in around 10% of patients. This syndrome is also associated with central nervous system defects, sensorineural hearing loss, diabe-

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tes mellitus, and cardiomyopathy.4 These diseases involve many systems in which ectopic melanocytes reside, perhaps suggesting that vitiligo is a manifestation of a systemic disease, with other manifestations occurring as a result of the loss of functional melanocytes. Conclusions The involvement of melanocytes in ocular, vestibulocochlear, neurologic, cardiac, and connective tissue systems rationalizes several extradermal diseases that occur concomitantly in the setting of vitiligo. These relationships provide insight into the pathogenesis of vitiligo as a systemic disease. With the exception of thyroid function tests, it is not common practice to screen asymptomatic patients with vitiligo for these comorbidities because of the lack of preventive service and the necessity of further studies to associate disease with vitiligo. Nevertheless, it is essential for the clinician to acknowledge that vitiligo may affect various systems in which melanocytes reside for the purposes of appropriate diagnostic testing and treatment. References 1 Yamaguchi Y, Brenner M, Hearing VJ. The regulation of skin pigmentation. J Biol Chem. 2007;282:27557–27561. 2 Park H, Yaar M. Biology of Melanocytes. Chapter 72. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012. 3 Plonka PM, Passeron T, Brenner M, et al. What are melanocytes really doing all day long...? Exp Dermatol. 2009;18:799–819. 4 Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol. 2011;65:473–491. 5 Huggins RH, Janusz CA, Schwartz RA. Vitiligo: a sign of systemic disease. Indian J Dermatol Venereol Leprol. 2006;72:68–71. 6 Borovansky J, Riley PA. Melanins and Melanosomes, Biosynthesis, Structure, Physiological and Pathological Functions. Hoboken, NJ: John Wiley & Sons; 2011:50–51. 7 Wagoner MD, Albert DM, Lerner AB, et al. New observations on vitiligo and ocular disease. Am J Ophthalmol. 1983;96:16–26.

10 Al-Mutairi N, Al-Sebeih KH. Late onset vitiligo and audiological abnormalities: is there any association? Indian J Dermatol Venereol Leprol. 2011;77:571–576. 11 Tosti A, Bardazzi F, Tosti G, Monti L. Audiologic abnormalities in cases of vitiligo. J Am Acad Dermatol. 1987;17:230–233. 12 Aydogan K, Turan OF, Onart S, Karadogan SK, Tunali S. Audiological abnormalities in patients with vitiligo. Clin Exp Dermatol. 2006;31:110–113. 13 Hong CK, Lee MH, Jeong KH, Cha CI, Yeo SG. Clinical analysis of hearing levels in vitiligo patients. Eur J Dermatol. 2009;19:50–56. 14 Mota LA, Santos AB. Vogt-Koyanagi-Harada’s syndrome and its multisystem involvement. Rev Assoc Med Bras. 2010;56:590–595. 15 Fang W, Yang P. Vogt-koyanagi-harada syndrome. Curr Eye Res. 2008;33:517–523. 16 Yacubian EM, Rosemberg S, Garrido Neto TL, et al. Rasmussen encephalitis associated with segmental vitiligo of the scalp: clinicopathologic report. J Child Neurol. 2001;16:374–377. 17 Goldgeier MH, Klein LE, Klein-Angerer S, Moellmann G, Nordlund JJ. The distribution of melanocytes in the leptomeninges of the human brain. J Invest Dermatol. 1984;82:235–238. 18 Greco A, Fusconi M, Gallo A, et al. Vogt-Koyanagi-Harada syndrome. Autoimmun Rev. 2013;12:1033–1038. 19 Stevens AW, Grossman ME, Barr ML. Orbital myositis, vitiligo, and giant cell myocarditis. J Am Acad Dermatol. 1996;35:310–312. 20 Gupta Y, Ammini AC. Vitiligo, hypothyroidism and cardiomyopathy. Indian J Endocrinol Metab. 2012;16:463–465. 21 Fairfax AJ, Leatham A. Idiopathic heart block: association with vitiligo, thyroid disease, pernicious anaemia, and diabetes mellitus. Br Med J. 1975;4:322–324. 22 Yuan SM. Congenital heart defects in Kabuki syndrome. Cardiol J. 2013;20:121–124. 23 Patel VV. Novel insights into the cellular basis of atrial fibrillation. Expert Rev Cardiovasc Ther. 2010;8:907–916. 24 Yajima I, Larue L. The location of heart melanocytes is specified and the level of pigmentation in the heart may correlate with coat color. Pigment Cell Melanoma Res. 2008;21:471–476. 25 Pietrzak A, Bartosińska J, Hercogová J, Lotti TM, Chodorowska G. Metabolic syndrome in vitiligo. Dermatol Ther. 2012;25:S41–S43. 26 Gupta M, Pande D, Lehl SS, Sachdev A. Alezzandrini syndrome. BMJ Case Rep. 2011;2011.

8 Bulbul Baskan E, Baykara M, Ercan I, Tunali S, Yucel A. Vitiligo and ocular findings: a study on possible associations. J Eur Acad Dermatol Venereol. 2006;20:829–833.

27 Tsuruta D, Hamada T, Teramae H, Mito H, Ishii M. Inflammatory vitiligo in Vogt-Koyanagi-Harada disease. J Am Acad Dermatol. 2001;44:129–131.

9 Orecchia G, Marelli MA, Fresa D, Robiolio L. Audiologic disturbances in vitiligo. J Am Acad Dermatol. 1989;21:1317–1318.

28 Ming JE, Russell KL, McDonald-McGinn DM, Zackai EH. Autoimmune disorders in Kabuki syndrome. Am J Med Genet A. 2005;132A:260–262.

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SELF ASSESSMENT EXAMINATION

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD 4. Which of the following is (are) found in VogtKoyanagi-Harada (VKH) disease: a. Altered mental status. b. Aphasia. c. Cerebellar ataxia. d. Dysarthria. e. Headaches. f. Hemiparesis. g. Meningismus. h. Photophobia. i. Transverse myelitis. j. All of the above.

Instructions: For each numbered question, answer the best single lettered response, unless instructed otherwise for that question. 1. Melanocytes may be found in (answer as many as apply. All, some, or none of the lettered choices may be correct): a. Auditory tissue. b. Cardiac tissue. c. Epidermis. d. Fat. e. Hair follicles. f. Nervous tissue. g. Ocular tissue.

5. It is common medical practice to screen vitiligo patients for: a. Coagulopathies. b. Kidney disease. c. Liver disease. d. Thyroid disease. e. Vascular disease

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

3. Proposed hypotheses regarding the pathophysiology of vitiligo include (an): a. Free radical damage. b. Neurohumoral dysfunction. c. Underlying autoimmune disorder. d. Viral infection. e. All of the above

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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2. The primary role of melanocytes located in adipose tissue is believed to be: a. Maintenance of balance. b. Maintenance of cell turnover (replication) rates. c. Prevention of oxidative damage. d. Role-playing as dendritic cells. e. None of the above.

March/April 2017

Volume 15 • Issue 2

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

Achieving Diagnosis: Importance of Proper Biopsy in Autoimmune Bullous Disorders Viral M. Patel, BS; Michael Sylvester, AB; Khushboo Baldev, BS; Ann M. John, BA; W. Clark Lambert, MD, PhD “If you always do what you’ve always done, you’ll always get what you’ve always got.”—Henry Ford

utoimmune bullous diseases are characterized by autoantibodies against structural proteins that normally serve to promote cell-matrix or cell-to-cell adhesions in skin or mucous membranes. Broadly, they cause impaired adhesion of the epidermis to the basement membrane (pemphigoid group of disorders), of epidermal cells to each other (pemphigus group of disorders), or of antibodies against tissue transglutaminases (dermatitis herpetiformis). Other diseases, such as vasculitis, may also present with bullae. Some Bullous Disorders Bullous pemphigoid is the most common autoimmune blistering disease that targets BP180 and BP230 antigens.1 It occurs most frequently in elderly patients without racial or sex predilection. It initially begins as a pruritic urticarial plaque that turns dark red after several weeks, as bullae rapidly appear on the surface.2 Diagnosis is achieved with histologic and direct immunofluorescence (DIF) studies of a skin biopsy. A linear deposition of IgG and/or C3 along basement membrane is seen on DIF. Linear IgA disease also falls within this group. Pemphigus is a rare group of autoimmune disorders with several variants that cause intraepidermal bullae. The primary autoimmune target of pemphigus disorders is desmoglein, a component of desmosomes that tethers keratin intermediate filaments.1 The most common form of pemphigus is pemphigus vulgaris, which presents with oral lesions and nonpruritic blisters on the scalp, face, and oral mucosa. The blisters rupture easily and demonstrate the Nikolsky sign. Diagnosis can be made clinically, but due to the profound implications a biopsy is often obtained and

the diagnosis has been confirmed by histologic and DIF studies.1 Dermatitis herpetiformis is an autoimmune blistering disorder often associated with gluten-sensitive enteropathy. It is characterized by excoriations, erythematous urticarial plaques, and papules involving the extensor surfaces of the elbows, knees, shoulders, buttocks, and sacral region, among other regions. Numerous antibodies are found in dermatitis herpetiformis patients, such as anti-tissue transglutaminase (the most sensitive and specific of these antibodies), anti-endomysium, and antiepidermal transglutaminase, among other antibodies.3 The gold standard of dermatitis herpetiformis diagnosis is DIF of uninvolved, perilesional skin demonstrating granular IgA deposits at the dermal-epidermal junction or the papillary tips.3 On Biopsying There are several methods of obtaining skin biopsies to diagnose these disorders. To obtain a biopsy for light microscopy, intact vesicles or bullae are preferred. For small lesions, punch biopsy removal of the entire lesion is preferred. For larger lesions, the biopsy should be obtained from the edge of the lesion and contain portions of the blister and of intact skin to visualize the edge of the blister and the inflammatory infiltrate.4 The specimen should be transported in formalin for hematoxylin and eosin staining. For DIF studies, biopsy of uninvolved perilesional skin within about 1 cm of a bulla is recommended.4 The specimen should be transported in 0.9% saline, saline-wrapped gauze, or Michel’s or Zeus medium. The specimen should be obtained from above the waist, preferably from the trunk as opposed to the extremities, which result in higher false-negative results.4,5

