Skinmed Nov / Dec 2015 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

COMMENTARY Electroporation as a New Treatment Modality for Melanoma and Other Cancers: The “Guilty Bystander” Hypothesis

Mian, Lambert, Kong, Gagna, Wassef, Sharma, Bhate, Donthireddy, and Lambert

ORIGINAL CONTRIBUTIONS Topical Timolol: A Novel Approach in Infantile Hemangioma Jha, Kumar, and Anand

Congenital Malalignment of the Great Toenail

Fierro-Arias, Morales-Martínez, Zazueta-López, Ramírez-Dovala, Bonifaz, and Ponce-Olivera

Use of an Interferon-γ Release Assay in the Detection of Latent Tuberculosis in Dermatology: A Descriptive Analysis

Oon, Tey, Chong, Theng, Lim, Tan, and Yeo

Guidelines for the Topical Treatment of Psoriasis Vulgaris in the Levant and Iraq Area

Abbas, Ammoury, Abbadi, Malek, Akkash, Al-Chakharah, Al-Hamdi, Al-Qarqaz, Al-Soudani, Al-Soudani, Dandashle, El-Sayed, Ghafir, Gargour, Kabalan, Kibbi, Oumeish, Tannous, and Tomb

Trichotillomania: Demographic and Clinical Features From a Nationally Representative US Sample Gupta, Gupta, and Knapp

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

November/December 2015 • Volume 13 • Issue 6

November/December 2015 • Volume 13 • Issue 6 EDITORIAL CORE CURRICULUM Infantile Hemangioma: A Product Oral Mucosal Lesions: Oral of In Utero Implantation From the Lichen Planus and Lichenoid Placenta to the Skin: A Possible Door Tissue Reaction/Interface to the Future Dermatitis––Part II Lambert and Parish

North American Clinical Dermatologic Society

Sehgal, Syed, Aggarwal, and Sehgal

DEPARTMENTS PERILS OF DERMATOPATHOLOGY A Wolf in Fox’s Clothing: Aggressive Skin Cancers Posing as Less Aggressive Cancers John, Vanchinathan, Singh, Gagna, and Lambert

NEW THERAPY UPDATE OPDIVO (Nivolumab)

Gupta, MacLeod, and Abramovits

THE HEYMANN FILE Should Moderately Atypical Dysplastic Nevi Be Re-excised? Follow the Yellow Brick Road!

CORRESPONDENCE Curative Electrochemotherapy in Lentigo Maligna Melanoma

Gatti, Stinco, di Meo, Bergamo, and Trevisan

Efficacy of a Single Daily Dose of Levofloxacin in Gram-Negative Folliculitis Complicating Acne Vulgaris Sardana, Gupta, Kumar, and Gautam

Unusual Presentation of Acanthosis Nigricans Associated With Metabolic Syndrome Chhabra, Prabha, Hussain, and Kulkarni

Hydroxychloroquine de NovoInduced Psoriasis in a Patient With Lichen Planus Pigmentosus Seminario-Vidald and Hughey

BOOK REVIEW Dermatopathology Lee

Heymann

PHOTO CAPSULE Eruptive Syringomas in Pigmented Skin

Janagond, Kumaran, Narang, and Saikia

INFECTIOUS DISEASE CAPSULE Here Chickie, Chickie: Chikungunya Has Arrived

Booher, Bernstein, and Bernstein

case studY Posttraumatic Onychoheterotopia: A Report of Two Cases Sharma, Verma, Singal, and Yadav

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TABLE OF CONTENTS November/December 2015 • Volume 13 • Issue 6

EDITORIAL

Infantile Hemangioma: A Product of In Utero Implantation From the Placenta to the Skin: A Possible Door to the Future ................................................................................................................... 421

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

COMMENTARY

Electroporation as a New Treatment Modality for Melanoma and Other Cancers: The “Guilty Bystander” