SKINmed - Nov/Dec 2017 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Dermatology Insights and Inquiries

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

November/December 2017 • Volume 15• Issue 6 EDITORIAL SKINmed Partners with Dermatology Insights and Inquiries: Perfect Together Heymann

COMMENTARIES Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation—Part II: Proactive Approach Sharma, Weiss, Handler, Shah, Lambert, and Lambert

Needlephilia versus Needlephobia Abramovits, Babaniji, and Vincent

ORIGINAL CONTRIBUTIONS Vitamin D Deficiency and Atopic Dermatitis: Consider Disease, Race, and Body Mass Darji, Tobin, Bryan, Jansenn, Armbrecht, and Siegfried

Self Assessment Examination

Immunologic Studies of Progesterone-Induced Neutrophilic Urticaria

Lambert

CORE CURRICULUM Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids Potter, Konda, Ren, Wang, Srinivasan, and Chilukuri

Mast Cell Activation Syndrome DEPARTMENTS Kramer, Barkoff, and Hernandez PERILS OF DERMATOPATHOLOGY Plantar Fibromatosis in a Mentally Compromising Patient Care: Challenged Man Treated with Gross Payment Disparities in Intralesional Corticosteroids November/December 2017 • Volume 15• Issue 6 Dermatopathology—Part II

Chinese Society of Dermatology

Lebanese Dermatological Society

Dermatology Insights and Inquiries

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

Patel, Sharma, Sylvester, Ring, Espinal-Mariotte, and Lambert

THE HEYMANN FILE Melanoma in Situ: The Power of One (Centimeter)? Heymann

PHOTO CAPSULES Blaschkoid (Linear and/or Bandlike) Psoriasis

Characterization of Patients’ Quality of Life and Experience in the Course of Acne Treatment

Cellular Blue Nevus: An Unusual Localization

Skaggs, Hix, Huang, and Feldman

Safety and Antipruritic Efficacy of a Menthol-Containing Moisturizing Cream Tey, Tay, and Tan

REVIEWS Hyaluronic Acid in Dermatology Keen

Persisting Ulcerating Lesions After Cyclosporine Therapy for Erosions Found in Flexural Sites Amin, Famenini, and Wu

Oral Mucosal Lesions in a Cross-Sectional Study of 200 Dermatologic Outpatients

Syed, Sehgal, Aggarwal, and Sehgal

Tuchinda, Erickson, Tammaro, Paterniti, Saini, and Gaspari

Sehgal and Aggarwal

Zor and Kaya

VIGNETTES OF DERMATOLOGIC HISTORY Vicente Pardo-Castelló, MD (1892–1967) Bernhardt

case studies Cutaneous Mucormycosis: A Fatal Complication of Immunosuppressant Therapy for Pemphigus Vulgaris

African Association for Dermatology

Karadag, Ozlu, Ceyran, Simsek, Uzuncakmak, Zindancı and Akdeniz

Role of Immune Status in Chemotherapy-Induced Transient Acantholytic Dermatosis Auh, Polcari, Petronic-Rosic, and Sethi

Chloracne in a Farming Family

Kushwaha, Kumar, Kulkarni, and Ghorpade

CORRESPONDENCE Multiple Treatment-Resistant Actinic Keratoses Secondary to Hydroxycarbamide Bhoyrul, Brent, Abdul-Kadir, and Mikeljevic

Sweet Syndrome Associated with Bilateral Nodular Scleritis Zaouak, Jrad, Bacha, Salah, Brahim, Hammami, and Fenniche

Advanced Therapy Treatment for Psoriasis: A Single-Site Retrospective Study of Prescribing Outcomes Kim, Joerg, and Levitt

Sahni De, Dogra, Kanwar, and Saikia Scan this QR code with your QR reader

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

Otezla was evaluated in 2 multicenter, double-blind, placebocontrolled 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 titration1,3 ◆ Inclusion criteria: Age ≥18 years, BSA involvement ≥10%, sPGA ≥3, PASI score ≥12, candidates for phototherapy or systemic therapy1,3 ◆ PASI-75 response at week 16 (primary endpoint) – ESTEEM 1: Otezla 33% vs placebo 5% (P < 0.0001)1-3 ◆

– Similar PASI-75 response was achieved in ESTEEM 21,2 BSA, body surface area; PASI, Psoriasis Area and Severity Index; sPGA, static Physician Global Assessment.

INDICATIONS Otezla® (apremilast) is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Otezla is indicated for the treatment of adult patients with active psoriatic arthritis.

IMPORTANT SAFETY INFORMATION Contraindications ◆ Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation Warnings and Precautions ◆ Diarrhea, Nausea and Vomiting: Cases of severe diarrhea, nausea, and vomiting have been reported with the use of Otezla. Most events occurred within the first few weeks of treatment. In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting ◆ Depression: Treatment with Otezla is associated with an increase in depression. During clinical trials 1.3% (12/920) of patients reported depression, compared to 0.4% (2/506) on placebo. Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla. Patients, 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 they should contact their healthcare provider if such changes occur ◆ 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. 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 (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended 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 ◆ 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. References: 1. Otezla [package insert]. Summit, NJ: Celgene Corporation. 2. Data on file, Celgene Corporation. 3. Papp K, Reich K, Leonardi CL, et al. J Am Acad Dermatol. 2015;73(1):37-49. 4. Information derived from Symphony Health Solutions PrescriberSource PatientFocus data, Celgene proprietary methodology. April 2014 through June 2017. * Data includes healthcare professionals (dermatologists, rheumatologists, nurse practitioners, and physician assistants) and their Otezla prescriptions (including refills) from April 2014 through June 2017 for patients with plaque psoriasis or psoriatic arthritis. Source: Data on file, Celgene Corporation.

Get the latest news at otezlapro.com

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 Diarrhea, Nausea, and Vomiting: There have been postmarketing reports of severe diarrhea, nausea, and vomiting associated with the use of OTEZLA. Most events occurred within the first few weeks of treatment. In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting. Monitor patients who are more susceptible to complications of diarrhea or vomiting. Patients who reduced dosage or discontinued OTEZLA generally improved quickly. Consider OTEZLA dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting. 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) Placebo OTEZLA 30 mg BID Preferred Term (N=506) (N=920) n (%) n (%) Diarrhea 32 (6) 160 (17) (17(17) (17) Nausea 35(6) (7) 155 (17) (7)(7) ((17) Upper respiratory tract infection 31 (6) 84 (9) Tension headache 21(6) (4) 75 (8) Headache 19(4) (4) 55 (6) ((4) Abdominal pain* 11 (2) 39 (4) Vomiting 8(2) (2) 35 (4) Fatigue 9 (2) 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) *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 ©2014-2017 Celgene Corporation, All Rights Reserved. Based on APRPI.006

OTZ_PsO_HCP_BSv.006 06_2017

TABLE OF CONTENTS November/December 2017 • Volume 15 • Issue 6

EDITORIAL

SKINmed Partners with Dermatology Insights and Inquiries: Perfect Together ......................................... 407

Warren R. Heymann, MD

COMMENTARIES

Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation—Part II: Proactive Approach ................................................................................................................................... 409

Divya Sharma BS; Amy Weiss, BA; Marc Z. Handler, MD; Radhika Shah, PharmD; Muriel W. Lambert, PhD; W. Clark Lambert, MD, PhD

Needlephilia versus Needlephobia ............................................................................................................ 413

William Abramovits, MD; Damilola Babaniji, MS-IV; Kimberly Dawn Vincent, MD

ORIGINAL CONTRIBUTIONS

Vitamin D Deficiency and Atopic Dermatitis: Consider Disease, Race, and Body Mass .............................. 415

Kavita Darji, BA; Courtney Tobin, MD; Zachary T. Bryan, MD; Mathew Jansenn, MD; Eric Armbrecht, PhD; Elaine Siegfried, MD

Oral Mucosal Lesions in a Cross-Sectional Study of 200 Dermatologic Outpatients .................................. 421

Nazim Hussain Syed, MD; Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond); Ashok Aggarwal, MD; Shruti Sehgal, MDS

Characterization of Patients’ Quality of Life and Experience in the Course of Acne Treatment .................. 431

Robert L. Skaggs, II, BS; Emily Hix, BA; Karen E. Huang, MS; Steven R. Feldman, MD, PhD

Safety and Antipruritic Efficacy of a Menthol-Containing Moisturizing Cream ........................................... 437

Hong Liang Tey, MBBS, FRCP(Edin); Evelyn Yuxin Tay, MBBS, MRCP(UK); Wei Ding Tan, MSc

REVIEW

Hyaluronic Acid in Dermatology ................................................................................................................ 441

Mohammad Abid Keen, MD

Self Assessment Examination ................................................................................................................... 449

W. Clark Lambert, MD, PhD

CORE CURRICULUM

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

Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids .................................. 451

Kathryn Potter, MD; Sailesh Konda, MD; Vicky Zhen Ren, MD; Apphia Lihan Wang, MD; Aditya Srinivasan, MS; Suneel Chilukuri, MD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Compromising Patient Care: Gross Payment Disparities in Dermatopathology—Part II ............................. 457

Viral M. Patel, BS; Divya Sharma, BS; Michael Sylvester, AB; Christina Ring, BS; Jose D. Espinal-Mariotte, MD; W. Clark Lambert, MD, PhD

The Heymann File

Warren R. Heymann, MD, Section Editor

Melanoma in Situ: The Power of One (Centimeter)? .................................................................................. 459

Warren R. Heymann, MD

402

TABLE OF CONTENTS September/October 2017 November/December 2017••Volume Volume15 15••Issue Issue56

Photo Capsules

Snejina Vassileva, MD, PhD, Section Editor

Blaschkoid (Linear and/or Bandlike) Psoriasis ......................................................................................... 461

Virendra N. Sehgal, MD; Ashok K. Aggarwal, MD

Cellular Blue Nevus: An Unusual Localization ........................................................................................... 463

Murat Zor, MD; Engin Kaya, MD

Vignettes of Dermatologic History Mark Bernhardt, MD, Section Editor

Vicente Pardo-Castelló, MD (1892–1967) .................................................................................................. 465

Mark Bernhardt, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Cutaneous Mucormycosis: A Fatal Complication of Immunosuppressant Therapy for Pemphigus Vulgaris .................................................................................................................................. 467

Kanika Sahni, MD; Dipankar De, MD; Sunil Dogra, MD; Amrinderjit Kanwar, MD; Uma Nahar Saikia, MD

Immunologic Studies of Progesterone-Induced Neutrophilic Urticaria ...................................................... 471

Papapit Tuchinda, MD; Corinne Erickson, MD; Antonella Tammaro, MD; Miya Okada Paterniti, MD; Sarbjit S. Saini, MD; Anthony A. Gaspari, MD

Persisting Ulcerating Lesions After Cyclosporine Therapy for Erosions Found in Flexural Sites ................. 474

Mina Amin, BS; Shannon Famenini, MD; Jashin J. Wu, MD

Mast Cell Activation Syndrome .................................................................................................................. 477

Owen N. Kramer, BS; Marla S. Barkoff, MD; Claudia Hernandez, MD

Plantar Fibromatosis in a Mentally Challenged Man Treated with Intralesional Corticosteroids ................ 480

Ayse Serap Karadag, MD; Emin Ozlu, MD; Ayse Bahar Ceyran, MD; Mehmet Simsek, MD; Tugba Kevser Uzuncakmak, MD; Ilkin Zindancı, MD; Necmettin Akdeniz, MD

Role of Immune Status in Chemotherapy-Induced Transient Acantholytic Dermatosis ............................... 483

Sogyong L. Auh, MD, PhD; Ingrid Polcari, MD; Vesna Petronic-Rosic, MD, MSc; Aisha Sethi, MD

Chloracne in a Farming Family .................................................................................................................. 485

Pragya Kushwaha, MBBS, MD; Harish Kumar, MBBS, DVD; Sandeep Kulkarni, MBBS, DNB; Ashok Ghorpade, MBBS, MD, MNAMS

Correspondence

Snejina Vassileva, MD, PhD, Section Editor

Multiple Treatment-Resistant Actinic Keratoses Secondary to Hydroxycarbamide ..................................... 489

Bevin Bhoyrul, MBBS; Geoffrey Brent, MBBS; Izzat Abdul-Kadir, MB ChB; Jasmina Mikeljevic, MD

Sweet Syndrome Associated with Bilateral Nodular Scleritis .................................................................... 491

Anissa Zaouak, MD; Meriem Jrad, MD; Takoua Bacha, MD; Meriem Bel Haj Salah, MD; Ehsen Ben Brahim, MD; Houda Hammami, MD; Samy Fenniche, MD

Advanced Therapy Treatment for Psoriasis: A Single-Site Retrospective Study of Prescribing Outcomes

Carey Kim, MD; Lucie Joerg; Jacob Levitt, MD

403

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November/December 2017

Volume 15 • Issue 6

Editorial

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Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

404

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

Dermatology Insights and Inquiries

November/December 2017

Volume 15 • Issue 6

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 Robert L. Baran, MD Cannes, France Anthony V. Benedetto, DO Philadelphia, PA

Ibrahim Hassan Galadari, MD, PhD, FRCP Dubai, United Arab Emirates Anthony A. Gaspari, MD Phildelphia, PA Michael Geiges, MD Zurich, Switzerland

Brian Berman, MD, PhD Miami, FL 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 Greenwood Village, 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 Howard A. Epstein, PhD Philadelphia, PA

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

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

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

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Todd E. Schlesinger, MD Charleston SC

SKINmed. 2017;15:405

405

Julian Trevino, MD Dayton, OH Maria M. Tsoukas, MD, PhD Chicago, IL 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

November/December 2017

Volume 15 • Issue 6

Editorial

SKINmed Partners with Dermatology Insights and Inquiries: Perfect Together Warren R. Heymann, MD

eeping up with the dermatologic literature is a daunting task! Personally, I have found that the best approach is reading broadly and participating in a monthly journal club. Several years ago, I decided to choose contributions of interest for our dermatology residents at the Cooper Medical School of Rowan University, Camden, NJ, offering my clinical perspectives on timely literature. Subsequently, this was shared with other academic institutions in the Delaware Valley and with members of the Philadelphia Dermatological Society on their website. “The Heymann File,”1 initiated in 2014 in SKINmed, based on selected items from the journal club, has proven to be a richly rewarding experience. I have found that being able to expound on a current topic that is relevant to practice has become a career highlight. ELECTRONIC INNOVATION As the worldwide dermatologic community has become electronically linked, it was only natural to develop a website devoted to keeping current with the literature, while providing a forum to share ideas among colleagues. Dermatology Insights and Inquiries (DI&I) was launched in April 2016 and has wit-

nessed tremendous growth and enthusiasm (Figure). For its raison d’être (as stated on the website, http://www.dermatologyinsightsandinquiries.com): The goal of this website is to improve the practice of dermatology, while being stimulating, practical, thought-provoking, and enlightening. Perspectives on current dermatologic literature are offered that are meant to be used in the clinic. The focus of DI&I is to provide commentaries on the most current literature presented in the English language in the major dermatology journals, ie, Journal of the American Academy of Dermatology, JAMA Dermatology, International Journal of Dermatology, Journal of Investigative Dermatology, Pediatric Dermatology, and Journal of Cutaneous Pathology. Readers may comment or provide other inquiries. DI&I focuses on medical dermatology, pediatric dermatology, and dermatopathology for the most part. The site itself is easy to navigate, with both a search function and archives. CME credit is available through the Department of Continuing Medical Education of The Cooper Health System (CME@ cooperhealth.edu).

Figure. Home page of http://www.dermatologyinsightsandinquiries.com.

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

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DI&I has been selected as the 2017 recipient of the American Academy of Dermatology’s Program for Innovative Continuing Medical Education in Dermatology (PICMED), as chosen by the Sulzberger Dermatologic Institute and Education Grants Committee. OUR PARTNERSHIP I am pleased to inform you that SKINmed and DI&I have now partnered to provide the latest in clinically relevant information for the practicing dermatologist. SKINmed will serve as the official print journal publication for DI&I. DI&I will now provide its subscribers a PDF version of each new issue

SKINmed. A link to the SKINmed website is also available in the “Useful Links” section of DI&I. The editors and I believe that combining the benefits of this outstanding clinical journal with the flexibility and interactive nature of the website will enhance the reader’s ability to stay current, and will be one more way to provide optimal care for our patients – which is our ultimate goal. All of us will benefit by joining forces – SKINmed, DI&I, and you – perfect together. Reference 1 Heymann WR. The Heymann File: Diagnosing atypical hand, foot, and mouth disease while avoiding the foot in mouth syndrome. SKINmed. 2014;12:46–47.

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Management of Cutaneous Cancers in Patients Undergoing Organ Transplantation—Part II: Proactive Approach Divya Sharma BS;1 Amy Weiss, BA;1 Marc Z. Handler, MD;2 Radhika Shah, PharmD;1 Muriel W. Lambert, PhD;2,3,4 W. Clark Lambert, MD, PhD2,3,4

atients with solid organ transplants must remain on lifelong immunosuppressive therapy. Although this is necessary to prevent transplant rejection, these drugs increase the risk for nonmelanoma skin cancer (NMSC). Cyclosporine, a commonly used immunosuppressant in transplant patients, has been shown to cause carcinogenesis via a variety of mechanisms, including interfering with immune cells of the skin and DNA repair, and causing activation of proto-oncogenes.1,2 IMPLEMENTING CHEMOPREVENTION: RECENT DEVELOPMENTS

The current approach to managing NMSC in posttransplant patients has been described as reactive rather than proactive.3 Alternative approaches are currently being devised and implemented to counter the development and progression of NMSC. The creation of multidisciplinary specialty clinics that involve dermatologists, dermatopathologists, and/or Mohs micrographic surgeons allows for responsive coordinated care.3 Dermatologists should play an integral role in transplant patient care by participating in pretransplant consultation, providing preventive education regarding photoprotection, revising the immunosuppressive regimen with input from other relevant subspecialists, suggesting chemoprophylaxis, and following up with patients after transplant for skin cancer surveillance and treatment.3 Immunosuppressive agents inadvertently promote cutaneous tumorigenesis because of their effects on signaling pathways involved in carcinogenesis and impairment of host tumor surveillance mechanisms.4 One recommendation is to decrease the level of immunosuppression to allow skin immunity to function nor-

mally again. This has been recommended by dermatologists and transplant specialists for high-risk cases of NMSC and melanoma in transplant patients.5 A randomized controlled trial has also demonstrated that lowering the degree of immunosuppression minimized the incidence of new skin cancers in posttransplant patients without resulting in significant impairment of graft viability.6 Another possibility is to administer a mechanistic target of rapamycin (mTOR) inhibitor (sirolimus, everolimus) in place of a calcineurin inhibitor for immunosuppressive treatment as they are associated with a lower risk of skin cancer;7 however, recent data have questioned whether mTOR inhibitors are truly associated with lower risk. Further studies are needed to understand the role of mTOR use in primary prevention.8 An approach that is more proactive than revising immuosuppressants is to implement active chemoprevention. Organ transplant patients are the largest special patient population who benefit from chemoprevention. Oral retinoids have proven to be effective in the suppression of new squamous cell carcinoma (SCC) in high-risk patients, such as transplant recipients, although there is not sufficient evidence that they reduce the risk of basal cell carcinoma. Randomized controlled trials with acitretin have demonstrated significant reductions in incidence of actinic keratoses (AK) and SCC. Acitretin also has a longterm effect in suppressing SCC, as shown in a retrospective longitudinal study.9 However, due to severe dose-dependent side effects, the goal of using oral retinoids is to decrease the number of NMSCs to a manageable level, and not to completely eliminate new NMSCs. Side effects of oral retinoids include mucocutaneous dryness and irritation, hair loss, hypertriglyceridemia and hyper-

From Rutgers University – New Jersey Medical School,1 Department of Dermatology,2 Department of Pathology,3 and Department of Laboratory Medicine,4 Rutgers University – New Jersey Medical School, Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Department of Pathology and Laboratory Medicine, Medical Science Building, Room C520, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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cholesterolemia, liver toxicity, increased intracranial pressure, and skeletal changes with long-term use that include demineralization and hyperostosis. Additionally, the chemopreventive effect of oral retinoids often disappears after discontinuation of therapy, and a rebound effect may occur, with an uncontrollable increase in the number of keratotic lesions. Indications for initiating systemic retinoid chemoprophylaxis in solid transplant recipients include developing multiple SCCs annually, developing SCCs in high-risk locations, developing SCC in the context of a history of lymphoma/leukemia, metastatic SCC, or emergence of eruptive keratoacanthomas.3 Retinoids are also potent teratogens and require special measures to prevent pregnancy during and shortly after treatment. Field therapies in areas of keratotic lesions have also shown chemopreventive effects. These include photodynamic therapy, topical diclofenac sodium, and T4 endonuclease V. Photodynamic therapy and diclofenac sodium have been shown to reduce the number of new AKs and new SCCs. T4 endonuclease V reduced the rate of development of new basal cell carcinoma and AK over 1 year in patients with xeroderma pigmentosum (XP), but needs further investigation to analyze its effect on the rate of SCC. Other potential chemopreventive agents are nonsteroidal anti-inflammatory agents and difluoromethylornithine.10 Nonsteroidal anti-inflammatory agents have shown evidence for a possible modest chemopreventive role against NMSC, but further studies are needed to support their use in clinical practice. Difluoromethylornithine has been shown to be safe in organ transplant recipients and moderately effective in decreasing the number of AKs. Although difluoromethylornithine has shown no significant effect in preventing SCCs, it may have a role in the prevention of AKs and basal cell carcinomas. 5-FLUOROURACIL AS SUCCESSFUL CHEMOPREVENTION AGAINST NMSC IN XP XP is an autosomal recessive disease in which affected individuals have impaired responses to DNA damage induced by ultraviolet radiation.11 Two of us (WCL and MWL) have shown that prophylactic use of 5-fluorouracil (5-FU) is very effective in preventing skin cancer in patients with XP.11 5-FU is an antimetabolite that blocks the pyrimidine thymidine, which is needed for DNA replication. We described five patients with XP who underwent surgical management for neoplasms, with adjuvant application of 2% to 8% 5-FU in an aqueous cream preparation applied daily for 3 weeks to all sun-exposed sites. After this 3-week regimen, the protocol was repeated 3 months later and then every 3 to 6 months indefinitely. These five patients were followed for 8 years or longer; they experienced effective skin cancer prevention in sun-exposed sites, with the exception of SKINmed. 2017;15:409–411

marginal sites, such as the eyelids, lips, and ears, which were not treated with 5-FU. These results support the prophylactic use of 5-FU in the prevention of cancer in sun-exposed sites in XP patients. RECOMMENDED USE OF 5-FU AND/OR IMIQUIMOD FOR CHEMOPROPHYLAXIS IN THE CONTEXT OF THE CURRENT PRETRANSPLANT PROTOCOL Topical 5-FU has been shown to be effective in preventing skin cancer, and therefore may prove to be a successful NMSC chemoprevention therapy for solid organ transplant recipients. Before transplantation, patients receive routine immunizations to protect against infections. We propose that topical 5-FU should be administered to sun-exposed sites at this time as well, when patients are still immunocompetent. Topical 5-FU is commercially available in five formulations: 0.5% cream, 1% cream, 2% solution, 4% cream, and 5% cream or solution. The 5% formulation is the gold standard for treatment of actinic keratosis. One obstacle in the use of topical 5% 5-FU (Efudex®, Carac®; 5-FU was patented in 1956 and came into medical use in 1962; it is available from multiple manufacturers) is the cost; however, physicians could prescribe oral 5-FU (capecitabine) capsules. Patients are advised to wear gloves for protection, open the capsules, and mix the contents into an aqueous base to create an inexpensive alternative that is equally efficacious.11 Alternatively, this may be done by a compounding pharmacist. In a typical topical 5-FU cycle of 4 to 6 weeks, active treatment is given for 2 to 4 weeks by applying a thin film to the lesions once or twice daily. After this, the skin first turns erythematous, then desquamates, then becomes necrotic with erosion, and finally is restored by re-epithelialization 2 weeks after the 5-FU has been terminated. Use of this regimen is limited by the unfavorable side effects of the medication on the lesions, such as photosensitivity and alopecia. The 0.5% formulation was developed to bypass the significant discomfort experienced by the patients receiving the 5% formulation treatment. Although the treatment duration is longer, this medication has been shown to significantly decrease the dermal agitation associated with 5% 5-FU. Topical imiquimod is also effective in clearing precancerous lesions, with clinical results comparable to or better than those observed with topical 5-FU.12 Imiquimod (Aldara®, Zyclara®) is more costly, but patients may prefer it if using 5-FU is problematic. It is available in a 5% strength cream to be applied on a treatment field of 25 cm2 or less, three times per week at bedtime. The cream is left on for 8 hours and then washed off with

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mild soap and water. This regimen is continued for 16 weeks on either the scalp or face—but not both simultaneously. Each application should require no more than one pack of cream, and the maximum number of packs to be used for 16 weeks is 36. Common adverse effects include localized dermatologic reactions such as erythema and xeroderma, fungal infection, and upper respiratory infection. A decrease in the size of the lesion indicates a favorable therapeutic response. Recently, a 3.75%-strength cream was introduced; this has shown similar effectiveness to the 5%-strength cream, with the added benefits of fewer side effects, a shorter treatment duration, and a greater surface area that can be treated. Other less commonly employed treatment regimens using imiquimod for treating actinic keratosis are cyclical treatments, alternating between three times weekly application and a rest period, and combination with cryotherapy, photodynamic therapy, or oral acitretin.

NMSC. Because 5-FU uses the body’s immune response, we believe that 5-FU (or, alternatively, imiquimod) would be more effective, if initially administered before immunosuppressive therapy is started. References

SPECIAL CONSIDERATIONS There are several factors to investigate regarding the use of using topical 5-FU as prophylaxis against skin cancer in posttransplant patients. One consideration is whether or not the 5-FU would interact with other medications that the patients need. However, this would be unlikely with topical administration. Furthermore, additional study is required to determine the extent of the surface area that 5-FU could be safely applied to. We have administered topical 5-FU to all sun-exposed sites in patients with XP and applied petroleum jelly over perioral treated areas to avoid accidental ingestion and resultant systemic adverse effects.11 Finally, there are marginal sites, which were deemed inappropriate for prophylactic treatment with topical 5-FU in patients with XP such as the eyelids, lips, and ears.11 It will be important to monitor these sites and involve specialists such as ophthalmologists and oral surgeons for early removal of tumors, should they arise. CONCLUSIONS Posttransplant recipients suffer from considerable morbidity because of immunosuppressive therapy increasing their risk for subsequent cutaneous malignancies. We recommend a proactive approach for lowering the incidence of NMSC through chemoprevention. Two of us (WCL and MWL) noted beneficial effects of administering topical 5-FU prophylactically to patients with XP who also have impaired defenses against

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1 Wu X, Nguyen B-C, Dziunycz P, et al. Opposing roles for calcineurin and ATF3 in squamous skin cancer. Nature. 2010;465:368–372. 2 Han W, Ming M, He T-C, He Y-Y. Immunosuppressive cyclosporin A activates AKT in keratinocytes through PTEN suppression. Implications in skin carcinogenesis. J Biol Chem. 2010;285:11369–11377. 3 Greenberg JN, Zwald FO. Management of skin cancer in solid-organ transplant recipients: A multidisciplinary approach. Dermatol Clin. 2011;29:231–2341. 4 Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–534. 5 Otley CC, Griffin MD, Charlton MR, et al. Reduction of immunosuppression for transplant-associated skin cancer: Thresholds and risks. Br J Dermatol. 2007;157:1183– 1188. 6 Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: Randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–628. 7 Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006;17:581–589. 8 Asgari MM, Arron ST, Warton EM, Quesenberry CP, Jr, Weisshaar D. Sirolimus use and risk of cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients (SOTRs). J Am Acad Dermatol. 2015;73:444– 450. 9 Harwood CA, Leedham-Green M, Leigh IM, Proby CM. Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: A 16-year retrospective study. Arch Dermatol 2005;141:456–464. 10 Soltani-Arabshahi R, Tristani-Firouzi P. Chemoprevention of nonmelanoma skin cancer. Facial Plast Surg. 2013;29:373–383. 11 Lambert WC, Lambert MW. Development of effectiveskin cancer treatment and prevention in xeroderma pigmentosum. Photochem Photobiol. 2015;91:475–483. 12 Bubna AK. Imiquimod–its role in the treatment of cutaneous malignancies. Indian J Pharmacol. 2015;47:354– 359.

Management of Cutaneous Cancers

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November/December 2017

Volume 15 • Issue 6

Commentary

Needlephilia versus Needlephobia William Abramovits, MD;1 Damilola Babaniji, MS-IV;2 Kimberly Dawn Vincent, MD3 Is there an endearment for needles or just a fear? Dealing with needlephobia and needlephilia.

ermatologists and surely other physicians often hear questions and requests like these: “Couldn’t you give me a shot instead of all these pills?” and “I could never be a heroin addict because of how badly I fear needles.” One patient presented with a persistent dermatitis for which the diagnosis and treatment plan hinged on a biopsy. During the explanation of the local anesthetic technique, she suddenly started shaking and sweating, stating that she might faint just thinking about the injection. Another patient, ironically an anesthesiologist, experiences anxiety attacks quarterly when due for his biologic injection, stating: “I have no issues giving shots or starting IVs on others, but when it comes to me getting them I panic.” At a dermatology office that commonly teaches patients to self-inject subcutaneously, many say “no biggie,” while others beg for pill alternatives. Experiences like these led us to investigate the very common, although scarcely talked about, topic of needlephobia. Borrowing from string theorists, who talk about supersymmetry to explain the likely existence of unidentified particles and forces, could a supersymmetric entity exist that contraposes needlephobia? If so, is the spectrum between the two conditions within or outside psychological normalcy? NEEDLEPHOBIA Needlephobia is the extreme fear of needles. It is a widespread illness that physicians should recognize and treat with compassion and respect. It should also require therapy based in medical evidence. It is an established medical condition with its own International Classification of Diseases 10th edition code (F40.8). An estimated 10% to 20% of the general US population has it.1 Related conditions include trypanophobia (fear of injections), belonephobia, aichmophobia, and enetophobia (abnormal fear

of sharp pointed objects like needles). The fear may not be of the needle itself, rather of the dread and anxiety that accompanies getting injected through the skin, something akin to thinking that it is not the fall from a high floor of the Empire State building that is painful, what is painful is hitting the ground. Needlephobia is a recently adopted diagnosis so it is not surprising that needlephilia is not listed. The phobia was not officially recognized by the medical community until 1997, when a paper by Dr. James Hamilton described vasovagal responses with feelings of fainting accompanied by various levels of and durations of unconsciousness, as well as other autonomic clinical manifestations and signs occurring in patients confronting the likelihood of an injection.1 Reported clinical manifestations and signs related to needlephobia include nervousness, anxiety, inconsolable crying, hyperventilation, sweating, nausea, pallor, vasovagal syncope with initial high blood pressure followed by bradycardia, hypotension, tachycardia, loss of consciousness, and death. DEFINITION The latest Diagnostic and Statistical Manual of Mental Disorders (DSM-V), of 2014, defines phobia as a marked fear or anxiety about an object or situation.2 The mental health community recognizes many specific phobias. Common ones include agoraphobia (fear of being in social places and situations), claustrophobia (fear of being closed in or entrapped in small spaces) and acrophobia (fear of heights). In the DSM-V, needle phobia can be found under the blood-injury-injection category of specific phobias. The etiology of needlephobia is not clearly understood; studies attribute it to genetics and learned behavior. Hamilton described it as “an inherited vasovagal reflex of shock, triggered by needle

From the Department of Dermatology, Baylor University Medical Center and the University of Texas Southwestern Medical School, Dallas, TX;1 the Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX; 2 and Private Practice, Belle Meade Dermatology, Nashville, TN3 Address for Correspondence: William Abramovits, MD, 5310 Harvest Hill Rd. #160, Dallas, TX 75230 • E-mail: dra@dermcenter.us

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puncture,” whereas other authors state that there exists “genetic evidence for the physiologic response to needle puncture and a significant familial psychological component showing evidence of inheritance.” Needlephobia can also be a learned behavior resulting from prior traumatic experiences involving needles in self or a relative or friend.3 A study showed 22% of 172 participants describing fear of needles in a general practice setting, with 46% of those reporting a previous traumatic needle experience.4 Hyperalgesic fear may be the trigger in about 10% of needlephobes. Parents make decisions to shun or delay immunizations for their children, perhaps because of their own personal fear of needles or the stress of seeing their children receive injections.

This may be true, but quite often the difference is of minutes or hours, which for a chronic condition may be of little relevance. For patients with such ideation, we would like to coin the word “needlephilia.”

An online survey by Target Corporation in 2012 found that 60% of adult Americans avoid annual vaccinations against the deadly influenza virus; 23% of those skipped the vaccination because of fear of needles, demonstrating the physical, emotional, psychological, and financial burden to both individuals and society.5,6 The Centers for Disease Control and Prevention has reported that the economic burden of flu-related illnesses amounts to more than US $87 billion annually.7

CONCLUSIONS

One caveat—needlephilia may not be an addiction-related behavior seen in association with drug abuse or acupuncture, etc; just as trichotillomania is not a mania, needlephilia likely falls within a spectrum of normalcy. Choosing a biologic injected subcutaneously every week over twice a day tablets may be a selection a patient does with a sound mind, even when the decision may be tainted by a personal tendency to needlephilia.