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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Alternatively, one punch biopsy can be obtained that can be bisected to produce two specimens, one for light microscopy and the other for DIF. Pre-bisecting a skin biopsy specimen for DIF studies should not increase the risk of a technically inadequate specimen.6 For small lesions, the entire lesion along with at least 2 mm of uninvolved perilesional skin (on one side

Figure 1. The red region indicates a blister, and the black regions depict biopsy sites. The ideal biopsy method is to obtain one third lesion and two thirds perilesional skin (*). Alternatively, a biopsy of one half lesion and one half perilesional skin (**), is also acceptable. Some incorrect methods of biopsy include biopsy of only the blister (***), and biopsy of only the perilesional skin (****).

of the lesion) is removed. For larger lesions, a biopsy should be obtained from the edge of the lesion and contain portions of the blister (one third of the biopsy) and of uninvolved perilesional skin (two thirds of the biopsy). The specimen is then bisected and each half is put into its respective medium as described above. The advantage of this method are its costeffectiveness with one biopsy instead of two, and it helps avoid improper sectioning by the laboratory technician.5 A potential limitation in Nikolsky-positive lesions is that perilesional epidermis may detach completely. Another limitation is that it requires the pathology staff to understand this technique so that the specimen is properly embedded for hematoxylin and eosin and DIF studies.5 Figure 1 illustrates this biopsy method of a large lesion, with the lesion depicted in red and biopsy sites depicted in black. Figure 2 illustrates how the specimen should be bisected perpendicular to the plane of the skin. Bullae resulting from autoimmune disease, vasculitis, and other causes should be biopsied in this manner. Not infrequently, skin biopsies are taken or processed incorrectly, leading to erroneous results. Several factors have been reported in the literature, including delay in processing the sample, incorrect selection of preserving media, sampling incorrect areas of the lesion, improper sectioning, and delaying biopsy in the course of the disease.5,7,8 If a sample is preserved in saline, the specimen should be processed in 24-48 hours; with Michel’s medium, prompt processing is preferred, but delays of up to 2 weeks may still yield valid results.2 Improper use of preserving medium can lead to false-negative results. If a DIF specimen is inadvertently placed in formalin, the specimen should be removed and rinsed in normal saline.4 For the pemphigus group of disorders, even brief formalin exposure may result in false-negative results; however, disorders involving the dermal-epidermal junction still retain variable specificity.9 The choice of preserving medium has also been studied to determine which media are superior. In a small study of 25 DIF specimens comparing normal saline, freezing in liquid nitrogen, and Michel’s medium, a correct diagnosis was achieved in 92% of cases after 24 hours in saline, 83% after 48 hours in saline, 68% after freezing in liquid nitrogen, and 62% after 48 hours in Michel’s medium. The likely explanation is that saline preservation decreases background fluorescence, resulting in better image contrast.10

Figure 2. The sample should be bisected perpendicular to the plane of the edge of the bulla rather than in parallel to it. SKINmed. 2017;15:129–131

Figure 1 illustrates other improper biopsies where only the lesion and perilesional skin are biopsied or inadequate perilesional skin is obtained. Finally, lesions should be biopsied early in the course of the disease before treatment, as false-negative results have been noted.8

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Conclusions Autoimmune bullous disorders are characterized by autoantibodies that lead to blister formation. Appropriate biopsy of blisters and perilesional skin along with additional DIF and light microscopy studies are carried out to achieve diagnosis. Numerous variables are reported to cause erroneous results when performing and analyzing skin biopsies. They include improper site selection such as lower extremities, improper biopsy of a blister, improper preserving media, delays in specimen processing, improper specimen sectioning and embedding, and delaying biopsy as treatment can produce false-negative results. References 1 Ishii K. Importance of serological tests in diagnosis of autoimmune blistering diseases. J Dermatol. 2015;42:310.

4 Elston DM, Stratman EJ, Miller SJ. Skin biopsy: Biopsy issues in specific diseases. J Am Acad Dermatol. 2016;74:1-16. 5 Braswell MA, McCowan NK, Schulmeier JS, et al. Highyield biopsy technique for subepidermal blisters. Cutis. 2015;95:237-240. 6 Loh E, Armstrong AW, Fung MA. Pre-bisection of a single skin biopsy does not produce technically inadequate specimens for direct immunofluorescence: A review of 3450 specimens. J Cutan Pathol. 2014;41:890892. 7 Llamas-Velasco M, Paredes BE. [Basic concepts in skin biopsy. Part II]. Actas Dermosifiliogr. 2012;103:100-110. 8 Minz RW, Chhabra S, Singh S, et al. Direct immunofluorescence of skin biopsy: Perspective of an immunopathologist. Indian J Dermatol Venereol Leprol. 2010;76:150157.

2 Habif T. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 6th ed. Philadelphia, PA: Saunders; 2015.

9 Arbesman J, Grover R, Helm TN, et al. Can direct immunofluorescence testing still be accurate if performed on biopsy specimens after brief inadvertent immersion in formalin? J Am Acad Dermatol. 2011;65:106-111.

3 Antiga E, Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmetic Invest Dermatol. 2015;8:257-265.

10 Vodegel RM, de Jong MCJM, Meijer HJ, et al. Enhanced diagnostic immunofluorescence using biopsies transported in saline. BMC Dermatology. 2004;4:10.

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Volume 15 • Issue 2

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

AMELUZ™ (BF-200 ALA) Aditya K. Gupta, MD, PhD, FRCPC;1,2 Sarah G. Versteeg, MSc;2 William Abramovits, MD3,4,5,6

ctinic keratosis (AK) is a skin disease characterized by slow-growing, usually asymptomatic, flesh-colored papules caused by long-term exposure to ultraviolet radiation.1,2 AK lesions have the potential to develop into squamous cell carcinoma, and effective treatment is critical in preventing this from occurring.3–5 These lesions can be located on multiple body regions (eg, the hands, face, neck, etc.) and can differ in severity.3 Mild to moderate AK lesions, located on the face and scalp, can be treated with the newly approved (US Food and Drug Administration) photosensitizer, BF-200 ALA (Ameluz™, Biofrontera Pharma, Wakefield, MA), in combination with photodynamic therapy (PDT) using a BF-RhodoLED lamp (Biofrontera Pharma).6,7 This photosensitizer contains 5-aminolevulinic acid (ALA, 10%) in a nanoemulsion-based gel.6 PDT FOR TREATMENT OF AK PDT can be used to irradiate pathogens or cells causing disease and infection. ALA, the main ingredient of BF-200 ALA, accumulates in cells as protoporphyrin IX (PPIX). When illuminated, PPIX can trigger a host cell response or photodynamic attack on diseased cells.8 When a nanoemulsion is added to ALA, its stability and penetration can be enhanced.9 The application of PDT to AK patients can allow individual AK lesions (lesion-directed therapy) or multiple AK lesions (fielddirected therapy) to be treated. Lesion-directed therapy focuses on treating isolated lesions or a few newly formed lesions.10 The main goal of field-directed therapy is treating the visible lesions as well as the surrounding tissues.10 CLINICAL TRIALS WITH BF-200 ALA BF-200 ALA has been successfully used for the treatment of AK. This was demonstrated in a phase III, randomized, double-blind,

multicenter study conducted with BF-200 ALA for field-directed treatment of mild to moderate AK.6 Treatment consisted of one to two sessions of PDT with a BF-RhodoLED lamp (635 nm, 37 J/cm2) in one to two fields (four to eight lesions), with a total area of 20 cm2 (n=87). Patient complete clearance rates (all lesions cleared as evaluated by clinical assessment) and histopathologically confirmed response rates (confirmation of a patient’s negative AK status as evaluated through biopsy) were evaluated 12 weeks after treatment. BF-200 ALA treatment produced significantly higher patient complete clearance rates (91% versus 22%, P<.0001) and significantly higher histopathology response rates (78% versus 22%, P<.0001) after the last PDT session compared with placebo (Table). Lesion complete clearance rates (clearance of individual lesions) were also higher with BF-200 ALA (94.3%) than placebo (32.9%, P<.0001). The overall cosmetic outcome was good with BF-200 ALA, and most patients (91%) were satisfied with results. Adverse effects were reported in all patients treated with BF-200 ALA. COMPARING BF-200 ALA WITH OTHER PHOTOSENSITIZERS BF-200 ALA can outperform other photosensitizers in the treatment of AK. This was evident in a phase III multicenter, randomized, observer-blind study that compared the efficacy of BF-200 ALA with methyl-5-aminolaevulinate (MAL) for treatment of mild to moderate AK lesions (n=571).11 Narrowspectrum (630 nm) and broad-spectrum (580 to 1400 nm) light sources were used during PDT treatments (one or two sessions) with treatments applied 3 hours prior to illumination. BF-200 ALA (78.2%) showed higher patient complete clearance (all lesions cleared as evaluated by clinical assessment) compared with MAL (64.2%, P<.05) and placebo (17.1%, P<.0001) 12 weeks after treatment (Table). Lesion complete clearance rates were

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada,1 and Mediprobe Research Inc., London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center,3 the Department of Dermatology,4 and the Department of Family Practice,5 University of Texas Southwestern Medical School, and the Dermatology Treatment and Research Center,6 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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also higher with BF-200 ALA (90.4%) as compared to MAL (83.2%) and placebo (37.1%, statistical analysis not reported). When the narrow-spectrum light source was used, an increase in patient complete clearance and lesion complete clearance rates occurred in the MAL and BF-200 treatment groups (statistical analysis not reported). Adverse effects (eg, erythema, burning, pain) were reported in both MAL (98%) and BF-200 (96.4%) treated patients. BF-200 ALA has also been compared with other modalities for the treatment of AK using network meta-analysis.12 Eleven treatment modalities were included (including MAL, diclofenac 3% in 2.5% hyaluronic acid, and imiquimod), encompassing 25 trials and 5562 patients. BF-200 ALA had the highest absolute complete clearance rates and was found to be the most effective treatment (Table). NONTRADITIONAL BF-200 ALA PDT TECHNIQUES Nontraditional BF-200 ALA PDT techniques have also been evaluated for their potential use in the treatment of patients with AK. Daylight (or the visual spectrum) falls within the absorption spectrum of PPIX and can therefore be used as an alternative and less painful light source.13 In a split-face, prospective, observerblinded, randomized study, AK patients (n=13) were treated with

one or two sessions of BF-200 ALA daylight-mediated PDT and MAL daylight-mediated PDT.5 Both photosensitizers were applied to each participant’s face, and after 30 minutes they were exposed to daylight for 2 hours. Higher complete clearance (lesion does not meet diagnostic criteria for AK, P=.099) occurred with BF-200 ALA (84.5% of lesions) compared with MAL (74.2% of lesions), with complete histological lesion clearance rates (P=.375) of 61.5% and 38.5%, respectively (Table). Lesion grading did not differ between lesions treated with BF-200 ALA and MAL as evaluated 3 months after treatment, although the number of lesions differed. At 3 months, BF-200 ALA–treated patients had fewer lesions as compared to MAL-treated patients (P=.044). Light-fractionated PDT has also been evaluated for use with BF-200 ALA.14 Light-fractionated PDT with long dark intervals can allow for a reaccumulation of PPIX as well as making cells more vulnerable, and therefore easier to eliminate.14 In preclinical mouse models, BF-200 ALA has been compared with ALA and MAL using light-fractionated PDT (630 nm).14 BF-200 ALA created significantly more PPIX in deeper skin layers (eg, arteriole wall, adipose tissues) than ALA (P<.05, n=10). Adverse effects included skin damage, photobleaching and a change in vascular volume. Future research will reveal how applicable this alternative PDT method is in treating AK.

Table. Efficacy Rates of BF-200 ALA for Treatment of Actinic Keratosis Treatment

Patient Complete Clearance Rates (Per Patient)

Histopathologically Confirmed Response/ Clearance Rate (Patients)

Lesion Complete Clearance Rates (Per Individual Lesion)

Reinhold et al.6

BF-200 ALA

50/55=91%*

42/54=78%*

281/298=94%*

Placebo

7/32=22%

6/27=22%

57/173=33%

Dirschka et al.11

BF-200 ALA

186/248=78%*,†

—

1359/1504=90%‡

MAL

158/246=64%

—

1295/1557=83%

Placebo

155/2250=7%a

—

BF-200 ALA

133/156=85%a

—

BF-200 ALA

—

8/13=62%

71/84=85%

MAL

—

5/13=38%

69/93=74%

Study

Vegter and Tolley12 Neittaanmäki-Perttu et al.5

Patient complete clearance rate: all lesions cleared as evaluated by clinical assessment. Histopathologically confirmed response/clearance rate: confirmation of a patient’s negative actinic keratosis status as evaluated through biopsy. Lesion complete clearance rate: clearance of individual lesions, lesion does not meet diagnostic criteria for actinic keratosis. Abbreviation: MAL, methyl-5-aminolaevulinate. a Calculated rate based on the number of patients with complete patient clearance divided by the number of patients per treatment. * P<.0001 compared with placebo. † P<.05 compared with MAL. ‡ P value not reported. SKINmed. 2017;15:133–135

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CONCLUSIONS BF-200 ALA has been successfully used with PDT to treat AK. BF-200 ALA in conjunction with PDT using the BF-RhodoLED lamp produced significantly higher patient complete clearance rates and lesion complete clearance rates compared with PDT using competitor photosensitizers (eg, MAL).8 Daylight-mediated PDT and light-fractionated PDT could be alternative PDT techniques that could be used with BF-200 ALA.5,14 Future research is still needed to address long-term responses and compare BF-200 ALA PDT with other fielddirected therapies. Patient compliance, due to the adverse effects associated with BF-200 ALA, could be a potential issue. BF-200 ALA, like most photosensitizers, can lead to pain during the PDT process.8 This treatment may not be appropriate for patients with low pain thresholds. Additionally, PDT can be expensive, requiring specialized equipment and staff utilization.10 Other treatment options that are less expensive and more convenient include cryosurgery, topical chemotherapy, and immunotherapy.10 Currently, this photosensitizer is only approved for treatment of mild to moderate AK. BF-200 ALA PDT may also be effective in treating oral leukoplakia and oral dysplasia.15,16 These conditions have been treated with ALA PDT; with the enhanced abilities (eg, stability, penetration) of BF-200 ALA, greater efficacy could be established. References 1 Rossi R, Mori M, Lotti T. Actinic keratosis. Int J Dermatol. 2007;46:895–904. 2 Peris K, Micantonio T, Piccolo D, Fargnoli MC. Dermoscopic features of actinic keratosis. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG. 2007;5:970–976. 3 Erlendsson AM, Egekvist H, Lorentzen HF, et al. Actinic keratosis: A cross-sectional study of disease characteristics and treatment patterns in Danish dermatology clinics. Int J Dermatol. 2016;55:309–316. 4 Braathen LR, Szeimies R-M, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: An international consensus. J Am Acad Dermatol. 2007;56:125–143. 5 Neittaanmäki-Perttu N, Karppinen TT, Grönroos M, Tani TT, Snellman E. Daylight photodynamic therapy for actinic keratoses: A randomized double-blinded nonsponsored prospective study comparing 5-aminolaevulinic

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acid nanoemulsion (BF-200) with methyl-5-aminolaevulinate. Br J Dermatol. 2014;171:1172–1180. 6 Reinhold U, Dirschka T, Ostendorf R, et al. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®)) vs. placebo in the field-directed treatment of mild-tomoderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED(®) lamp. Br J Dermatol. 2016;175:696–705. 7 Ameluz (aminolevulinic acid hydrochloride) gel, 10%, for topical use [Internet]. FDA U.S. Food and Drug Administration. 2016. Available from: http://www.accessdata. fda.gov/drugsatfda_docs/label/2016/208081s000lbl. pdf. Accessed July 15, 2016. 8 Harris F, Pierpoint L. Photodynamic therapy based on 5-aminolevulinic acid and its use as an antimicrobial agent. Med Res Rev. 2012;32:1292–1327. 9 Maisch T, Santarelli F, Schreml S, Babilas P, Szeimies R-M. Fluorescence induction of protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion used for photodynamic therapy in a full-thickness ex vivo skin model. Exp Dermatol. 2010;19:e302–e305. 10 Ceilley RI, Jorizzo JL. Current issues in the management of actinic keratosis. J Am Acad Dermatol. 2013;68(1 suppl 1):S28–S38. 11 Dirschka T, Radny P, Dominicus R, et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: Results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol. 2012;166:137–146. 12 Vegter S, Tolley K. A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe. PloS One. 2014;9:e96829. 13 Wiegell SR, Haedersdal M, Philipsen PA, Eriksen P, Enk CD, Wulf HC. Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study. Br J Dermatol. 2008;158:740–746. 14 de Bruijn HS, Brooks S, van der Ploeg-van den Heuvel A, Ten Hagen TLM, de Haas ERM, Robinson DJ. Light fractionation significantly increases the efficacy of photodynamic therapy using BF-200 ALA in normal mouse skin. PloS One. 2016;11:e0148850. 15 Kawczyk-Krupka A, Waskowska J, Raczkowska-Siostrzonek A, et al. Comparison of cryotherapy and photodynamic therapy in treatment of oral leukoplakia. Photodiagnosis Photodyn Ther. 2012;9:148–155. 16 Jerjes W, Upile T, Hamdoon Z, Mosse CA, Akram S, Hopper C. Photodynamic therapy outcome for oral dysplasia. Lasers Surg Med. 2011;43:192–199.

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Volume 15 • Issue 2

New Therapy Update

Targeted Treatment of Atopic Dermatitis Simon Arda Metin, MA (Cantab);1 Marc Wallace, MB ChB, BSc (Hons)2

topic dermatitis (AD) is a common and chronic skin condition presenting with clinical manifestations that can range from mild to disabling. Management involves a multifactorial approach and aims to prevent initiation or exacerbation of lesions. Mild disease can be managed topically, whereas more severe disease often requires systemic treatment. Treatment of moderate to severe AD is challenging, and the approach may vary according to the clinician. Current therapeutics focus on immunosuppression, but none implements a targeted approach. Recent research has identified new molecular mechanisms in AD, offering opportunities for targeted therapy. Biologic therapies are highly specific and generally offer more convenient dosing with fewer side effects than current systemic therapies. Here, we recap some recent considerations.

CD20 TARGETING Although it is largely T-cell–mediated, B cells may also have a role in AD, with interleukin (IL) and T helper type 2–induced isotype-switching to produce IgE. Rituximab (Rituxan®, MabThera®) is a chimeric monoclonal antibody against the B-cell CD20 receptor. As above, supporting data for rituximab are limited, being exclusively based on case reports or series. One study showed that 1000 mg of rituximab every 2 weeks led to significant improvements in 6/6 patients with AD.5 Conversely, another group failed to show long-term improvements when 500 mg of rituximab was given every 2 weeks. However, this study only enrolled two patients, and the dose was halved.6 Further larger-scale trials are required to explore this. IL-12/23 TARGETING

Immunoglobulin E Targeting Omalizumab (Xolair®) is a recombinant, humanized monoclonal antibody against the Fc-receptor of human immunoglobulin E (Ige) and is licensed for severe asthma and chronic spontaneous urticaria.1 Because IgE plays a role in asthma and in many patients with AD, omalizumab would be a natural consideration for treating AD, but data are currently scant and controversial. One study showed that 450 mg of omalizumab every 3 weeks significantly improved the quality of life in 7/9 adults with severe AD.2 Another study showed that 150 mg of omalizumab every 2 weeks decreased the Scoring Atopic Dermatitis (SCORAD) rating by more than 50% and 25% to 50% in 2/11 and 4/11 patients, respectively.3 However, a randomized, double-blind, placebo-controlled study was less promising. Here, 20 adults given 0.016 mg/kg/IgE omalizumab for 16 weeks showed no significant clinical improvement, despite significant reductions in laboratory parameters.4 The Atopic Dermatitis Anti-IgE Paediatric Trial (ADAPT) is currently assessing omalizumab in childhood AD.