Although needlephobia and needlephilia are opposites within a spectrum, only extremes beyond the two poles fall outside normalcy. References

“Phobia” comes from the Greek word “phobos” meaning “excessive or irrational fear of something.” “Philia,” also derived from Greek, means “strong feeling of love or admiration for something; tendency for; inclination or affiliation towards something; friendly.” This explains why Philadelphia is called the city of “Brotherly Love.” Remember the physics concept of supersymmetry? It simplistically states that for each particle there exists a possible, sometimes yet-to-be-discovered, antiparticle that is the exact opposite.8 We borrow from this to support our assumption that for needlephobia there is a supersymmetric entity we chose to call needlephilia. CONCEPT The concept behind needlephilia came to mind after a patient on long-term prescription pills expressed reluctance and anxiety about continuing oral medications as they made her “gag.” She requested shots instead. Not rarely, patients magically believe that injections are more effective and work faster than pills.

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1 Hamilton JG. Needle phobia: a neglected diagnosis. J Fam Pract. 1995;41:169. 2 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA, APA; 2014:198–199. 3 Sokolowski CJ, Giovannitti JA, Jr, Boynes SG. Needle phobia: Etiology, adverse consequences, and patient management. Dent Clin North Am. 2010;54:4731–4744. 4 Wright S, Yelland M, Heathcote K, Ng SK, Wright G. Fear of needles—nature and prevalence in general practice. Aust Fam Physician. 2009;38:172–176. 5 Business Wire. Target Survey Shows Adult Americans May Avoid the Flu Shot Due to Fear of Needles. http://www. businesswire.com/news/home/20120814005359/en/ Target-Survey-Shows-Adult-Americans-Avoid-FluTarget. Accessed September 16, 2016. 6 Molinari N, Ortega-Sanchez I, Messonnier M, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25:5086– 5096. 7 Centers for Disease Control and Prevention. Flu Prevention. http://www.cdcfoundation.org/businesspulse/fluprevention-infographic. Accessed September 16, 2016. 8 Murayama H. Introduction to Supersymmetry. http:// hitoshi.berkeley.edu/public_html/susy/susy.html. Accessed September 16, 2016.

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ORIGINAL CONTRIBUTION

Vitamin D Deficiency and Atopic Dermatitis: Consider Disease, Race, and Body Mass Kavita Darji, BA;1 Courtney Tobin, MD;2 Zachary T. Bryan, MD;3 Mathew Jansenn, MD;4 Eric Armbrecht, PhD;5 Elaine Siegfried, MD6,7 Abstract Vitamin D deficiency causes rickets, but has been associated with various diseases, including atopic dermatitis (AD). This study analyzes serum vitamin D in pediatric medical center patients with AD and potential confounding factors. At Cardinal Glennon Children’s Hospital, charts of 665 children with serum 25-hydroxyvitamin D levels taken between 2009 and 2013 were retrospectively reviewed. Defining vitamin D deficiency as <20 ng/mL, neither average 25-hydroxyvitamin D nor deficiency prevalence varied among disease groups, except for cystic fibrosis (CF), which demonstrated significantly higher average vitamin D and lower deficiency prevalence. Children with AD had the lowest prevalence of vitamin D sufficiency, without significant association with disease severity. No seasonal variation was detected. Strong correlations were observed between 25-hydroxyvitamin D levels, body mass index (BMI), and race. Our data showed no strong association between vitamin D levels and AD or AD severity. A strong association was noted between skin type and BMI. The lower prevalence of vitamin D deficiency among children with CF may be explained by lighter skin and lower BMI. A high prevalence of vitamin D insufficiency and deficiency as currently defined among children with dark skin and high BMI suggests a need to reevaluate normal vitamin D levels in these populations. (SKINmed. 2017;15:415–420)

itamin D deficiency is one of the most common nutritional deficiencies in children and is becoming the fastest growing clinical laboratory test in the United States.1 The Endocrine Society currently advocates thresholds for deficiency, insufficiency, and sufficiency as less than 20 ng/ mL, 20.0 to 29.9 ng/mL, and 30.0 ng/mL or more.1 Using these cutoffs, a considerable number of healthy children are flagged as vitamin D–deficient despite the fact that they may not suffer from decreased bone mineral density or be at high risk for rickets. The implications of deficiency in such a large proportion of otherwise healthy individuals have been a subject of recent controversy. Vitamin D is acquired by the body via two independent pathways: 10% by dietary consumption and 90% by photo-induced synthesis in the skin. The liver and the kidneys are involved in the subsequent activation of vitamin D. Studies assessing the prevalence of vitamin D deficiency cite several confounding variables

as potential study limitations. To evaluate these variables, we assessed the impact of disease, race, sex, BMI, and seasonal variation in a large unselected group of children. Moreover, a recent randomized controlled trial suggests a reduction in AD severity after supplementation with vitamin D.2 As there is growing interest in vitamin D supplementation to treat children with AD, we evaluated the severity of AD in relation to vitamin D levels. MATERIALS AND METHODS This study was a retrospective chart review, conducted with the approval of the Institutional Review Boards at Saint Louis University School of Medicine (SSM) and Cardinal Glennon Children’s Hospital. Cardinal Glennon Children’s Hospital is an urban-based tertiary care center in St. Louis, MO, affiliated with SSM, a large, regional health care system. Data were collected via an SSM Cardinal Glennon Children’s Hospital Epic Clarity report during a 4-year period (October 15, 2009 to October 1, 2013). Additional information was collected by individual chart

From the SSM Saint Louis University Hospital, St. Louis, MO;1 Distinctive Dermatology, Swansea, IL;2 Department of Dermatology, Kansas University Medical Center, Kansas City, KS;3 Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA;4 Saint Louis University Center for Health Outcomes Research, St. Louis, MO;5 and Department of Pediatrics6 and Department of Dermatology,7 Saint Louis University School of Medicine, St. Louis, MO Address for Correspondence: Elaine Siegfried, MD, Saint Louis University School of Medicine, 1755 South Grand Boulevard, St. Louis, MO 63104 • E-mail: esiegfri@slu.edu

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review for each identified subject: date of birth, ethnicity, race, sex, BMI, problem list diagnoses, and AD severity. Eligible patients were separated by disease group and compared. A subgroup analysis was conducted for patients with AD in which vitamin D levels were compared between AD severity groups.

Inclusion criteria Included subjects were age newborn to 21 years old with at least one serum 25-hydroxyvitamin D level result taken between October 15, 2009 and October 1, 2013.

Disease groups After individual chart review, patients were categorized as healthy or affected by chronic illness in one of four organ-specific disease groups. Patients affected by disease in two or more groups were excluded. Organ-specific disease groups were chosen based on the relative contribution of skin, kidneys, and gastrointestinal (GI) system with regards to vitamin D metabolism. AD was selected to represent chronic skin disease. Renal disease included nephritic and nephrotic syndromes (including lupus nephritis), chronic kidney disease, renal insufficiency, polycystic kidney disease, vesicouteral reflux, hydronephrosis, Fanconi’s anemia, renal cortical necrosis, nephrolithiasis, and renal dysplasia. GI disease included Crohn’s disease, ulcerative colitis, celiac disease, biliary atresia, pancreatic insufficiency, gastroesophageal reflux disease, short bowel syndrome, or a history of necrotizing enterocolitis. CF was selected as a single disease group because of its multiorgan system morbidities and a large prevalence within the study population. With the exception of CF, subjects with diseases involving two or more disease groups were excluded from the study. Children with non-AD, nonrenal, non-GI, and non-CF diseases (eg, lupus without nephritis) were also excluded.

Ethnicity and race Race was an independent category with the following choices: American Indian/Native Hawaiian/Alaskan, Asian, AfricanAmerican, multiracial, and white/Caucasian. Our database did not include Hispanic/Latino ethnicity as a separate racial group category.

Vitamin D All subjects had at least one recorded vitamin D level. For the purposes of this study, only the first documented level was used for patients who had more than one recorded level. Use of vitamin D supplementation at the time the level was obtained was not known. Vitamin D deficiency, insufficiency, and sufficiency were defined as less than 20 ng/mL, 20.0 to 29.9 ng/mL, and 30.0 to 99.9 ng/mL, respectively. SKINmed. 2017;15:415–420

BMI Underweight, normal weight, overweight, and obese were defined by age-matched, growth curve BMI parameters: <5 percentile, 5 to 95 percentile, 95 to 99 percentile, and >99 percentile, respectively. Patients less than 2 years of age were excluded from BMI analysis because neither normal nor abnormal status by BMI has been well defined for this age group.

AD severity To explore a potential association between vitamin D deficiency and AD severity, each patient was categorized by one investigator as mild (two or fewer body areas noted, eg, antecubital fossa and popliteal fossa), moderate (more than 2 areas affected but neither erythrodermic nor labeled severe in the medical record), or severe (erythrodermic or identified as severe in the medical record). All descriptions of AD severity were determined by a pediatric dermatologist and recorded within 90 days before vitamin D levels were obtained.

Statistical analyses Two approaches were employed to assess differences in vitamin D level between disease groups. First, one-way analysis of variance with a Tukey post-hoc text was used to examine differences in vitamin D level, as measured by a continuous variable (ng/mL). The second approach relied on the measurement of vitamin D by the conventional clinical categorical definitions for deficiency, insufficiency, and sufficiency; statistical inference was made using a Pearson χ2 test. Racial group and sex differences were assessed independently with the latter approach only. The subgroup analysis for AD severity, which included stratification by race group, also employed this approach. The association between obesity status (four BMI categories) and vitamin D level (sufficiency versus insufficiency) was assessed with a Pearson χ2 test. To explore the possibility of seasonal variation as a potential confounder, monthly variation in vitamin D level was examined using analysis of variance. Statistical significance was set at alpha=0.05 for all analyses. RESULTS

Demographics A total of 665 patients between 0 and 21 years of age (average 10 years) met the inclusion criteria. The distribution among racial groups was: 421 Caucasians, 187 African-American, 8 Asian, 3 American Indian/Native Hawaiian/Alaskan, 23 multiracial, and 23 unknown. There were 331 female and 334 male participants. A total of 226 (34%) individuals were designated as healthy, 132 (20%) had CF, 88 (13%) had renal disease, 128 (19%) had GI disease, and 91 (14%) had AD.

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There was a female predominance in healthy patients and a male predominance in all the disease groups. The healthy group was 59% female, with an average age of 11 years. The CF group was 48% female, with an average age of 9. The renal group was 48% female, with an average age of 11 years. The GI group was 43% female, with an average age of 11. The AD group was 41% female, with an average age of 7.

Disease groups and vitamin D levels The average vitamin D levels were 24.54 ng/mL in the healthy cohort, 31.06 ng/mL in the CF cohort, 26.44 ng/mL in the renal cohort, 26.29 ng/mL in the GI cohort, and 22.24 ng/mL in the AD cohort. The mean vitamin D level was significantly higher in CF than any of the other disease categories (P<.0001). The difference in the average vitamin D level among the other groups was not significant (P>.05; Figure 1). Across all patients, only 30% had sufficient vitamin D levels. The prevalence of adequate vitamin D levels was lowest (15%) for children with AD. Percentage deficiency and insufficiency was similar among all groups, except CF, which included a significantly lower percentage of deficiency (P<.0001; Figure 1).

Race and vitamin D status Among the African-American participants, 64% were vitamin D–deficient, 25% were insufficient, and 11% were sufficient.

Among the Caucasian group, 32% were deficient, 35% were insufficient, and 33% were sufficient. Among the Asian group, 67% were deficient, 0% were insufficient, and 33% were sufficient. Among multiracial patients, 57% were vitamin D–deficient, 14% were insufficient, and 29% were sufficient. Caucasian participants had a significantly lower percentage of deficiency than the other groups. There was no difference in the prevalence of deficiency among African-American or multiracial children (Figure 2). Given the small number of Asian individuals in the sample (n=3), no comparative analysis was conducted for this group.

Sex and vitamin D status Of the 331 female participants, 40% were vitamin D–deficient, 31% were insufficient, and 29% were sufficient. Of the 334 males, 34% were deficient, 35% were insufficient, and 31% were sufficient. There was no significant difference between sex and vitamin D status (P>.05).

BMI and vitamin D status Deficiency was seen in 33% of underweight, 32% of normal, 49% of overweight, and 59% of obese patients. There was a significant association between vitamin D deficiency and BMI (P=.000008; Figure 3).

Figure 1. Less than 50% of children in all groups had sufficient vitamin D levels. Serum average vitamin D levels (black circles) and prevalence of deficiency were similar among all groups, except cystic fibrosis (CF), which demonstrated significantly higher average levels and lower percentage deficiency. AD, atopic dermatitis; GI, gastrointestinal. SKINmed. 2017;15:415–420

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Figure 2. Caucasian patients had significantly lower levels of deficiency than African-American and multiracial patients.

Figure 3. Of all the variables assessed, vitamin D status was most strongly correlated to body mass index (BMI). There was an obvious direct association between deficiency and BMI, while sufficiency was inversely associated.

AD severity and vitamin D status AD severity was assessed within 90 days before obtaining the vitamin D level. Among the AD cohort with mild disease, 56% were deficient, 31% were insufficient, and 13% were sufficient. Among the AD cohort with moderate disease, 38% were deficient, 43% were insufficient, and 19% were sufficient. Among the AD cohort with severe disease, 46% were vitamin Dâ&#x20AC;&#x201C;deficient, 43% were insufficient, and 11% were sufficient. There was no significant difference between AD severity and vitamin D status (P>0.05; Figure 4). Further subgroup analysis by race and BMI similarly did not detect any differences.

Season and vitamin D status There was a wide range of vitamin D levels (1.8 to 96.7 ng/mL), with both extremes detected in April 2013. The average vitamin D SKINmed. 2017;15:415â&#x20AC;&#x201C;420

levels (ng/mL) were 29.27 in January, 26.42 in February, 26.80 in March, 20.96 in April, 30.53 in May, 27.41 in June, 26.52 in July, 27.32 in August, 23.60 in September, 24.02 in October, 25.63 in November, and 27.25 in December. Analysis of vitamin D levels by month did not reveal a seasonal variation (P>0.05; Figure 5). DISCUSSION Despite the lack of strong evidence supporting benefit, vitamin D has become a popular supplement for treating a variety of diseases, including AD.3 Previous studies have reached conflicting conclusions about the relationship between vitamin D and AD, with both low and high levels listed as risk factors for the disease.4 One study found no significant difference in vitamin D concentrations between AD and healthy adult subgroups, but subjects with AD experienced substantial disease improve-

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Figure 4. There was no observed association between atopic dermatitis (AD) severity and vitamin D status.

Average Vitamin D levels by Date Vitamin D level (ng/ml)

120 100 80 60 40 20 0

Figure 5. Among all patients, there was no observed trend in individual values by season (left) and no significant variation of average Vitamin D levels by month (right).

ment after supplementation.2 Although the prevalence of vitamin D sufficiency was lowest in our AD group, more than half of healthy children as well as those in every disease group had vitamin D deficiency or insufficiency. We found no correlation between AD severity and vitamin D levels. We found no significant differences in average vitamin D levels or percentage deficiency among healthy, GI, and renal disease groups. Lack of significant difference between the GI and healthy groups may be attributed to the fact that only a minority of the bodyâ&#x20AC;&#x2122;s total vitamin D is attained from the diet; thus, malabsorption would not significantly impact serum 25-hydroxyvitamin D. Children in the CF group had highest mean vitamin D concentration, likely reflecting a Caucasian predominance (96%), low BMI, or high rate of adherence to vitamin D supplementation. SKINmed. 2017;15:415â&#x20AC;&#x201C;420

We found a significantly higher percentage of vitamin D deficiency in African-American children, as previously reported.4 Greater skin pigmentation limits the penetration of ultraviolet B, reducing initial cutaneous photochemical production. Higher prevalence of lactose intolerance among African-American individuals is another likely contributing factor.5 Although the prevalence of rickets is relatively higher among African-American people, a difference in threshold for deficiency has not been thoroughly evaluated among racial subgroups. We found no seasonal variation in vitamin D levels, in contrast to a prior study that documented lower concentrations during the winter among children living in Wisconsin.4 Our findings could reflect an inability to control for sunlight exposure, inclusion of urban and rural children, and the lower latitude of Missouri.

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Although prior reports suggested a possible association between female sex and deficiency, thought to be due to differences in religious or cultural dress,1,6 we found no significant sex difference. Underrepresentation of Muslim participants and an inconsequential impact of cultural dress in our pediatric population may have contributed to the lack of an observed sex difference. Of all the variables assessed in this study, low levels of vitamin D most strongly correlated with high BMI. This inverse association has been well documented and is likely influenced by at least two factors: vitamin D lipophilicity favors storage in excess adipose tissue over serum, and obesity may discourage outdoor activity or skin exposure during summer months.3,7,8

photochemical production. Children with CF had a significantly higher average vitamin D level and lower percentage deficiency, most likely due to the Caucasian predominance, low BMI, and high rate of supplementation among this group. A very high prevalence of vitamin D insufficiency and deficiency as currently defined among children with dark skin and high BMI suggests a need to reconsider the normal range for serum vitamin D in these populations, especially with respect to the risk of comorbidities such as bone health. References

Study design was enhanced by analysis of cofounding variables and inclusion of a large patient population. Conversely, the single-center and nonblinded nature of the study may have limited the generalizability of our findings. Other limitations include imperfect subjective categorization of mild, moderate, and severe AD. For example, a child with severe nummular eczema in relatively few spots may have been classified as mild rather than severe based on our definitions. Furthermore, inability to control for AD treatment and vitamin D replacement likely influenced our analysis. Larger multicenter and multilatitude investigations with close monitoring of vitamin D supplementation are needed to address these limitations. CONCLUSIONS Low serum 25-hydroxy vitamin D is common in pediatric patients, occurring in more than 50%. Although children with AD had the lowest average vitamin D level, we found no association between vitamin D deficiency and sex, season, AD, AD severity, or other disease groups. Skin type and BMI were the only parameters identified with a significant association. A high prevalence of deficiency among obese patients may reflect low serum bioavailability, while dark-skinned children may have less

1 Pramyothin P, Holick M. Vitamin D supplementation guidelines and evidence for subclinical deficiency. Curr Opin Gastroenterol. 2012;28:139–150. 2 Camargo CA, Jr, Ganmaa D, Sidbury R, et al. Randomized trial of vitamin D supplementation for winter-related atopic dermatitis in children. J Allergy Clin Immunol. 2014;134:831–835. 3 Samochicki Z, Bogaczewicz J, Jeziorkowska R, et al. Vitamin D effects in atopic dermatitis. J Am Acad Dermatol. 2013;69:238–244. 4 Chiu YE, Havens PL, Siegel DH, et al. Serum 25-hydroxyvitamin D concentration does not correlate with atopic dermatitis severity. J Am Acad Dermatol. 2013;69:40–46. 5 O’Connor MY, Thoreson CK, Ramsey NLM, et al. The uncertain significance of low vitamin D levels in African descent populations: A review of the bone and cardiometabolic literature. Prog Cardiovasc Dis. 2013;56:262– 269. 6 Hatun S, Islam O, Cizmecioglu F, et al. Subclinical vitamin D deficiency is increased in adolescent girls who wear concealing clothing. J Nutr. 2005;135:218–222. 7 Hata TR, Audish D, Kotol P, et al. A randomized controlled double-blind investigation of the effects of vitamin D dietary supplementation in subjects with atopic dermatitis. J Eur Acad Dermatol Venereol. 2013;28:781– 789. 8 Lagunova Z, Porojnicu AC, Lindberg F, et al. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res. 2009;29:3713–3720.

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Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:415–420

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Volume 15 • Issue 6

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Oral Mucosal Lesions in a Cross-Sectional Study of 200 Dermatologic Outpatients Nazim Hussain Syed, MD;1 Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond);2 Ashok Aggarwal, MD;1 Shruti Sehgal, MDS3 Abstract Oral mucosal lesions (OMLs) present with a variety of manifestations, emanating largely from tobacco chewing, smoking, and consumption of alcohol. Evolution of the lesions may be facilitated by poor oral hygiene and restorative dental materials, as well as by trauma, infections, and immune-mediated diseases. Two hundred consecutive patients seen at a pre-eminent dermatologic clinic formed the study group. They were interviewed about clinical manifestations, duration of the lesion, patient’s age and sex, and incriminating factors. After informed consent had been gained, a thorough clinical examination was performed to define the precise morphology, site, and distribution of lesions. Confirmation of the clinical diagnosis by histopathology and other relevant techniques was confirmed. (SKINmed. 2017;15:421–429)

disorders.3 Several factors, such as lifestyle, food habits, smoking, and/or tobacco chewing, have been incriminated. Geographic variations in the prevalence of OMLs are well recognized.4,5

BACKGROUND

Two hundred consecutive patients, drawn from skilled/educated and unskilled strata of society from both sexes and all age groups, presenting primarily with oral cavity lesions alone or with cutaneous complaints, were included after giving informed consent. A history of oral complaints, such as pain, burning sensation, discoloration, mass, and roughness, associated dermatologic and systemic conditions, were noted. Duration, age at onset, progression, site, distribution, and type of lesion were documented, in addition to aggravating and/or relieving factors. Past medical history involving hospitalization, major illness, sexually transmitted diseases, tuberculosis, drug intake, and associated allergic reactions were recorded. A note of any associated systemic disease(s) was made. Oral hygiene and periodontal status were analyzed as per the Greene and Vermillion criteria.6 Causative factors, such as tobacco, alcohol consumption, and dental amalgam (mercury), were analyzed. Dietary habits were considered, recording whether participants were vegetarian or nonvegetarian.

MLs are a commonly encountered clinical expression of local and/or systemic disorders, affecting women (51%) and men (49%) of all age groups. The chronicity of the lesions was the hallmark. Students, housewives, and skilled and unskilled workers were all its victims. The lesions could be classified into inflammatory, developmental, and neoplastic categories. A unique finding was a predisposition to lesions in nonvegetarian participants. Oral lichen planus (OLP) and Fordyce granules topped the list, followed by aphthous stomatitis and candidosis. An awareness of OMLs is paramount for practising dermatologists for early diagnosis and appropriate management strategies including periodic evaluation of the lesions.

The oral cavity and oropharynx comprise a vital pathway for food intake and vocalization. Their anatomic structure and physiologic functions are well known.1 The oral epithelium is formed of functional compartments corresponding to sites of cell division, maturation, and superficial cornification. Overt keratinization and granular cells are conspicuous by their absence in the buccal mucosa and floor of the mouth.2 The latter, therefore, is the diagnostic mirror of the body for several local and systemic

MATERIAL AND METHODS

From the Skin Institute and School of Dermatology, Greater Kailash, New Delhi,1 Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi,2 and Department of Conservative Dentistry and Endodontics, Government Dental College, Raipur,3 India Address for Correspondence: Virendra N. Sehgal MD, FNASc, FAMS, FRAS (Lond), Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi 110 033, India • E-mail: drsehgal@ndf.vsnl.net.in or sehgalvn@yahoo.com

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A thorough clinical inspection of the oral cavity was performed by dermatologists and oral pathologists according to World Health Organization guidelines.7 Close visual inspection using a head light and wooden tongue depressor was considered mandatory. Each of the anatomic regions of the oral cavity was palpated. The sites of involvement were divided into buccal and labial mucosa, floor of the mouth, tongue, lip, palate, and gingiva. The labial mucosa and floor of the mouth formed one group, the palate and gingiva the other. In addition, examination of the skin and skin appendages, mucous membranes of the genitalia, and conjunctiva was carried out as a part of a general physical examination.

workers, and 7% in professionals. The remaining 15.5% were seen in individuals engaged in other forms of work.

Incriminating factors These included tobacco and/or alcohol, dental amalgam (mercury), oral hygiene, and diet, and are summarized in Table III.

Clinical pattern Clinical manifestations Clinical manifestations associated with OML were recorded in 94 (47%) and were absent in 106 (53%) patients (Table IV).

Each of the morphologic changes was recorded by a colored photograph using a Sony 14 megapixel digital camera with 5× optical zoom in macro mode on a standard setting. The clinical data collected were divided into inflammatory, developmental, and neoplastic group.8 Histopathology and immunofluorescence were undertaken only when clinical features were not diagnostic. Tzanck smear and potassium hydroxide digestion/mount were performed wherever required. Ultimately, the proforma recordings were transferred onto SPSS software (Statistical Package for the Social Sciences, version 10.0; SSPS Inc., Chicago, IL) and subjected to statistical analysis.

Table I. Oral Mucosal Lesions: Distribution of Age Groups Clinical Classification

Age Groups 0–19

20–39

40–59

≥60

Count (n=130)

% within group

16.9

43.1

23.1

16.9

6.4

72.3

12.8

8.5

Count (n=23)

% within group

26.1

34.8

39.1

Count (n=200)

% within group

12.5

48.0

22.0

17.5

Inflammatory

Developmental

RESULTS

Count (n=47)

Demographic characteristics

% within group

Age and sex distribution Of the 200 patients, 102 (51%) were women and 98 (49%) were men (1:0.9). The mean age was 38.13 years (standard deviation 18.06 years). The age range was 9 to 87 years.

Neoplastic

Total

Age groups A total of 96 (48%) participants were 20 to 39 years, 44 (22.0%) were 40 to 59 years, 35 (17.5%) were 60 years and above, and 25 (12.5%) were younger than 20 years. Statistically, there were highly significant differences between the different age groups with respect to the type of OML (P<.05); these are outlined in Table I.

Duration Of the lesions, 113 (56.5%) had been present for less than a year (Table II), while 87 (43.5%) were of more than a year’s duration.

Occupation The frequency of occurrence of the lesions was 23% in students, 21.5% in housewives, 17% in skilled and 16% in unskilled SKINmed. 2017;15:421–429

422

P<.05

Table II. Oral Mucosal Lesions: Duration in Months Duration

Frequency

Percentage

<1 month

18.0

1–6 months

24.5

6 months–1 year

14.0

>1 year

43.5

Total

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Morphology This conformed to a plaque (38.5% of patients), ulcer/erosion (27.5%), papule/nodule (24.5%), or “other,” comprising a vesicle, mass, swelling, or fissure (9.5%).

Based on the morphology and site of the lesions, the OMLs were classified9,10 into inflammatory 130 (65.0%), developmental 47 (23.5%), and neoplastic 23 (11.5%). Some of these are shown in Figures 1 to 5. Their frequencies are detailed in Table V.

Site Buccal mucosa was involved in 73 (36.5%) of patients, followed by labial mucosa/floor of the mouth in 60 (30.0%), tongue in 47 (23.5%), lip in 38 (19.0%), and palate/gingiva in 36 (18.0%). Buccal mucosa, labial mucosa, and tongue were the most common sites for inflammatory lesions, whereas the lip was the frequent site for neoplastic lesions such as basal cell carcinoma, verrucous carcinoma, and other preneoplastic conditions like actinic cheilitis. Multiple sites, on the other hand, were involved in pemphigus vulgaris, erythema multiforme, bullous pemphigoid, and a few cases of OLP and candidosis.

Figure 1. Candidosis, depicting curdy-white lesions. Table III. Oral Mucosal Lesions: Incriminating Factors Frequency

Percentage

Tobacco

23.5

Alcohol

27.5

Both

16.0

Dental amalgam

14.5

Good

44.5

Poor/mediocre

111

55.5

Vegetarian

44.0

Non-vegetarian

112

56.0

Incriminating factors

Oral hygiene

Diet

Table IV. Oral Mucosal Lesions: Associated Symptoms Symptoms

Frequency (%)

Pain and burning

68 (34.0)

Roughness, tingling, and loss of taste

14 (7.0)

Bleeding

10 (5.0)

Difficulty in mouth opening

2 (1.0)

Figure 2. Benign migratory glossitis/geographic tongue with psoriasis vulgaris.

Symptoms were present in 94 (47.0%) and absent in 106 (53.0%). SKINmed. 2017;15:421–429

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Figure 3. Granulamatous cheilitis.

Figure 6. Section showing very few neutrophils and uncharacteristic spongiform pustule of benign migratory glossitis (geographic tongue) (hematoxylin and eosin stain, magnification ×10).

Figure 4. Fordyce granules on the buccal mucosa.

Figure 7. Aphthous stomatitis showing a fibrinopurulent membrane covering the ulcer area, with an intense inflammatory cell infiltrate and necrosis (hematoxylin and eosin stain, magnification ×10).

Histopathology

Figure 5. Verrucous carcinoma. SKINmed. 2017;15:421–429

This was performed in 149 (74.5%) patients. A diagnosis of herpes labialis was supported by a Tzanck smear and serology. Histopathology was performed in a patient with benign migratory glossitis who also had cutaneous psoriasis that revealed a psoriasiform pattern11 and a thickened layer of keratin infiltrated with neutrophils (Figure 6). Patients with aphthous ulcers showed features, such as fibrinopurulent membrane covering the ulcer area, intense inflammatory cell infiltrate, and necrosis (Figure 7). Among 15 (7.5%) participants with leukoplakia, one man had grade II dysplasia, and another showed verrucous carcinoma of the lower lip extending to the labial mucosa (Figure 8). Basal cell carcinoma showed islands and nests of basaloid cells, with

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Table V. Oral Mucosal Lesions: Clinical Diagnosis Oral conditions

Male n (%)

Female n (%)

Frequency

Percentage

Mean age

Oral lichen planus

13 (39.39)

20 (60.61)

16.5

44.25

Aphthous stomatitis

12 (40.00)

18 (60.00)

15.0

24.96

Candidosis (Figure 1)

9 (56.25)

7 (43.75)

8.0

60.00

Pyogenic granuloma

0 (0.00)

8 (100.00)

4.0

36.12

Pemphigus vulgaris

3 (37.50)

5 (62.50)

4.0

43.00

Benign migratory glossitis (Figure 2)

2 (28.57)

5 (71.43)

3.5

24.57

Herpes labialis

3 (50.00)

3.0

17.67

Mucocele

2 (40.00)

3 (60.00)

2.5

23.40

Vitiligo

1 (33.33)

2 (66.67)

1.5

24.33

Lichenoid reaction

1 (50.00)

1.0

51.00

Bullous pemphigoid

1 (50.00)

1.0

65.50

Granulomatous cheilitis (Figure 3)

2 (100.00)

0 (0.00)

1.0

21.00

Herpes stomatitis

1 (50.00)

1.0

43.50

Capillary hemangioma

0 (0.00)

2 (100.00)

1.0

25.50

Erythema multiforme

1 (50.00)

1.0

26.00

Molluscum contagiosum

0 (0.00)

1 (100.00)

0.5

27.00

BehĂ§et disease

0 (0.00)

1 (100.00)

0.5

22.00

51 (25.50)

79 (39.50)

130

65.0

Fordyce granules (Figure 4)

22 (66.67)

11 (33.33)

16.5

28.12

Glossal fissuring

7 (63.63)

4 (36.37)

5.5

52.10

Nevus of Ota

2 (66.67)

1 (33.33)

1.5

35.33

Subtotal

31(15.50)

16 (8.00)

23.5

Leukoplakia

10 (66.67)

5 (33.33)

7.5

50.00

Basal cell carcinoma

2 (66.67)

1 (33.33)

1.5

71.33

Submucosal fibrosis

2 (100.00)

0 (0.00)

1.0

27.00

Actinic cheilitis

2 (100.00)

0 (0.00)

1.0

59.50

Verrucous carcinoma (Figure 5)

1 (100.00)

0 (0.00)

0.5

57.00

Subtotal

17 (8.50)

6 (3.00)

11.5

Total

98 (49.00)

102 (51.00)

200

100.0

Inflammatory

Subtotal Developmental

Neoplastic

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Figure 10. Granulomatous cheilitis: epithelioid cells forming noncaseating granulomas (hematoxylin and eosin stain, magnification ×10).

Figure 8. Verrucous carcinoma of the labial mucosa (hematoxylin and eosin stain, magnification ×4).

Associated cutaneous manifestations Concurrent cutaneous association were present only in 42 (21.0%) patients. One patient with OLP presented with generalized widespread skin involvement, unusual diffuse hyperkeratosis of the palms and soles, and multiple sites of oral involvement.12 Patients with mucosal vitiligo had cutaneous depigmented lesions over the face, including the periorbital region. One patient had bilateral nevus of Ota involving both sides of the face and both sclera. Target lesions were present in patients with erythema multiforme, of whom one gave a history of herpes labialis 3 weeks prior to the onset of the mucosal lesions. Of the seven participants with benign migratory glossitis, only 1 man had generalized psoriasis. Vesiculo-bullous eruption in the right thoracic dermatome consistent with herpes zoster was noticed in a patient with oral candidosis. The frequency of associated skin illnesses is depicted in Table VI.