The pathogenesis of AD involves T helper type 2/22 cells, with contributions from T helper type 1/17 cells and IL-12/23.7 Data targeting IL-12/23 with ustekinumab (Stelara®) are limited to case reports or series. One patient with refractory disease showed complete clinical resolution after 12 months with ustekinumab dosed according to psoriasis (45 mg/kg if ≤100 kg, 90 mg/kg if >100 kg at 0 and 4 weeks, then every 12 weeks).8 Another group dosed 10 patients similarly, but only four responded after 10 months.9 With variable results, a phase II, double-blind, placebo-controlled trial was initiated in 33 adults with moderate to severe AD; here, 16 participants were given ustekinumab dosed according to psoriasis and 17 were given a placebo, with crossover at 16 weeks. Despite a numerical increase in those with SCORAD results of more than 50% when given ustekinumab, this was insignificant.10 IL-4 TARGETING Another T helper 2 cell–mediated pathway in the pathogenesis of AD involves IL-4/13; dupilumab (Dupixent) is a human

From the Cambridge University School of Clinical Medicine,1 and Department of Dermatology, Addenbrooke’s Hospital,2 Cambridge, UK Address for Correspondence: Simon Arda Metin, MA Cantab, 252 Kings College, Cambridge, CB2 1ST, UK • E-mail: simon.metin@gmail.com

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monoclonal antibody against the IL-4α -receptor.11 In all studies for its use in AD, dupilumab has shown good efficacy and safety without dose-limiting toxicities.12,13

References

The best supporting data come from two phase III randomized, placebo-controlled trials (SOLO 1, SOLO 2), involving 671 and 708 patients with moderate to severe AD, respectively. In both, candidates were given a placebo or 300 mg of dupilumab weekly (group 1) or biweekly (group 2) for 16 weeks. In SOLO 1, 37% and 38% of patients had an Investigator’s Global Assessment score of 0 to 1 (clear to almost clear) in groups 1 and 2, respectively, compared with 10% who were given a placebo. In SOLO 2, 36% and 36% of patients were Investigator’s Global Assessment 0 to 1 in groups 1 and 2, respectively, compared with 8% given a placebo.14 In a phase IIB randomized, placebo-controlled, dose-ranging trial, dupilumab’s most consistent benefits were seen when dosed as 300 mg weekly or biweekly.13 With substantial evidence, dupilumab has received breakthrough therapy designation by the United States Food and Drug Administration. It has also been accepted for priority review for the treatment of moderate to severe AD.15 FUTURE TARGETS Dupilumab looks extremely promising, but other agents may also be on the horizon. Lebrikizumab and tralokinumab have shown promise in phase II trials targeting IL-13, and nemolizumab has similarly shown efficacy targeting IL-31 in another phase II trial. Further afield, tezepelumab has novel action targeting thymic stromal lymphoprotein, a cytokine that has a role in T-cell and Langerhans cell maturation, and it is also undergoing phase II trials. With so much activity in this field, the possibility of new options in the effective management of moderate to severe AD may become a reality. CONCLUSIONS Current forms of treatment for moderate- to severe AD are nonspecific and have variable efficacy. A better understanding of the molecular mechanisms in AD has made targeted treatment a realistic goal. Biological therapies are already being used in other dermatologic conditions, and studies have supported their efficacy to treat AD. Although dupilumab currently shows the most promise, new candidates are also in the pipeline. With so much activity in this field, effective management of moderate to severe AD may be within reach.

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1 Godse K, Mehta A, Patil S, et al. Omalizumab—a review. Indian J Dermatol. 2015;60:381–384. 2 Fernández-Antón Martínez MC, Leis-Dosil V, AlfagemeRoldán F, et al. Omalizumab for the treatment of atopic dermatitis. Actas Dermosifiliogr. 2012;103:624–628. 3 Belloni B, Ziai M, Lim A, et al. Low-dose anti-IgE therapy in patients with atopic eczema with high serum IgE levels. J Allergy Clin Immunol. 2007;120:1223–1225. 4 Heil PM, Maurer D, Klein B, et al. Omalizumab therapy in atopic dermatitis: Depletion of IgE does not improve the clinical course—a randomized, placebo-controlled and double blind pilot study. J Dtsch Dermatol Ges. 2010;8:990–998. 5 Simon D, Hösli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol. 2008;121:122–128. 6 Sedivá A, Kayserová J, Vernerová E, et al. Anti-CD20 (rituximab) treatment for atopic eczema. J Allergy Clin Immunol. 2008;121;1515–1516. 7 Nograles KE, Zaba LC, Shemer A. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing Th17 T cells. J Allergy Clin Immunol. 2009;123:1244–1252. 8 Puya R, Alvarez-López M, Velez A, et al. Treatment of severe refractory adult atopic dermatitis with ustekinumab. Int J Dermatol. 2012;51:115–116. 9 Nic Dhonncha E, Clowry J, Dunphy M, et al. Treatment of severe atopic dermatitis with ustekinumab: A case series of 10 patients. Br J Dermatol. 2016 Dec 22. doi:10.1111/bjd.15262. [Epub ahead of print] 10 Khattri S, Brunner PM, Garcet S, et al. Efficacy and safety of ustekinumab treatment in adults with moderate-tosevere atopic dermatitis. Exp Dermatol. 2017;26:28–35. 11 Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–139. 12 Hamilton JD, Ungar B, Guttman-Yassky E. Drug evaluation review: Dupilumab in atopic dermatitis. Immunotherapy. 2015;7:1043–1058. 13 Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: A randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016;2:40–52. 14 Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335–2348. 15 Blakely K, Gooderham M, Papp K. Dupilumab, a monoclonal antibody for atopic dermatitis: A review of current literature. Skin Therapy Lett. 2016;21:1–5.

Targeted Treatment of Atopic Dermatitis

March/April 2017

Volume 15 • Issue 2

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

Eosinophilic Fasciitis: A Firm Warning Warren R. Heymann, MD

“D

iffuse fasciitis with eosinophilia: a new syndrome?” In 1975, Shulman posed this question as he subsequently described two men, aged 53 and 19, who presented with “firm taut skin bound down to underlying structures,” with flexion contractures of the elbows and knees that appeared a few weeks after onset of the illness. Both patients had a peripheral eosinophila, elevated sedimentation rates, and hypergammaglobulinemia.1,2 Four decades later, eosinophilic fasciitis (EF, or Shulman syndrome) is recognized as a rare scleroderma-like entity with an unknown etiology and pathogenesis that is considered an immune-allergic disorder.3

EF generally has a good prognosis, with visceral involvement usually limited to hematologic abnormalities.4 This contribution will focus on the association of EF with aplastic anemia (AA). Clinical Features of EF Dermatologically, EF is characterized by erythema, edema, and induration of the extremities associated with joint contractures. The trunk and neck may be affected, with typical sparing of the face, hands, and feet.5 The “groove sign” (linear depressions along the course of veins) and a “peau d’orange” appearance may be noted. Nail fold capillary changes, Raynaud phenomenon, and sclerodactyly, as appreciated in systemic sclerosis, are not observed. In a recent series of EF patients, 28% (8 of 29) had a history of trauma or intense exercise that preceded the illness.4 Aside from trauma and hematologic associations, other reported correlations or inciting factors include: 1. drugs (simvastatin, atorvastatin, phenytoin, ramipril, heparin, trichloroethylene exposure); 2. infections (Borrelia burgdorferi, Borrelia afzelii, Mycoplasma arginini);

3. solid tumors (choroidal melanoma, prostate cancer, lung cancer, breast cancer); 4. autoimmune disorders (Hashimoto thyroiditis, Graves disease, primary biliary cirrhosis, lupus erythematosus, vasculitis, hemolytic anemia, idiopathic thrombocytopenic purpura, Sjögren syndrome); and 5. physical factors (radiotherapy, burns).3 The prevalence of hematologic disorders associated with EF approaches 10%, with aplastic anemia being most common.6 Other hematologic associations include thrombocytopenia, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders (myelomonocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin disease), and graft-versus-host disease.3,6 The diagnosis of EF may be confirmed by magnetic resonance imaging revealing a high signal intensity of the deep and superficial fasciae, and/or histologic confirmation demonstrating fascial thickening associated with a polymorphous inflammatory infiltrate composed of plasma cells, eosinophils, histiocytes, and lymphocytes that ultimately result in fibrosis.5 Although EF may resolve spontaneously, corticosteroids are considered first-line therapy; combination treatment with other immunosuppressive agents, such as methotrexate, may yield a higher complete response rate. Physical therapy is of value for those at risk of joint contractures.4 The Association of Eosinophilic Fasciitis and Aplastic Anemia To date, there have been 23 cases of EF associated with AA.7 The initial report in 1980 was that of a 66-year-old farmer.8 As both AA and EF are considered within the realm of autoimmune

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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disorders, their occasional association is not surprising, although it is still uncertain if EF could be the initial manifestation of an evolving clonal myeloid disorder. Their pathophysiologic links may be attributed to increased CD8 and Th1/Th17 T cell responses, decreased Tregs, abnormal telomere repair homeostasis, and dysregulated B-cell responses with autoantibody production. The review of 23 cases was comprised of 4 cases from the authors’ experience and 19 from the literature. Compared to patients with isolated EF, patients with EF associated with severe AA were more likely to be older (mean age 56 years) and men (70%). In most cases, the interval between the diagnosis of EF and the onset of AA was less than six months (range 0–60 months, with a mean delay of 7.2 months, and a median of 4 months). In 8 cases, EF and AA were diagnosed simultaneously. Eight patients died, with 6 succumbing to sepsis. The clinical course of EF and AA did not correlate with each other; remission of EF was not predictive of AA improvement, and no relapse of EF was observed in patients with relapsing AA. Although corticosteroid-containing regimens improved EF in 5 of 12 cases (42%) they were ineffective in treating AA in 5 of 6 (83%) of patients. Among three of the author’s cases that were refractory to antithymocyte globulin and cyclosporine (prescribed for AA), one patient demonstrated cutaneous and hematologic improvement with rituximab. As the response of AA to immunosuppressive therapy may be slow, and because AA relapses occur, even if EF remits, the authors recommend long-term immunosuppression with cyclosporine. Allogeneic hematopoietic stem cell transplantation should be considered in patients with an available human leukocyte antigen– matched donor.7

Conclusions Dermatologists must monitor patients with EF for the possibility of developing life-threatening AA. This is especially crucial within the first year of diagnosing EF in older men, so that early immunosuppressive therapy may be instituted as soon as possible. If induration is detected upon clinical exam, confirm the diagnosis EF, and realize that the skin is giving a firm warning. References 1 Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Assoc Am Physicians. 1975;88:70–86. 2 Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol. 1984;11:569–570. 3 Pinal-Fernandez I, Selva-O’Callaghan A, Grau JM. Diagnosis and classification of eosinophilic fasciitis. Autoimmun Rev. 2014;13:379–382. 4 Wright NA, Mazori DR, Patel M, Merola JF, et al. Epidemiology and treatment of eosinophilic fasciitis: an analysis of 63 patients from 3 tertiary care centers. JAMA Dermatology. 2016;152;97–99. 5 Ensanyat SH, Larian AA, Fuchs BS, Gordon ML. Eosinophilic fasciitis. In: Lebwohl MG, Heymann WR, BerthJones J, Coulson I, eds. Treatment of Skin Disease. 4th ed. London: Elsevier; 2014:200–203. 6 Haddad H, Sundaram S, Magro C, Gergis U. Eosinophilic fasciitis as a paraneoplastic syndrome, a case report and review of the literature. Hematol Oncol Stem Cell Ther. 2014;7:90–92. 7 de Masson A, Bouaziz JD, Peffault de Latour R, Benhamou Y, et al. Severe aplastic anemia associated with eosinophilic fasciitis: report of 4 cases and review of the literature. Medicine (Baltimore). 2013;92:69–81. 8 Littlejohn GO, Keystone EC. Eosinophilic fasciitis and aplastic anaemia. J Rheumatol. 1980;7:730–732.

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Volume 15 • Issue 2

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

Reiter’s Syndrome Mark Bernhardt, MD Izena duen guzia omen da. (That which has a name exists.)—Basque proverb

riting in the December 14, 1916, issue of the Deutsche Medizinische Wochenschrift. Dr Hans Reiter described an army officer who presented with urethritis, conjunctivitis, and arthritis. Thinking his patient’s illness was previously undescribed and spirochetal in origin, he christened it, Spirochaetosis arthritica. Unbeknownst to Reiter, Drs Fiessinger and Leroy simultaneously reported the same condition in the Bulletins et Mémoires de la Société Médicale des Hôpitaux de Paris. They called it syndrome oculo-uretro-synovial. Given their countries were locked in the Great War, it is not surprising that no agreement could be reached regarding who deserved priority and by what name this new disease should be known. Two American physicians, Drs Engleman and Bauer, proposed the term Reiter’s syndrome in 1942. This appellation was soon universally adopted, except in France where Fiessinger-Leroy syndrome was the preferred usage. The relationship between Reiter’s syndrome and keratosis blenorrhagica was controversial both diagnostically and terminologically, but the eponymous homage to Dr Reiter became firmly entrenched. Reiter died peacefully in 1969 at the age of 88. He had been showered with honors during his later life and was immortalized by his eponymous namesake.

In 1998, Dr Daniel Wallace, a rheumatologist in Los Angeles, CA, was given a book about medicine in Nazi Germany. Dr Wallace was shocked to read the details of Reiter’s early and rabid endorsement of Hitler’s politics. Wallace and his colleague, Dr Michael Weisman, researched Reiter’s Nazi past and came to the inescapable conclusion that Reiter was guilty of helping implement Hitler’s genocidal program and of personally conducting horrific “medical experiments” on hundreds of inmates at the notorious concentration camp, Buchenwald, where Reiter was the chief medical officer. Despite the irrefutable evidence of Reiter’s wartime atrocities, he had not been charged with war crimes and was released after just 2 years’ incarceration, most likely because he offered the Allies details on Germany’s germ warfare projects. Wallace and Weisman went public with their findings in 2000, urging their fellow practitioners to reject Reiter’s claim to eponymous glory. In 2003, editors of the leading rheumatology journals agreed to expunge the term Reiter’s syndrome in favor of reactive arthritis. In 2007, Engleman, himself, urged that the name he had proposed 65 years earlier be banished from the medical lexicon. If Hans Reiter were to be mentioned at all, it should only be in condemnation of his unethical, unprofessional, and inhumane actions. Keratosis blenorrhagica is still accepted medical terminology. Reiter’s syndrome has been consigned to ignoble anonymity.

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PHOTO CAPSULE Snejina Vassileva, MD, PhD, Section Editor

Perianal Bacterial Disease Philip R. Cohen, MD

healthy 53-year-old man presented with 4 months of itching and occasional burning of his proximal penile shaft and perianal region. Examination showed an erythematous patch extending from the proximal to distal penile shaft and an irregular margined area of erythematous plaques adjacent to and surrounding the anus. Biopsy of the right perianal area revealed psoriasiform and spongiotic dermatitis. Topical treatment included triamcinolone 0.1% ointment for 2 weeks. The penile and perianal symptoms and erythematous areas with superficial erosions persisted (Figure 1); a bacterial culture of the perianal area grew Escherichia coli and he was treated with cefdinir 300 mg twice daily for 10 days. The penile and perianal burning and pruritus resolved within 3 days and the erythema cleared after 1 week (Figure 2). Correlation of the patient’s clinical presentation and response to therapy established the diagnosis of concurrent perianal bacterial disease and dermatitis.

Perianal bacterial disease is not only caused by beta-hemolytic group B Streptococcus, but also other bacteria including beta-hemolytic nongroup B Streptococcus, Staphylococcus aureus, and E. coli. 1,2 Traditionally, perianal bacterial disease has been observed in healthy children; however, it can occur in immunocompetent or immunosuppressed adults. 3 While the skin around the anus is always affected, the infection can also involve the penis, vulva and/or umbilicus. 1 The diagnosis of intertrigo or a primary dermatosis (such as dermatitis or psoriasis) around the anus does not exclude the possibility of concurrent perianal bacterial disease 4,5; therefore, a culture for bacteria may be helpful to elucidate coexisting perianal bacterial disease in patients with Candida infection or primary skin conditions in the perianal area that are not improving with disease-directed therapy.

Figure 1. Escherichia coli culture-positive irregular margined areas of erythema with superficial erosions adjacent to and surrounding the anus.

Figure 2. Resolution of perianal bacterial disease with postinflammatory hyperpigmentation at prior area of erythema.

From the Department of Dermatology, University of California San Diego, San Diego, California Address for Correspondence: Philip R. Cohen, MD, 10991 Twinleaf Court, San Diego, CA 92131-3643 • E-mail: mitehead@gmail.com

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References 1 Kallini JR, Cohen PR. Perianal and periumbilical dermatitis: report of a woman with group G streptococcal infection and review of perianal and periumbilical dermatoses. Dermatol Online J. 2013;19:3. 2 Heath C, Desai N, Silverberg NB. Recent microbial shifts in perianal bacterial dermatitis: Staphylococcus aureus predominance. Pediatr Dermatol. 2009;26:696–700.

3 Gunawardane ND, Laumann A. An immunocompromised patient with recent-onset skin lesions. JAMA. 2014;311:957–958. 4 de Wit PM, Rode H, Van Dyk A, Millar AJW. Perianal candidosis—a comparative study with mupirocin and nystatin. Int J Dermatol. 1999;38:618–622. 5 Rasi A, Pour-Heidari N. Association between plaque-type psoriasis and perianal Streptococcal cellulitis and review of the literature. Arch Iran Med. 2009;12:591–594.

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

Multifocal Tuberculosis Verrucosa Cutis: A Manifestation Extraordinary of Reactivation Secondary Tuberculosis Virendra N. Sehgal, MD, FNASc, FAMS;1 Prashant Verma, MD;2 Sambit N. Bhattacharya, MD;2 Sonal Sharma, MD;3 Navjeevan Singh, MD3 A BCG (Bacillus Calmette-Guérin)-vaccinated 78-year-old man, a native Indian, reported with numerous asymptomatic, peanut-sized, dirty gray, elevated eruptions of 1 year’s duration appearing over apparently normal skin on the upper and lower extremities (Figure 1). The onset of the eruptions had been sudden, but they had progressed slowly. A history of cough and/or expectoration, evening rise of temperature, night sweats, or loss of appetite and weight was denied. (SKINmed. 2017;15:145–147)

kin surface examination showed conspicuous peanut/ groundnut-sized, grayish-white, scaly, irregular lesions with cracks that were located on an apparently normal skin. A few of them had a pinkish hue. The lesions were multiple and bilateral, occupying the dorsa of the hands, forearms, dorsa of the feet, and legs. A BCG vaccination scar was prominent on the left deltoid. A standard tuberculin purified protein derivative test was read after 48 to 72 hours; this revealed erythema without induration and was disregarded (negative result). Erythrocytic sedimentation rate (Westergren) was 78 mm/1 hour. Total and differential leukocyte count, blood sugar, and glycated hemoglobin were within normal ranges. Bilateral apical opacities indicative of calcification were an outstanding radiographic finding. A Mycosure polymerase chain reaction DNA analysis for Mycobacterium tuberculosis and nontuberculous mycobacteria carried out on peripheral blood was negative. The result of Mycobacterium tuberculosis immunoglobulin M enzymelinked immunosorbent assay (A60-tb test) of peripheral blood was 0.72 (positive is >1.00). Antibodies/antigen for human immunodeficiency virus I and II were nonreactive.