Figure 9. Molluscum contagiosum of the labial mucosa. Henderson-Paterson inclusions occupying the cells (hematoxylin and eosin stain, magnification ×4).

palisading at the periphery. A lichenoid reaction was present in two patients, associated with dental amalgam. Patients with OLP had associated oral candidosis, showing hyphae and mycelia in the superficial layers of epithelium in periodic acid-Schiff stain. Molluscum contagiosum, a rare buccal mucosal lesion, was seen in a 27-year-old woman. She presented with thickening and downgrowth of the epithelium with the formation of large eosinophilic intracytoplasmic inclusion bodies, Henderson-Paterson inclusions (Figure 9). Of 149 biopsies, two with persistent lip swelling and facial edema, histopathologically noncaseating granulomas were demonstrated in the dermis consistent with granulomatous cheilitis (Figure 10), one patient had an associated fissured tongue, recurrent lip and facial swelling, and intermittent facial nerve palsy, illustrating the triad of the rare neurologic disorder Melkersson-Rosenthal syndrome. SKINmed. 2017;15:421–429

DISCUSSION OMLs are one of the most challenging, frequently encountered bothersome manifestations of a wide range of local and systemic conditions, triggered by detrimental habits and socioeconomic conditions indigenous to a specific region. Hence its periodic assessment is the outcome of the current dissertation, the salient features of which are elaborated. The mean age of OML and the prevalence of women over men is intriguing, and conform to reports by from India,13 from Saudi Arabia,5 and from China.14 The female to male ratio in our study was 1:0.9, which is at variance with other reports15,16 and may be attributed to the increased incidence of smoking and tobacco chewing. Pain and burning were the common clinical manifestations associated primarily with the inflammatory group of lesions, con-

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sisting of aphthous stomatitis, erosive OLP, pemphigus vulgaris, bullous pemphigoid, erythema multiforme, herpes stomatitis, and Behçet disease/syndrome, in line with reports from others.4,14,17–19 In contrast, bleeding was explicit in pyogenic granuloma, capillary hemangioma, and basal cell carcinoma in the participants under review.

Table VI. Oral Mucosal Lesions: Associated Cutaneous Diseases Frequency

Percentage

178

89.0

Lichen planus (n=33)

3.0

The sites involved, in order of decreasing frequency, were the buccal mucosa, labial mucosa/floor of the mouth, tongue, lip, palate, and gingiva, which is consistent with additional reports.20,21 In a similar study,14 from the semiurban district of Vidisha in Central India, the most common sites involved were the right and left regions of the buccal mucosa, followed by the labial mucosa, tongue, gingiva, hard/soft palate, and alveolar mucosa.

Pemphigus vulgaris (n=8)

2.5

Nevus of Ota (n=3)

1.5

Bullous pemphigoid (n=2)

1.0

Vitiligo (n=3)

1.0

Erythema multiforme (n=2)

1.0

Psoriasis (in n=7 benign migratory glossitis patients)

0.5

Smoking, drinking, and chewing tobacco have positively been associated with oral submucous fibrosis, leukoplakia, and OLP, considered to have the potential for malignant transformation,7,22–24 which was amply demonstrated in the current study, where 23.5% of participants consumed tobacco, 27.5% alcohol, and 16.5% both. The frequency of alcohol and tobacco consumption was higher in men. These interesting findings are similar to those elaborated in the studies from Chennai, India,4 and from Italy.16

Herpes zoster (in n=16 candidosis patients)

0.5

200

100.0

In addition, dental amalgam or its components may cause type IV hypersensitivity reactions in the oral mucosa.25 Amalgam dental fillings contain mercury, silver, and other metals that may inadvertently be implanted into adjacent gingival, buccal, palatal, or lingual mucosa at the time of tooth restoration. A biopsy of the lesion may reveal interstitial accumulation of brown and black particles within the submucosa. A biopsy may confirm amalgam26 as the cause of OML. This substance was found to be associated with 14.5% of cases, more commonly with inflammatory OML, agreeing with earlier findings.27,28 Poor oral hygiene may be an important contributing factor for nonhealthy oral mucosa.18 In the current study, 55.5% of participants had poor or mediocre oral hygiene, which is almost consistent with the findings of Fleishman et al18 from Israel, while in a study from Italy,15 only 3% of patients showed good oral hygiene. In a Mexican study,29 70.93% of cases of OML were secondary to poor oral hygiene. A higher prevalence of OML in lower socioeconomic groups is now well accepted and has been attributed to bad oral hygiene.30 Poor hygiene can contribute to superinfection and complicate OML. A higher prevalence of oro-dental disorders has also been recorded in upper socioeconomic strata, secondary to the higher prevalence of binge (candy) eating.31 SKINmed. 2017;15:421–429

Cutaneous diseases Absent

Total

There have been reports32,33 of contact allergic reactions of the oral mucosa to foods, oral hygiene products, and dental materials. Dietary assessment of the patients in our study revealed that most of the patients were nonvegetarians, a unique finding being reported for the first time. Intraoral allergic reactions can result from potent flavoring agents, such as cinnamon, a highly flavoured spice and an essential ingredient of many nonvegetarian foods, candies, and chewing gum.34 OLP and Fordyce granules were the most common lesions, each contributing 16.5% of lesions. In contrast to a Mexican study35 in which the prevalence of OLP was reported to be 8.3%, another study from Iran36 reported a prevalence of 18.2%. The high frequency of OLP in the present study could be because of selection bias, with sociocultural factors such as the easy availability and financial affordability for the urban population of dental procedures, prosthesis, and smoking. Fordyce granules have been seen in only 0.6% of participants in one study;37 although others13,18 have reported higher occurrences. Pyogenic granuloma was exclusively seen in women, including during pregnancy, whereas leukoplakia, submucosal fibrosis, basal cell carcinoma, and fissured tongue were more common among men. The sex distribution in the current study is almost the same as reported in others. A PubMed search revealed that, the majority of the studies conducted in India and abroad come from dentistry and otolaryngology faculities,2,3,5,13,16,29,38–41 making the type and distribution of lesions likely to be different from those found in dermatology clinics.35 The finding of oral mol-

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luscum contagiosum was highly unusual, having only been sparingly reported before.42–44 Clinicopathologic correlation is an important parameter, and was successfully achieved. More often than not, the diagnosis was made on the basis of clinical findings supported by histopathology. Largely, the histopathologic features were found to be consistent with the clinical diagnosis. A few conditions did challenge the clinicopathologic correlation: oral molluscum contagiosum, granulomatous cheilitis, Melkersson-Rosenthal syndrome,45 benign migratory glossitis/geographic tongue,46 leukoplakia, and submucous fibrosis.47 CONCLUSIONS OMLs comprise a great variety of diseases affecting the oral cavity and oropharynx, including oral lichen planus, aphthous stomatitis, candidosis, pyogenic granuloma, pemphigus vulgaris, benign migratory glossitis, herpes labialis, mucocele, vitiligo, lichenoid reaction, bullous pemphigoid, granulomatous cheilitis, herpes stomatitis, capillary hemangioma, erythema multiforme, molluscum contagiosum, and Behçet disease. We have defined several demographic and morphologic characteristics, delineating their current status. This should not only create awareness of the condition, but also encourage the undertaking of studies aiming to develop management strategies. References 1 Sehgal VN, Syed NH, Aggarwal A, Sehgal S. Oral mucosal lesions: Oral cavity biology (Part 1). SKINmed. 2015;13:297–300. 2 Hume WJ, Potten CS. Advances in epithelial kinetics—an oral view. J Oral Pathol. 1979;8:3–22. 3 McCarthy FP, McCarthy PL. Diseases of the mouth: A statistical review of 4728 patients. N Engl J Med.1954;250:493–498. 4 Saraswathi TR, Ranganathan K, Shanmugam S, et al. Prevalence of oral lesions in relation to habits: Crosssectional study in South India. Indian J Dent Res. 2006;17:121–125. 5 Al-Mobeeriek A, AlDosari AM. Prevalence of oral lesions among Saudi dental patients. Ann Saudi Med. 2009;29:365–368. 6 Greene JC, Vermillion JR. The simplified oral hygiene index. J Am Dent Assoc. 1964;68:7–13. 7 Kramer IR, Pindborg JJ, Bezroukov V, Infirri JS. Guide to epidemiology and diagnosis of oral mucosal diseases and conditions. World Health Organization. Community Dent Oral Epidemiol. 1980;8:1–26. 8 Carpenter WM, Jacobsen PL, Eversole LR. Two approaches to the diagnosis of lesions of the oral mucosa. J Calif Dent Assoc. 1999;27:619–624. 9 Eversole LR. Clinical Outline of Oral Pathology: Diagnosis

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and Treatment. 2nd ed. Philadelphia: Lea & Febiger; 1984. 10 Regezi AR, Sciubba J. Oral Pathology: Clinical-Pathologic Correlations. 3rd ed. Philadelphia: WB Saunders; 1998. 11 Sehgal VN, Dogra S, Srivastava G, Aggarwal AK. Psoriasiform dermatoses. Indian J Dermatol Venereol Leprol. 2008;74:94–99. 12 Sehgal VN, Aggarwal A, Syed NH, et al. Palmoplantar keratoderma an exquisite variant of lichen planus. Skinmed. 2016;14:56–60. 13 Mathew AL, Pai KM, Sholapurkar AA, Vengal M. The prevalence of oral mucosal lesions in patients visiting a dental school in Southern India. Indian J Dent Res. 2008;19:99–103. 14 Lin HC, Corbet EF, Lo EC. Oral mucosal lesions in adult Chinese. J Dent Res. 2001;80:1486–1490. 15 Mehrotra R, Thomas S, Nair P, et al. Prevalence of oral soft tissue lesions in Vidisha. BMC Res Notes. 2010;3:23. 16 Campisi G, Margiotta V. Oral mucosal lesions and risk habits among men in an Italian study population. J Oral Pathol Med. 2001;30:22–28. 17 Vigild M. Oral mucosal lesions among institutionalized elderly in Denmark. Community Dent Oral Epidemiol. 1987;15:309–313. 18 Fleishman R, Peles DB, Pisanti S. Oral mucosal lesions among elderly in Israel. J Dent Res. 1985;64:831–836. 19 Cebeci AR, Gülsahı A, Kamburoglu K, Orhan BK, Öztas B. Prevalence and distribution of oral mucosal lesions in an adult Turkish population. Med Oral Patol Oral Cir Bucal. 2009;14:E272–E277. 20 Jáhn M, Schmidt J, Fejérdy L, et al. The prevalence of oral mucosal lesions in Hungary. Fogorv Sz. 2007;100:59– 63. 21 Gonçalves LM, Bezerra Júnior JR, Cruz MC. Clinical evaluation of oral lesions associated with dermatologic diseases. An Bras Dermatol. 2010;85:150–156. 22 Gangadhran P, Paymaster JC. Leukoplakia—An epidemologic study of 1504 cases observed at the Tata Memorial Hospital, Bombay, India. Br J Cancer. 1971;25:657–668. 23 Gupta PC, Mehta FS, Daftary DK, et al. Incidence rates of oral cancer and natural history in a 10-year follow up study of Indian villages. Community Dent Oral Epidemiol. 1980;8:283–333. 24 Gupta PC, Bhonsle RB, Murti PR, et al. An epidemologic assessment of cancer risk in oral precancerous lesions in India with special reference to nodular leukoplakia. Cancer. 1989;63:2247–2252. 25 Aggarwal V, Jain A, Kabi D. Oral lichenoid reaction associated with tin component of amalgam restorations: A case report. Am J Dermatopathol. 2010;32:46–48. 26 Dubach P, Caversaccio M. Images in clinical medicine. Amalgam tattoo. N Engl J Med. 2011;364:e29. 27 MacEntee MI, Glick N, Stolar E. Age, gender, dentures and oral mucosal disorders. Oral Dis. 1998;4:32–36. 28 da Silva SR, Valsecki Júnior A. Evaluation of oral health conditions among the elderly in a Brazilian city. Rev Panam Salud Publica. 2000;8:268–271.

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29 Espinosa-Zapata M, Loza-Hernández G, Mondragón-Ballesteros R. Prevalence of buccal mucosa lesions in pediatric patients. Preliminary report. Cir Cir 2006;74:153– 157. 30 World Health Organization: Epidemiology, etiology, and prevention of periodontal diseases. WHO Technical Report Series No. 621. Geneva: WHO; 1978. 31 Doifode VV, Ambadekar NN, Lanewar AG. Assessment of oral health status and its association with some epidemiological factors in population of Nagpur, India. Indian J Med Sci. 2000;54:261–269. 32 Eriksson NF, Formgren H, Svenonius E. Food hypersensitivity in patients with pollen allergy. Allergy. 1982;37:437–443. 33 Amlot PL, Kemeny DM, Zachary C, Parkes P, Lessof MH. Oral allergy syndrome (OAS): Symptoms of IgE mediated hypersensitivities to foods. Clin Allergy. 1987;17:33– 42. 34 Miller RL, Gould AR, Bernstein ML. Cinnamon-induced stomatitis venenata clinical and characteristic histopathologic features. Oral Surg Oral Med Oral Pathol. 1992;73:708–716. 35 Ramírez-Amador VA, Esquivel-Pedraza L, Orozco-Topete R. Frequency of oral conditions in a dermatology clinic. Int J Dermatol. 2000;39:501–505. 36 Pakfetrat A, Javadzadeh-Bolouri A, Basir-Shabestari S, Falaki F. Oral lichen planus: A retrospective study of 420 Iranian patients. Med Oral Patol Oral Cir Bucal. 2009;14:E315–E318. 37 Corbet EF, Holmgren CJ, Philipsen HP. Oral mucosal lesions in 65–74-year-old Hong Kong Chinese. Community Dent Oral Epidemiol. 1994;22:392–395.

38 Eveson JW, Scully C. Colour Atlas of Oral Pathology. London: Mosby; 1995. 39 Shulman JD, Beach MM, Rivera-Hidalgo F. The prevalence of oral mucosal lesions in U.S. adults: Data from the Third National Health and Nutrition Examination Survey, 1988–1994. J Am Dent Assoc. 2004;135:1279– 1286. 40 Shulman JD. Prevalence of oral mucosal lesions in children and youths in the USA. Int J Paediatr Dent. 2005;15:89–97. 41 Jahanbani J, Sandvik L, Lyberg T, Ahlfors E. Evaluation of oral mucosal lesions in 598 referred Iranian patients. Open Dent J. 2009;3:42–47. 42 Hanson D, Diven DG. Molluscum contagiosum. Dermatol Online J. 2003;9:2. 43 Connell CO, Oranje A, Van Gysel D, Silverberg NB. Congenital molluscum contagiosum: Report of four cases and review of the literature. Pediatr Dermatol. 2008;25:553–556. 44 Fornatora ML, Reich RF, Gray RG, Freedman PD. Intraoral molluscum contagiosum: A report of a case and a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92:318–320. 45 El-Hakim M, Chauvin P. Orofacial granulomatosis presenting as persistent lip swelling: Review of 6 new cases. J Oral Maxillofac Surg. 2004;62:1114–1117. 46 Barton DH, Spier SK, Crovello TJ. Benign migratory glossitis and allergy. Pediatr Dent. 1982;4:249–250. 47 Corrêa L, Frigerio ML, Sousa SC, Novelli MD. Oral lesions in elderly population: A biopsy survey using 2250 histopathological records. Gerodontology. 2006;23:48– 54.

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Volume 15 • Issue 6

ORIGINAL CONTRIBUTION

Characterization of Patients’ Quality of Life and Experience in the Course of Acne Treatment Robert L. Skaggs, II, BS;1 Emily Hix, BA;1 Karen E. Huang, MS;1 Steven R. Feldman, MD, PhD1,2,3 Abstract Few studies provide qualitative data on the acne treatment experience. This study describes patients’ personal experiences of acne treatment. Video interviews were made of 27 teenagers and young adults with acne treated for 12 weeks with adapalene/benzoyl peroxide gel. Transcripts were then coded and qualitatively analyzed. Four thematic domains affecting quality of life and experience were identified: clinical manifestations, self-perception, social placement, and perception of control. Successful treatment increased self-esteem and performance at work and school. Successful acne treatment improves patients’ quality of life by improving appearance and self-perception, satisfaction with social placement, and perception of control. (SKINmed. 2017;15:431–435)

cne vulgaris has broad psychosocial effects, reducing self-esteem and mood, which can lead to anxiety, depression, or even suicidal ideation.1–3 Acne affects quality of life similarly to systemic diseases such as epilepsy or diabetes.4–6 Quantitative studies of acne impact may miss nuances of patient experiences with acne. Qualitative studies can be complementary, but current literature has limited qualitative findings assessing acne.1,7–11 This contribution aims to identify key themes and factors that influence the life quality of patients with acne. METHODS Video transcripts were collected at baseline and weeks 4, 8, and 12 of treatment from 27 of 30 subjects who participated in an acne clinical trial with adapalene/benzoyl peroxide gel (Epiduo® Gel, Galderma Laboratories, L.P., Fort Worth, TX) after informed consent had been obtained (Clinical Trials.gov registration number: NCT01209949).12 The patients were asked questions regarding the impact of treatment on their quality of life and perception of effectiveness (Table). K.E.H and E.H. reviewed the transcripts, developed a set of themes, and co-coded 10% of the transcripts, analyzing patients’

subjective responses.13 Baseline codes included symptoms, side effects, daily routine, appearance, self-esteem, emotional changes, social norms/schemas, general social effects, perception of control, and effects of the treatment. After each researcher had independently coded one half of the remaining transcripts, they agreed upon a final coding structure. Intercoder reliability was determined from coding an additional 10% of transcripts. The coding was managed by Weft QDA software (version 1.0.1, available from https://www.pressure.to/qda). After coding had been finalized, R.L.S. read each transcript from each participant twice by looking at all patients within a survey week, and then looking across each week for each patient. Finally, R.L.S. used the thematically coded data to form larger domains. Thematic domains identified were physical appearance, self-perception, social placement, and perception of control. RESULTS The interviewees were predominately men (n=19, 70%), with ages ranging from 15 to 21 years (average 17.4 years). At baseline, two-thirds of patients (n=18) had moderate acne and onethird (n=9) had mild acne according to investigator global assessment scoring.12 Intercoder reliability was 86%.

From the Department of Dermatology,1 Department of Pathology,2 and Department of Public Health Sciences,3 Center for Dermatology Research, Wake Forest School of Medicine, Winston-Salem, NC Address for Correspondence: Karen E. Huang, MS, Department of Dermatology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1071 • E-mail: khuang@mail.harvard.edu

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Table. Questions Asked at Each Visit Baseline 1. How long have you had acne? 2. Which of the following words would you use to describe your acne: clear, almost clear, mild, moderate, or severe? 3. Tell me how acne has affected your life. 4. Has acne affected your daily activities in any way like going to school or work or anything? 5. Has acne affected your appearance in any way in like how you wear your hair, how you dress, or anything? 6. Tell me about what treatment you tried for your acne. 7. What have you liked about those treatments? 8. How long have you used any of those treatments? 9. What face soaps or cleansers are you using, and what do you like about those? 10. How would your life change if you no longer had acne? 11. How does your acne bother you? 12. On a scale from one to five with one meaning not at all and five meaning totally, how would you rate the control you have over your acne today? Weeks 4, 8, and 12 1. Tell me how your acne has changed since your last visit. 2. Do you think your skin condition has improved, remained the same, or become worse? 3. Which of the following words would you use to describe your acne now: clear, almost clear, mild, moderate, or severe? 4. Were you bothered by how your face felt after using [the treatment]? 5. [Since the last time we took your picture—baseline] Have you noticed any changes since this photo was taken? 6. Since you took this photo [baseline], has your social life changed in any way? 7. Since this photo [baseline] was taken, how do you feel about how you look? 8. Since the [baseline] photo was taken, how do you feel about going to school or work now? 9. Since this photo [baseline] was taken, did you change your hairstyle? And did you do it on purpose? 10. Have other people noticed a change in you? 11. Tell me what did you think of [the treatment]. 12. Is [the treatment] easy to use? 13. On a scale from one to five with one meaning not at all and five meaning totally, how would you rate the control you have over your acne today? Week 12: Additional questions 1. If you had a choice, would you continue to use [adapalene/benzoyl peroxide gel] to treat your acne? 2. What have you told your friends or family about [this treatment]? 3. Have you recommended [this treatment] to anyone? 4. How satisfied are you with [adapalene/benzoyl peroxide gel] as a treatment for acne?

Physical domain Almost every patient interviewed complained about the physical appearance of his or her acne: “I don’t like the little bumps on my face. It looks nasty to me. I pop them when they get big because I just don’t like the way that they look, but then they look worse after that.” Along with being frustrated with their appearance, some patients mentioned pain, itching, and burning as clinical manifestations of their disease. One of the most common themes in baseline interviews was how acne had caused patients to alter their appearance or daily routine. Patients described growing their hair out longer than usual to cover the acne on their forehead. One SKINmed. 2017;15:431–435

patient made a dramatic change to alter her appearance to take the attention away from her acne, changing from a conservative hairstyle and general appearance to a “gothic” style of hair and clothing. Acne caused most patients to spend more time putting on makeup, fixing their hair, and choosing their clothing when they had flares of their disease. Patients reported constantly checking their appearance and spending time touching up their face. Acne treatment resulted in beneficial changes, including less visible disease, worry about blemishes, and time spent on daily acne routine. Every patient noticed a positive change in their appearance including fewer comedones, less inflammation, and fewer sequelae of disease.

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Self-perception domain Not only did acne cause patients to alter their appearance, it also changed the way they felt about themselves. Patients were less confident and more self-conscious when they had acne flares: “it’s just a constant reminder that I’m not looking my best … so you know, every time you just kind of look at yourself. It’s always just nagging at you.” Patients reported that dealing with acne kept them from expressing themselves as they would if they had clearer skin. Constant worrying about acne was emotionally distressing for patients. They often mentioned being embarrassed, “touchy” or irritable, stressed out, and frustrated about their acne. Some patients expressed negative acne-related emotions, including dramatically affected moods and depression-like features. Patients who gained control of their acne and had clearer skin dramatically changed how they viewed themselves. Many patients described having increased confidence in themselves and no longer feeling embarrassed about their acne. In addition to better health, clearer skin led to better performance in work and school because of increased self-confidence and less fear of judgment from authority figures. Acne caused patients to have low self-esteem, negative body-image, and constant concern about their appearance. Successful treatment resulted in more self-confidence and emotional stability for patients with acne. Social placement Before acne treatment, patients had difficulties in their social life. Avoiding situations where patients would have to interact with friends, peers, and coworkers was common. Patients reported altering their personalities and compromising their interpersonal skills to the point that normal interactions were not possible: “it has affected my social life dramatically. I don’t really go out much. My friends only see me rarely outside of the house. I go out at night, so you can’t really see the acne, and I don’t know how to put on makeup, so I can’t cover it up.” Everyday conversations were difficult sometimes for patients because criticism or body language from peers drove them to feel dirty and judged. Patients also reported that conversations with those whom they wanted to date were very difficult to initiate because of the patient’s fear of what the other person would think of their acne. Patients with acne expressed pessimistic or skewed schemas, such as believing that they were not as good as people without acne, and believing everyone else in the world was acne-free. Successful acne treatment resulted in striking changes in acne patients’ social lives. Patients felt more confident with better SKINmed. 2017;15:431–435

control of their acne, which made them more outgoing and helped them interact in ways they previously felt they could not because of their acne: “I’m pretty much out there and playing football, soccer, basketball for the first time and I won. I feel like a champion.” In their interviews, patients expressed more positive and elaborate responses about their peers’ and families’ comments than about their own observations about changes in their acne. Not only did patients receive compliments on their clearer complexion, they also received feedback about how their personality had changed since treatment began. As their acne improved, patients reported being bullied less and accepted more in social settings. Perception of control At baseline, the majority of patients were despondent because they had very little control over their acne: “I really can’t control it. It’s just no matter what I do. It’s there, I can’t get rid of it. I can’t slow it down, or fade it away, or anything.” Adequate treatment resulted in patients having much better perceived control of their acne and satisfaction with their acne clinical manifestations. Regardless of how patients graded their own acne qualitatively at each visit, they were happy when they believed they had gained better control of their disease. Some patients actually gave themselves the same or poorer qualitative assessments of their acne compared with baseline, but were happier with their acne because of their increased control. For example, one patient who reported the same qualitative assessment of their acne as at baseline said: “ever since I’ve been using [the treatment] my control over my acne has improved. I feel like I have pretty much complete control over my acne now.” Although treatment sometimes quickly resulted in clearer skin, some patients did not report increased quality of life until they felt they had control of their acne. By week 4, most patients described their own skin as clearer than at week 0; however, it was not until weeks 8 and 12 that many of these patients began to describe increased quality of life that correlated with better perceived control (Table). Additionally, several patients were more satisfied with study treatment and more likely to recommend the product when they felt like they had control of the clinical manifestations of their acne. DISCUSSION Our data corroborate previous findings that acne affects patients’ performance at school, in their vocation, and, most notably, in social settings. The physical appearance of acne and the associated clinical manifestations cause patients to feel distress, re-

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shape their image, and alter their appearance to cover up their acne. Acne treatment results in better control of the disease, clearer skin, a decrease in the extraneous activities involved in acne management, a return to normal appearance style, as well as increased performance at work and school. Improved selfperception helps patients express themselves without the feeling of shame that burdened them during acne flares. Preoccupation with acne causes patients to alter their personalities and social outings to keep attention away from themselves. Patients with acne most commonly suffer from a perception of “antisocial” teasing, which is demoralizing. This “antisocial” teasing often results in patients developing a schema that “normal people” have clear skin, and that to have acne deems you to be of lesser value than those with clear skin. With treatment, patients report less frequently bullying and greater acceptance into their social groups. The degree to which patients believe their disease or treatment is under their own control can be characterized using a description of internal-external locus of control. Patients with an internal locus of control believe that their disease is largely under their own control, while those with an external locus of control believe their disease is mostly controlled by luck or other forces.14 A previous study reported that self-efficacy or an internal locus of control could attenuate the psychological sequelae of acne, and that quality of life was driven by perception of an internal locus of control as opposed to realization of disease improvement.1 Patients were less confident during previous regimens that involved multiple or complicated steps, and long treatment times. They reported difficulty adhering to these routines. Alternatively, those interviewed commonly mentioned ease of use as a positive aspect that they associated with increased control of their acne. Simplifying routines leads to better adherence, which results in better treatment response and an internal locus of control.15,16 Helping patients achieve this increased perceived control is very important in quality of life improvement.

CONCLUSIONS Although acne vulgaris is sometimes considered a cosmetic problem, patient suffering extends beyond cosmetic concerns.1,2,9 Physicians can address these issues with psychological support along with a focus on providing a manageable treatment plan for acne to avoid more serious complications such as anxiety and depression.2,3 Physicians can improve the quality of life of patients with acne and increase patient satisfaction by helping them attain an internal locus of control of their acne with a successful and sustainable treatment strategy. DISCLOSURES This study was funded by a grant from Galderma Laboratories, L.P. The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Stephen R. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, PhotoMedex, Genentech, Biogen Idec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, PhotoMedex, Genentech, Biogen Idec, Coria/Valeant, PharmaDerm, Ortho Pharmaceutical, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor, and has received stock options from PhotoMedex. Robert L. Skaggs, Emily Hix, and Karen E. Huang have no conflicts of interest to disclose. References

For our analysis, our good intercoder reliability score of 86% suggests consistent categorization of text by our two coders.13 This study is limited by possible self-reporting bias due to the data coming solely from patient descriptions. Another limitation is that this study is a single-center study, but we speculate this is a minor limitation because other patients probably experience similar social interactions and problems. The findings may not be generalizable to individuals who do not seek medical care for their acne. Such individuals not seeking help may have a lesser or greater burden of disease, and consequently may experience different qualities of life. SKINmed. 2017;15:431–435

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1 Magin P, Adams J, Heading G, Pond D, Smith W. Psychological sequelae of acne vulgaris: Results of a qualitative study. Can Fam Physician. 2006;52:978–979. 2 Dunn LK, O’Neill JL, Feldman SR. Acne in adolescents: Quality of life, self-esteem, mood, and psychological disorders. Dermatol Online J. 2011;17:1. 3 Bowe WP, Doyle AK, Crerand CE, Margolis DJ, Shalita AR. Body image disturbance in patients with acne vulgaris. J Clin Aesthet Dermatol. 2011;4:35–41. 4 Mallon E, Newton JN, Klassen A, et al. The quality of life in acne: A comparison with general medical conditions using generic questionnaires. Br J Dermatol. 1999;140:672–676. 5 Dalgard F, Gieler U, Holm JO, Bjertness E, Hauser S. Selfesteem and body satisfaction among late adolescents with acne: Results from a population survey. J Am Acad Dermatol. 2008;59:746–751. 6 Uhlenhake E, Yentzer BA, Feldman SR. Acne vulgaris and depression: A retrospective examination. J Cosmet Dermatol. 2010;9:59–63. 7 Magin P, Adams J, Heading G, Pond D. ‘Perfect skin’, the media and patients with skin disease: A qualitative study

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of patients with acne, psoriasis and atopic eczema. Aust J Prim Health. 2011;17:181–185. 8 Magin P, Heading G, Adams J, Pond D. Sex and the skin: A qualitative study of patients with acne, psoriasis and atopic eczema. Psychol Health Med. 2010;15:454–462.

ing adapalene-benzoyl peroxide gel in the treatment of acne vulgaris. J Drugs Dermatol. 2012;11:919– 925. 13 Miles M, Huberman A. Early steps in analysis. Qualitative Data Analysis: An Expanded Sourcebook. 2nd ed. Thousand Oaks, CA: Sage Publications; 1994:64.

9 Magin P, Adams J, Heading G, Pond D, Smith W. Experiences of appearance-related teasing and bullying in skin diseases and their psychological sequelae: Results of a qualitative study. Scand J Caring Sci. 2008;22:430–436.

14 Rotter J. Generalized expectancies for internal versus external control of reinforement. Pychol Monogr. 1966;80:1–28.

10 Magin P, Adams J, Heading G, Pond D, Smith W. The causes of acne: A qualitative study of patient perceptions of acne causation and their implications for acne care. Dermatol Nurs. 2006;18:344–349, 370.

15 Yentzer BA, Alikhan A, Teuschler H, et al. An exploratory study of adherence to topical benzoyl peroxide in patients with acne vulgaris. J Am Acad Dermatol. 2009;60:879–880.

11 Pruthi GK, Babu N. Physical and psychosocial impact of acne in adult females. Indian J Dermatol. 2012;57:26–29.

16 Yentzer BA, Ade RA, Fountain JM, et al. Simplifying regimens promotes greater adherence and outcomes with topical acne medications: A randomized controlled trial. Cutis. 2010;86:103–108.

12 Feldman SR, Fried RG, Herndon JH, Jr., et al. Digital videography assessment of patients’ experiences us-

Decisions Decisions Decisions As clinicians, we are constantly making decisions. Medical decisions of course, but also legal decisions at times and even (blush) financial decisions. The ethical decisions are often the most confounding because the rules are not as clear cut as the law proscribes and the moral economics not as obvious as monetary calculations. With this feature, Rash Decisions, SKINmed introduces a forum to consider some of the ethical decisions we must make in our daily practice of dermatology. The Editors welcome any suggestions regarding ethical dilemmas to be considered in upcoming issues and are open to guest columnists who would like to offer their own opinion about specific issues in ethics. Please send inquiries or submissions to Mark Bernhardt MD at cheesedb@aol.com and include “Rash Decisions” in the tagline. About the Logo The ostrich feather is the symbol for the ancient Egyptian concept of “maat”. Maat is usually translated as truth or justice. The most common representation of maat is when it is shown in a scale with a human heart on the other side. When a person dies the dog-headed god Anubis weighs their heart against a single feather. If the person has lived a god, just life their heart does not outweigh maat and they may enter the eternal afterlife.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 13th World Congress of the International Academy of Cosmetic Dermatology Dubrovnik, Croatia June 28–July 1, 2018 Abstract deadline: March 31, 2018 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28–July 1, 2018. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, and cosmetic (or combined) in nature. The author whose abstract obtains the highest score during the review process will receive a scholarship by the IACD to present the full paper at the 13th World Congress of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from June 28-July 1, 2018. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Please submit your case report abstract via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, March 31, 2018. The abstract should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been, or is in consideration for, publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31, 2018. The applicant must be in training at the time of the Congress presentation. All applicants will receive e-mail notice of the Resident Case Report Review Committee’s decision by May 1, 2018. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Professor and Chief The University of Chicago Pritzker School of Medicine Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

November/December 2017

Volume 15 • Issue 6

ORIGINAL CONTRIBUTION

Safety and Antipruritic Efficacy of a Menthol-Containing Moisturizing Cream Hong Liang Tey, MBBS, FRCP(Edin); Evelyn Yuxin Tay, MBBS, MRCP(UK); Wei Ding Tan, MSc Abstract Itch is frequently associated with dermatoses characterized by a defective skin barrier. We formulated an itch-relieving moisturizing cream containing 3% menthol and ceramides. Our aim was to evaluate the safety and antipruritic efficacy of application of this cream in volunteers with and without skin diseases. Volunteers were asked to apply the cream for 1 month on a minimum body surface area of 6%. Safety was assessed by the absence of contact dermatitis or other side effects, using a self-administered questionnaire completed at 5 minutes, 1 week, and 1 month after application. To determine efficacy, volunteers with pruritic dermatoses were asked to grade their average itch intensity at baseline, 1 week, and 1 month after application. Sixty volunteers were recruited, of whom 41 had no skin disease; no adverse events were reported in the latter. Of the 19 volunteers with dermatoses, 18 reportedly had atopic dermatitis. One of the 60 volunteers stopped application due to stinging sensations induced by menthol. Itch scores of volunteers with dermatitis improved from baseline at 1 week (P=.01) and 1 month (P<.01) after application. Application of a 3% menthol-containing moisturizing cream was safe in healthy individuals and participants with dermatitis. In the latter, itch scores were significantly reduced during follow-up. (SKINmed. 2017;15:437–439)

tch is the major cause of morbidity and the most frequently encountered clinical manifestation in dermatology, especially in diseases characterized by a defective skin barrier.1,2 A prototypic example is atopic dermatitis (AD), which affects 20% of children and 10% of adults.3,4 A study found that 87% of patients with AD experience pruritus on a daily basis for a mean duration of 10 years.5 Menthol is a naturally occurring alcohol known to have antiitch properties against the various types of cutaneous itch. It activates transient receptor potential M8 ion channels on cutaneous nerves to induce the same cooling sensation as low temperatures, which inhibits the transmission of itch signals.6,7 Despite centuries of use of menthol in medicine, there remains limited literature on the safety of menthol application in dermatitis, and the optimal concentration of menthol to be included in a moisturizer. In addition to menthol, application of moisturizers relieves pruritus through an improvement in skin barrier function.8 Mois-

turizers have demonstrated efficacy in reducing the use of topical corticosteroids, as well as the frequency and severity of AD flares.9 Ceramide-dominant moisturizers, formulated to mimic the natural skin-moisturizing factors and lipids deficient in AD, have shown promise in reducing transepidermal water loss and improving the expression of antimicrobial peptides in AD skin.10 Despite the purported benefits, adherence to regular application of moisturizers in chronic skin diseases is poor.11 One of the reasons is that the positive effects of adequate moisturizing are not immediate and are only evident to patients after prolonged usage. In this study, we report the use of a novel topical cream comprising 3% menthol in a moisturizer base. The latter includes ceramides (0.5% CeraSkin O; Bionest, Taiwan) and a ceramidelike emollient (phytosteryl/octyldodecyl lauroyl glutamate). Our primary aim was to evaluate the safety of regular application of the above-mentioned topical cream over a wide surface area and over a prolonged period of time in volunteers with and without skin diseases. A secondary endpoint was to assess its antipruritic efficacy in volunteers with pruritic skin diseases.

From the National Skin Centre, Singapore Address for Correspondence: Hong Liang Tey, MBBS, FRCP(Edin), National Skin Centre, 1 Mandalay Road, Singapore 308205 • E-mail: teyhongliang111@yahoo.com

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METHODS Individuals with and without skin problems were invited to participate in our study. The volunteers were instructed to apply the cream regularly at least twice daily for a month, over a total body surface area of at least 6%. The individual’s palm was used as a reference for 1% of the individual’s body surface area. Volunteers with skin diseases were asked to apply the cream over their dermatoses and also to continue their usual treatment. Safety of application was assessed by absence of the development of contact dermatitis or other side effects (besides the cutaneous sensation induced by menthol). Contact dermatitis was defined in this analysis as the development of itch/pain and redness that prohibited further application. The volunteers were required to complete a written questionnaire at 5 minutes, 1 week, and 1 month after application. The questionnaire assessed if there was any itch, pain, or redness after application. Volunteers were instructed to write down any other side effects and to provide additional feedback. In addition, volunteers with skin problems were required to grade the average intensity of itch experienced over the preceding week on a numerical scale of 1 to 10. This was assessed at baseline and at 1 week and 1 month after application. The differences in itch scores between baseline and 1 week and 1 month after application was analysed using the Wilcoxon signed-rank test. RESULTS A total of 60 volunteers were recruited, of whom 41 (68.3%) had no skin disease and 19 (31.7%) had self-reported pre-existing skin disease. The demography of the volunteers is presented in Table I.

In volunteers without skin disease, 1 out of 41 (2.4%) stopped application after 1 week as the participant did not like the sensation induced by the cream; however, she used the cream subsequently to effectively soothe her sunburn with no development of adverse effects. The rest of the volunteers tolerated application of the cream and did not develop contact dermatitis. No other side effects were reported. Of the 19 volunteers with skin disease, 18 (94.7%) had atopic dermatitis, and one (5.3%) had epidermolysis bullosa pruriginosa. One participant with dermatitis stopped after the first application upon experiencing a stinging sensation. This subject, however, did not report any itch or redness. The remaining 18 volunteers completed 1 month’s application of the cream. None developed features of contact dermatitis except for one volunteer with dermatitis on the neck. After application, this subject developed mild itch (itch score of 1/10) in association with moderate pink skin coloration. These clinical manifestations developed and resolved spontaneously within 15 minutes after every application. This participant’s itch score improved from 3/10 at baseline to 1/10 at 1 week and 1/10 at 1 month after regular application. There were otherwise no adverse effects reported by the volunteers. Seventeen out of 19 volunteers (89.5%) had their itch scores analyzed. One participant had stopped after the first application (mentioned above), and another had not filled in the itch scores. The mean itch score improved from 4.3 at baseline to 2.9 at 1 week (P<.01), and to 2.0 at 1 month (P<.01). A subgroup analysis was performed on the 16 individuals with atopic dermatitis, and their mean itch scores was found to improve from 4.1 at baseline to 2.7 at 1 week (P=.01), and 1.8 at 1 month (P<.01) (Table II).

Table I. Demography of Volunteers (n=60) Volunteers Without Skin Disease (n=41)

Volunteers With Skin Disease (n=19)

7 to 67

9 to 74

28 (68.3)

11 (57.9)

36 (87.8)

19 (100)

Malay

2 (4.9)

0 (0)

Indian

1 (2.4)

0 (0)

Eurasian

1 (2.4)

0 (0)

Caucasian

1 (2.4)

0 (0)

Age range (years) Male (%) Ethnicity Chinese

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Table II. Subgroup Analysis of Itch Scores in 16 Volunteers Who Reported Having Atopic Dermatitis Average Itch Intensity Over Preceding Week: Itch Score, 0 to 10

Baseline

One Week After Cream Application

One Month After Cream Application

Mean ± SD

4.1 ± 2.7

2.7 ± 2.7

1.8 ± 2.3

.0129

.0085

P-value for test of difference from baseline (Wilcoxon signed-rank test ) Abbreviation: NA, not applicable.

DISCUSSION

References

A rationale for development of the formulation was to address the intricately related problems of itch and skin barrier defect in many skin diseases, such as the various forms of dermatitis and asteatosis associated with advanced aging, renal disease, diabetes mellitus, and human immunodeficiency virus infection. When this formulation was used in our clinical practice, we observed that the fast onset of itch relief experienced from applying the cream provided patients with positive feedback to use the cream again. First, this improves the compliance of our patients with the use of moisturizers, which is known to be a major issue in the management of atopic dermatitis.11 Second, although the antipruritic effect of the menthol was temporary, with repeated application of the cream, the moisturizer base served to repair the underlying skin barrier defect and led to sustained relief from itch. We found such a psychotherapeutic approach to be clinically effective in the management of pruritic dermatoses associated with a skin barrier defect. A limitation of our study was the self-reported nature of the data in relation to the diagnosis of skin disease and the adverse effects encountered from topical application. CONCLUSIONS The results indicated that application of a 3% menthol-containing moisturizing cream was safe in healthy individuals and individuals who reported having atopic dermatitis. In the latter, there was a significant reduction in itch scores after 1 week and 1 month. ACKNOWLEDGMENT Good Pharmaceutical Pte Ltd, Singapore, provided the topical agent used in the study. SKINmed. 2017;15:437–439

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1 Kini SP, DeLong LK, Veledar E, et al. The impact of pruritus on quality of life. Arch Dermatol. 2011;147:1153–1156. 2 Weisshaar E, Matterne U. Epidemiology of itch. In: Carstens E, Akiyama T, eds. Itch: Mechanisms and Treatment. Boca Raton, FL: CRC Press; 2014:1–14. 3 Asher MI, Montefort S, Bjorksten B, et al. Worldwide trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood. ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–743. 4 Silverberg Jl, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: A US population-based study. J Allergy Clin Immunol. 2013;132:1132–1138. 5 Yosipovitch G, Goon ATJ, Wee J, et al. Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int J Dermatol. 2002;41:212–216. 6 Peier AM, Moqrich A, Hergarden AC, et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–717. 7 McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–58. 8 Patel T, Yosipovitch G. Therapy of pruritus. Expert Opin Pharmacother. 2010;11:1673–1682. 9 Hon KL, Leung AKC, Barankin B. Barrier repair therapy in atopic dermatitis: An overview. Am J Clin Dermatol. 2013;14: 389–399. 10 Park KY, Kim DH, Jeong MS, et al. Changes of antimicrobial peptides and transepidermal water loss after topical application of tacrolimus and ceramide-dominant emollient in patients with atopic dermatitis. J Korean Med Sci. 2010; 25:766–771. 11 Lee IA, Maibach HI. Pharmionics in dermatology: A review of topical medication adherence. Am J Clin Dermatol. 2006;7:231–236.

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Hyaluronic Acid in Dermatology Mohammad Abid Keen, MD Abstract Hyaluronic acid (HA) is a major component of the extracellular matrix of the skin and plays an important role in the metabolism of the dermis. It has a key position in wound healing and tissue repair processes owing to its ability to maintain a humid environment favorable to healing and the stimulation of growth factors, cellular constituents, and the migration of various cells essential for healing. This review aims to describe brieﬂy the physical, chemical, and biologic properties of HA, together with some details of the dermatologic indications of this unique molecule. (SKINmed. 2017;15:441–448)

n 1934, Karl Meyer (1899–1990) and his colleague John W. Palmer isolated a chemical substance from the vitreous jelly of cow’s eyes.1 They proposed the name hyaluronic acid, as it was derived from hyaloid (vitreous) and contained two sugar molecules, one of which was uronic acid.2 HA was first employed commercially in 1942 when Endre Balazs applied for a patent to use it as a substitute for egg white in bakery products.2 It is present in the intercellular matrix of most vertebrate connective tissues, especially skin, where it has a protective, structure-stabilizing, and shock-absorbing role. For commercial purposes, it can be isolated either from animal sources such as synovial ﬂuid, umbilical cord, skin, and rooster comb, or from bacteria through a process of fermentation or direct isolation. Its unique properties of biocompatibility, nonimmunogenicity, biodegradability, and viscoelasticity have rendered it an ideal biomaterial for cosmetic, medical, and pharmaceutical applications. PHYSIOCHEMICAL AND BIOLOGIC PROPERTIES OF HA HA is a nonsulfated glycosaminoglycan composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-Dglucosamine linked by a glucuronidic β (1→3) bond.3 HA has a β-sheet tertiary structure as a result of molecular aggregation and is stabilized by the presence of intermolecular hydrogen bonding.4 It is one of the main constituents of the extracellular matrix and is therefore indispensable for the cellular framework.5

HA has a variety of physicochemical properties and encompasses a large volume of water, giving solutions high viscosity, even at low concentrations.6 Due to its water-binding capacity, it is responsible for hydrating the skin and increasing its moisture content.7 HA also plays an important role in exchange between cells and blood, as well as in cellular migration; furthermore, recent studies have shown a role for HA in increasing cellular differentiation7 as well as cellular motility, thus promoting wound healing.8 Another function of HA is prevention of cellular damage from free radicals, which have an important role to play in skin aging.9,10 Recently, HA has been shown to mediate various physiologic functions via interaction with binding proteins and cell surface receptors such as CD4411–13 in the epidermis, suggesting that the molecule may be involved in cell function.14 HA in combination with other glycosaminoglycans, such as dermatan sulfate, chondroitin sulfate, and keratin sulfate in the skin, bind to water, and this induces the proteoglycans to become hydrated to such an extent that a gel-like system is formed. DISTRIBUTION HA is present in many places in the human body. It gives volume to the skin, shape to the eyes, and elasticity to the joints. In humans, HA is abundantly present in the skin,15,16 accounting for 50% of total body HA,17 vitreous of the eye,18 umbilical cord,19 and synovial fluid.20,21 HA has also been found to be present in all tissues and fluids of the body, such as skeletal tissues,22 heart

From the Department of Dermatology, STD and Leprosy, Government Medical College and Associated SMHS Hospital Srinagar, Jammu and Kashmir, India Address for Correspondence: Mohammad Abid Keen, MD, Department of Dermatology, STD and Leprosy, Government Medical College Srinagar, Jammu and Kashmir, India 190010 • E-mail: keenabid31@gmail.com

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valves,23 lungs,24 aorta,25 prostate,26 tunica albuginea, and corpora cavernosa and corpus spongiosum of the penis.27

layers, whereas in the basal layer HA is predominantly intracellular.45

METABOLISM

The hydration of the skin critically depends on the HA-bound water in the dermis and in the vital area of the epidermis, while maintenance of hydration essentially depends on the stratum granulosum.46 HA of the dermis along with the lymphatic and vascular systems regulates water balance, osmotic pressure, and ion flow, and functions as a sieve, excluding certain molecules, enhancing the extracellular domain of cell surfaces, and stabilizes skin structures by electrostatic interactions.47

HA is synthesized by membrane-bound enzymes called HA synthases, which synthesize HA on the inner surface of the plasma membrane.28 HA is then extruded through pore-like structures into the extracellular space.29 The half-life of HA is variable, being 3 to 5 minutes in the blood, less than a day in the skin, and 1 to 3 weeks in the cartilage.30,31 HA is degraded into fragments by hyaluronidases by hydrolyzing the hexosaminidic β (1→4) linkages between the N-acetyl-D-glucosamine and D-glucuronic acid residues in HA. In the presence of reducing agents such as ascorbic acid or thiols, ferrous, or cuprous ions, HA can also be degraded nonenzymatically by a free-radical mechanism.32 MEDICAL APPLICATIONS OF HA HA finds application in various medical and surgical indications. The success of the medical applications of HA has led to the production of several successful commercial products. Various medical indications of HA are summarized as follows: 1. Osteoarthritis: HA provides a liberal amount of lubrication and mechanical support to joints affected with osteoarthritis. Administration of puriﬁed high-molecular-weight HA into osteoarthritic joints can restore the desirable rheologic properties and alleviate some of the clinical manifestations of osteoarthritis.33,34 2. Surgery and wound healing: Due to its viscoelastic and biocompatible properties, HA is used as a growth scaffold in surgery35 and wound healing.36 3. Ophthalmic indications: HA is used in ocular surgeries for the implantation of artificial intraocular lenses and as a viscoelastic gel.37–39 4. Embryo implantation: HA has also been used as a culture medium for in vitro fertilization.40,41

DERMATOLOGIC INDICATIONS Because of its viscoelastic properties and excellent biocompatibility, HA has been extensively used in cosmetology.48 HAcontaining cosmetic products restore moisture and elasticity to the skin, thereby achieving an antiwrinkle effect. Various dermatologic indications of this unique molecule are listed as follows.

Soft tissue augmentation Soft tissue augmentation has revolutionized the treatment of the aging face. HA dermal fillers have frequently been used over the past decade for facial soft tissue augmentation because of their longevity, ease of use, and low immunogenicity.49 Stabilized HA gels can stimulate collagen synthesis and inhibit collagen degradation, which can further contribute to their long-lasting effects.50 Due to its nonanimal source, HA also has a minimal risk of inducing previously reported hypersensitivity reactions.51–53 In cases of facial lines resulting from the loss of volume associated with aging, injectable fillers, which efface and support the static rhytides, are the most suitable treatment.54 HA fillers from different manufacturers differ in characteristics, such as total HA concentration, modulus, particle size, degree of crosslinking, percentage of crosslinked HA, amount of unmodified HA present, and extrusion force.55 Various HA products used as fillers for soft tissue augmentation are:2

HA AND THE SKIN The highest concentrations of HA are found in connective tissues, and most HA (about 56%) is found in the skin. The estimated total amount of HA in human skin has been reported to be 5 g.42 HA is present in the dermis (approximately 0.5 mg/g wet tissue) and the epidermis (approximately 0.1 mg/g wet tissue).43 The use of biotinylated HA-binding peptide44 has enabled the visualization of HA in the epidermis, mainly in the extracellular matrix of the upper spinous and granular SKINmed. 2017;15:441–448

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• Restylane and Perlane® (Q-Med, Uppsala, Sweden): biosynthetically produced by bacterial fermentation, with the advantage of being free from the risk of disease transmission or eliciting allergic reactions in hypersensitive patients. • Dermalive® (Dermatech, Paris, France): 14.5% HA and molecules of hydro-ethyl-methacrylate; consists of nonanimal, stabilized HA. • Hyalaform® (Genzyme Corp., Boston, MA): processed from the coxcombs of domestic fowl. Hyaluronic Acid in Dermatology

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• Ac Hyal® (Laborata es Filorga, Paris, France): 1% solution of the sodium salt of HA—a Japanese product that is available in Europe. • Hylan Rofilan Gel® (Rofil Medical International NV, Breda, The Netherlands): HA crosslinked with a natural acid. • Reviderm Intra® (Rofil Medical International): contains 40 to 60 µm dextran beads of the Sephadex® type in hylan gel; nonimmunogenic, biocompatible, and biodegradable. As per the American Society of Plastic Surgeons, around 2 million procedures using dermal fillers were carried out in 2012, 5% more than in 2011 and 205% more than in 2000.56 Adverse effects of HA dermal fillers can be injection related or substance related. Injection-related adverse effects are more common and consist of erythema, swelling, pain, itching, discoloration, and tenderness at the implant site.2 Resolution is spontaneous within 1 or 2 days. Substance-related adverse effects are rare (fewer than 1 in 2000 treatments).2 They are thought to be of a hypersensitive nature and consist of swelling and induration at the implant site.2 A short course of oral steroids or intralesional hyaluronidase may be needed. A case of arterial embolization after the injection of dermal filler in the glabellar area has also been reported.57 Because HA fillers are costly, invasive, and painful, and may have side effects, there is a dire need for a topical, noninvasive, effective cosmetic treatment to replenish the skin with the lost HA. Recently, a study has shown the filling efficacy of a commercially available HA-based dermocosmetic treatment (Fillerina® [Labo Cosprophar Suisse, Switzerland]) in the appearance of chronoaged skin in subjects showing mild to moderate clinical signs of skin aging on the face.58 Similar to the skin, lips are vulnerable to intrinsic and extrinsic factors that can change their appearance over time.59 Treatment with HA-based dermal fillers can enhance the lips and perioral area, thereby reducing some of the signs of aging, and lip augmentation is currently recognized as one of the most common uses for these fillers.60 Subjects undergoing lip enhancement procedures can expect treatment-emergent adverse events, such as swelling and bruising. These can affect daily activities and lengthen the time taken to return to social engagements while waiting for these side effects to resolve. It has also been observed that adverse events experienced by patients undergoing lip enhancement can be linked to factors relating to injection technique, such as the rapid injection of a large volume of filler.61 SKINmed. 2017;15:441–448

The midface region tends to be the primary area affected by agerelated volume loss, clinically presenting as tear-trough deformities, molar hollowing, formation of a double convexity, and loss of cheek definition. Adding volume to the midface with filler provides a means of addressing all these signs of aging using a single procedure. HA fillers range in viscosity and enable the filling of wrinkles in addition to increasing cheek volume, thus replacing collagen as the “gold standard” among fillers. Recently, it has been shown that intradermal needle radiofrequency treatment with HA filler may be a more safe and effective method than HA filler alone for correcting midface volume deficit.62 In the temporal fossa, volume loss leads to an undesirable, gaunt appearance. By altering the temporal fossa and upper face with fillers, dermatologists are able to achieve a balanced and more youthful facial structure.63 Many techniques have been described to inject filler into the fossa, including a “fanned” pattern of injections and highly diluted filler injection.63 Complications of filler in the temporal fossa include bruising, tenderness, swelling, Tyndall effect, overcorrection, and chewing discomfort; the rare, more serious complications include infection, foreign body granuloma, intravascular necrosis, and blindness due to embolization into the ophthalmic artery.63 Using reversible HA fillers, hyaluronidase can be used to relieve any discomfort felt by the patient.

Skin rejuvenation Maintaining a youthful and pleasant appearance of the face in today’s culture impacts quality of life for many patients. Facial aging is a complex and dynamic process. All people age differently as a result of imbalance, disharmony, and disproportion of the aging process between the overlying soft tissue and the underlying bony frameworks.64 Even if the mechanism of skin aging has not yet been fully unravelled, it is evident that, during aging, the epidermis loses the principal molecule responsible for binding and retaining water molecules This results in loss of skin moisture and accounts for some of the most striking alterations of aged skin, including decreased turgidity, less support for microvessels, wrinkling, altered elasticity, and loss of face volumes, especially with regard to the cheekbones and lips.65 Recently, fillers have been developed to restore diminished skin volume and these are commonly used in the treatment of wrinkles. A variety of HA fillers are approved for the treatment of exaggerated nasolabial folds.66 HA fillers offer good outcome, are easy to inject, and have been associated with only a few adverse effects, such as mild pain, redness, and bruising. The major drawback of HA fillers is the relatively short duration of effect, necessitating frequent injections for maintenance.67 One group has evaluated the clinical efficacy and safety of combination

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therapy comprising intradermal radiofrequency application and HA filler for the reduction of nasolabial folds wrinkles and demonstrated synergistic and long-lasting effects.68 A nasojugal groove or infraorbital hollow appears in the early stages of aging and is considered one of the landmarks of aging. It is characterized by a sunken appearance of the globe that results in the casting of a dark shadow over the nasal lower eyelid, giving the patient a fatigued appearance.69 The use of HA dermal fillers to correct infraorbital hollows has evolved as a rapid nonsurgical option to improve the appearance of this area; however, due to the delicate and vascular nature of this area, several complications may occur with filler treatment in this area, such as edema, postinjection purpura, and arterial embolization of the retinal artery.70 For rejuvenation of the periorbital area, researchers have advocated the use of HA in conjunction with botulinum toxin.71 The combination of botulinum toxin A and HA appears to rejuvenate the periorbital, temporal, glabellar, and crow’s feet areas with minimal adverse effects.72 Recently, a clinical study demonstrated a significant improvement in the treatment of photoaging-induced wrinkles using the topical application of human growth factors and HA in women with facial photodamage.73 HA may protect growth factors from degradation by proteases, making HA and growth factor a promising combination.74 There is also some evidence that HA growth factors act synergistically to accelerate the healing process.75 As a result, topical products containing HA in combination with human growth factors might be particularly well suited for skin rejuvenation. Recently, mesotherapy with an intradermal HA formulation has also been used for skin rejuvenation.76 Wound healing HA extracts are safe and efficacious products for use in skin repair. Different gel formulations of HA have been used in patients with burns77 and for the treatment of persistent ulcers.78 HA has also been used in combination with platelet-rich plasma in the treatment of postoperative wound dehiscence and tendon exposure after surgery in patients with Morton’s neuroma.79

Skin tissue engineering Skin tissue engineering remains a valid option to treat difficult skin defects. The scaffold should act as a biodegradable template to mimic the natural skin microenvironment, containing the barrier function of the epidermal component and the mechanical stability and elasticity of the dermal component.80 HA has SKINmed. 2017;15:441–448

been used as a component of scaffolds for wound healing. A number of animal studies using wound models have assessed the usefulness of HA-based scaffold.81 These scaffolds, made up of various biologic components, promote dermal regeneration and wound healing. In a retrospective study, an HA sheet was used as scaffold with or without autologous cultured dermal fibroblasts after removal of a basal cell carcinoma on the face.82 The use of autologous skin grafting on an HA scaffold in patients undergoing surgical scar removal facilitates better integration of the graft into the surrounding tissues, with dermis regeneration.83

En coup de sabre En coup de sabre is a localized variant of scleroderma that presents as a linear, atrophic depression affecting the frontoparietal aspect of the face and scalp. The disfigurement may have a significantly negative impact on the patient’s quality of life, and it is often the cosmetic aspect for which patients seek out care and intervention. Dermal filler treatments offer an attractive option as they are much less invasive and possess distinct advantages. HA filler may be safely and successfully used as monotherapy for temporary cosmetic improvement of en coup de sabre lesions.84 The benefit is most prominent in well-selected patients who may experience atrophy but in whom the prominent feature is not tethering to underlying structures.84 There is a case report of HA filler used in conjunction with AlloDERM® (LifeCell Corporation, Branchburg, NJ) tissue matrix, which is essentially cadaveric dermis.85 HA filler has been used in the correction of hemifacial atrophy seen in Parry-Romberg syndrome, a distinct but related variant of linear scleroderma;86,87 however, these were both used in combination with other modalities: in one case autologous fat transfer, and in the other calcium hydroxylapatite filler.86,87

Diabetic foot Diabetic foot ulceration is a major complication of diabetes mellitus. Current treatment for foot ulcers consists of restoration of adequate vascular supply, debridement, treatment of infections, and relief of pressure.88 Several randomized controlled trials have evaluated the efficacy of HA-based wound healing techniques versus control in patients with diabetic foot.89–91 HA is beneficial in treating diabetic wound ulcers by increasing the rate of wound healing and is beneficial independent of the form in which the compound is applied to the wound.92

Mucositis Virtually all patients receiving radio- and chemotherapy for cancer develop oral mucositis, a severe and highly debilitating condition. It is well established that the mechanisms initiating

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chemoradiation-induced mucosal injury, including oral mucositis, are linked to the production of reactive oxygen species.93 The binding of high-molecular-mass HA to free radicals catalyzes the breakdown of HA into smaller fragments and thus inactivates reactive oxygen species.94 Thus, it is possible that HA prevents the propagation of oxidative stress by sequestrating reactive oxygen species. A possible protective effect of a commercial formulation of HA enriched with amino acids (Mucosamin® [Professional Dietetics SRL, Italy]) against the damage induced by oxidative stress in vitro and in vivo has been investigated.95 Data from a case series of patients undergoing radio/chemotherapy have strongly suggested that prophylactic use of the HA-based compound in the form of a spray may be effective in preventing the onset of oral mucositis.95

Melasma HA in combination with hydroquinone and glycolic acid has been evaluated to be efficacious and safe in the treatment of melasma after topical application.96 CONCLUSIONS HA is an essential component of the connective tissues, with the task of hydrating, lubricating, and returning elasticity to the skin, maintaining the shape of the tissues and strengthening their tone. It is now known to be the most important substance in “antiaging” research, mainly because of its safety and efficacy. The desire to turn back the clock while enjoying an active lifestyle has expanded the popularity of this unique molecule.

8 Nehls V, Hayen W. Are hyaluronan receptors involved in three-dimensional cell migration? Histol Histopathol. 2000;15:629–636. 9 Scott JE. Hyaluronan, multum in parvo. Eur J Rheumatol Inflamm. 1995;15:3–8. 10 Presti D, Scott JE. Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH) radicals is dependent on hyaluronan molecular mass. Cell Biochem Funct. 1994;12:281–288. 11 Banerji S, Ni J, Wang SX, Clasper S, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999;144:789– 801. 12 Knudson W, Chow G, Knudson CB. CD44-mediated uptake and degradation of hyaluronan. Matrix Biol. 2002;21:15–23. 13 Laugier JP, Shuster S, Rosdy M, et al. Topical hyaluronidase decreases hyaluronic acid and CD44 in human skin and in reconstituted human epidermis: Evidence that hyaluronidase can permeate the stratum corneum. Br J Dermatol. 2000;142:226–233. 14 Isacke CM, Yarwood H. The hyaluronan receptor, CD44. Int J Biochem Cell Biol. 2002;34:718–721. 15 Tammi R, Ripellino JA, Margolis RU, Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe. J Invest Dermatol. 1988;90:412–414. 16 Tzellos TG, Sinopidis X, Kyrgidis A, et al. Differential hyaluronan homeostasis and expression of proteoglycans in juvenile and adult human skin. J Dermatol Sci. 2011;61:69–72. 17 Reed RK, Lilja K, Laurent TC. Hyaluronan in the rat with special reference to the skin. Acta Physiol Scand. 1988;134:405–411. 18 Meyer K, Palmer JW. The polysaccharide of the vitreous humor. J Biol Chem. 1934;107:629–634.

References 1 Meyer L, Palmer J. The polysaccharide of the vitreous humour. Biol Chem. 1934;107:629–634. 2 Vedamurthy M. Soft tissue augmentation – Use of hyaluronic acid as dermal filler. Indian J Dermatol Venereol Leprol. 2004;70:383–387. 3 Weissmann B, Meyer K, Sampson P, Linker A. Isolation of oligosaccharides enzymatically produced from hyaluronic acid. J Biol Chem. 1954;208:417–429. 4 Scott JE, Heatley F. Hyaluronan forms specific stable tertiary structures in aqueous solution: A C-13 NMR study. Proc Natl Acad Sci U S A. 1999;96:4850–4855. 5 Fraser JR, Laurent TC, Laurent UB. Hyaluronan: Its nature, distribution, functions and turnover. J Intern Med. 1997;242:27–33.

19 Weissmann B, Meyer K. The structure of hyalobiuronic acid and of hyaluronic acid from umbilical cord. J Am Chem Soc. 1954;76:1753–1757. 20 Hamerman D, Schuster H. Hyaluronate in normal human synovial fluid. J Clin Invest. 1958;37:57–64. 21 Ragan C, Meyer K. The hyaluronic acid of synovial fluid in rheumatoid arthritis. J Clin Invest. 1949;28:56–59. 22 Armstrong SE, Bell DR. Relationship between lymph and tissue hyaluronan in skin and skeletal muscle. Am J Physiol Heart Circ Physiol. 2002;283:2485–2494. 23 Toole BP. Hyaluronan: From extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4:528–539.

6 Turino GM, Cantor JO. Hyaluronan in respiratory injury and repair. Am J Respir Crit Care Med. 2003;167:1169– 1175.

24 Papakonstantinou E, Roth M, Tamm M, et al. Hypoxia differentially enhances the effects of transforming growth factor-beta isoforms on the synthesis and secretion of glycosaminoglycans by human lung fibroblasts. J Pharmacol Exp Ther. 2002;301:830–837.

7 Neudecker BA, Csoka AB, Mio K, Maibach HI, Stern R. Hyaluronan: The Natural Skin Moisturizer. In: Elsner P, Maibach HI, eds. Cosmeceuticals: Drugs vs. Cosmetics. New York, NY: Marcel Dekker; 2000:319–352.

25 Papakonstantinou E, Karakiulakis G, Eickelberg O, et al. A 340 kDa hyaluronic acid secreted by human vascular smooth muscle cells regulates their proliferation and migration. Glycobiology. 1998;8:821–830.

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26 Goulas A, Hatzichristou DG, Karakiulakis G, et al. Benign hyperplasia of the human prostate is associated with tissue enrichment in chondroitin sulphate of wide size distribution. Prostate. 2000;44:104–110. 27 Goulas A, Papakonstantinou E, Karakiulakis G, et al. Tissue structure-specific distribution of glycosaminoglycans in the human penis. Int J Biochem Cell Biol. 2000;32:975–982. 28 McKee CM, Lowenstein CJ, Horton MR, et al. Hyaluronan fragments induce nitric-oxide synthase in murine macrophages through a nuclear factor kappa B-dependent mechanism. J Biol Chem. 1997;272:8013– 8018. 29 Prehm P. Release of hyaluronate from eukaryotic cells. Biochem J. 1990;267:185–189. 30 Fraser JR, Laurent TC, Pertoft H, Baxter E. Plasma clearance, tissue distribution and metabolism of hyaluronic acid injected intravenously in the rabbit. Biochem J. 1981;200:415–424. 31 Laurent UB, Dahl LB, Reed RK. Catabolism of hyaluronan in rabbit skin takes place locally, in lymph nodes and liver. Exp Physiol. 1991;76:695–703. 32 Lapcík L Jr., Chabrecek P, Stasko A. Photodegradation of hyaluronic acid: EPR and size exclusion chromatography study. Biopolymers. 1991;31:1429–1435. 33 Balazs EA, Denlinger JL. Viscosupplementation: A new concept in the treatment of osteoarthritis. J Rheumatol. 1993;20:3–9. 34 Balazs EA, Denlinger JL. Clinical uses of hyaluronan. Ciba Found Symp. 1989;143:265–280. 35 Risberg B. Adhesions: Preventive strategies. Eur J Surg. 1997;163:32–39. 36 Ghosh S, Jassal M. Use of polysaccharide fibres for modem wound dressings. Indian J Fibre Textile Res. 2002;27:434–450. 37 Inoue M, Katakami C. The effect of hyaluronic-acid on corneal epithelial-cell proliferation. Invest Ophthalmol Vis Sci. 1993;34:2313–2315. 38 Miyazaki T, Miyauchi S, Nakamura T, et al. The effect of sodium hyaluronate on the growth of rabbit cornea epithelial cells in vitro. J Ocul Pharmacol Ther. 1996;12:409– 415. 39 Stiebel-Kalish H, Gaton DD, Weinberger D, et al. A comparison of the effect of hyaluronic acid versus gentamicin on corneal epithelial healing. Eye. 1998;12:829–833. 40 Simon A, Safran A, Revel A, et al. Hyaluronic acid can successfully replace albumin as the sole macromolecule in a human embryo transfer medium. Fertil Steril. 2003;79:1434–1438.