Hematoxylin and eosin–stained serial sections depicted partly crusted epidermis with marked hyperkeratosis, focal parakeratosis, epidermal hyperplasia with papillomatosis, and hypergranulosis (Figure 2). There was a perivascular lymphoplasmacytic infiltrate, with a few neutrophils in the upper and middle layers of the dermis. A few epithelioid cell granulomas without caseation were identified in the mid-region of the dermis. As a diagnostic tool, the patient was given AKT-3, which incorporated a combination of ethambutol hydrochloride 800 mg, isoniazid 300 mg, and rifampicin 450 mg, for 6 weeks; this was followed by completion of antitubercular therapy in accordance with World Health Organization schedule. The treatment was completed in 6 months, following which complete regression was achieved; this reiterates the role of treatment as a substantive diagnostic tool should investigative procedures prove inconclusive. Tuberculosis verrucosa cutis (TBVC),1 a paucibacillary variant of tuberculosis, is one of the significant constituents of secondary/reinfective cutaneous tuberculosis. Scrofuloderma and tuberculosis cutis orificialis are the multibacillary components that are seen.2

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India;1 Department of Dermatology and STD,2 and Department of Pathology,3 University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara, 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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CASE STUDY secondary tuberculosis, which is being reported for the first time. Appropriate elucidation, comprising Mycosure polymerase chain reaction DNA analysis for Mycobacterium tuberculosis and nontuberculous mycobateria, was considered essential, and was found to be negative; however, an elevated erythrocytic sedimentation rate supported the diagnosis, as did bilateral apical opacities and/ or calcifications indicative of previous pulmonary tuberculosis, for which no treatment had been administered. It is likely that Mycobacterium tuberculosis had remained, in a state of dormancy or latency. Reactivation, proliferation, and subsequent dissemination of Mycobacterium tuberculosis to two or more locations primarily affecting the extremities certainly were intriguing in an elderly individual. Reactivation secondary cutaneous tuberculosis resulting in the sudden appearance of lesions with a specific morphology conforming to TBVC is distinctive. Despite this, papulonecrotic tuberculids was entertained as an alternative diagnosis. This was excluded due to the absence of clinical features, namely the occurrence of lesions in a young or adolescent patient, recurrence of necrotic lesions in crops, and healing marked by scars. In addition, papulonecrotic tuberculids has a peculiar histopathology characterized by epidermal ulceration, a large zone of dermal necrosis, fibrinoid necrosis of the vessel wall, and occlusion of the vessels by thrombi, in addition to a positive purified protein derivative test.3

Figure 1. Tuberculosis verrucosa cutis—multifocal lesions on the arms and legs.

The precise nature of such an episode needs clarification. A few studies have evaluated the immunologic status in pulmonary tuberculosis in elderly age groups and have documented no deficiency in humoral responses.4 The same is true for cytokines production in response to stimulation with Mycobacterium tuberculosis.5 It is worthwhile focusing attention on the well-known age-related decline in cell-mediated immunity.6 In individual cases, the presence of intercurrent illnesses such as diabetes mellitus, chronic renal failure, malnutrition, alcohol abuse, and certain malignancies, and the use of immunosuppressive drugs such, as corticosteroids, can impair cell-mediated immunity.7 This may be compounded by adverse social factors and poor living conditions.

Figure 2. Section showing epithelial hyperplasia, papillomatosis, and perivascular inflammation in the upper and middle layers of the dermis. Inset showing loose epithelioid cell granuloma (arrows) (hematoxylin and eosin stain ×100; inset: hematoxylin and eosin stain ×400).

Conclusions

Usually, TBVC is an outcome of incidental inoculation of Mycobacterium tuberculosis after an injury/trauma to the skin. This is in contrast to the current report, where two or more multifocal, bilateral, symmetrical lesions were the extraordinary presentation of multifocal TBVC, a manifestation extraordinary of reactivation SKINmed. 2017;15:145–147

Cutaneous tuberculosis is a diagnostic dilemma,8 even in the contemporary scenario of molecular diagnostics. It is worth reiterating the role of microscopic pathology in the diagnosis of TBVC in particular.9 A trial of a three- or four-drug anti-tubercular therapy10,11 regimen is another useful tool to establish the diagnosis of cutaneous tuberculosis including TBVC, in the event of inadequate clinical and/or laboratory criteria for the diagnosis of reinfection cutaneous tuberculosis.10

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References 1 Sehgal VN, Sehgal R, Bajaj P, et al. Tuberculosis verrucosa cutis (TBVC). J Eur Acad Dermatol Venereol. 2000;14:319–321. 2 Sehgal VN. Cutaneous tuberculosis. Dermatol Clin. 1994;12:645–653. 3 Jordaan HF, Van Niekerk DJ, Louw M. Papulonecrotic tuberculid. A clinical, histopathological, and immunohistochemical study of 15 patients. Am J Dermatopathol. 1994;16:474–485. 4 Arora VK, Bedi RS. Immunoglobulin status of geriatric pulmonary tuberculosis patients of Himachal Pradesh. Ind J Chest Dis Allied Sci. 1989;31:233–236. 5 Bodnar Z, Steger MM, Saurwein-Teissel M et al. Cytokine production in response to stimulation with tetanus toxoid, Mycobacterium tuberculosis and influenza antigens in peripheral blood mononuclear cells and T cell lines from healthy elderlies. Int Arch Allergy Immunol. 1997;112:323–330. 6 Mirza N, Pollock K, Hoelzinger DB, et al. Comparative kinetic analyses of gene profiles of naïve CD4+ and

CD8+ T cells from young and old animals reveal novel age-related alterations. Aging Cell. 2011;10:853–867. 7 Plouffe JF, Silva J Jr, Fekety R, et al. Cell-mediated immunity in diabetes mellitus. Infect Immun. 1978;21:425– 429. 8 Sehgal VN, Verma P, Bhattacharya SN, et al. Cutaneous tuberculosis a diagnostic dilemma: laboratory inputs. Skinmed. 2012;10:82–89. 9 Sehgal VN, Sharma S, Verma P, Pahwa M, Mendiratta V. Disseminated cutaneous tuberculosis: an atypical presentation of reinfection (secondary) tuberculosis in an immunocompetent individual. Am J Dermatopathol. 2013;35:e128–e130. 10 World Health Organization. Drugs Used in Mycobacterial Disease. Geneva: WHO; 1991. 11 Sehgal VN, Sardana K, Sharma S. Inadequacy of clinical and/or laboratory criteria for the diagnosis of lupus vulgaris, re-infection cutaneous tuberculosis: fallout/ implication of 6 weeks of anti-tubular therapy (ATT) as a precise diagnostic supplement to complete the scheduled regimen. J Dermatolog Treat. 2008;19:164–167.

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Volume 15 • Issue 2

CASE STUDY

Chronic Tender Ulcers on the Calf and Both Forearms Michael C. Cameron, MD;1 Mitsuya Katayama, MD;2 Nishit S. Patel, MD;3 Philip D. Shenefelt, MD;3 Charurut Somboonwit, MD2

An elderly woman presented with a 3-month history of nonhealing, tender ulcers involving the right calf and both forearms. She denied any history of similar lesions or trauma. Two trials of oral antibiotics had led to no improvement. Her medical history was significant for rheumatoid arthritis treated with methotrexate, hydroxychloroquine, and prednisone. A review of clinical manifestations was otherwise negative for disease. Physical examination of the patient’s right calf revealed two punched-out ulcers with central necrotic black eschars, underlying retiform purpuric pattern, and mild fibrinopurulent drainage (Figure 1). Similar lesions were present on her forearms (Figures 2 and 3). No other remarkable skin changes were noted. The differential diagnosis included polyarteritis nodosa, cutaneous necrosis secondary to antiphospholipid syndrome, cryoglobulinemic vasculitis, and an atypical presentation of pyoderma gangernosum. (SKINmed. 2017;15:149–151)

indings from laboratory investigation showed grossly normal complete metabolic panel and complete blood cell count. Results from further laboratory studies, including serum antinuclear antibody, cryoglobulin, cardiolipin antibody, lupus anticoagulant, as well as acute hepatitis panel, were also negative. Bacterial cultures were obtained from lesions and intravenous piperacillin/tazobactam and vancomycin were empirically started. After 1 week, there was no clinical improvement and wound cultures showed no growth. A punch biopsy of the right calf lesion was performed (Figure 4). The biopsy results revealed intraepidermal vesicle formation with intracellular edema and ballooning degeneration consisting of enlarged multinucleated keratinocytes, acantholysis, and keratinocyte necrosis. Additionally, ground glass change with margination of nuclear material was noted. Minor vascular damage exemplified by perivascular neutrophils in small venules was also noted, but there was an absence of typical findings for vasculitis (ie, obliterative vasculitis, vessel occlusion, and fibrinoid material in vasculature). Varicella zoster virus (VZV) infection was confirmed by direct immunofluorescence staining, which was positive for VZV-specific antibody and negative for herpes simplex virus–specific antibody. Because of a national shortage of intravenous acyclovir, the patient was treated with 21 days of oral valacyclovir with continued long-term wound care, and there was subsequent resolution of all active lesions.