43 Brown MB, Jones SA. Hyaluronic acid: A unique topical vehicle for the localized delivery of drugs to the skin. J Eur Acad Dermatol Venereol. 2005;19:308–318. 44 Ripellino JA, Bailo M, Margolis RU, Margolis RK. Light and electron microscopic studies on the localization of hyaluronic acid in developing rat cerebellum. J Cell Biol. 1988;106:845–855. 45 Tammi R, Ripellino JA, Margolis RU, Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe. J Invest Dermatol. 1988;90:412–414. 46 Papakonstantinou E, Roth M, Karakiulakis G. Hyaluronic acid: A key molecule in skin aging. Dermatoendocrinol. 2012;4:253–258. 47 Stern R, Maibach HI. Hyaluronan in skin: Aspects of aging and its pharmacologic modulation. Clin Dermatol. 2008;26:106–122. 48 Manuskiatti W, Maibach HI. Hyaluronic acid and skin: Wound healing and aging. Int J Dermatol. 1996;35:539–544. 49 Rao J, Chi GC, Goldman MP. Clinical comparison between two hyaluronic acid-derived fillers in the treatment of nasolabial folds: Hylaform versus Restylane. Dermatol Surg. 2005;31:1587–1590. 50 Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol. 2007;143:155–163. 51 Larsen NE, Pollak CT, Reiner K, Leshchiner E, Balazs EA. Hylan gel biomaterial: Dermal and immunologic compatibility. J Biomed Mater Res. 1993;27:1129–1134. 52 Friedman PM, Mafong EA, Kauvar AN, Geronemus RG. Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg. 2002;28:491–494. 53 Hamilton RG, Strobos J, Adkinson NF Jr. Immunogenicity studies of cosmetically administered nonanimalstabilized hyaluronic acid particles. Dermatol Surg. 2007;33:176–185. 54 Carruthers J, Carruthers A. Volumising the glabella and forehead. Dermatol Surg. 2010;36:1905–1909. 55 Kablik J, Monheit GD, Yu L, Chang G, Gershkovich J. Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. 2009;35:302–312. 56 Balassiano LKA, Bravo BSF. Hyaluronidase: A necessity for any dermatologist applying injectable hyaluronic acid. Surg Cosmet Dermatol. 2014;6:338–343. 57 Schanz S, Schippert W, Ulmer A, Rassner G, Fierlbeck G. Arterial embolisation caused by injection of hyaluronic acid (Restylane). Br J Dermatol. 2002;146:928–929.

41 Gardner DK, Rodriegez-Martinez H, Lane M. Fetal development after transfer is increased by replacing protein with the glycosaminoglycan hyaluronan for mouse embryo culture and transfer. Hum Reprod. 1999;14:2575– 2580.

58 Nobile V, Buonocore D, Michelotti A, Marzatico F. Antiaging and filling efficacy of six types hyaluronic acid based dermo-cosmetic treatment: Double blind, randomized clinical trial of efficacy and safety. J Cosmet Dermatol. 2014;13:277–287.

42 Banks J, Kreider JW, Bhavanadan VP, Davidson EA. Anionic polysaccharide production and tyrosine activation in cultured human melanoma cells. Cancer Res. 1976;36:424–431.

59 Bogle MA, Arndt KA, Dover JS et al. Evaluation of the aging face. In: Kaminer MS, Arndt KA, Dover JS, et al., eds. Atlas of Cosmetic Surgery. 2nd ed. Philadelphia, PA: Saunders Elsevier; 2009:37–43.

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60 Sarnoff DS, Saini R, Gotkin RH. Comparison of filling agents for lip augmentation. Aesth Surg. 2008;28:556– 563. 61 Glogau RG, Kane MA. Effect of injection techniques on the rate of local adverse events in patients implanted with nonanimal hyaluronic acid gel dermal fillers. Dermatol Surg. 2008;34:105–109. 62 Ko EJ, Kim H, Park WS, Kim BJ. Correction of midface volume deficiency using hyaluronic acid filler and intradermal radiofrequency. J Cosmet Laser Ther. 2015;17:46–48. 63 Juhasz MLW, Marmur ES. Temporal fossa defects: Techniques for injecting hyaluronic acid filler and complications after hyaluronic acid filler injection. J Cosmet Dermatol. 2015;14:254–259. 64 Kahn D, Shaw R. Aging of the bony orbit: A three dimensional computed tomographic study. Aesthetic Surg J. 2008;28:258–264. 65 Ghersetich I, Lotti T, Campanile G, et al. Hyaluronic acid in cutaneous intrinsic aging. Int J Dermatol. 1994;33:119–122. 66 Schachter D, Sapra S. Randomized, double-blind comparison of the efficacy of two hyaluronic acid derivatives, Restylane Perlane and Hylaform, in the treatment of nasolabial folds. Dermatol Surg. 2005;31:1591– 1598. 67 el-Domyati M, el-Ammawi TS , Medhat W, et al. Radiofrequency facial rejuvenation: Evidence-based effect. J Am Acad Dermatol. 2011;64:524–535. 68 Choi SY, Lee YH, Kim H, et al. A combination trial of intradermal radiofrequency and hyaluronic acid filler for the treatment of nasolabial fold wrinkles: A pilot study. J Cosmet Laser Ther. 2014;16:37–42. 69 Hirmand H. Anatomy and nonsurgical correction of the tear trough deformity. Plast Reconstr Surg. 2010;125:699–708. 70 Hirsch RJ, Carruthers JD, Carruthers A. Infraorbital hollow treatment by dermal fillers. Dermatol Surg. 2007;33:1116–1119. 71 Carruthers JD, Glogau RG, Blitzer A, Facial Aesthetics Consensus Group Faculty. Advances in facial rejuvenation: Botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies–consensus recommendations. Plast Reconstr Surg. 2008;121:5–30. 72 Beer KR, Julius H, Dunn M, RN, Wilson F. Remodeling of periorbital, temporal, glabellar, and crow’s feet areas with hyaluronic acid and botulinum toxin. J Cosmet Dermatol. 2014;13:143–150. 73 Lee DH, Oh IY, Koo KT, et al. Improvement in skin wrinkles using a preparation containing human growth factors and hyaluronic acid serum. J Cosmet Laser Ther. 2015;17:20–23. 74 Locci P, Marinucci L, Lilli C, Martinese D, Becchetti E. Transforming growth factor beta 1-hyaluronic acid interaction. Cell Tissue Res. 1995;281:317–324. 75 Radomsky ML, Thompson AY, Spiro RC, Poser JW. Potential role of fibroblast growth factor in enhancement of fracture healing. Clin Orthop Relat Res. 1998;355:283– 293.

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76 Tedeschi A, Lacarrubba F, Micali G. Mesotherapy with an intradermal hyaluronic acid formulation for skin rejuvenation: An intrapatient, placebo-controlled, long-term trial using high-frequency ultrasound. Aesth Plast Surg. 2015;39:129–133. 77 Juhász I, Zoltán P, Erdei I. Treatment of partial thickness burns with Zn-hyaluronan: Lessons of a clinical pilot study. Ann Burns Fire Disasters. 2012;25:82–85. 78 Humbert P, Mikosinki J, Benchikhi H, Allaert FA. Efficacy and safety of a gauze pad containing hyaluronic acid in treatment of leg ulcers of venous or mixed origin: A double-blind, randomised, controlled trial. Int Wound J. 2013;10:159–166. 79 De Angelis B, Lucarini L, Orlandi F, et al. Regenerative surgery of the complications with Morton’s neuroma surgery: Use of platelet rich plasma and hyaluronic acid. Int Wound J. 2013;10:372–376. 80 Huang S, Zhang YJ, Tang L, et al. Functional bilayered skin substitute constructed by tissue-engineered extracellular matrix and microsphere-incorporated gelatin hydrogel for wound repair. Tissue Eng Part A. 2009;15:2617–2624. 81 Yan S, Zhang Q, Wang J, et al. Silk fibroin/chondroitin sulfate/hyaluronic acid ternary scaffolds for dermal tissue reconstruction. Acta Biomater. 2013;9:6771– 6782. 82 Han SK, Kim SY, Choi RJ, Jeong SH, Kim WK. Comparison of tissue-engineered and artificial dermis grafts after removal of basal cell carcinoma on face—a pilot study. Dermatol Surg. 2014;40:460–467. 83 Faga A, Nicoletti G, Brenta F, et al. Hyaluronic acid three-dimensional scaffold for surgical revision of retracting scars: A human experimental study. Int Wound J. 2013;10:329–335. 84 Thareja SK, Sadhwani D, BS, Fenske NA. En coup de sabre morphea treated with hyaluronic acid filler. Report of a case and review of the literature. Int J Dermatol. 2015;54:823–826. 85 Robitschek J,Wang D, Hall D. Treatment of linear scleroderma en coup de sabre with AlloDerm tissue matrix. Otolaryngol Head Neck Surg. 2008;138:540–541. 86 Cox SE, Soderberg JM. Idiopathic hemifacial atrophy treated with serial injections of calcium hydroxylapatite. Dermatol Surg. 2010;34:542–545. 87 Lane TK, Cheung J, Schaffer JV. Parry-Romberg syndrome with coexistent morphea. Dermatol Online J. 2008;14:21. 88 Saap LJ, Falanga V. Debridement performance index and its correlation with complete closure of diabetic foot ulcers. Wound Repair Regen. 2002;10:354–359. 89 Abbruzzese L, Rizzo L, Fanelli G, et al. Effectiveness and safety of a novel gel dressing in the management of neuropathic leg ulcers in diabetic patients: A prospective double-blind randomized trial. Int J Low Extrem Wounds. 2009;8:134–140. 90 Tankova T, Dakovska G, Dragomir K. Zinc hyaluronate in the treatment of diabetic foot ulcers: A controlled randomized open-label study. Diabetol Croat. 2001;30:93–96.

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91 Caravaggi C, De Giglio R, Pritelli C, et al. HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: a prospective, multicenter, controlled, randomized clinical trial. Diabetes Care. 2003;26:2853–2859. 92 Chen CP, Hung W, Lin SH. Effectiveness of hyaluronic acid for treating diabetic foot: A systematic review and meta-analysis. Dermatol Ther. 2014;27:331–336. 93 Sonis ST. Mucositis: The impact, biology and therapeutic opportunities of oral mucositis. Oral Oncol. 2009;45:1015–1020.

94 Mendoza G, Alvarez AI, Pulido MM, et al. Inhibitory effects of different antioxidants on hyaluronan depolymerization. Carbohydr Res. 2007;342:96–102. 95 Cirillo N, Vicidomini A, McCullough MJ, et al. A hyaluronic acid-based compound inhibits fibroblast senescence induced by oxidative stress in vitro and prevents oral mucositis in vivo. J Cell Physiol. 2015;230:1421–1429. 96 Ibrahim ZA, Gheida SF, El Maghraby GM, Farag ZE. Evaluation of the efficacy and safety of combinations of hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma. J Cosmet Dermatol. 2014;14:113–123.

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Volume 15 • Issue 6

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD

1. a. b. c. d. e.

Properties of hyaluronic acid include: A high water-binding capacity. Facilitation of cell migration. Facilitation of wound healing. Increasing cellular differentiation. Mediation of interactions between binding proteins and cell surface receptors such as CD44. f. Prevention of cellular damage by free radicals. g. All of the above are correct. 2. Hyaluronic acid: (Answer as many as apply. All, some, or none of the lettered responses may be correct.) a. Has a half-life of 3 to 5 minutes in blood, one to three weeks in cartilage, and less than one day in skin. b. In the presence of oxidizing agents, is degraded enzymatically by free radicals. c. Is degraded enzymatically by hyaluronidases. d. Is more abundant in skin than in all other tissues combined. e. Is synthesized in the intercellular matrix in skin. 3. a. b. c.

Clinical uses of hyaluronic acid include: As a culture medium for in vitro fertilization. Direct injection into joints in osteoarthritis. In ophthalmology, in implantation of artificial intraocular lenses. d. In surgery, use as a growth scaffold. e. In surgery, use in facilitating wound healing. f. All of the above are correct.

4. Hyaluronic acids from different manufacturers vary in: a. Amount of unmodified hyaluronic acid present. b. Degree of crosslinking. c. Extrusion force. d. Modulus. e. Particle size. f. Percentage of crosslinked hyaluronic acid. g. Total hyaluronic acid concentration. h. All of the above. 5. Regarding adverse effects of hyaluronic acid fillers: a. They can be injection-related or substance-related. b. Injection-related adverse effects are much more common than substance-related adverse effects. c. Injection related adverse effects include erythema, pain, swelling, pruritus (itching), discoloration and tenderness at the implant site. d. Resolution of injection-related adverse effects should be spontaneous within one to two days. e. Substance-related adverse effects are thought to be of a hypersensitive nature. f. Substance-related adverse effects include swelling and induration of the involved site. g. Substance-related adverse effects may be treated with a short course of oral steroids or with intralesional hyaluronidase. h. All of the above statements are correct.

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

Instructions: For each numbered question, choose the one most appropriate lettered response unless otherwise instructed.

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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W W W. T N L A S E R S O C I E T Y. C O M

November/December 2017

Volume 15 • Issue 6

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

Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids Kathryn Potter, MD;1 Sailesh Konda, MD;1,2 Vicky Zhen Ren, MD;3 Apphia Lihan Wang, MD;4 Aditya Srinivasan, MS;5 Suneel Chilukuri, MD6

Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three-part review. Part 2 focuses on scar revision for hypertrophic and keloids scars. Scar revision options for hypertrophic and keloid scars include corticosteroids, bleomycin, fluorouracil, verapamil, avotermin, hydrogel scaffold, nonablative fractional lasers, ablative and fractional ablative lasers, pulsed dye laser (PDL), flurandrenolide tape, imiquimod, onion extract, silicone, and scar massage. (SKINmed. 2017;15:451–456)

his review examines the scar revision outcomes for each technique, discusses potential adverse effects, and highlights the importance of further studies to optimize postsurgical scar revision. HYPERTROPHIC SCARS AND KELOIDS

Corticosteroids Intralesional corticosteroids are frequently used as first-line therapy in the treatment of hypertrophic scars and keloids. Corticosteroids reduce excessive scarring by reduction of collagen, glucosaminoglycan synthesis, inflammatory mediators, fibroblast proliferation, and endothelial buds from blood vessels during wound healing. Triamcinolone acetonide (TAC) is commonly used in concentrations ranging from 10 to 40 mg/mL at 4- to 6-week intervals. TAC causes a significant decrease in levels of α1-antitrypsin and α-2-macroglobulin, which are natural inhibitors of collagenase in human skin.1 The cost-effectiveness of intralesional corticosteroid therapy has been studied, and found that sternal and chest keloids had the highest mean total steroid cost ($91.73) and the nonbearded facial area had the lowest cost ($22.44).2

The use of three-dimensional imaging can objectively monitor the response of keloids to intralesional TAC. Twelve patients with keloid scars had a mean scar volume of 0.73 ± 0.701 cm3, and this was reduced to 0.14 ± 0.302 cm3 after monthly injections of intralesional TAC for at least 2 months.3 Interestingly, a recent case series of 65 patients found that keloidal scars were more likely to respond to treatment if they had higher contour scores before treatment and frequent injections.4 If a previously treated hypertrophic scar or keloid is excised, the intralesional corticosteroid will appear on histopathology as a lightly staining, delineated area of granular to amorphous, acellular mucinlike material interspersed within dense collagen bundles.5 Side effects include atrophy, telangiectasias, and dyspigmentation.6

Bleomycin Bleomycin is an antineoplastic antibiotic produced by Streptomyces verticillus that generates double- and single-stranded DNA breaks. A case series demonstrated complete regression of 25 of 36 keloids and hypertrophic scars treated with three to five injections of bleomycin.7 Another study administered bleomycin

From the Department of Dermatology, University of Florida College of Medicine, Gainesville, FL;1 the Department of Dermatology, Loma Linda University Medical Center, Loma Linda, CA;2 the Department of Dermatology, Baylor College of Medicine, Houston, TX;3 the Department of Dermatology, University of Alabama at Birmingham School of Medicine, Birmingham, AL;4 McGovern Medical School, Houston, TX;5 and Refresh Dermatology, Houston, TX6 Address for Correspondence: Suneel Chilukuri, MD, Refresh Dermatology, 4914 Bissonnet Street, #100A, Houston, TX 77401 • Email: dermsurg@gmail.com

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November/December 2017 to 13 keloid and hypertrophic scars using a multiple-puncture method on the surface of the skin and showed greater than 90% flattening in 12 cases.8 Similar results have been obtained when administering bleomycin via needleless pressure syringes or tattooing modalities.9,10 Bleomycin has been shown to inhibit collagen synthesis in fibroblasts, which may explain its efficacy in treating keloids and hypertrophic scars.11

Fluorouracil 5-Fluorouracil is a pyrimidine analog with inhibitory activity against thymidylate synthase, and is widely used in cancer chemotherapy and glaucoma surgery. Low-dose 5-fluorouracil has been shown in vitro to block the transforming growth factor (TGF)-β2 gene in human fibroblasts, resulting in inhibition of their proliferation, G2/M cycle arrest, apoptosis without necrosis, and a decrease in collagen production.12,13 Twenty patients received an average of seven weekly intralesional injections of 5-fluorouracil, and 17 showed more than 50% improvement. Histopathologic examination demonstrated a decrease in the amount of hyalinized collagen fibers, significant reduction of Ki-67 expression, and a slight reduction of TGF-β expression.14 Twenty-one patients with hypertrophic scars were treated with monthly injections of 5-fluorouracil for 10 months with a significant 40% reduction in median scar volumes at 1-year followup.15 Side effects include pain, hyperpigmentation, and tissue sloughing.14

Verapamil Verapamil is a calcium channel blocker typically used to treat hypertension. This antihypertensive results in decreased calcium influx into the cell, and has been shown to increase procollagenase in keloids and hypertrophic scars. Patients were treated with topical silicone combined with adjuvant intralesional verapamil (2.5 mg/mL) and compared to patients receiving only topical silicone. At 18-month follow-up, 54% of keloids in the combination treatment group resolved, compared to only 18% in the monotherapy group.16 A randomized, single blind, parallel study compared intralesional verapamil to intralesional TAC in 54 patients. Patients received an intralesional injection of 1 mL of either verapamil (2.5 mg) or TAC (40 mg) every 3 weeks. Assessments with the Vancouver Scar Scale revealed a reduction in vascularity, pliability, height, and width every third week with maintenance at 52 weeks in both treatment groups; however, the rate of reduction of these parameters was faster with TAC than with verapamil. Advantages of verapamil over TAC include lower cost, less injection site pain, and a lower incidence of side effects.17 SKINmed. 2017;15:451–456

Keloids of the ear lobes have also been successfully treated with a combination of surgical excision, intralesional verapamil, and pressure earrings.18

Avotermin Avotermin, a recombinant human TGF-β3, plays an important role in wound healing, and has effects on the deposition and organization of new extracellular matrix, modulation of the inflammatory response, and myofibroblast differentiation.19 When compared to adults, fetuses have increased ratios of TGF-β3 to TGF-β1, and this may be the reason why they heal with little or no scarring. Sixty patients were treated with intradermal avotermin (200 ng/100 μL/linear cm wound margin) injected into the outer wound segments immediately after scar excision and again 24 hours later. Administration of avotermin significantly improved scar appearance compared to placebo. Additionally, histologic evaluation revealed that avotermin-treated scars more closely resembled normal skin.19 Three double-blind, placebocontrolled studies with intradermal avotermin administered to wound margins before and 24 hours after full-thickness skin incisions found significantly improved scores on a visual analogue scale.20 Transient erythema and edema were more frequently seen with avotermin than placebo, which may be attributable to normal wound healing.

Hydrogel scaffold Porcine gelatin-dextran hydrogel scaffold, which may serve as a lattice for fibroblast adherence, was studied in the prevention of keloid recurrence in 19 patients with 26 ear keloids. A maximum of 3 mL of the scaffold per 2.5 cm of each wound margin was injected after keloid excision. At 1-year follow-up, five keloids had recurrences, and those that did recur were on average less than 15% of their original size. The 1-year recurrence rate with hydrogel scaffold was 19.2%, which is superior to recurrence rates in the literature ranging from 50% to 100%.21

Nonablative fractional lasers Thirteen adults with facial surgical scars present for longer than 6 months were treated with a 1550 nm fractional nonablative laser once a month for a total of four treatments. Patients noted a statistically significant improvement in stiffness and thickness, and the observer noted a statistically significant improvement in thickness, relief, and pliability.22 Additionally, a 55-year-old Caucasian woman was treated with a single 1550-nm fractional nonablative laser treatment and had greater than 75% improvement in scarring at 2 weeks follow-up.23 Interestingly, another study involving the 1540-nm nonablative fractional laser in the treatment of hypertrophic scars did not find a statistically signifi-

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cant difference between the treated and untreated control sides of 18 patients, although patients believed the treated side had a better cosmetic appearance.24 Side effects are as described in the section under atrophic scarring in Part 1 of this three-part series.25

Ablative and fractional ablative lasers High-energy pulsed CO2 laser was used to treat 50 patients with moderate to severe keloids, and significant immediate and prolonged clinical improvement was noted in skin tone, texture, and appearance, along with dermal remodeling on histologic examination.26 Thirteen patients with hypertrophic scars were treated with a 2940-nm Er:YAG fractional laser, and 10 patients with 10,600-nm CO2 fractional laser. Assessment with the Vancouver Scar Scale revealed average changes of 28.2% for Er:YAG and 49.8% for CO2, and a significant improvement in pliability.27 As discussed earlier, fractionated ablative lasers create microthermal treatment zones allowing for quicker reepithelialization from islands of untreated skin. Twenty-three Korean women with thyroidectomy scars were treated with a single session of a fractionated CO2 laser 2 to 3 weeks after surgery, and 12 of 23 patients demonstrated clinical improvement of more than 51% at 3 months.28 A split-scar study intraoperatively treated half of each surgical wound in 10 patients with one or two passes of a fractionated CO2 laser and demonstrated a significant improvement in the appearance and texture of the laser-treated sides of scars 2 to 3 months after surgery when compared to the control sides.29 Another split-scar study involved 30 patients who received four treatments spaced 6 weeks apart; it demonstrated significantly improved Vancouver Scale Scar scores on the treated side at 3 and 6 months posttreatment, which was predominantly attributed to improved pliability.30 Side effects are as described in the section under atrophic scarring in Part 1 of this three-part series.25

PDL The PDL selectively targets cutaneous vasculature, which leads to thrombosis, vasculitis, and gradual local repair with neovascularization.31 The 585-nm PDL is the preferred wavelength due to its ability to normalize scar height.32 A single-blinded splitscar study treated 12 postoperative linear scars three times at monthly intervals with the 585-nm PDL, and found significant improvements in the overall average of the Vancouver Scar Scale (pigmentation, vascularity, pliability, height) and the average cosmetic appearance score.33 Nineteen patients with keloidal and hypertrophic medial sternotomy scars were treated with a 595nm PDL (fluence 7 J/cm2, pulse width 0.45 ms) every month SKINmed. 2017;15:451–456

for a total of three treatments, and demonstrated a significant decrease in scar volume and height, and a significant increase in scar pliability.34 While induction of purpura may result in greater improvement of scars, a recent prospective study demonstrated that nonpurpuric settings on the PDL still resulted in significant improvement in the appearance of surgical scars.35 Regression of keloids after PDL therapy may be due to downregulation of TGF-β1 and connective tissue growth factor expression, upregulation of MMP-13, ERK, and p38 MAP kinase activity, suppression of fibroblast proliferation, and induction of apoptosis.36–38 Side effects include purpura, transient hyperpigmentation, and crusting, scabbing, and blistering at higher energy levels.

Flurandrenolide tape Flurandrenolide tape can be applied to hypertrophic scars and keloids for 12 to 20 hours a day, and will usually help soften and flatten the keloid and decrease associated pruritus. Flurandrenolide is widely accepted to be an efficacious treatment for keloids and hypertrophic scars; however, there have been no controlled trials evaluating its use in the treatment of postsurgical scars.

Imiquimod Topical imiquimod 5% cream, an immune response modifier, has been shown to stimulate significant increases in interferonalpha and interferon-gamma, and alter expression of genes associated with apoptosis.39,40 Interferons are antifibrotic cytokines that can reduce excessive production of collagen and glyosaminoglycans by fibroblasts. Imiquimod cream was applied to breast scars starting 8 weeks after surgery, twice weekly for 8 weeks, and compared to control scars. Scars treated with imiquimod had significantly better scar quality; however, they all developed erythema and crusting during the treatment phase.41 Another study selected 20 patients with two skin lesions clinically diagnosed as melanocytic nevi, which were subsequently excised. Immediately after surgery, one sutured excision site was treated nightly with imiquimod 5% cream, and the other sutured excision site was treated with vehicle cream. Placebo-treated surgical sites had better cosmetic evaluations than imiquimod treated sites at week 8, which was thought to be secondary to increased local inflammation associated with imiquimod application.42 More studies are needed to evaluate if the timing of imiquimod cream treatment has an effect on postsurgical scar cosmesis.

Onion extract Onion extract, derived from Allium cepa, is available over the counter in a gel formulation and has anti-inflammatory, bacte-

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riostatic, and collagen downregulatory properties.43 Significant improvements have been observed with onion extract gel over placebo in investigator cosmetic assessment, lesion induration, pigmentation, and erythema.44 A study found that application of a gel containing Allium cepa-allantoin-pentaglycan twice a day for 24 weeks significantly reduced erythema and neoangiogenesis in hypertrophic scars and keloids; however, tension, pruritus, burning, and height showed an insignificant decrease.45 Oncedaily application of onion extract gel for 2 months in 44 patients with new dermal scars resulted in a significant improvement in overall appearance, texture, redness, and softness when compared to controls;46 however, a double-blinded split-scar study treated 24 patients with new surgical wounds with either onion extract gel or petrolatum ointment. There was no significant difference in two treatment arms with respect to scar cosmesis or clinical manifestations.47

Silicone Silicone polymers, or polydimethylsiloxanes, can be crosslinked to form gel sheeting, creams, and topical gels. Several mechanisms have been proposed, including increased temperature, hydration caused by occlusion of the underlying skin, increased oxygen tension, direct action of the silicone oil, and polarization of the scar tissue caused by the negative static electric charge generated by movement of the silicone.48 Silicone-based products include elastomer sheeting, polyurethane foam, pressure garments, splints, fabric bandages, liquids, gels, ointments, and sprays.48

circulation. Burn patients with hypertrophic scars were randomized to receive standard treatment including range of motion exercises or standard treatment plus scar massage three times a week for 30-minute sessions. Eighty patients were randomized to each group, with a total of 76 patients completing the study in the massage arm, and 70 in the control group. There was a significant decrease in scar thickness in the scar massage group compared to the control group.51 CONCLUSIONS Hypertrophic scars and keloids occur during the wound healing process secondary to deposition of excess collagen. Intralesional TAC has been a first-line treatment for hypertrophic scars and keloids for many years and remains an excellent treatment option. Emerging intralesional treatments that have also proven efficacious include bleomycin, fluorouracil, verapamil, avotermin, and hydrogel scaffold. Nonablative fractional lasers, ablative and fractional ablative lasers, and PDL have also earned their place in the treatment armamentarium. Topical treatments including flurandrenolide tape, imiquimod, onion extract, silicone, and scar massage have had varying degrees of success. The third and final part of this review will discuss scar revision options for erythema, hyperpigmentation, and hypopigmentation. References

Patients undergoing skin surgery were stratified into either a low-risk or high-risk group depending on whether or not they had a history of abnormal scarring. After surgery, patients were randomized to receive routine postoperative care or silicone gel sheeting, and were followed for 6 months. In the high-risk group, 71% of patients treated with topical silicone gel sheeting and 39% of patients treated with routine postoperative care did not develop abnormal scars.50 Another study randomized 110 patients with postsurgical scars to receive either twice-daily silicone gel for 60 days or the control treatment, zinc oxide cream. Only 27% of patients had formation of a nonphysiologic scar in the treatment group, while 55% in the control group had a nonphysiologic scar.49 Side effects are mild and include pruritus, contact dermatitis, skin breakdown, skin maceration, dry skin, and odor emanating from the gel sheet.48

Scar massage Massage therapy is thought to decrease hypertrophic scar formation by several mechanisms, including stimulation of peripheral nerves, which results in muscle relaxation and improvement of SKINmed. 2017;15:451–456

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1 Hochman B, Locali RF, Matsuoka PK, Ferreira LM. Intralesional triamcinolone acetonide for keloid treatment: A systematic review. Aesthetic Plast Surg. 2008;32:705– 709. 2 Anthony ET, Lemonas P, Navsaria HA, Moir GC. The cost effectiveness of intralesional steroid therapy for keloids. Dermatol Surg. 2010;36:1624–1626. 3 Ardehali B, Nouraei SA, Van Dam H, et al. Objective assessment of keloid scars with three-dimensional imaging: Quantifying response to intralesional steroid therapy. Plast Reconstr Surg. 2007;119:556–561. 4 Ud-Din S, Bowring A, Derbyshire B, Morris J, Bayat A. Identification of steroid sensitive responders versus non-responders in the treatment of keloid disease. Arch Dermatol Res. 2013;305:423–432. 5 Kaur S, Amanjeet, Thami GP, Mohan H. Intralesional steroid induced histological changes in the skin. Indian J Dermatol Venereol Leprol. 2003;69:232–234. 6 Berman B, Flores F. The treatment of hypertrophic scars and keloids. Eur J Dermatol. 1998;8:591–595. 7 Bodokh I, Brun P. Treatment of keloid with intralesional bleomycin. Ann Dermatol Venereol. 1996;123:791–794. 8 Espana A, Solano T, Quintanilla E. Bleomycin in the treatment of keloids and hypertrophic scars by multiple needle punctures. Dermatol Surg. 2001;27:23–27.

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9 Saray Y, Gulec AT. Treatment of keloids and hypertrophic scars with dermojet injections of bleomycin: A preliminary study. Int J Dermatol. 2005;44:777–784. 10 Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg. 2006;32:1023– 1029; discussion 1029–1030. 11 Hendricks T, Martens MF, Huyben CM, Wobbes T. Inhibition of basal and TGF beta-induced fibroblast collagen synthesis by antineoplastic agents. Implications for wound healing. Br J Cancer. 1993;67:545–550. 12 Huang L, Wong YP, Cai YJ, et al. Low-dose 5-fluorouracil induces cell cycle G2 arrest and apoptosis in keloid fibroblasts. Br J Dermatol. 2010;163:1181–1185.

24 Verhaeghe E, Ongenae K, Bostoen J, Lambert J. Nonablative fractional laser resurfacing for the treatment of hypertrophic scars: A randomized controlled trial. Dermatol Surg. 2013;39:426–434. 25 Konda S, Potter K, Ren VZ, et al. Techniques for optimizing surgical scars, part 1: Wound healing and depressed/atrophic scars. Skinmed. 2017;15:271–276. 26 Nicoletti G, De Francesco F, Mele CM, et al. Clinical and histologic effects from CO2 laser treatment of keloids. Lasers Med Sci. 2013;28:957–964. 27 Choi JE, Oh GN, Kim JY, et al. Ablative fractional laser treatment for hypertrophic scars: Comparison between Er:YAG and CO2 fractional lasers. J Dermatolog Treat. 2014;25:299–303.

13 Wendling J, Marchand A, Mauviel A, Verrecchia F. 5-Fluorouracil blocks transforming growth factor-betainduced alpha 2 type I collagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 activation. Mol Pharmacol. 2003;64:707–713.

28 Jung JY, Jeong JJ, Roh HJ, et al. Early postoperative treatment of thyroidectomy scars using a fractional carbon dioxide laser. Dermatol Surg. 2011;37:217–223.

14 Kontochristopoulos G, Stefanaki C, Panagiotopoulos A, et al. Intralesional 5-fluorouracil in the treatment of keloids: an open clinical and histopathologic study. J Am Acad Dermatol. 2005;52:474–479.

30 Azzam OA, Bassiouny DA, El-Hawary MS, et al. Treatment of hypertrophic scars and keloids by fractional carbon dioxide laser: A clinical, histological, and immunohistochemical study. Lasers Med Sci. 2016;31:9– 18.

15 Haurani MJ, Foreman K, Yang JJ, Siddiqui A. 5-Fluorouracil treatment of problematic scars. Plast Reconstr Surg. 2009;123:139–148; discussion 149–151. 16 D’Andrea F, Brongo S, Ferraro G, Baroni A. Prevention and treatment of keloids with intralesional verapamil. Dermatology. 2002;204:60–62. 17 Margaret Shanthi FX, Ernest K, Dhanraj P. Comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. Indian J Dermatol Venereol Leprol. 2008;74:343–348. 18 Lawrence WT. Treatment of earlobe keloids with surgery plus adjuvant intralesional verapamil and pressure earrings. Ann Plast Surg. 1996;37:167–169. 19 So K, McGrouther DA, Bush JA, et al. Avotermin for scar improvement following scar revision surgery: A randomized, double-blind, within-patient, placebo-controlled, phase II clinical trial. Plast Reconstr Surg. 2011;128:163– 172. 20 Ferguson MW, Duncan J, Bond J, et al. Prophylactic administration of avotermin for improvement of skin scarring: Three double-blind, placebo-controlled, phase I/II studies. Lancet. 2009;373:1264–1274.

29 Ozog DM, Moy RL. A randomized split-scar study of intraoperative treatment of surgical wound edges to minimize scarring. Arch Dermatol. 2011;147:1108–1110.

31 Garden JM, Tan OT, Kerschmann R, et al. Effect of dye laser pulse duration on selective cutaneous vascular injury. J Invest Dermatol. 1986;87:653–657. 32 Nouri K, Rivas MP, Stevens M, et al. Comparison of the effectiveness of the pulsed dye laser 585 nm versus 595 nm in the treatment of new surgical scars. Lasers Med Sci. 2009;24:801–810. 33 Nouri K, Jimenez GP, Harrison-Balestra C, Elgart GW. 585-nm pulsed dye laser in the treatment of surgical scars starting on the suture removal day. Dermatol Surg. 2003;29:65–73; discussion 73. 34 Manuskiatti W, Wanitphakdeedecha R, Fitzpatrick RE. Effect of pulse width of a 595-nm flashlamp-pumped pulsed dye laser on the treatment response of keloidal and hypertrophic sternotomy scars. Dermatol Surg. 2007;33:152–161. 35 Gladsjo JA, Jiang SI. Treatment of surgical scars using a 595-nm pulsed dye laser using purpuric and nonpurpuric parameters: A comparative study. Dermatol Surg. 2014;40:118–126.

21 Berman B, Garikaparthi S, Smith E, Newburger J. A novel hydrogel scaffold for the prevention or reduction of the recurrence of keloid scars postsurgical excision. J Am Acad Dermatol. 2013;69:828–830.

36 Kuo YR, Wu WS, Jeng SF, et al. Suppressed TGF-beta1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatment. Lasers Surg Med. 2005;36:38–42.

22 Pham AM, Greene RM, Woolery-Lloyd H, Kaufman J, Grunebaum LD. 1550-nm nonablative laser resurfacing for facial surgical scars. Arch Facial Plast Surg. 2011;13:203–210.

37 Yang Q, Ma Y, Zhu R, et al. The effect of flashlamp pulsed dye laser on the expression of connective tissue growth factor in keloids. Lasers Surg Med. 2012;44:377–383.

23 Behroozan DS, Goldberg LH, Dai T, Geronemus RG, Friedman PM. Fractional photothermolysis for the treatment of surgical scars: A case report. J Cosmet Laser Ther. 2006;8:35–38.

38 Kuo YR, Wu WS, Jeng SF, et al. Activation of ERK and p38 kinase mediated keloid fibroblast apoptosis after flashlamp pulsed-dye laser treatment. Lasers Surg Med. 2005;36:31–37.

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39 Jacob SE, Berman B, Nassiri M, Vincek V. Topical application of imiquimod 5% cream to keloids alters expression genes associated with apoptosis. Br J Dermatol. 2003;149(suppl 66):62–65. 40 Arany I, Tyring SK, Stanley MA, et al. Enhancement of the innate and cellular immune response in patients with genital warts treated with topical imiquimod cream 5%. Antiviral Res. 1999;43:55–63. 41 Prado A, Andrades P, Benitez S, Umana M. Scar management after breast surgery: Preliminary results of a prospective, randomized, and double-blind clinical study with Aldara cream 5% (imiquimod). Plast Reconstr Surg. 2005;115:966–972. 42 Berman B, Frankel S, Villa AM, et al. Double-blind, randomized, placebo-controlled, prospective study evaluating the tolerability and effectiveness of imiquimod applied to postsurgical excisions on scar cosmesis. Dermatol Surg. 2005;31:1399–1403. 43 Saulis AS, Mogford JH, Mustoe TA. Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plast Reconstr Surg. 2002;110:177–183; discussion 184–186. 44 Perez OA, Viera MH, Patel JK, et al. A comparative study evaluating the tolerability and efficacy of two topical therapies for the treatment of keloids and hypertrophic scars. J Drugs Dermatol. 2010;9:514–518. 45 Campanati A, Savelli A, Sandroni L, et al. Effect of allium cepa-allantoin-pentaglycan gel on skin hypertro-

phic scars: Clinical and video-capillaroscopic results of an open-label, controlled, nonrandomized clinical trial. Dermatol Surg. 2010;36:1439–1444. 46 Draelos ZD, Baumann L, Fleischer AB, Jr, et al. A new proprietary onion extract gel improves the appearance of new scars: A randomized, controlled, blinded-investigator study. J Clin Aesthet Dermatol. 2012;5:18–24. 47 Chung VQ, Kelley L, Marra D, Jiang SB. Onion extract gel versus petrolatum emollient on new surgical scars: Prospective double-blinded study. Dermatol Surg. 2006;32:193–197. 48 Berman B, Perez OA, Konda S, et al. A review of the biologic effects, clinical efficacy, and safety of silicone elastomer sheeting for hypertrophic and keloid scar treatment and management. Dermatol Surg. 2007;33:1291–1302; discussion 1302–1303. 49 Gold MH, Foster TD, Adair MA, Burlison K, Lewis T. Prevention of hypertrophic scars and keloids by the prophylactic use of topical silicone gel sheets following a surgical procedure in an office setting. Dermatol Surg. 2001;27:641–644. 50 de Giorgi V, Sestini S, Mannone F, et al. The use of silicone gel in the treatment of fresh surgical scars: A randomized study. Clin Exp Dermatol. 2009;34:688–693. 51 Cho YS, Jeon JH, Hong A, et al. The effect of burn rehabilitation massage therapy on hypertrophic scar after burn: A randomized controlled trial. Burns. 2014;40:1513– 1520.

“Varizella and Herpes zoster”, made by Lotte Volger in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2017;15:451–456

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

Compromising Patient Care: Gross Payment Disparities in Dermatopathology—Part II Viral M. Patel, BS; Divya Sharma, BS; Michael Sylvester, AB; Christina Ring, BS; Jose D. Espinal-Mariotte, MD; W. Clark Lambert, MD, PhD We couldn’t make this stuff up.- Anonymous

pecimens of skin submitted by physicians or other health care professionals vary greatly in complexity and the number of sections that should be generated to insure proper patient care. Some specimens require that margins be analyzed; others do not. Although many specimens require only a 3 or 4 mm punch biopsy to be analyzed, others may measure as much as 5 cm or more in diameter. What does not vary is the payment to the laboratory: all skin specimens are reimbursed at the same rate—code 88305. There is enormous economic pressure on the laboratory to prepare only two blocks or even a single block or section, when many more may be required for adequate patient care. ADDITIONAL INEQUALITIES Recent changes to the pathology laboratory payment structure have worsened the preexisting reimbursement inequalities.1,2 For years, the American Medical Association/College of American Pathologists and Centers for Medicare & Medicaid Services were at odds over the fundamental definition of a unit of service for immunohistochemistry (IHC) coding. “Unit of service” refers to whether laboratories get paid for a service on a per specimen, per block, or per slide basis. Because a specimen is processed into multiple blocks and the blocks are then processed into multiple slides, a unit of service has important implications for laboratories. This is illustrated by the CPT code 88342 (“Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure”). Code 88342 is used to obtain reimbursement for IHCs for the first single antibody stain procedure per specimen. For instance, if multiple slides are created from a specimen and more than one slide requires IHC staining with a particular antibody, only one payment is made, because the reimbursement is per specimen.

If additional single antibody stain procedures are performed for that specimen using another antibody, only one additional payment will be made using the CPT code 1+88342 (+denoting an add-on to CPT code 88342). These changes were rationalized by CMS as necessary to avoid overuse and unnecessary testing; however, the science behind IHC is constantly evolving as new antibodies are produced for diagnostic and prognostic applications. These stains provide valuable information that guides treatment, rather than relying on trial and error. Such expansions in therapeutic applications have led to a justifiable increase in the use of IHC stains. Although there have indeed been unnecessary testing and treatment costs submitted in the past, necessary and indicated IHC testing has also been strongly discouraged economically by these regulations. These subtle changes in payment of CPT codes have substantial implications for laboratories, clinicians, and, most importantly, patients. Laboratories must understand these new changes and bill properly using new codes; otherwise payments will be denied. Because laboratories are not receiving proper reimbursements for the services they render, this may lead to cost-cutting measures that compromise the quality of results, or to deviations from proper protocol, which may create erroneous results. Consider the following scenario. Patient A has a lesion that is punch biopsied and sent for analysis. The laboratory processes the specimen into one block and then one slide. An S-100 IHC stain is performed to determine whether this lesion is melanoma. The laboratory is reimbursed with one payment for processing the specimen (88305) plus one for the IHC: one payment 88342—one specimen, one block, one slide, one IHC stain.

From the Departments of Pathology and Dermatology, 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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Now consider patient B, who has a suspicious lesion that requires an excisional biopsy with margin analysis. The laboratory processes the specimen into 40 blocks and, for the sake of simplicity, one slide per block. Again, an S-100 IHC stain is performed per slide to determine if the lesion is melanoma, and if the margins are positive. The laboratory is reimbursed for only one payment (88342) (the specimen 88305 plus one more for the IHC), because the reimbursement is per specimen (one specimen, 40 blocks, 40 slides, 40 IHC stains). Compared to patient A’s biopsy specimen, patient B’s excisional biopsy with margin analysis will require much more personnel time, more laboratory resources, and a higher cost for the laboratory; however, the laboratory payment for both patients will be the same. As a result, the laboratory has little incentive to prepare and analyze all 40 margins on patient B’s specimen, because they will not be paid more for doing so. THE ROLE OF THE SUBMITTING PHYSICIAN When clinicians submit samples for analysis, they should be aware of how the laboratory processes specimens and of the payment structure, which incentivizes laboratories to do little. A negative result may not be truly negative, as the specimen may not have been adequately processed. The clinician can assist laboratories during this process by properly documenting patient signs, clinical manifestations, and reasons or necessity for ordering tests. Unfortunately, this does not ensure that payment for these studies will have positive results. In addition, all of this does not prevent demands for refunds during audits. More importantly, these changes substantially impact patient care, as these tests are relied upon to manage patients. If these results are compromised or their utility is limited under the pretext of

avoiding overuse of a test, the result may become a great disservice to patients. THE RESULT Unfortunately, once CMS creates and enforces such changes, private insurers often follow in an effort to reduce costs. This would be a nightmare scenario, especially given the deep cuts to other “bread and butter” pathology codes such as 88305, which reimburse for preparing and examining biopsy tissue slides. Advocacy groups are raising awareness of these issues, but positive changes are yet to be seen. These changes can only negatively impact laboratories and patient care, further contributing to the already growing payment disparities for pathology laboratories. CONCLUSIONS Enormous economic pressures, many of them patently absurd, are placed on dermatopathology laboratories to cut corners and issue reports that are inadequate and incomplete. It is critical that the physician/health care providers know well, and are able to have implicit trust in, the laboratory to which they submit specimens. They must also be aware of any changes, such as in management or ownership, that may lead to a trustworthy laboratory becoming less so. References 1 Oliver R. CPT Code Changes for 2015 Pathology/ Laboratory. McKesson’s Business Performance Services. http://mptrms.mckesson.com/rs/McKessonPT/ imaGES/2015cptcHANGESpath.PDF. Accessed June 12, 2016. 2 American Clinical Laboratory Association. Comments Regarding the 2012 PFS Proposed Rule. http://www. acla.com/comments-regarding-the2012-pfs-proposedrule/. Accessed June 12, 2016.

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Volume 15 • Issue 6

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

Melanoma in Situ: The Power of One (Centimeter)? Warren R. Heymann, MD

remember Marie. She was a delightful elderly woman whom I would see for routine follow-up after the excision of a melanoma in situ (MIS) from her right arm. I shall never forget my astonishment upon feeling the large lymph node in her right axilla, the first metastasis of her ultimate demise. I shall always appreciate her grace in how she handled her illness; she realized how devastated I was—during our visits, she was more comforting to me than I ever was to her.

wider margins. For example, LM and non-LM are distinct; in a study of 36 cases of confirmed non-LM MIS, there was no clinical recurrence in 34 of these patients who had follow-up, although the follow-up time was short for several patients. Their average margin of clearance was 4.38 mm (range 1.3–7.75 mm), and the authors suggested that 5 mm margins are adequate for non-LM MIS (although I am not sure why they would reach this conclusion, given the range they reported).3

CURRENT GUIDELINES FOR MIS EXCISION

Another study used a nonrandomized, single-institution, retrospective design, studying long-term outcomes in 882 cases of MIS treated with Mohs micrographic surgery that were analyzed and compared with historical controls. Rates of complete excision were determined for increasing surgical margin intervals. One local recurrence occurred in their cohort (0.1%). Only 83% of MIS were excised with a 6-mm margin. Margins of 9 mm were needed to excise 97% of MISs, statistically equivalent to thin melanomas. The authors concluded that Mohs micrographic surgery might cure the 17% of MIS that exceed traditional excision margins of 5 mm and is a valuable option for these patients. Surgical margins of at least 0.9 cm should be considered for MIS of the trunk and extremities when total margin evaluation is not used.4

According to the American Academy of Dermatology guidelines for excising MIS, “Based on consensus opinion, wide excision with 0.5- to 1.0-cm margin has been recommended; however, due to the characteristic, potentially extensive, subclinical extension of melanoma in situ, lentigo maligna [LM] type, alternative surgical approaches may be considered. Particularly for larger lesions on the head and neck, greater than 0.5-cm margins may be necessary to achieve negative margins.”1 Unfortunately, the Cochrane Database offers this: “there is a lack of high-quality evidence for the treatment of MIS and LM, with no randomized clinical trials of surgical interventions aiming to optimise margin control (square method, perimeter technique, ‘slow Mohs’, staged radial sections, staged ‘mapped’ excisions, or Mohs micrographic surgery), which are the most widely used interventions recommended as first-line therapy.”2 The use of non-surgical therapies such as imiquimod may be effective and considered when surgery is contraindicated.2 RECENT LITERATURE ABOUT MIS EXCISION There is a plethora of literature regarding the proper surgical margins for MIS and LM, with the understanding that margins may be ill defined in LM, leading to more difficulty and necessitating

In a study of 345 cases of MIS on the head and neck treated by Mohs surgery, 65% cleared with a 5 mm margin; for 97% clearance, 15 mm was necessary. When Mohs surgery is not an option, the authors advocate excision margins of at least 10 mm.5 With a protocol utilizing Mohs surgery with MART-1 immunostain for excising melanomas, the margin size did not show a significant difference between in situ and invasive melanomas—7.10 mm versus 7.23 mm, respectively.6 Theoretically, the risk of metastasis of MIS that has been excised should be zero; therefore, by definition, if a patient like

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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Marie dies, she did not have MIS, but rather melanoma. The diagnosis would be missed either because microinvasion is not detected or because the tissue block is not completely examined. To address this issue, 34 cases of unequivocal MIS (an index case and 33 consecutive patients—20 LM, 13 superficial spreading, 1 acral lentiginous) were studied. The patients did not have associated nevi or regression, the authors utilized routine microscopy (H&E), and immunohistochemistry (melan-A, SOX10) was performed. Occult invasive melanoma was detected in 11 of 33 consecutive cases (33%) of previously diagnosed unequivocal in situ melanoma. Six of 11 melanomas (55%) were diagnosable only by immunohistochemistry. The remaining five tumors (45%) were diagnosable by both melanA and H-E staining, likely as a result of simply cutting deeper into the tissue block.7

to make the official recommendations; however, my prediction is that with further studies, advocates of the 1 cm margin will prevail. References

CONCLUSIONS I agree with Bax et al7 that their data should not be used to justify either exhausting the tissue block by extensive serial sectioning or using immunohistochemistry excessively on such cases. I also concur with informing patients that because pathology is not perfect, with a diagnosis of MIS there is a small risk of metastasis, and they should be monitored. Finally, the authors state that, “The implications for modification of current surgical margin recommendations for in situ melanoma are uncertain but probably unwarranted.”7 I will defer to the dermato-oncologists

1 Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol .2011;65:1032–1047. 2 Tzellos T, Kyrgidis A, Mocellin S, et al. Interventions for melanoma in situ, including lentigo maligna. Cochrane Database Syst Rev. 2014;12:CD010308. 3 Duffy KL, Truong A, Bowen A, et al. Adequacy of 5-mm surgical excision margins for non-lentiginous melanoma in situ. J Am Acad Dermatol. 2014;71:835–838. 4 Stigall LE, Brodland DG, Zitelli JA. The use of Mohs micrographic surgery (MMS) for melanoma in situ (MIS) of the trunk and extremities. J Am Acad Dermatol. 2016;75:1015–1021. 5 Felton S, Taylor RS, Srivastava D. Excision margins for melanoma in situ on the head and neck. Dermatol Surg. 2016;42:327–334. 6 Valentin-Nogueras SM, Brodland DG, Zitelli JA, González-Sepúveda L, Nazario CM. Mohs micrographic surgery using MART-1 immunostain in the treatment of invasive melanoma and melanoma in situ. Dermatol Surg. 2016;42:733–744. 7 Bax MJ, et al. Detection of occult invasion of melanoma in situ. JAMA Dermatol. 2016;152:1201–1208.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:459–460

460

Melanoma in Situ: The Power of One (Centimeter)?

November/December 2017

Volume 15 • Issue 6

PHOTO CAPSULE Snejina Vassileva, MD, PhD, Section Editor

Blaschkoid (Linear and/or Bandlike) Psoriasis Virendra N. Sehgal, MD;1 Ashok K. Aggarwal, MD2

25-year-old man presented with slowly progressive, itchy, red, raised eruptions, occupying the middle of the left leg, of 5 months’ duration. The eruptions were also affecting the abdomen. They were topped by chalky-white dry scales. Their configuration was peculiarly bizarre, and they had shown exacerbations during the winter. Skin surface examination revealed multiple, red, scaling papules and/or plaques. Their size was 5 to 7 centimeters. The tops of the lesions showed shiny, silvery-white, lamellated, and brittle scales. The Auspitz sign was positive. The configuration of the lesions was linear on the upper and lower extremities, but bandlike on the abdomen (Figure 1), corresponding to the lines of Blaschko.

Figure 1. Blaschkoid (linear and/or bandlike) psoriasis: bandlike psoriasis lesions on the abdomen.

Hematoxylin and eosin staining revealed flowing together or merging (confluent) parakeratosis, distinct collections of neutrophils in the stratum corneum, elongation of the rete ridges (pegs), and corresponding elongation of the papillae, in addition to suprapapillary thinning. Dilated and tortuous capillaries were conspicuous in the papillae. Spongiform pustule of Kogoj was also identified. Superficial perivascular lymphohistiocytes were a prominent feature, along with a few eosinophils (Figure 2). DISCUSSION The morphology of the psoriasis lesions was typical and was substantiated by a positive Auspitz sign, but their configuration and distribution was captivatingly unusual and has been rarely reported.1–4 The hallmark was the linear or bandlike configuration, a feature seen in epidermal nevi and other dermatoses. Revisiting the characteristics of Blaschko lines5 may provide a clue here. In pigmentary disorders, the pattern seen is linear on the extremities, S-shaped on the abdomen, and V-shaped on the back. It is thought to result from genetic mosaicism6 and the interplay of transverse clonal proliferation and longitudinal growth and flexion of the embryo.7–9

Figure 2. Blaschkoid (linear and/or bandlike) psoriasis, depicting confluent parakeratosis, distinct collections of neutrophils in the stratum corneum, acanthosis, elongation of the rete ridges with corresponding elongation of the papillae, and papillary thinning (hematoxylin and eosin stain, magnification ×100).

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati Delhi,1 and Skin Institute, School of Dermatology, Greater Kailash, New Delhi,2 India Address for Correspondence: Virendra N. Sehgal, MD, DermatoVenerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi 110 033, India • E-mail: drsehgal@ndf.vsnl.net.in, sehgalvn@yahoo.co.in

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References 1 Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826–850. 2 Ghorpade AK. Naevoid Blaschkoid psoriasis. Indian J Dermatol Venereol Leprol. 2010;76:449.

5 Blaschko A. Die Nervenverteilung in der Haut in Ihrer Beziehung Zu Den Erkrankungen der Haut. Vienna, Leipzig: Braumuller; 1901. 6 Happle R. Mosaicism in human skin: Understanding the pattern and mechanisms. Arch Dermatol. 1993;129:1460–1470. 7 Atherton DJ, Kahana M, Russell-Jones R. Naevoid psoriasis. Br J Dermatol. 1989;120:837–841.

3 Bondi EE. Psoriasis overlying an epidermal naevus. Arch Dermatol. 1979;115:624–625.

8 Lehners-Weber C, de la Brassinne M, Dezfoulian B, et al. Congenital psoriasis following the lines of Blaschko. Pediatr Dermatol. 1996;13:219–221.

4 Ghorpade A. Accentuated Blaschko-linear manifestation of psoriasis. Eur J Dermatol. 2008;18;196–197.

9 Goujon C, Pierini AM, Thivolet J. Does linear psoriasis exist? Ann Dermatol Venereol. 1981;108:643–650.

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

(Continued on page 488)

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November/December 2017

Volume 15 • Issue 6

PHOTO CAPSULE

Cellular Blue Nevus: An Unusual Localization Murat Zor, MD; Engin Kaya, MD

21-year-old man presented with a painless mass on the shaft of his penis. The lesion had been present for a long time, and the patient did not provide any details. Physical examination revealed a nodular, dome-shaped, smooth-surfaced, hairless, approximately 1.5-cm blue-black–colored lesion on the left side of the penile shaft (Figure). An excisional biopsy was performed. Histopathologic evaluation revealed a cellular blue nevus with no sign of mitosis, necrosis, or epidermal invasion. At 1 year, there was no recurrence or metastasis. Blue nevi of the genital mucosa are exceedingly rare.

The blue nevus is an uncommon pigmented lesion of dermal melanocytes. Conventionally, two well-defined histologic variants are designated as “common” and “cellular.”1 Cellular blue nevi are of special diagnostic interest due to the potential for clinical and histopathologic confusion with melanoma. The low to absent mitotic activity and the absence of necrosis are the key features for confirming the diagnosis. Histologically, the cellular blue nevus is a compact lesion found in the dermis. Among the most salient cytologic features is the absence of nuclear pleomorphism and alternation of clear cells with intensely pigmented spindle cells.1 Mitotic activity can be seen (≤1 mitoses/mm²), while necrosis, junctional activity, and epidermal invasion are typically absent. Long-term follow-up data suggest that, following complete conservative surgical excision, there is a very small risk for recurrence and metastasis.2 In some instances, a cellular blue nevus can be associated with malignant transformation. Extensive necrosis, increased mitotic activity, atypical mitoses, and marked cytologic atypia are the key features of malignant transformation.2 References 1 González-Cámpora R, Galera-Davidson H, VázquezRamírez FJ, Díaz-Cano S. Blue nevus: Classical types and new related entities. A differential diagnostic review. Pathol Res Pract. 1994;190:627–635. 2 Shumway BS, Rawal YB, Allen CM, Kalmar JR, Magro CM. Oral atypical cellular blue nevus: an infiltrative melanocytic proliferation. Head Neck Pathol. 2013;7:171– 177.

Figure. A nodular, dome-shaped, smooth-surfaced, hairless, blue-black–colored, approximately 1.5-cm pigmented lesion on the left side of the penile shaft.

From the Department of Urology, Gulhane Training and Research Hospital, Kecıoren, Turkey Address for Correspondence: Engin Kaya, MD, Department of Urology, Gulhane Training and Research Hospital, Kecıoren, Turkey • E-mail: drenginkaya@yahoo.com

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November/December 2017

Volume 15 • Issue 6

Vignettes of Dermatologic History Mark Bernhardt, MD, Section Editor

Vicente Pardo-Castelló, MD (1892–1967) Mark Bernhardt, MD

icente Pardo-Castelló (the addition of his mother’s surname follows Hispanic usage) was born in Havana, Cuba, in 1892. After graduating from the University of Havana School of Medicine, Pardo (Figure) interned under the tutelage of the patron of Cuban dermatology, Professor Raimundo G. Menocal (1856–1917). He followed this with 4 years of postgraduate study in the United States, first at the Vanderbilt Clinic of Columbia University and then the University of Pennsylvania. Returning to Havana, Pardo built a successful private practice and began a rapid ascent to the highest reaches of academia. In 1925, Pardo was appointed head of the Dermatology Service at Calixto Garcia Hospital, one of Cuba’s most prestigious. Two years later, he published his authoritative textbook Notions of Dermatology and Syphilography.1 Despite this busy schedule at home, Pardo maintained an active engagement with his American colleagues. In 1921, he was the youngest person ever admitted into the American Dermatological Association, of which he was elected Vice-President in 1932 and President in 1955. He was a member of the American Academy of Dermatology and a Diplomate of the American Board of Dermatology. Pardo founded the Sociedad Cubana de Dermatologia and held memberships in dermatologic societies throughout Europe, the Middle East, and Central and South America. Life was good. PARDO POST CASTRO When Fidel Castro ousted Fulgencio Batista on January 1, 1959, the cozy, comfortable Cuba in which Pardo was such an esteemed citizen ceased to exist. Abandoning all his worldly possessions, Pardo joined the vast majority of the University of Havana’s medical faculty and fled to the United States. Pardo’s strong connections in America, including a previous stint as a Visiting Professor at the University of Miami Medical School, enabled him to acclimate much faster than many of his compa-

Figure. Vicente Pardo-Castelló, MD (1892–1967).

dres whose medical opportunities were severely limited by their lack of English, American citizenship, and professional licensure. A year after Castro’s coup, the Chairman of Medicine at the University of Miami, Dr. Ralph Jones Jr, established the University of Havana Medical School in Exile. This unique program offered émigré physicians a salaried position at the medical school, as well as free English language classes plus mentoring for the examinations needed to obtain a medical license. From its inception, Dr. Pardo was the teacher of the dermatology section at this remarkable school. Dr. Pardo maintained an active association with the University of Miami Medical School until his death from cardiac arrest on May 21, 1967. References 1 Díaz Almeida JG, Daniel AA. Historical outline of dermatology in Cuba. In: Galimberti R, Pierini AM, Cervini AB. History of Latin American Dermatology. Toulouse, France: Éditions Privat; 2007:151–161.

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

SKINmed. 2017;15:465

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November/December 2017

Volume 15 • Issue 6

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

Cutaneous Mucormycosis: A Fatal Complication of Immunosuppressant Therapy for Pemphigus Vulgaris Kanika Sahni, MD;1 Dipankar De, MD;1 Sunil Dogra, MD;1 Amrinderjit Kanwar, MD;1 Uma Nahar Saikia, MD2

A 62-year-old man with no comorbidities presented to the outpatient department of our Institute with a history of extensive vesiculobullous and erosive skin lesions and oral erosions for 2 months and fever for 1 week. A diagnosis of pemphigus vulgaris was made based on histopathology and direct immunofluorescence of a skin biopsy specimen, and the patient was started on oral prednisolone 40 mg per day along with intravenous antibiotics (amoxicillin-clavulanic acid, gentamicin, and metronidazole) empirically, pending blood and skin swab culture and sensitivity reports. His biochemical and hematologic investigations revealed no abnormalities (hemoglobin 12.4 g/dl, leukocyte count 6500/mm3, platelet count 250,000/mm3), and blood and skin cultures were sterile. When the fever had subsided and while he was receiving antibiotics, he was administered intravenous dexamethasone-cyclophosphamide pulse therapy over 3 days. After this, he was discharged on oral amoxicllin/clavulinc acid 625 mg tid, prednisolone 40 mg daily, and cyclophosphamide 50 mg daily. At the time of discharge, the erosions on the anterior region of the chest were reepithelializing without any evidence of eschar. (SKINmed. 2017;15:467–469)

n the sixth day after discharge, the patient returned with fever of 1 day’s duration and a rapidly enlarging black patch overlying the eroded skin over the left side of the chest that had arisen 4 days previously. The patient was readmitted and started on empirical broad-spectrum antimicrobials (intravenous co-amoxiclav, gentamicin, and metronidazole). On examination, the pemphigus erosions were reepithelializing; however, a 4 cm × 4 cm black, firmly adherent, necrotic escharlike lesion was observed overlying the anterior aspect of the left second to fourth ribs (Figure 1).

His blood count on the day of admission revealed striking bicytopenia (hemoglobin 11.9 g/dl, leukocyte count 1200/mm3, platelet count 79,000/mm3). Cyclophosphamide was immediately discontinued, despite which the counts fell further, reaching a nadir on day 4 of admission (hemoglobin 7.4/mm3, leukocyte

count 400/mm3, platelet count 15,000/mm3). Antimicrobials were changed in line with the sensitivity results of blood culture, which grew Staphylococcus aureus and later Acinetobacter sp. The patient’s condition deteriorated rapidly, as he developed disseminated intravascular coagulation, bleeding from the pemphigus erosions, septic shock, and deranged renal parameters. The black necrotic lesion increased rapidly in size to 15 cm × 12 cm. Skin biopsy from the necrotic lesion showed broad aseptate fungal hyphae in the dermis, with vascular invasion and thrombosis (Figures 2 and 3). Despite repeated attempts, it was impossible to isolate any fungal pathogen on culture from tissue and blood. Based on the skin biopsy report, a diagnosis of mucormycosis was made, and the patient was started on intravenous

This case was presented as a poster at the National Conference of the Indian Association of Dermatologists, Venereologists and Leprologists, February 2011, Gurgaon, India. From the Department of Dermatology, Venereology and Leprology1 and the Department of Histopathology,2 Postgraduate Institution of Medical Education and Research, Chandigarh, India Address for Correspondence: Sunil Dogra, MD, Department of Dermatology, Venereology and Leprology, Postgraduate Institution of Medical Education and Research, Sector 12, Chandigarh, India 160012 • Email: sundogra@hotmail.com

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Figure 1. (a) A 62-year-old man with a large black necrotic plaque over the anterior aspect of the chest wall surrounded by widespread superficial erosions of pemphigus vulgaris. (b) Large raw erosions of pemphigus over the patient’s back.

(b)

(a)

Figure 2. (a) Photomicrograph showing sloughed-off epidermis with necrotic dermis with vascular thrombosis in the dermis and subcutis (hematoxylin and eosin stain, magnification ×40). (b) Photomicrograph showing broad aseptate fungal hyphae in the dermis with vessel invasion and thrombosis (hematoxylin and eosin stain, magnification ×400).

amphotericin B on the fifth day after admission. This was followed by partial surgical debridement in view of the deranged coagulation profile. Despite the debridement and antifungal therapy, the lesion continued to increase in size over the next week, and contrast enhanced computed tomography showed it to be extending into the muscles of the SKINmed. 2017;15:467–469

anterior region of the chest wall. An attempt at complete debridement under general anaesthesia was made; however, intraoperatively, even the intercostal spaces were found to be involved, and complete debridement was not possible. The patient suffered a cardiac arrest in the immediate postoperative period and died.

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November/December 2017

CASE STUDY curring in a patient receiving dexamethasone-cyclophosphamide pulses (search terms included “cutaneous zygomycosis,” “cutaneous mucormycosis,” and “pemphigus”). Unlike in an immunocompetent host, where the infection is often localized, in the immunocompromised host it usually presents as a rapidly progressive gangrene with a variable degree of surrounding cellulitis and invasion of deeper tissue, and it may eventually disseminate. Treatment options include surgical debridement and parenteral antifungal agents. In a large series, a combination of aggressive surgical debridement of necrotic tissue and amphotericin B was found to be the best treatment protocol as 81.3% patients treated with surgical debridement and amphotericin B were cured, compared with 46.7% of patients treated with amphotericin B alone.6 Our case was complicated by the concomitant presence of sepsis, disseminated intravascular coagulation, and thrombocytopenia, which prevented early and complete debridement of the lesion. This may have been responsible for the ultimately fatal outcome in our patient.

Figure 3. Photomicrograph showing broad aseptate hyphae (periodic acid-Schiff stain, magnification ×400).

DISCUSSION Pemphigus vulgaris is an intraepidermal autoimmune blistering disorder affecting the skin and mucosae that is often extensive and associated with significant morbidity and, at times, mortality. Several immunosuppressants have been used for its treatment, of which dexamethasone-cyclophosphamide pulse therapy is believed, in most centers in India and also in other countries, to be one of the best regimens. Leukopenia is a rarely reported adverse effect of the above regimen, being reported in only 2 of the 36 patients in a study conducted at our center.1 After initial reports of use in pemphigus, dexamethasone-cyclophosphamide pulse therapy has been validated in further studies as being an effective therapeutic option with minimal adverse effects.2 Similarly, most intercurrent infections in patients treated with pulse therapy for pemphigus have been mild, barring a few reports of sepsis.3 This is a novel case of cutaneous mucormycosis as a complication of pulse therapy for pemphigus vulgaris.

CONCLUSIONS Dermatologists, as well as other physicians, should be aware of such rare occurrences of cutaneous mucormycosis in patients with immunobullous disorders who are on immunosuppressive or pulse therapy. In addition, it is important to watch out for the rare possibility of the development of severe pancytopenia in patients receiving dexamethasone-cyclophosphamide pulse therapy. References

Cutaneous mucormycosis is a rare opportunistic and fulminant fungal infection of the skin, being reported mostly in immunosuppressed or diabetic patients, most commonly caused by fungi of the genus Mucor. It has been previously reported in association with the leukopenia and immunosuppression associated with hematologic malignancies,4 as well as in patients on immunosuppressive drugs including corticosteroids. Cutaneous mucormycosis has also been reported in burns and trauma patients, where disruption of the cutaneous barrier seems to be implicated in the inoculation of mould spores.5 A search of PubMed did not reveal any previous report of cutaneous mucormycosis ocSKINmed. 2017;15:467–469

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1 Kanwar AJ, Kaur S, Thami GP. Long-term efficacy of dexamethasone-cyclophosphamide pulse therapy in pemphigus. Dermatology. 2002;204:228–231. 2 Pasricha JS, Khaitan BK, Raman RS, Chandra M. Dexamethasone cyclophosphamide pulse therapy for pemphigus. Int J Dermatol. 1995;34:875–882. 3 Zivanovic D, Medenica L, Tanasilovic S, et al. Dexamethasone-cyclophosphamide pulse therapy in pemphigus: a review of 72 cases. Am J Clin Dermatol. 2010;11:123– 129. 4 Abuali MM, Posada R, Del Toro G, et al. Rhizomucor variabilis var. regularior and Hormographiella aspergillata infections in a leukemic bone marrow transplant recipient with refractory neutropenia. J Clin Microbiol. 2009;47:4176–4179. 5 Ledgard JP, van Hal S, Greenwood JE. Primary cutaneous zygomycosis in a burns patient: a review. J Burn Care Res. 2008;29:286–290. 6 Chakrabarti A, Das A, Sharma A, et al. Ten years’ experience in zygomycosis at a tertiary care centre in India. J Infect. 2001;42:261–266.