Discussion Immunosuppression as a risk factor for disseminated VZV infection has been well-documented.1 Disseminated cutaneous zoster, defined as greater than 20 vesicles outside the primary and immediately adjacent dermatomes, occurs in up to 40% of immunocompromised zoster patients.2 Such dissemination is due to viremia and is followed by visceral involvement in an estimated 10% of these immunocompromised disseminated zoster patients.2 Our patient, however, did not present with the classic herpes zoster progression of an erythematous maculopapular eruption evolving into vesicles, pustules, and then crusting. She had a history of varicella as a child, but denied any prior episodes of herpes zoster. Atypical presentations such as this put a patient at risk for delayed diagnosis and visceral dissemination. A variety of atypical cutaneous herpes zoster presentations, both clinical and histopathologic, have been reported in immunosuppressed patients. A case of painful, hemorrhagic vesicles and erosions on the leg with biopsy-proven VZV secondary vasculitis was described in an immunosuppressed patient.3 Despite the necrotic appearance of our patient’s lesions, vasculitis was not seen on histopathology. Nodular then ulcerating painless lesions without preceding vesicular phase—thought to be due to a VZV

From the Department of Dermatology, University of Colorado, Aurora, CO,1 and Department of Dermatology and Cutaneous Surgery,2 and Department of Internal Medicine,3 University of South Florida Morsani College of Medicine, Tampa, FL Address for Correspondence: Michael C. Cameron, MD, 1665 Aurora Court, Room 3234, Mail Stop F703, Aurora, CO 80045 • E-mail: michael.cameron@ucdenver.edu

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Figure 1. The patient’s right calf revealing two punchedout ulcers with central necrotic black eschars, underlying retiform purpuric pattern, and mild fibrinopurulent drainage.

Figure 3. Similar lesions as Figure 1 seen on the patient’s forearms.

Figure 2. Similar lesions as Figure 1 seen on the patient’s forearms.

primary vasculitis with direct endothelial cell infection—was reported in a patient on long-term methotrexate.4 In addition, chronic zoster lesions of a verrucous, hyperkeratotic character that are painless and well-demarcated have been described in immunocompromised patients and are associated with acyclovir resistance.5 Lastly, an immunocompromised chronic lymphocytic leukemia patient with a painful edematous, ulcerative plaque of the fifth toe—originally scheduled for amputation secondary to suggestion of an embolic cause—was then diagnosed by biopsy with VZV and subsequently improved with antiviral therapy.6 Conclusions Our patient’s unusual, deeply ulcerative presentation of disseminated zoster without traditional herpes dermatitis demonstrates that we cannot ignore atypical presentations of common infectious etiologies in immunosuppressed patients. With delayed diagnosis, significant morbidity and even mortality can occur. SKINmed. 2017;15:149–151

Figure 4. Results from a punch biopsy of the right calf lesion revealing intraepidermal vesicle formation with intracellular edema and ballooning degeneration consisting of enlarged multinucleated keratinocytes, acantholysis, and keratinocyte necrosis.

Life-threatening disseminated VZV has been reported in a rheumatoid arthritis patient treated with methotrexate.7 Herpes zoster, in particular, appears to have a variety of atypical presentations both clinically and histopathologically under the setting of immunosuppression. The immunocompromised patient with disseminated VZV will often present exclusively with the characteristic herpetiform vesicles on an erythematous base in multiple

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March/April 2017 dermatomes.8 As our patient demonstrates, it is not prudent to rule out herpes zoster based on the relative absence of such a classic presentation. In cases such as ours, definitive tissue diagnosis and empiric treatment may be warranted. References 1 Gnann JW, Whitley RJ. Natural history and treatment of varicella-zoster in high-risk populations. J Hosp Infect. 1991;18 suppl A:317–329. 2 McCrary ML, Severson J, Tyring SK. Varicella zoster virus. J Am Acad Dermatol. 1999;41:1–14; quiz 15–16. 3 Westermann L, Dilling A, Pajouh P, Rose C, Schmidt E. Longstanding painful hemorrhagic vesicles and erosions on the lower leg. Arch Dermatol. 2011;147:235–240. 4 Erhard H, Runger TM, Kreienkamp M, et al. Atypical varicella-zoster virus infection in an immunocompromised

patient: result of a virus-induced vasculitis. J Am Acad Dermatol. 1995;32(5 pt 2):908–911. 5 Nikkels AF, Snoeck R, Rentier B, Pierard GE. Chronic verrucous varicella zoster virus skin lesions: clinical, histological, molecular and therapeutic aspects. Clin and Exper Derm. 1999;24:346–353. 6 Khera P, Haught JM, McSorley J, English JC 3rd. Atypical presentations of herpesvirus infections in patients with chronic lymphocytic leukemia. J Am Acad Dermatol. 2009;60:484–486. 7 Ching DW. Severe, disseminated, life threatening herpes zoster infection in a patient with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis. 1995;54:155. 8 Angit C, Daly BM. Disseminated varicella zoster infection in a patient with rheumatoid arthritis treated with methotrexate. Clin Exper Dermatol. 2009;34:e453–e454.

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CASE STUDY

Secondary Skin Plasmacytomas Pedro Mendes-Bastos, MD; Susana Brás, MD; Cristina Amaro, MD; Jorge Cardoso, MD A 78-year old man was diagnosed in 2006 with IgAκ multiple myeloma (MM) (stage III-A).1 The patient was referred to our dermatology department in 2012 for evaluation of erythematous skin nodules on the anterior right aspect of the thorax; the skin lesions were noted during hospitalization for multiple bone fractures. He was on fourth-line chemotherapy (with vincristine/adriamycin/dexamethasone) because of constant disease progression. The patient was unaware of the skin lesions’ evolution over time and did not recall when they had first appeared. He had no pain, itching, or spontaneous bleeding. (SKINmed. 2017;15:153–155)

n physical examination, there were two well-defined erythematous nodules (20×15 mm and 9×7 mm), with a friable surface and superficial telangiectasias (Figure 1 and Figure 2). On palpation, the nodules had an elastic consistency and were both painless and nonadherent to the subcutaneous tissue. Because we considered the diagnostic hypothesis of a secondary extramedullary skin plasmacytoma, a skin punch biopsy was performed. Histopathologic examination confirmed the diagnosis, showing an unchanged epidermis and diffuse infiltration of the dermis by numerous atypical plasma cells (Figure 3).

ized by proliferation of neoplastic plasma cells in tissue, either as part of MM or, less commonly, in the absence of MM. Either way, plasmacytomas generally arise in bone marrow and only rarely in other tissues.2 The presence of skin plasmacytomas in MM patients is seldom seen,3 and it is one of the many skin disorders associated with monoclonal gammopathies.3 Many dermatologic disorders have been associated with monoclonal gammopathies. They can be divided into three main categories2:

In spite of a poor initial prognosis (median life expectancy of 29 months for MM International Staging System [ISS] stage III), this patient survived 72 months, when cutaneous involvement was noticed. We decided against adding any additional therapy directed against the secondary cutaneous plasmacytomas because of the patient’s advanced disease status. He died 2 months later. Discussion The monoclonal gammopathies are characterized by clonal proliferation of plasma cells that produce a homogeneous (monoclonal) immunoglobulin protein easily detected in urine and blood. MM is a plasma cell malignancy that accounts for slightly more than 10% of all hematologic malignancies. Bone pain, anemia, fatigue, multiple osteolytic lesions, pathologic fractures, osteoporosis, renal insufficiency, and serum and urinary protein abnormalities suggest its diagnosis. A plasmacytoma is character-

• Group I: these diseases are infiltrative and result from either extension or proliferation of malignant plasma cells in the skin (eg, myeloma, Waldenström macroglobulinemia) or deposition of proteins related to the primary M protein (eg, amyloid, cryoglobulin). • Group II comprises skin disorders that have a strong association with monoclonal gammopathy, not resulting from malignant cell infiltration or deposition of biologic material produced by clonal plasma cells, regarded as “paraneoplastic” (eg, necrobiotic xantogranuloma, Sweet syndrome, or pyoderma gangrenosum). • Group III: this group includes many cutaneous conditions, symptoms, and complications related to M proteins, but not specific for the diagnosis of a monoclonal gammopathy (eg, increased susceptibility to cutaneous infection secondary to decreased immunoglobulin and compromised immunity, purpura, pruritus, or mucous membrane bleeding).

From the Department of Dermatology and Venereology, Hospital de Curry Cabral, Centro Hospitalar de Lisboa Central, Lisbon, Portugal Address for Correspondence: Pedro Mendes-Bastos, Department of Dermatology and Venereology, Hospital de Curry Cabral, R. Beneficiência, n. 8; 1069-166 Lisboa, Portugal • E-mail: pmendesbastos@gmail.com

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Figure 1. Secondary skin plasmacytomas on the right side of the thorax of a patient with multiple myeloma. Figure 3. Histopathologic examination revealing an unchanged epidermis and diffuse infiltration of the dermis by plasma cells (hematoxylin and eosin [H&E] stain, original magnification ×40, and a detail on the lower right H&E, original magnification ×100).

vations are not unexpected, because IgG monoclonal immunoglobulin is more common than IgA in MM (53% vs 22%).9 Of interest is that skin plasmacytoma (metastatic plasmacytoma) is more likely to develop in patients with IgD myeloma (63%) than in patients with any other immunoglobulin type.9 Conclusions

Figure 2. Secondary skin plasmacytoma in detail. Erythematous, friable, well-demarcated nodules.

Skin plasmacytomas, included in group I, may occur in three forms: in association with MM (called “metastatic plasmacytoma”), without evidence of myeloma, and as a direct extension from an underlying bone lesion.2 The reported case illustrates the presence of secondary extramedullary skin plasmacytomas in a man with a 72-month history of IgAκ MM stage III-A.