Cutaneous Mucormycosis

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November/December 2017

Volume 15 • Issue 6

CASE STUDY

Immunologic Studies of Progesterone-Induced Neutrophilic Urticaria Papapit Tuchinda, MD;1,2 Corinne Erickson, MD;1 Antonella Tammaro, MD;1,3 Miya Okada Paterniti, MD;4 Sarbjit S. Saini, MD;5 Anthony A. Gaspari, MD1

A 33-year-old woman presented with recurring pruritic, erythematous papules around the mouth and on the hands, of 1.5 years’ duration. These flares typically began several days before her menstrual cycle and persisted for approximately 1 week. Physical examination revealed urticarial plaques on the neck. Due to the nature of the eruption, which corresponded with her menstrual cycle, a diagnosis of autoimmune progesterone urticaria was considered and workup pursued. (SKINmed. 2017;15:471–472)

cratch testing was used to assess for a type 1 hypersensitivity reaction to progesterone. Progesterone 50 mg/mL was applied to the patient’s left forearm, and preserved sesame oil was applied to the patient’s right forearm as a control. A 30-gauge needle was then used to lightly scratch the test spots. Neither area demonstrated a positive reaction after 15 minutes. Intradermal testing by injecting 0.1 ml of progesterone 50 mg/1 mL oil diluted in a 1:10 ratio with normal saline intradermally into the left forearm produced an immediate response of induration and erythema (Figure). A control site with 0.1 ml of sesame oil diluted in a 1:10 ratio with normal saline and intradermally injected into the right forearm produced a negative result. Twenty-four hours later, the progesterone arm exhibited persistent erythema and induration, while the control arm was clear. The 4-mm punch biopsies taken of the skin test site showed a superficial and deep perivascular and interstitial predominantly lymphoid infiltrate with many neutrophils and a few mast cells in the dermis. The lymphoid cells were mostly perivascular. Eosinophils were notably absent. Immunohistochemical staining revealed 100% positivity for CD3, CD4, CD5, and CD45, and 50% positivity for CD7. For basophil histamine release testing, 30 mL of blood was collected in syringes containing 10 mM PBS-EDTA from the patient and a non-atopic control participant. Basophils were first

enriched using a single Percoll-based density-gradient centrifugation technique (specific gravity 1.083) with Accuspin (Sigma, St. Louis, MO) separation tubes, as described.1 Enriched basophils were enumerated and stimulated for histamine release using anti-IgE (0.03, 0.3, and 1 µg/mL HP6061 mouse monoclonal IgM anti-human IgE Fc; Hybridoma Reagent Laboratory, Baltimore, MD) and progesterone (0.1, 0.5, 1, 5, 10, 80, 200, 500 μg/ mL diluted with DMSO with the highest concentration being 0.20%; Sigma Laboratories, St. Louis, MO) in duplicate for 45 minutes at 37°C using calcium-containing buffers, as described previously.2 Automated fluorimetry was used to measure histamine release in cell-free supernatants.3 Results for each stimulus are reported as a percentage of the total histamine content found in an aliquot of lysed leukocytes after subtraction of spontaneous histamine release from cells in buffer alone from the complete lysates. Both subjects showed anti-IgE-stimulated release and low spontaneous histamine release, but neither demonstrated release to any dose of progesterone. DISCUSSION Autoimmune progesterone dermatitis (APD) is a rare cutaneous sensitivity to progesterone in the luteal phase of a woman’s menstrual cycle. Due to the variety of clinical manifestations, the pathogenesis is not clearly defined. APD represents an autoimmune hypersensitivity to progesterone. The typical erup-

From the Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD;1 Department of Dermatology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok Thailand;2 Department of Dermatology, University la Sapienza, Rome, Italy;3 Department of Medicine,4 and Division of Clinical Immunology,5 Johns Hopkins School of Medicine, Baltimore, MD Address for Correspondence: Anthony A. Gaspari, MD, Department of Dermatology, University of Maryland School of Medicine, 419 West Redwood Street, Suite 240, Baltimore, MD 21201 • E-mail: agasp001@umaryland.edu

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CASE STUDY CONCLUSIONS APD should be considered in women with cyclical eruptions that coincide with the luteal phase of the menstrual cycle. Because a variety of morphologies have been described, intradermal progesterone testing can be key in differentiating between potential diagnoses. Tests such as the basophil histamine release assay may also be helpful in further elucidating the etiology of APD. These studies define the profile of a rare cause of chronic urticaria: progesterone-associated neutrophilic urticaria in the absence of detectable progesterone-specific IgE (ie, a negative histamine release assay). References

Figure. Left forearm, 20 minutes after intra-dermal injection of progesterone, revealing erythema, induration and edema. The right forearm, which had been treated with an injection of vehicle control, did not exhibit this type of reactivity (negative skin test, not shown).

1 Eckman JA, Sterba PM, Kelly D, et al. Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J Allergy Clin Immunol. 2010;125:889–895.

tions occur 5 to 8 days before menstruation due to the rising postovulatory concentration of progesterone, and spontaneously subside a few days after the beginning of the menses. To prove the diagnosis, intradermal testing with progesterone should be carried out. Concentrations of progesterone are varied from 0.1 to 50 mg/mL.4 The positive reactions can be immediate or delayed. Immediate reactions usually present within 30 minutes as urticarial lesions, and delayed reactions appear as erythema and induration within 24 to 96 hours.5–8 The pathogenesis of APD is not clearly understood and is likely multifactorial. Individuals who have been previously exposed to exogenous progesterone such as oral contraceptives likely have an IgE-mediated process. The role of antibodies in APD has also been demonstrated by basophil degranulation tests and immunofluorescence studies;9,10 however, prior history of exogenous progesterone exposure is not present in all APD patients, including our patient, and the pathogenesis in these cases likely differs. Our patient’s negative scratch test to progesterone and the basophil histamine release test argues against an IgE-mediated hypersensitivity, but the positive progesterone intradermal test and histology support the diagnosis of APD. The absence of inflammation at the negative control site supports this being an allergic rather than an irritant process.

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2 Vonakis BM, Vasagar K, Gibbons SP, et al. Basophil FcepsilonRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria. J Allergy Clin Immunol. 2007;119:441–448. 3 Saini SS, Richardson JJ, Wofsy C, et al. Expression and modulation of FcepsilonRIalpha and FcepsilonRIbeta in human blood basophils. J Allergy Clin Immunol. 2001;107:832–841. 4 Maguire T. Autoimmune progesterone dermatitis. Dermatol Nurs. 2009;21:190–192. 5 Stranahan D, Rausch D, Deng A, et al. The role of intradermal skin testing and patch testing in the diagnosis of autoimmune progesterone dermatitis. Dermatitis. 2006;17:39–42. 6 Herzberg AJ, Strohmeyer CR, Cirillo-Hyland VA. Autoimmune progesterone dermatitis. J Am Acad Dermatol. 1995;32:333–338. 7 Garcia-Ortega P, Scorza E. Progesterone autoimmune dermatitis with positive autologous serum skin test result. Obstet Gynecol. 117:495–498. 8 Vasconcelos C, Xavier P, Vieira AP, et al. Autoimmune progesterone urticaria. Gynecol Endocrinol. 2000;14:245– 247. 9 Jones WN, Gordon VH. Auto-immune progesterone eczema. An endogenous progesterone hypersensitivity. Arch Dermatol. 1969;99:57–59. 10 Miura T, Matsuda M, Yanbe H, et al. Two cases of autoimmune progesterone dermatitis. Immunohistochemical and serological studies. Acta Derm Venereol. 1989;69:308–310.

Progesterone-Induced Neutrophilic Urticaria

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November/December 2017

Volume 15 • Issue 6

CASE STUDY

Persisting Ulcerating Lesions After Cyclosporine Therapy for Erosions Found in Flexural Sites Mina Amin, BS;1 Shannon Famenini, MD;2 Jashin J. Wu, MD3

In February 2012, a patient with a 15-year history of painful, pruritic eruptions presented with a severe exacerbation that had lasted for the previous week. The patient also reported severe headaches, a fever of 38.9°C (102.1°F), a cough, and diarrhea, which had now resolved. Physical examination showed erythematous macerated patches with erosions in the left submammary region, bilateral axillae, and vaginal area (Figure 1), and greasy scale covering the scalp. Despite lessening of the lesions in the submammary region and abdomen with the administration of minocycline 100 mg twice per day and cyclosporine 100 mg three times per day, the patient continued to complain of persistent painful ulcerations in the labia majora and perianal area (Figure 2). The patient was started on acyclovir 400 mg three times per day for 10 days for positive herpes simplex viral culture and ampicillin for Proteus infection of the area. (SKINmed. 2017;15:474–475)

istologic sections of the axilla demonstrated prominent areas of suprabasilar and intraepidermal acantholysis, or loss of cohesion between the keratinocytes, including areas of full-thickness acantholysis, resembling a “dilapidated brick wall” pattern. Areas of subcorneal neutrophils and apparent bacterial organisms were also present, consistent with secondary impetiginization (Figure 3). The histologic and clinical findings supported a diagnosis of eczema herpeticum in Hailey-Hailey disease.

complex is defective and epidermal acantholysis occurs. Treatment is difficult, and topical corticosteroids, and antibacterial agents have been used.1 Recalcitrant cases have been shown to improve with methotrexate, narrow-band ultraviolet B therapy, and topical immunomodulators.1 Heat and friction worsen the disease. Viral infections are also suggested to lead to disease exacerbation.

DISCUSSION Hailey-Hailey disease is an autosomal dominant condition with incomplete penetrance that is characterized by vesicles, erosions, and erythematous plaques occurring at flexural sites, such as the axillae and groin. Longitudinal leukonychia presenting as longitudinal lines and ridges on the fingernails may also be present. Superimposed bacterial infections are common, producing malodorous lesions. Hailey-Hailey disease is caused by a defect on chromosome 3q21–-24, which codes for ATP2C1 (also known as SPCA1), a calcium and manganese pump that controls calcium release from the Golgi apparatus. Calcium is required for the assembly of functional adherens junctions and desmosomes. Without sufficient calcium release, the tonofilament-desmosome

Figure 1. Erythematous macerated patches with erosions in the genital region.

From the University of California, Riverside, School of Medicine, Riverside, CA;1 Department of Internal Medicine, University of California College of Medicine, Irvine, Irvine, CA;2 and Department of Dermatology, Kaiser Permanente Medical Center, Los Angeles, CA3 Address for Correspondence: Jashin J. Wu, MD, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Ave, 5th Floor, Los Angeles, CA 90027 • E-mail: jashinwu@hotmail.com

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CASE STUDY tum corneum, including pemphigus vulgaris, and Darier disease, even when eczema is not present.2 Eczema herpeticum has also been associated with autografted skin and second-degree burns.3,4 It presents as vesicles on an erythematous base that eventually ulcerate with crusting and are commonly complicated by bacterial superinfection.5 Diagnosis can be confirmed by a Tzanck smear showing multinucleated giant cells, or by viral cultures. In equivocal cases, the polymerase chain reaction can also be employed.5 Given a high clinical suspicion or positive cultures, treatment should be implemented immediately to prevent the life-threatening consequences of disseminated infection and death. Therapy should not be withheld pending positive cultures. Treatment should include an antiviral agent and an antibacterial for any superimposed bacterial infections.

Figure 2. Ulcerations in the labia majora.

CONCLUSIONS Acantholysis, as seen in Hailey-Hailey disease, renders the epidermal cells fragile and, therefore, accessible for infection and proliferation with the herpes virus. In the face of persisting ulcerating lesions during therapy for Hailey-Hailey disease, clinical suspicion for eczema herpeticum is advised. References 1 Hovnanian A. Acantholytic disorders of the skin. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2008:550–563. 2 Mackley CL, Miller JJ. Photo Quiz. What is your diagnosis? Eczema herpeticum superinfection in a patient with pemphigus vulgaris. Cutis. 2004;73:301–317. 3 Manders SM, Chetty BV. Eczema herpeticum occurring in autografted skin. J Am Acad Dermatol.1991;24:509–510.

Figure 3. Histologic section (×10 magnification) of the axilla showing suprabasilar, as well as intraepidermal acantholysis, including areas of full-thickness acantholysis, resembling a “dilapidated brick wall” pattern.

4 Bartralot R, García-Patos V, Rodríguez-Cano L, et al. Kaposi’s varicelliform eruption in a patient with healing second degree burns. Clin Exp Dermatol. 1996;21:127– 130.

Eczema herpeticum is a term referring to herpes simplex viral infection of atopic dermatitis but has also been applied to Herpes simplex viral infections of other skin diseases that disrupt the stra-

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5 Thomas JJ, Perron AD, Brady WJ. Serious generalized skin disorders. In: Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ, Cydulka RK, Meckler GD, eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th ed. New York, NY: McGraw-Hill; 2011:1642–1646.

Persisting Ulcerating Lesions

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November/December 2017

Volume 15 • Issue 6

CASE STUDY

Mast Cell Activation Syndrome Owen N. Kramer, BS;1 Marla S. Barkoff, MD;2 Claudia Hernandez, MD3

A 51-year-old woman with a history of asthma and Hashimoto’s thyroiditis presented to the dermatology service with a chief complaint of “itchy bumpy rashes” that persisted beyond 24 hours. She noted that, 3 days prior to the onset of urticaria, a pyrroloquinoline quinone supplement had been started. The urticaria was accompanied by variable episodes of transient facial swelling and difficulty breathing. The patient noted that exposure to fish, nuts, and nonsteroidal anti-inflammatory drugs triggered facial swelling. Other reported findings included a 5-year history of diarrhea, sense of memory deterioration, concentration difficulties, and clinical manifestations of anomic aphasia. Although her allergy testing was “negative,” she had been given the diagnoses of lactose intolerance and gastroesophageal reflux disease. Laboratory studies on initial presentation were significant for a positive history of antithyroperoxidase antibodies and elevated total complement activity. Medications included budesonide/formoterol, fluticasone/salmeterol, levothyroxine, albuterol, and fexofenadine 180 mg twice daily. Although her “rash” had initially responded to fexofenadine, it soon became refractory to treatment. Her family history was significant only for thyroid disease. (SKINmed. 2017;15:477–479)

hysical examination revealed mild flushing and numerous erythematous, edematous plaques with a surrounding halo of hypopigmentation consistent with wheals on her chest, back, abdomen, and extremities. No dermatographism was elicited with a scratch test, and no excoriations were noted. A punch biopsy was performed from a lesion on her right forearm. The histopathologic study revealed superficial and deep perivascular and interstitial neutrophils with scattered eosinophils. This suggested hypersensitivity dermatitis with urticarial features and without features of vasculitis. A mast cell disorder was suspected. Serum tryptase and 24hour urinary N-methylhistamine, as well as 2,3-dinor-11βprostaglandin F2α (2,3-BPG), were assessed (Table), with only her 2,3-BPG level elevated to 1538 pg/mg of creatinine (normal <1382 pg/mg creatinine). Given the strong suspicion for a mast cell disorder, a mast cell–stabilizing medication, cromolyn sodium oral solution, was started, which relieved her diarrhea. A proprietary blend of mast cell stabilizers, including luteolin 100 mg, quercetin 70 mg, and rutin 30 mg taken twice daily, was also initiated, which improved her sleep quality and general feeling of well-being. A diagnosis of mast cell activation syndrome (MCAS) was made.

DISCUSSION A proposal conference held in 2010 suggested a new classification for mast cell disorders. Four proposed terms include: (1) mast cell hyperplasia, (2) MCAS, (3) mastocytosis (± MCAS), and (4) myelomastocytic conditions.1 Of these four terms, MCAS can be further subclassified into primary MCAS, secondary MCAS, and idiopathic MCAS.1 These conditions are used to describe patients who present with a variety of signs and clinical manifestations suggestive of mast cell activation2 (MCA) episodes that affect multiple organ systems. Affected organ systems may include, but are not limited to, the skin, gastrointestinal tract, pulmonary system, naso-ocular system, and central nervous system.2 Specific proposed diagnostic criteria for MCAS include (1) clinical signs of severe recurrent (or chronic) systemic MCA, (2) biochemical elevations in mast cell mediators, and (3) response to therapy with mast cell–stabilizing agents or drugs directed against mast cell mediator production, release, or effects.1–4 All three of these diagnostic criteria were fulfilled in our patient and thus allowed for a diagnosis of MCAS. Cutaneous MCAS manifestations, although variable, include pruritus, urticaria, flushing, and dermatographism.2,5 A 2011

From the University of Illinois at Chicago College of Medicine,1 Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago College of Medicine,2 and Department of Dermatology, Rush University Medical Center,3 Chicago, IL Address for Correspondence: Claudia Hernandez, MD, Department of Dermatology, Rush University Medical Center, 1653 W. Congress Parkway, 220 Annex Building Chicago, IL 60612 • E-mail: Claudia_Hernandez@rush.edu

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Table I. Demographic Data Pertinent Positives

Pertinent Negatives

Autoantibody testing positive for antithyroperoxidase

Autoantibody testing negative for the following antigens: ANA, dsDNA, RNP, chromatin, ribosomal, SSA/SSB, SCL-70, JO-1, thyroglobulin, centromere, IgE receptor

Total complement activity CH50 elevated: >60 (31–60) U/mL

C4 and C3 within normal range on two occasions

24-hour-urine elevated 2,3-BPG: 1538 pg/mg of creatinine (<1382 pg/mg creatinine)a

Complete blood count and erythrocyte sedimentation rate within normal range Serum protein electrophoresis, serum immunofixation and IgE within normal range Serum tryptase on two occasions: 10.4 and 6.8 ng/mL (<10.9 ng/mL) 24-hour-urine N-methylhistamine: 182 μg/g creatinine (30–200)

Abbreviations: 2,3-BPG, 2,3-dinor 11B-prostaglandin F2a; ANA, antinuclear antibody; dsDNA, double-stranded DNA; Ig, immunoglobulin; RNP, ribonucleoprotein; SCL-70, topoisomerase I.; SSA/SSB, Sjögren’s-syndrome–related antigen A and B. Numbers in parentheses indicate the normal values. a At the time this patient was tested, a normal value was defined as <1382 pg/mg Cr. After the diagnosis in this patient, the Mayo Medical Laboratory changed the 24-hour-urine 2,3-BPG assay as well as the normal value.

prospective study of 18 patients with MCAS found that 89% had both dermatographism and flushing.2 A separate study in 2014 of 25 MCAS patients revealed that 84% had flushing, 68% had pruritus, and 48% had urticaria.5 These signs have been noted in other studies as well.6,7 Facial swelling, a complaint in our patient, occurs in 75% of reported patients with MCAS.1 In terms of non-dermatologic findings, reported in MCAS patients in the 2011 study, 94% of patients had abdominal pain with a variable presence of diarrhea, headache, and difficulties with memory or concentration.2 These observations were reinforced by a separate cohort in 2014 that reported abdominal pain and diarrhea in 52% and 48% of their patients, respectively.5 It is interesting that our patient also had gastrointestinal complaints that were felt to be the result of lactose intolerance; rather, cow’s milk may be a trigger for mast-cell release in our patient, as a dietary exclusion of this resulted in a reduction of gastrointestinal clinical manifestations.2 Because MCAS can present with many non-specific clinical manifestations of MCA, it may mimic diseases such as acute lupus erythematosus, hereditary and acquired angioedema, druginduced side effects, endocarditits, acute hypothyroidism, pheochromocytoma, gastrinomas, and medullary thyroid tumors. Other conditions to consider in the workup of MCAS should include identification of additional possible underlying inflammatory, infectious, or neoplastic etiologies.1 It is not uncommon for these diseases to be part of the initial differential diagnosis of MCAS patients.2,3,7 Although a biopsy may be helpful in excluding some of these disorders, including a cutaneous clonal mast cell disorder, it does not appear to be as useful in the direct identification of MCAS.2 SKINmed. 2017;15:477–479

Detecting the elevation of mast cell mediators in serum and/ or urine is key in the evaluation of MCAS.3,8–10 Attempts to measure these biochemical markers should ideally be performed 30 minutes to 4 hours after an episode suggestive of mast cell degranulation.5 Of these markers, tryptase is fairly specific for MCA,8 while other less specific mediators include plasma histamine, urine histamine, metabolite N-methylhistamine, prostaglandin D2, and metabolite 11-βPGF2α.11–14 Unlike systemic mastocytosis, MCAS often presents with a normal baseline tryptase measurement that can transiently increase during symptomatic episodes; it is essential to measure this marker.6 A minimal increase in tryptase of 20% from baseline plus an absolute increase of 2 ng/ml are required to meet the definition of MCA.1 If serum tryptase measurements are not available or are unchanged, other markers become important to assess.3,5 Other investigators have observed that an elevated 11-βPGF2α is the most common laboratory marker elevated in MCAS.5 Most patients with MCAS appear to have only one elevated laboratory measurement, as seen in our patient.2 It is important to note that our patient’s urinary prostaglandin was measured via the 2,3BPG level, which has been reported to be highly specific (84%) for systemic mast cell disorder.15 Patients may need to undergo additional testing for a primary disorder via detection of the ckit D816V mutation or CD25 positivity via peripheral blood analysis, with additional investigation of the bone marrow being prompted by a positive result.7 Various MCAS therapies were reviewed in 2015 publications, suggesting that most manifestations can be best managed with histamine 1 and/or 2 receptor antagonists as well as other medications that interfere with MC mediators and prevent MCA.7 Multiple different therapies should be used before concluding that the patient is not responding to treatment.3 Certain findings can be

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triggered by multiple mast cell mediators and may be alleviated when drug therapies targeting multiple effectors, ie, leukotriene receptors as well as histamine-1 receptors, are used.3 In addition to standard antihistamine therapy, the flavone luteolin has also been found to inhibit mast cell degranulation and can be beneficial.7 CONCLUSIONS MCAS is a rare disorder, with 80% of cases having some type of cutaneous findings. Given this high level of skin involvement, it appears likely that some of these patients will present to dermatologists for diagnostic assistance and therapeutic options. A high index of suspicion for MCAS is indicated in appropriate patients who present with cutaneous as well as systemic clinical manifestations. This awareness may help to guide biochemical testing in order to reduce diagnostic delays in this condition.2 References 1 Valent P, Akin C, Arock M, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: A consensus proposal. Int Arch Allergy Immunol. 2012;157:215–225. 2 Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011;128:147–152 e142. 3 Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013;68:417–424. 4 Akin C. Mast cell activation syndromes presenting as anaphylaxis. Immunol Allergy Clin North Am. 2015;35:277–285. 5 Ravi A, Butterfield J, Weiler CR. Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11beta-prostaglandin2alpha. J Allergy Clin Immunol Pract. 2014;2:775–778.

6 Lee MJ, Akin C. Mast cell activation syndromes. Ann Allergy Asthma Immunol. 2013;111:5–8. 7 Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373:163– 172. 8 Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:1622–1626. 9 Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26:451–463. 10 Vegh AB, George KC, Lotfi-Emran S, Butler NE, Schwartz LB. Total tryptase levels indicate risk for systemic reactions to rush immunotherapy and mast cell activation. Ann Allergy Asthma Immunol. 2011;106:342–343 e346. 11 Awad JA, Morrow JD, Roberts LJ, 2nd. Detection of the major urinary metabolite of prostaglandin D2 in the circulation: Demonstration of elevated levels in patients with disorders of systemic mast cell activation. J Allergy Clin Immunol. 1994;93:817–824. 12 Keyzer JJ, de Monchy JG, van Doormaal JJ, van Voorst Vader PC. Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites. N Engl J Med. 1983;309:1603–1605. 13 Ono E, Taniguchi M, Mita H, Akiyama K. Salicylamideinduced anaphylaxis: Increased urinary leukotriene E4 and prostaglandin D2 metabolite. Allergy. 2008;63:480– 482. 14 Watkins J, Wild G. Improved diagnosis of anaphylactoid reactions by measurement of serum tryptase and urinary methylhistamine. Ann Fr Anesth Reanim. 1993;12:169–172. 15 Mayo Foundation For Medical Education And Research. Test ID: 23BPG 2,3-Dinor-11Beta-Prostaglandin F2 Alpha, Urine. 2016; http://www.mayomedicallaboratories. com/test-catalog/Clinical+and+Interpretive/37931.

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Volume 15 • Issue 6

CASE STUDY

Plantar Fibromatosis in a Mentally Challenged Man Treated with Intralesional Corticosteroids Ayse Serap Karadag, MD;1 Emin Ozlu, MD;2 Ayse Bahar Ceyran, MD;3 Mehmet Simsek, MD;1 Tugba Kevser Uzuncakmak, MD;1 Ilkin Zindancı, MD;1 Necmettin Akdeniz, MD1

A 21-year-old mentally challenged man presented with a fixed plaque lesion on the right foot, which had been present for 10 years. Dermatologic examination revealed an erythematous, painful, firm, fixed plaque-nodular lesion on the plantar aspect of the right foot (Figure 1A). Nothing of distinction was noted from his family history or his laboratory tests. An incisional biopsy revealed parallel, regular bundles composed of uniform, plump spindle cells. Thin collagen fibers were seen in contact with and located between the spindle cells. This mass was separated from the surrounding soft tissue by an irregular, unclear border (Figure 2A). İmmunohistochemically, the spindle cells showed diffuse, strong reactivity to vimentin (Figure 2B) and smooth muscle actin (Figure 2C). (SKINmed. 2017;15:480–482)

agnetic resonance imaging (MRI) of the right foot demonstrated a lobule-contoured mass, measuring 25 mm × 50 mm × 80 mm along the plantar fascia adjacent to the plantar muscles. This mass was isointense to muscle on T1-weighted sequences and showed low intensity on T2-weighted sequences. In addition, MRI showed linear hypointense streaks on the lesion (Figure 3A). The patient was diagnosed with plantar fibromatosis based on the clinical, ra-

diologic, and histopathologic findings. İntralesional triamcinolone acetonide 20 mg/ml was given five times per month. MRI was repeated after treatment and showed a lobule-contoured mass measuring 24 mm × 27 mm × 56 mm along the plantar fascia (Figure 3B). This reduction in lesion size shown by MRI was remarkable (see Figure 1B). The severity of the patient’s pain was significantly reduced, and at 1 year there had been no recurrence.

Figure 1. (A) Erythematous, firm, fixed plaque-nodular lesion on the plantar aspect of the right foot. (B) Appearance after treatment.

From the Department of Dermatology1 and Department of Pathology,3 Goztepe Research and Training Hospital, Istanbul Medeniyet University, Istanbul, Turkey; Department of Dermatology, Duzce University Faculty of Medicine, Duzce,Turkey2 Address for Correspondence: Emin Ozlu, MD, Department of Dermatology, Duzce University Faculty of Medicine, Apt 125, Duzce, Turkey, 81620 • E-mail: dermatologg@gmail.com

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Figure 2. (A) Parallel, regular bundles composed of uniform, plump spindle cells (hematoxylin and eosin stain, magnification ×100). (B) Diffuse strong vimentin immunoreactivity (vimentin stain, magnification ×200). (C) Diffuse strong smooth muscle actin immunoreactivity (smooth muscle actin stain, magnification ×100).

produce plantar mass lesions. The diagnosis may be determined based on the clinical, radiologic, and histopathologic findings.4 Radiologic imaging methods are commonly used in the diagnosis of plantar fibromatosis. Ultrasonography and MRI may confirm the diagnosis.5 On MRI, plantar fibromatosis characteristically shows soft tissue nodules, frequently on the medical aspect of the plantar aponeurosis. The inferior region of the lesion has a welldefined margin, whereas the superior region shows an irregular structure with extensions into the deep plantar tissues. Plantar fibromatosis has a distinct appearance on MRI. Additionally, MRI plays an integral role in diagnosing the lesion, as well as in assessing disease severity and determining the appropriate treatment approach.6 Also, our patient underwent MRI before and after therapy, demonstrating a marked reduction in lesion size.

Figure 3. (A) Magnetic resonance imaging of the right foot before treatment (coronal plane). (B) Magnetic resonance imaging of the right foot after treatment (coronal plane).

DISCUSSION Plantar fibromatosis is characterized by local proliferation of abnormal fibrous tissue within the plantar fascia. Slow-growing nodular lesions are commonly located in the medial part of the plantar fascia. This condition can occur at any age, but it is more commonly observed in middle and late adulthood. Its etiology is unknown.1 Dupuytren’s contracture, chronic alcohol consumption, use of anticonvulsants, and diabetes mellitus have been examined as potential factors in the development of lesions in plantar fibromatosis.1,2 The condition may be clinically asymptomatic but can present with swelling of the foot, difficulty wearing shoes, pain, and contractures. Clinical manifestations can occur as a result of enlargement of the lesions, local invasion, and compression of the neighboring muscle and neurovascular tissues.3 Leiomyoma, rhabdomyosarcoma, liposarcoma, and neurofibroma may also SKINmed. 2017;15:480–482

Many treatment options are available for plantar fibromatosis. Conservative therapies, including orthopedic insoles, anti-inflammatory drugs, physical therapy, and intralesional steroids should be considered in symptomatic cases.5 Local corticosteroid injections reduce fibroblast proliferation and concurrently accelerate apoptosis of the fibroblasts and inflammatory cells.7 Intralesional steroid injections in one patient with plantar fibromatosis given for 5 months produced an improvement in clinical manifestations and a reduction in lesion size. In the our patient, a marked reduction in lesion size and pain level was noted 3 to 4 months after the initiation of intralesional steroid therapy.8 Surgery must be considered for patients with severe clinical manifestations or those unresponsive to conservative therapies; however, high recurrence rates have been reported after surgical treatment for plantar fibromatosis.9 In addition, some reports have shown extracorporeal shock wave therapy and antiestrogen therapy as alternative treatment methods for plantar fibromatosis.5

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CASE STUDY characteristic appearance on MR images. Radiology. 1994;193:841–845.

CONCLUSIONS There is no cause-oriented therapy for plantar fibromatosis, and there are many options for the treatment of this disease. Corticosteroids have a different mechanism of action and are successful in the treatment of many dermatologic disorders. We suggest that local corticosteroid injections may be an effective and reliable nonsurgical means of therapy for plantar fibromatosis. References 1 Souza BG, de Souza Junior GZ, Rodriques RM, et al. Surgical treatment of a case of Ledderhose’s disease: A safe plantar approach to subtotal fasciectomy. Case Rep Orthop. 2015;2015:509732. 2 Elhadd TA, Ghosh S, Malik MI, et al. Plantar fibromatosis and Dupuytren’s disease: An association to remember in patients with diabetes. Diabet Med. 2007;24:1305. 3 Morrison WB, Schwietzer ME, Wapner KL, et al. Plantar fibromatosis: A benign aggressive neoplasm with

4 Lee TH, Wapner KL, Hecht PJ. Current concepts review: Plantar fibromatosis. J Bone Joint Surg Am. 1993;75:1080–1084. 5 Veith NT, Tschernig T, Histing T, et al. Plantar fibromatosis—topical review. Foot Ankle Int. 2013;34:1742– 1746. 6 English C, Coughlan R, Carey J, et al. Plantar and palmar fibromatosis: Characteristic imaging features and role of MRI in clinical management. Rheumatology (Oxford). 2012;51:1134–1136. 7 Meek RM, McLellan S, Reilly J, et al. The effect of steroids on Dupuytren’s disease: Role of programmed cell death. J Hand Surg Br. 2002;27:270–273. 8 Pentland AP, Anderson TF. Plantar fibromatosis responds to intralesional steroids. J Am Acad Dermatol. 1985;12:212–214. 9 Van der veer WM, Hamburg SM, de Gast A, et al. Recurrence of plantar fibromatosis after plantar fasciectomy: Single-center long-term results. Plast Reconstr Surg. 2008;122:486–491.

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Volume 15 • Issue 6

CASE STUDY

Role of Immune Status in Chemotherapy-Induced Transient Acantholytic Dermatosis Sogyong L. Auh, MD, PhD; 1 Ingrid Polcari, MD;2 Vesna Petronic-Rosic, MD, MSc;1 Aisha Sethi, MD1 A 79-year-old man with a recent diagnosis of acute myeloblastic leukemia received induction chemotherapy with daunorubicin and cytarabine, plus moxifloxacin and fluconazole prophylaxis. Approximately 2 weeks later, an asymptomatic eruption appeared on his trunk. He then developed a neutropenic fever and was started on aztreonam, vancomycin, voriconazole, and amikacin and was transferred to our facility from an outside hospital. Micafungin was subsequently added, and the patient defervesced within a few days. (SKINmed. 2017;15:483–484)

t the time the dermatology service was consulted, the eruption had been present for 5 days. Erythematous papules, flaccid vesicles, and pustules were noted on the back and central area of the chest (Figure 1). A skin biopsy was taken from the chest. Histopathologic evaluation showed acantholysis and dyskeratosis with grains and corps ronds confined to small areas of the epidermis, and a perivascular and periadnexal lymphoid infiltrate without eosinophils (Figure 2). The Gram stain was negative for bacteria. These features were characteristic for transient acantholytic dermatosis (TAD), otherwise known as Grover’s disease. Given the clinical context, we suspected a drug- or chemotherapy-induced etiology. A topical corticosteroid was offered but the patient declined due to lack of clinical manifestations. The lesions resolved spontaneously within 10 days.

tation,6 immunosuppresion,3 and malignancy,7 suggesting a role for altered immunity as a possible mechanism of chemotherapyinduced Grover’s disease.