In most of the reported cases, skin plasmacytomas are described as erythematous/violaceous well-defined nodules or plaques on the head, trunk, or extremities.4,5,7 Few clinical images of this entity have been published, and a late clinical recognition hinders the right diagnosis, thus delaying appropriate therapeutic measures. As such, a skin plasmacytoma should be considered metastatic until proven otherwise, and an existing hematologic malignancy must be excluded. Despite the fact that cutaneous metastization is not considered on the ISS for multiple myeloma, metastatic skin plasmacytomas carry out an unfavorable prognosis. References

Cutaneous involvement of MM is rare.4,5 In a review of the literature,8 IgG was present in 56% of 26 patients with cutaneous plasmacytoma and MM, followed by IgA in 24%, Bence Jones protein in 12%, and IgD and IgM each in 4%. These obserSKINmed. 2017;15:153–155

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1 Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple. J Clin Oncol. 2005;23:3412– 3420. 2 Daoud MS, Lust JA, Kyle RA, Pittelkow MR. Monoclonal gammopathies and associated skin disorders. J Am Acad Dermatol. 1999;40:507–535. 3 Alexiou C, Kau RJ, Dietzfelbinger H, et al. Extramedullary plasmacytoma. Cancer. 1999;85:2305–2314.

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4 Yoon YH, Cho WI, Seo SJ. Case of multiple myeloma associated with extramedullary cutaneous plasmacytoma and pyoderma gangrenosum. Int J Dermatol. 2006;45:594–597. 5 Garcia-Malo MD, Vallejo C, Vicente V. The irreplaceable image: IgA multiple myeloma with multiple cutaneous plasmacytomas. Haematologica. 2001;86:1118. 6 Hedinger E. Zur Frage des Plasmacytomas. Frankfurt Z Path. 1911;7:343–350.

7 Kois JM, Sexton FM, Lookingbill DP. Cutaneous manifestations of Multiple myeloma. Arch Dermatol. 1991;127:69–74. 8 Patterson JW, Parsons JM, White RM, et al. Cutaneous involvement of multiple myeloma and extramedullary plasmacytoma. J Am Acad Dermatol. 1988;19:879–890. 9 Hobbs JR, Corbett AA. Younger age of presentation and extraosseous tumour in IgD myelomatosis. Br Med J. 1969;1:412–414.

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Volume 15 • Issue 2

CASE STUDY

Grotesque Face Secondary to Immunotherapy: Cure Circumvallating to Curse Keshavamurthy Vinay, MD, DNB;1 Tarun Narang, MD;1 Sunil Dogra, MD, FRCP;1 Uma N. Saikia, MD2

A 45-year-old woman presented with multiple, slightly painful, reddish, nodular facial lesions that had developed at the site of Mycobacterium w vaccine injections given for her facial warts 4 weeks prior. She had not received a sensitization dose of Mycobacterium w vaccine, and all of the inflamed lesions were injected at the same time. On examination, approximately 20 erythematous, succulent nodules of variable size were noted over the cheeks and forehead (Figure 1). Some of these lesions had purulent discharge due to secondary infection. After a course of oral amoxicillin, a punch biopsy was performed from one of the nodules and submitted for histopathologic examination. (SKINmed. 2017;15:157–159)

esults from a skin biopsy showed noncaseating granulomatous inflammation of the dermis and subcutis with multinucleated giant cells, mixed inflammatory infiltrate, and occasional eosinophils (Figure 2a and 2b). No acidfast bacilli could be identified. The patient’s serum calcium and angiotensin-converting enzyme levels were within the normal range, and findings from chest x-ray did not reveal any hilar lymphadenopathy. Based on the clinical and histopathologic features, a diagnosis of granulomatous reaction to Mycobacterium w (Mw) vaccine was made. Post-vaccination, her facial warts subsided completely; however, she was given oral minocycline 100 mg/d for the granulomatous response and showed marked improvement after 4 weeks (Figure 3). Discussion

Intralesional antigen immunotherapy is increasingly used to treat extensive and recalcitrant cutaneous warts.1,2 The Mw vaccine is a novel, commercially available (Immuvac, Cadila Pharmaceuticals Ltd.; Ahmedabad, Gujarat, India) vaccine, originally introduced as immunotherapy for multibacillary leprosy, but more recently it has been used successfully in treating cutaneous and genital warts.3–5 The multidose vial (0.6 mL) of Mw vaccine con-

Figure 1. Multiple erythematous, succulent, nodular lesion on the cheeks of our patient.

This case report was the recipient of the Edward L. Keyes Resident Award for Outstanding Case Reports presented at the 10th World Congress of the International Academy of Cosmetic Dermatology, November 14, 2015, Rio de Janeiro, Brazil. From the Department of Dermatology, Venereology and Leprology,1 and the Department of Histopathology,2 Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India Address for Correspondence: Tarun Narang, MD, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India • E-mail: narangtarun@yahoo.co.in

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Figure 3. Marked clinical improvement in our patient after treatment.

mum of three lesions for multiple warts. Injections are repeated every week until the resolution of the warts or a maximum of 12 injections.5 Granulomatous reaction over the face has been reported with use of various injectables, including liquid silicone,6 dermal fillers (collagen, hyaluronic acid, polyacrylamide, polymethyl methacrylate),7 tattoo ink,8 autologous fat transplantation,9 and microneedle therapy;10 however, facial granulomas secondary to intralesional immunotherapy have not been previously described. The granulomatous response in our patient is probably due to a hypersensitivity reaction to heat-killed bacilli. The presence of eosinophils and panniculitis on histopathology also supported hypersensitivity reaction.7

B Figure 2. (A) Loose collection of histiocytes forming granulomas, admixed with neutrophils and few eosinophils (hematoxylin and eosin stain, original magnification ×20). (B) Ill-formed granulomas with Langhans-type giant cell seen admixed with eosinophils and neutrophils (hematoxylin and eosin stain, original magnification ×20).

tains 500 million heat-killed saprophytic mycobacteria per milliliter, 0.9% sodium chloride, and 0.01% thiomersol. Although extensively used, information regarding its safety is scarce. Briefly, the procedure of Mw immunotherapy for warts involves sensitization with 0.1-mL vaccine intradermally in both deltoids. Sensitized individuals are then administered the vaccine intralesionally at a dose of 0.1 mL per sitting every week. This is given either as a single injection in the largest wart or in a maxiSKINmed. 2017;15:157–159

Faulty drug schedule (not giving a sensitizing dose and injecting at multiple sites) or deeper injections may have contributed to the severe immune response seen in this case. Although a sarcoidal granulomatous reaction to cosmetics has been described in patients with systemic sarcoidosis, our patient had no clinical or radiologic features to suggest sarcoidosis.11 Adjuvants are pharmacologic or immunologic agents that enhance the vaccine recipient’s immune response to the supplied antigen. Aluminum adjuvant is notorious for causing a granulomatous reaction.12 Similarly, thimerosal, present in Mw vaccine preparation, is a known allergen, but it is not known to cause a granulomatous reaction.

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Minocycline was used to treat our patient due to its immunomodulatory and antigranuloma effect.13,14 Minocycline was chosen over corticosteroids, because it does not carry a risk of exacerbation of cutaneous warts. Conclusions Our case demonstrates that newer therapies should be used with caution, especially over cosmetically and functionally important sites. Immunotherapy should be avoided on the face. References 1 Nofal A, Salah E, Nofal E, Yosef A. Intralesional antigen immunotherapy for the treatment of warts: current concepts and future prospects. Am J Clin Dermatol. 2013;14:253–260. 2 Dhakar AK, Dogra S, Vinay K, et al. Intralesional Mycobacterium w vaccine versus cryotherapy in treatment of refractory extragenital warts: a randomized, open-label, comparative study. J Cutan Med Surg. 2016;20:123– 129. 3 Gupta S, Malhotra AK, Verma KK, Sharma VK. Intralesional immunotherapy with killed Mycobacterium w vaccine for the treatment of ano-genital warts: an open label pilot study. J Eur Acad Dermatol Venereol. 2008;22:1089– 1093. 4 Kumar P, Dar L, Saldiwal S, et al. Intralesional injection of Mycobacterium w vaccine vs imiquimod, 5%, cream in patients with anogenital warts: a randomized clinical trial. JAMA Dermatol. 2014;150:1072–1078. 5 Meena JK, Malhotra AK, Mathur DK, Mathur DC. Intralesional immunotherapy with Mycobacterium w vaccine

in patients with multiple cutaneous warts: uncontrolled open study. JAMA Dermatol. 2013;149:237–239. 6 Chen YC, Chen ML, Chiu YM. A case of mimicking angioedema: chin silicone granulomatous reaction spreading all over the face after receiving liquid silicone injection forty years previously. Chin Med J (Engl). 2011;124:1747– 1750. 7 Haneke E. Adverse effects of fillers and their histopathology. Facial Plast Surg. 2014;30:599–614. 8 Quint KD, Genders RE, Vermeer MH. A delayed granulomatous reaction to a cosmetic tattoo of the eyebrows: a report of total regression after intralesional corticosteroid injections. Dermatol Surg. 2012;38:951–953. 9 Park HE, Kim HT, Lee CH, Bae JH. Delayed lipogranuloma of the cheek following autologous fat injection: report of 2 cases. Int J Clin Exp Pathol. 2014;7:6391–6394. 10 Soltani-Arabshahi R, Wong JW, Duffy KL, Powell DL. Facial allergic granulomatous reaction and systemic hypersensitivity associated with microneedle therapy for skin rejuvenation. JAMA Dermatol. 2014;150:68–72. 11 Baumgartner M, Feldmann R, Breier F, Steiner A. Sarcoidal granulomas in a cosmetic tattoo in association with pulmonary sarcoidosis. J Dtsch Dermatol Ges. 2010;8:900–902. 12 Rosenblatt AE, Stein SL. Cutaneous reactions to vaccinations. Clin Dermatol. 2015;33:327–332. 13 Webster GF, Toso SM, Hegemann L. Inhibition of a model of in vitro granuloma formation by tetracyclines and ciprofloxacin. Involvement of protein kinase C. Arch Dermatol. 1994;130:748–752. 14 Arin MJ, Bate J, Krieg T, Hunzelmann N. Silicone granuloma of the face treated with minocycline. J Am Acad Dermatol. 2005;52:53–56.

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