DISCUSSION

In contrast to typical TAD, the lesions were not pruritic in our patient or other patients with associated chemotherapy or malignancy.3,4,7 This suggests that, although histopathologically indistinguishable, the clinical spectrum of TAD may vary depending on the etiology.

In 1970, Grover described TAD as a distinct entity characterized by pruritic papules and vesicles predominantly on the trunk, with epidermal acantholysis as the primary histopathological feature.1 TAD is a self-limited eruption that typically presents in patients over the age of 40 years. Although the specific etiology of TAD remains unknown, it has been associated with heat and sweating,2 and fever.3 A previous report of chemotherapy-induced Grover’s disease focused on elimination of the chemotherapeutic agent by sweating as a potential cause for the development of skin lesions.4 Grover’s disease has also been reported in patients with HIV infection,5 renal transplan-

Chronologically, the eruption appeared shortly after the expected nadir for cytarabine (7 to 10 days), suggesting a link between the emergence of the eruption coinciding with either general immunosuppression or repopulation of individual immune compartments at different rates, resulting in an imbalance between certain immune cell populations. Complete immune cell recovery occurs within the following 10 to 18 days, which might lead to spontaneous resolution of lesions as immune compartments normalize. This could explain the resolution of the skin lesions in our patient after the discontinuation of chemotherapy.

Grover’s disease is typically limited to older patients. With aging, there is a decline in T helper type 1 cells, which produce interferon-γ and promote cell-mediated immunity. There is also an increase in helper T (Th0) cells producing both type 1 and type 2 cytokines, potentially leading to a relative increase in the type 2 cytokine interleukin-4 (IL-4).8 Studies in mice have shown increasing production of IL-4 with age.9 IL-4 is a cytokine

From the Section of Dermatology, Department of Medicine, University of Chicago, Pritzker School of Medicine; Chicago, IL,1 and the Department of Pediatric Dermatology, University of Minnesota School of Medicine, Minneapolis, MN2 Address for Correspondence: Aisha Sethi, MD, Department of Dermatology, 333 Cedar St, LCI 501, New Haven, CT 06520 • E-mail: aisha.sethi@yale.edu

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Figure 2. Acantholysis and dyskeratosis within the epidermis. A lymphoid infiltrate is present in the dermis.

Acknowledgment Justin Wasserman, MD, performed the photomicrography. References 1 Grover RW. Transient acantholytic dermatosis. Arch Dermatol. 1970;101:426–434. 2 Hu CH, Michel B, Farber EM. Transient acantholytic dermatosis: A skin disorder related to heat and sweating. Arch Dermatol. 1985;121:1439–1441. 3 Horn TD, Groleau GE. Transient acantholytic dermatosis in immunocompromised febrile patients with cancer. Arch Dermatol. 1987;123:238–240. 4 Villalon G, Martin JM, Monteagudo C, et al. Clinicopathological spectrum of chemotherapy induced Grover’s disease. J Eur Acad Dermatol Venereol. 2007;21(8):1145–1147.

5 Breustedt W, Audring H, Sonnichsen N. [Transitory acantholytic dermatosis (Grover) in an HIV infected patient]. Z Hautkr. 1990;65:754–756.

Figure 1. Erythematous papules, flaccid vesicles, and pustules on central chest (A) and back (B).

that supports differentiation of naive T cells to T helper type 2 cells. T helper type 2 cells are implicated in driving humoral immunity, and overproduction is associated with allergic disease. CONCLUSIONS Grover’s disease induced by exogenous administration of IL-4 has been described.10 It would be of interest to investigate whether patients undergoing chemotherapy or other immunosuppressive regimens show a shift in the immune compartment that favors T helper type 2 cells and IL-4 production, resulting in Grover’s disease. SKINmed. 2017;15:483–484

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6 Boutli F, Voyatzi M, Lefaki I, et al. Transient acantholytic dermatosis (Grover’s disease) in a renal transplant patient. J Dermatol. 2006;33(3):178–181. 7 Guana AL, Cohen PR. Transient acantholytic dermatosis in oncology patients. J Clin Oncol. 1994;12:1703–1709. 8 Paganelli R, Scala E, Rosso R, et al. A shift to Th0 cytokine production by CD4+ cells in human longevity: Studies on two healthy centenarians. Eur J Immunol. 1996;26:2030–2034. 9 Kubo M, Cinader B. Polymorphism of age-related changes in interleukin (IL) production: Differential changes of T helper subpopulations, synthesizing IL 2, IL 3 and IL 4. Eur J Immunol. 1990;20:1289–1296. 10 Mahler SJ, DeVillez RL, Pulitzer DR. Transient acantholytic dermatosis induced by recombinant human interleukin 4. J Am Acad Dermatol. 1993;29:206–209.

Chemotherapy-Induced Transient Acantholytic Dermatosis

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Volume 15 • Issue 6

CASE STUDY

Chloracne in a Farming Family Pragya Kushwaha, MBBS, MD;1 Harish Kumar, MBBS, DVD;1 Sandeep Kulkarni, MBBS, DNB;2 Ashok Ghorpade, MBBS, MD, MNAMS3

An 11-year-old boy presented with a 1-year history of multiple comedonal lesions distributed over his body. The lesions (Figure 1) were densely distributed throughout his body. Ophthalmologic examination revealed hyperpigmented conjunctival mucosae and enlarged meibomian glands (Figure 2). His nails were also hyperpigmented. In addition, he had been coughing and had a fever, each present for a month. Significant laboratory studies included mild anemia (hemoglobin 11.6 gm%) and leukocytosis of 20,800. A chest x-ray was suggestive of interstitial lung disease. Similar lesions were present on his two siblings and parents. Additionally, his father had developed multiple, acne-like lesions, large abscesses, palmar and plantar peeling, and severe jaundice with hepatic failure. He had a history of frequent exposure to a pesticide mixed with a herbicide, as a result of leakage from a spray container. The patient was diagnosed with chloracne, based on the history, clinical features, and histologic examination. (SKINmed. 2017;15:485–488)

ccupational acne may include oil acne, coal tar acne, and chloracne, which occurs after exposure to chlorinated aromatic hydrocarbons . It is caused by compounds containing polyhalogenated naphthalene, polyhalogenated biphenyls, polychlorophenols, 3,4-dichloroanilines and 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). All chloracnegens are structurally similar, containing two benzene rings with halogen atoms occupying at least three of the lateral ring positions.1 TCDD and other dioxins are the most potent of the environmental chloracnegens and are always produced in the process of creating phenoxy herbicides. Chloracne can be diagnosed by the history of exposure to chloracnegens and by its defining clinical features , by finding comedones, papules, nodules, cysts, and abscesses on histopathology, and by the detection of high serum concentrations of chloracnegens. Cholracne is a systemic disease in which skin involvement is the most prominent clinical feature. It was first described by Siegfried Bettmann (1869–1939) in 1897, and the term “chloracne” was proposed by Karl Herxheimer (1861–1942) in 1899,2 due to its suspected relation to chlorine exposure and the similarity between its clinical features and those of acne vulgaris.

Epidemiology There are thought to be fewer than 41,000 cases of chloracne worldwide. Several large-scale accidents involving occupational exposure and food contaminations have been reported over time, the most famous being the following. Hundreds of Vietnam War veterans were exposed to a herbicide known as Agent Orange, which was found to be contaminated with TCDD.3,4 A chemical plant accident occurred near Saveso, Italy in 1976,5 and the latest famous case report was the TCDD poisoning of Victor Andriyovych Yushchenko (1954– ), a former president of Ukraine, in late December 2004.6,7 Toxicology All chlorancegenic compounds contain two benzene rings with halogen atoms occupying at least three of the lateral ring positions.1 Absorption occurs through the skin, or by inhalation or ingestion. These compounds are highly lipophilic and can remain in body fat for long periods.8 Clinical features usually appear 2–4 weeks after exposure and tend to persist for 2–3 years, although they may persist for up to 30 years after cessation of exposure.9 Lesions consist of comedo-

From the Department of Dermatology, Venereology and Leprology, Muzaffar Nagar Medical College, Uttar Pradesh, India;1 AIIMS Raipur, Chhattisgarh, India;2 and JLN Hospital and Research Centre, Bhilai Steel Plant, Bhilai, Chattisgarh, India3 Address for Correspondence: Pragya Kushwaha, MBBS, MD, 29 Tej Garhi, P.O. Medical College, Meerut, Uttar Pradesh, India 250004 • E-mail: dr.pragya28@gmail.com

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Figure 1. Clinical photograph showing the distribution of multiple open comedones, papules, and cysts on the patient’s forehead, malar area, and nose.

Figure 3. The patient with his younger sibling, who displays monomorphic comedonal lesions in a similar distribution.

manifestations include fatigue, anorexia, liver dysfunction, hyperlipidemia , anemia, transient weight loss, and delayed nerve conduction on testing.13 Clustering of similar cases can occur in workplaces and at home. Dioxins can pass via the placenta or breast milk and induce chloracne without direct exposure.14 With this patient, we found similar clinical features and a clustering of cases in exposed individuals (Figure 3). Histopathology Histopathology is characterized by miniature or absent sebaceous glands, hyperplasia of the epidermis, and hyperpigmentation of the stratum corneum (Figure 4). Follicular hyperkeratosis with orthokeratosis, infundibular dilatation, and infundibular cysts can be detected.15

Figure 2. Close-up view of comedones with bilateral pigmentation of the palpebral conjunctivae.

Pathogenesis

nes, straw-colored cysts, pustules, inflammatory nodules, and abscesses. The sites most commonly involved are the face and neck (malar crescent, ear lobes, postauricular triangles, suboccipital hair lines), trunk, extremities, groins, and genitalia. Other features are decreased sebum production with skin xerosis, hyperpigmentation, hirsutism, skin thickening, palmoplantar hidrosis, and hyperkeratosis.10–12 Hyperpigmentation of the conjunctivae and conjunctival discharge are also found due to defective meibomian glands secretions. Non-cutaneous, systemic SKINmed. 2017;15:485–488

Binding of environmental toxicant molecular ligands (eg dioxin) to aryl hydrocarbon receptors results in altered nuclear transcription and subsequently altered keratinocyte and sebaceous gland differentiation.16–18 Usual cAMP-mediated activation of aryl hydrocarbon receptors is disrupted by toxicant ligands. This forms the basis for dioxin toxicity. Sources of chloracnegens Halogen waxes, chlorinated naphthalenes, and biphenols were recognized in the 1920s, and chloronaphthalenes and polychlo-

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CASE STUDY rinated biphenyls in the 1940s. More recently, chlorinated phenols and benzenes used as herbicides and insecticides have been a source of chloracne,19 as in the present case. Certain drugs, such as like sorafenib,20 used in the treatment of renal cell carcinoma, have been implicated in causing chloracne-like drug eruptions. Treatment There is no satisfactory treatment for chloracne. The only way to manage the condition is to prevent exposure to chloracnegens. Regimens used involve retinoids,21,22 dermabrasion, and light electrodesiccation.23 The synthetic dietary fat substitute olestra has been discovered to have the ability to bind to chloracnegens and enhance their fecal excretion.24

Figure 4. Histologic photomicrograph showing follicular plugging, epidermal hyperplasia, and absence of epidermal adnexa (sebaceous glands).

We managed the current patient by giving oral retinoids (20 mg isotretinoin for 2 months) and performing comedone extraction (Figure 5), along with moving the patient from exposure site. CONCLUSIONS Growing concentrations of chloracnegens have been noted in the vicinity of industrial zones and farmlands where pesticides are being used indiscriminately. Most of the chemicals are polyhalogenated aromatic hydrocarbons with long half-lives, which makes them persist for longer in the environment and in the bodies of individuals who have been exposed persons, thus posing a significant occupational health hazard. This patient is being reported on to create awareness of the situation and because chloracne warrants differentiation from other acnelike conditions. References 1 McDonnell JK, Taylor JS. Occupational and environmental acne. In: Kanerva L, Eisner P, Wahlberg JE, Maibach HL, eds. Handbook of Occupational Dermatology. Berlin: Springer Verlag; 2000 :225–233. 2 Hay A. The Chemical Scythe: Lessons of 2.4.5-T and Dioxin. New York: Plenum Press; 1982. 3 Tamburro CH. Chronic liver injury in phenoxy herbicide– exposed Vietnam veterans. Environ Res. 1992;59:175– 188. 4 Patterson AT, Kaffenberger BH, Keller RA, Elston DM. Skin diseases associated with Agent Orange and other organochlorine exposures. J Am Acad Dermatol. 2016;74:143–170. 5 Caramaschi F, del Como G, Giambelluca SE, et al. Chloracne following environmental contamination by TCDD in Seveso, Italy. Int J Epidemiol. 1981; 10:135–143. 6 Sorg O, Zennegg M, Schmid P, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: Identification and measurement of TCDD metabolites. Lancet 2009;374:1179–1185.

Figure 5. Posttreatment photograph showing partially resolved open comedones and papules on the forehead and malar area. SKINmed. 2017;15:485–488

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7 Saurat JH, Kaya G, Saxer-Sekulic N, et al. The cutaneous lesions of dioxin exposure: Lessons from the poisoning of Victor Yushchenko. Toxicol Sci. 2012;125:310–317. 8 Qiang J, Christos CZ, Longquing X. Environmental pollution and acne: Chloracne. Dermato-Endocrinology. 2009;1:125–128. 9 Kerger BD, Leung HW, Scott P, et al. Age- and concentration-dependent elimination half-life of 2,3,7,8-tetrachlordibenzo-p-dioxin in Seveso children. Environ Health Perspect. 2006;114:1596–1602.

15 Ju Q, Yang K, Zouboulis CC, Ring J, Chen W. Chloracne: From clinic to research. Dermatol Sin. 2012;30:2–6. 16 Schmidt JV. Ah receptor signaling pathways. Annu Rev Cell Dev Biol. 1996;12:55–89. 17 Panteleyev AA, Bickers DR. Dioxin-induced chloracne— reconstructing the cellular and molecular mechanisms of a classic environmental disease. Exp Dermatol. 2006;15:705–730. 18 Sorg O. AhR signalling and dioxin toxicity. Toxicol Lett. 2014;230:225–233.

10 Zugerman C. Chloracne. Clinical manifestations and etiology. Dermatol Clin. 1990;8:209–213.

19 Suskind RR. Chloracne, “the hallmark of dioxin intoxication”. Scand J Work Environ Health. 1985;11:165–171.

11 Jensen NE. Chloracne: Three cases. Proc R Soc Med. 1972;65:687–688.

20 Pickert A, Hughes M, Wells M. Chloracne-like drug eruption associated with sorafenib. J Drugs Dermatol. 2011;10:1331–1334.

12 Geusau A, Jurecka W, Nahavandi H, et al. Punctate keratoderma-like lesions on palm and soles in a patient with chloracne: A new clinical manifestation of dioxin intoxication? Br J Dermatol. 2000;143:1067–1071. 13 Pelclova D, Urban P, Preiss J, et al. Adverse health effects in humans exposed to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Rev Environ Health. 2006;21:119–138. 14 Gladen BC, Taylor JS, Wu YC, Ragan NB, Rogan WJ, Hsu CC. Dermatological findings in children exposed transplacentally to heat- degraded polychlorinated biphenyls in Taiwan. Br J Dermatol. 1990;122:799–808.

21 Piewig G. Local treatment of chlorine acne (halowax acne) with vitamin A acid. Hautarzt. 1970;21:465–470. 22 Gawkrodger DJ. Chloracne: Causation, diagnosis and treatment. J Dermatol Treat. 1991;2:73–76. 23 Yip J, Peppall L, Gawkrodger DJ, Cunlife WJ. Light cautery and EMLA in the treatment of cholracne lesions. Br J Dermatol. 1993;128:313–316. 24 Geusau A, Tschachler E, Meixner M, et al. Olestra increases faecal excretion of 2,3,7,8-tetrachlorodibenzop-dioxin. Lancet. 1999;354:1266–1267.

Historical Diagnosis and treatment

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Volume 15 • Issue 6

correspondence Snejina Vassileva, MD, PhD, Section Editor

Multiple Treatment-Resistant Actinic Keratoses Secondary to Hydroxycarbamide Bevin Bhoyrul, MBBS;1 Geoffrey Brent, MBBS;2 Izzat Abdul-Kadir, MBChB;3 Jasmina Mikeljevic, MD1 To the Editor: Actinic keratoses (AKs) are crusty, scaly growths caused by epidermal damage from years of sun exposure. Risk factors for the development of AKs include skin phototypes I and II, long-term ultraviolet exposure, and immunosuppression after organ transplantation. Case report A 50-year-old white woman presented in May 2011 with an erythematous, scaly papule on the dorsum of the left hand. She had a past history of essential thrombocythemia, first diagnosed in 1985, for which she was taking hydroxycarbamide 1.5 g daily. She was of Fitzpatrick skin type II but had maintained cautious sun behavior throughout her lifetime. A biopsy showed parakeratosis and basal keratinocyte atypia, in keeping with an AK (Figure 1). She was treated with 5% 5-fluorouracil cream (Efudix®; Meda Pharmaceuticals, Bishop’s Stortford, UK) once at night for 4 weeks. The AK only partially resolved. Four months later, she developed more AKs on the dorsa of the hands (Figure 2). This time, she was treated with 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Bishop’s Stortford, UK) three times per week for 4 weeks. Due to a suboptimal response, the AKs were re-treated with 5% imiquimod five times per week for 6 weeks (superficial basal cell carcinoma regimem), with limited benefit. Over the next 4 years, a number of AKs on the sun-exposed areas of the hands and face were treated with cryotherapy, 5% 5-fluorouracil cream, 3% diclofenac gel (Solaraze®; Bioglan Pharma, FL), ingenol mebutate 500 μg/g (hands) or 150 μg/g (face) (Picato®; Leo Laboratories, Hurley, UK), 5% imiquimod cream, and pho-

todynamic therapy. None of the above treatments resulted in full resolution of her lesions. Sequential biopsies all confirmed AKs. Surgery was deemed inappropriate as she had multiple, scattered, nonhyperkeratotic lesions. The resistance of her multiple AKs to conventional therapies was attributed to hydroxycarbamide. In February 2017, hydroxycarbamide was stopped and changed to anagrelide 1 mg per day. This resulted in a significant reduction in the number of AKs, as well as an improved response to topical therapies. DISCUSSION Hydroxycarbamide is an antimetabolite commonly used in the treatment of essential thrombocythemia, polycythemia rubra vera, primary myelofibrosis, sickle cell disease, and cervical cancer. It is thought to inhibit the action of ribonucleotide reductase, thereby reducing deoxyribonucleotide production and interfering with DNA replication and repair.1 It is well known that patients who are immunosuppressed, for example organ transplant recipients, are more likely to develop AKs.2 Hydroxycarbamide, however, is an antineoplastic but not an immunosuppressant drug. Lova et al demonstrated that it exerts a cytostatic effect on T lymphocytes, without altering their activation and without having an immunosuppressive effect.3 Multiple AKs secondary to hydroxycarbamide have rarely been reported. A multicenter series of 3411 patients with chronic myeloproliferative neoplasms found that seven patients developed AKs after a median period of 46 months of hydroxycarbamide treatment. Temporary interruption of treatment or dose reduction in three patients resulted in some, albeit incomplete, im-

From the Department of Dermatology1 and the Department of Histopathology,3 York Hospital, York, UK; and the Department of Dermatology, Chapel Allerton Hospital, Leeds, UK2 Address for Correspondence: Bevin Bhoyrul, MBBS, Department of Dermatology, York Hospital, Wigginton Road, York YO31 8HE, UK • E-mail: bevin.bhoyrul@nhs.net

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Figure 1. (A) Biopsy from the dorsum of the left hand showing parakeratosis and an atypical basal layer with pleomorphic and mitotically active keratinocytes (hematoxylin and eosin stain, original magnification ×20). (B) Biopsy from the dorsum of the left hand showing parakeratosis and an atypical basal layer with pleomorphic and mitotically active keratinocytes (hematoxylin and eosin stain, original magnification ×100).

A B Figure 2. (A) Erythematous, scaly macules and papules on the dorsum of the right hand. (B) Erythematous, scaly macules and papules on the dorsum of the left hand.

provement of the lesions; of individuals on prolonged treatment, one experienced worsening of lesions, and three developed squamous cell carcinoma.4 Sanchez-Palacios et al reported multiple AKs in a 69-year-old man with essential thrombocythemia and a 66-year-old man with chronic myelogenous leukemia, both of whom were on hydroxycarbamide.5 A 72-year-old woman on long-term hydroxySKINmed. 2017;15:489–495

carbamide for polycythemia rubra vera developed several AKs over the forehead and nose, which were treated with cryotherapy.6 Schleussinger et al described an interesting case of monozygotic twins, one of whom was on hydroxycarbamide for essential thrombocythemia and developed multiple AKs on the face, and the other, who did not take any medication, never developing any lesions despite a similar skin phenotype and amount of cumulative sun exposure.7

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Our report not only highlights that hydroxycarbamide can induce AKs in the absence of other risk factors, but also demonstrates, for the first time, the refractoriness of the lesions to conventional treatment. Further research is needed to confirm this proposed association.

3 Lova L, Groff A, Ravot E, et al. Hydroxyurea exerts a cytostatic but not immunosuppressive effect on T lymphocytes. AIDS. 2005;19:137–144. 4 Antonioli E, Guglielmelli P, Pieri L, et al. Hydroxyurearelated toxicity in 3,411 patients with Ph’-negative MPN. Am J Hematol. 2012;87:552–554. 5 Sanchez-Palacios C, Guitart J. Hydroxyurea-associated squamous dysplasia. J Am Acad Dermatol. 2004;51:293–300.

References 1 Koc A, Wheeler LJ, Mathews CK, et al. Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J Biol Chem. 2004;279: 223–230.

6 Young HS, Khan AS, Kendra JR, et al. The cutaneous side-effects of hydroxyurea. Clin Lab Haematol. 2000;22:229–232. 7 Schleussinger TM, Dyall-Smith D, Field LM. Hydroxyurea-associated squamous dysplasia in a monozygotic twin. J Am Acad Dermatol. 2011;65:679–680.

2 Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic review. Br J Dermatol. 2013;169:502–518.

Sweet Syndrome Associated with Bilateral Nodular Scleritis Anissa Zaouak, MD;1 Meriem Jrad, MD;1 Takoua Bacha, MD;1 Meriem Bel Haj Salah, MD;2 Ehsen Ben Brahim, MD;2 Houda Hammami, MD;1 Samy Fenniche, MD1 To the Editor: A healthy 41-year-old man with no significant medical history was referred to our department for a sudden onset of multiple painful nodules located on the face and extremities associated with arthralgia for the previous 48 hours. The patient was febrile. Concomitant with the cutaneous eruption, he also had red painful eyes with no blurred vision. Examination revealed large erythematous tender annular plaques located on the face, the neck, and the extremities (Figure 1). There were two scleral nodules with surrounding episcleral injection located on the temporal and the medial aspects of the left (Figure 2) and right eyes. The cornea was clear, and there was no anterior chamber activity consistent with the diagnosis of nodular scleritis. A skin biopsy taken from a tender plaque revealed a dense dermal neutrophilic infiltrate with no evidence of vasculitis

consistent with the diagnosis of Sweet syndrome (Figure 3). Laboratory tests showed an elevated leukocyte count with neutrophilia (neutrophils 85%). The erythrocyte sedimentation rate and C-reactive protein concentration were elevated at 90 mm and 54 mg/L. Renal and liver function were normal. HIV serology was also performed and was nonreactive. The diagnosis of idiopathic Sweet syndrome associated with bilateral nodular scleritis was confirmed, and the patient was treated with indomethacin 100 mg/day and dexamethasone 0.1% eyedrops, with a favorable outcome. His skin lesions diminished, as did the ocular redness, after 1 week of treatment. The regimen was maintained for 2 months, and there was no recurrence of the lesions after a 6-month follow-up. DISCUSSION Sweet syndrome, also known as febrile neutrophilic dermatosis, is a multisystem syndrome consisting of cutaneous lesions with

From the Departments of Dermatology1 and Anatomopathology,2 Habib Thameur Teaching Hospital, Tunis, Tunisia Address for Correspondence: Anissa Zaouak, MD, Department of Dermatology, Habib Thameur Hospital, 8 Street Ali Ben Ayed, 1008 Montfleury Tunis, Tunisia • E-mail: anissa_zaouak@yahoo.fr

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Figure 3. Diffuse neutrophilic infiltrate located in the dermis, with no vasculitis (hematoxylin and eosin stain, ×40).

Ocular involvement in Sweet syndrome occurs in 4% to 72% of patients,1 and is common. It is important to diagnose and treat this to prevent ocular morbidity. Most commonly, ocular involvement in Sweet syndrome affects the anterior structures of the eye, presenting as episcleritis, scleritis, peripheral ulcerative keratitis, iritis, limbal nodules, uveitis, and limbal nodules.3–7 Inflammation of anterior structures may also cause blurry vision. It can also affect the retina and the posterior structures of the eye, with a real risk that sight will be threatened.

Figure 1. Annular erythematous and edematous papules and nodules on the neck and forehead.

In our patient, indomethacin dramatically diminished the cutaneous eruption, as well as the red eyes resulting from the bilateral nodular scleritis. Indomethacin is a nonsteroidal anti-inflammatory drug with proven efficacy in treating Sweet syndrome even as a first-line treatment, and has a safe side effect profile. It acts by inhibiting chemotaxis, migration, and oxidative metabolism of neutrophils. When using indomethacin, there are low risks for relapse of Sweet syndrome after reduction or discontinuation of the treatment.8 Some patients, especially those with HIV infection, also require systemic corticosteroids and dapsone.9

Figure 2. Redness of the eye with scleral nodules on the temporal and medial aspects of the left eye.

CONCLUSIONS

potential involvement of nearly any organ system. The occurrence of Sweet syndrome in a young man is unusual because more than 80% of the affected individuals are women.1,2 SKINmed. 2017;15:489–495

Bilateral nodular scleritis appears to be an uncommon extracutaneous manifestation in Sweet syndrome. This case highlights the fact that any visual impairment in Sweet syndrome should prompt referral to an ophthalmologist to prevent ocular morbidity.

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CORRESPONDENCE 6 Benzimra J, Low-Beer J, Twomey J. A case of peripheral ulcerative keratitis associated with neutrophilic dermatosis of the dorsal hand. Int Ophthalmol. 2011;31:149– 151.

References 1 Cohen PR. Sweet’s syndrome presenting as conjunctivitis. Arch Ophthalmol. 1993;111:587–588. 2 Wong MH, Su DH, Loh RS. Nodular scleritis and Sweet’s syndrome. Clin Exp Ophthalmol. 2007;35:858–860.

7 Gupta N, Chawla B, Venkatesh P, et al. Necrotizing scleritis and peripheral ulcerative keratitis in a case of Sweet’s syndrome found culture-positive for Mycobacterium tuberculosis. Ann Trop Med Parasitol. 2008;102:557–560.

3 Kato T, Kunikata N, Taira H, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) with nodular episcleritis and polyneuropathy. Int J Dermatol. 2002;41:107–109.

8 Jeanfils S, Joly P, Young P, et al. Indomethacin treatment of eighteen patients with Sweet’s syndrome. J Am Acad Dermatol. 1997;36:436–439.

4 Gottlieb CC, Mishra A, Belliveau D, et al. Ocular involvement in acute febrile neutrophilic dermatosis (Sweet syndrome): New cases and review of the literature. Surv Ophthalmol. 2008;53:219–226.

9 Inamadar AC, Anitha B. HIV-seropositive patient with Sweet’s syndrome and nodular scleritis, showing dramatic response after adding dapsone to systemic corticosteroid therapy. Int J Dermatol. 2008;47:836– 838.

5 Bilgin AB, Tavas P, Turkoglu EB, et al. An uncommon ocular manifestation of Sweet syndrome: peripheral ulcerative keratitis and nodular scleritis. Arq Bras Oftalmol. 2015;78:53–55.

Advanced Therapy Treatment for Psoriasis: A Single-Site Retrospective Study of Prescribing Outcomes Carey Kim, MD;1 Lucie Joerg, BS;2 Jacob Levitt, MD2 To the Editor: Psoriasis affects approximately 3% of the US, population with an estimated annual cost of $35 billion.1 The cost of treating psoriasis has drastically increased within the last 5 years with the success of biologic therapies. Biologics are more effective and have fewer side effects than traditional medications, and their use has been shown to decrease hospital lengths of stay and improve patient outcomes.2 However, the high cost associated with biologics has restricted patient access to these medically advisable therapies. In a single-center study, mandatory prior authorizations for patients obtaining biologics increased from 16% in 2009 to 75% in 2014, with a concomitant increase in denial rates from 0% to 19%.3 Studies investigating the ballooning cost of psoriasis treat-

ment are well documented, but those on prescribing behaviors and outcomes for advanced therapies are limited.4,5 Our retrospective study aims to determine the denial rates and follow-up results for psoriatic patients prescribed advanced therapies in a single center. Data were collected from the Mount Sinai FPA Dermatology Faculty Practice medical records database, and patients with an International Classification of Diseases 9th revision code for psoriasis (696.1) were numerically assigned and randomly selected through a random number generator. We included patients who were prescribed an advanced therapy defined as adalimumab, etanercept, infliximab, ustekinumab, apremilast, secukinumab, or acitretin during the period January 2011 to April 2016. Patients who were awaiting approval for

From the Department of Medicine, Mount Sinai Beth Israel,1 and the Department of Dermatology, The Mount Sinai Hospital,2 New York, NY Address for Correspondence: Carey Kim, MD, Mount Sinai Beth Israel, 350 East 17th Street, 20th Floor, New York, NY 10003 • E-mail: Carey_Kim@nymc.edu

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Table I. Psoriasis Medication Denials Denials

Total Prior Authorizations

% Denial

Ustekinumab

28.6

Apremilast

26.3

Etanercept

18.8

Adalimumab

3.85

Secukinumab

33.3

Infliximab

33.3

Acitretin

50.0

Failure to Attempt Biologic Agent

Failure to Attempt Nonbiologic Agent

Limited Insurance Coverage/Other

Ustekinumab

Apremilast

Etanercept

Adalimumab

Secukinumab

Infliximab

Acitretin

Table 2. Causes of Therapy Denial

Table 3. Insurance Company Denials Denials

Total Requests

% Denied

Medicare

40.0

Oxford

18.8

United

8.70

CIGNA

33.3

Emblem Health

100

AETNA

12.5

Blue Cross

12.5

Health Net

50.0

an advanced therapy and uninsured patients were excluded from the study. We examined 220 charts, excluded 20 patients, and limited our study to 100 patients. Our results show that 20% of patients were denied coverage for an advanced therapy, with 25% of these patients unable to obtain approval on a follow-up visit. The remaining patients who obtained an advanced therapy waited a mean of 90 days from their initial visit to the time of therapy approval. Patients prescribed ustekinumab had a 28.6% chance of denial, and patients prescribed apremilast had a likelihood of SKINmed. 2017;15:489â&#x20AC;&#x201C;495

26.3% of being denied (Table I). Ustekinumab and apremilast contributed to 65% of all prior authorizations denials, and the most common reason for denial (60%) was failure to attempt a biologic/nonbiologic agent (Table II). Medicare, the public insurer for elderly Americans, administered the greatest number of absolute denials (eight patients); the next highest figure was three patients covered through the private insurer Oxford (Table III). The remaining patients who were approved received their medications through copay assistance, full insurance coverage, or self-payment.

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CORRESPONDENCE

CONCLUSIONS

References

Our study identifies a substantial subset of patients who were denied proper treatment and those who received delayed care. The increase in denial rates is concerning as advanced therapies continue to show effective results, but with little change in costs. Unfortunately, drug makers with the widest penetrance have the most leverage by offering financial incentives through sizable rebates for insurance companies to maintain their medication as a first-line therapy, thereby denying other competing medications. Restructuring the rebate system is an important step to remove financially motivated decisions in the coverage of psoriatic medications. The expansion of our study to additional sites would help in understanding the depth of the problem with current insurance practices, and bring the focus back to patient care.

1 Jacqueline VO, Yang Z, Jackie L, et al. Evaluating the economic burden of psoriasis in the United States. J Am Acad Dermatol. 2015;72:961–967.e5. 2 Fonia A, Jackson K, LeReun C, et al. A retrospective cohort study of the impact of biologic therapy initiation on medical resource use and costs in patients with moderate to severe psoriasis. Br J Dermatol. 2010;163:806– 816. 3 Abdelnabi M, Patel A, Rengifo-Pardo M, Ehrlich A. Insurance coverage of biologics for moderate-to-severe psoriasis: A retrospective, observational 5-year chart review. J Am Clin Dermatol. 2016;17:421–424. 4 James SM, Hill JDE, Feldman SR. Costs of common psoriasis medications, 2010-2014. J Drugs Dermatol. 2016;15:305–308. 5 Cheng J, Feldman SR. The cost of biologics for psoriasis is increasing. Drugs Context. 2014;3:1–10.

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Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2017;15:489–495

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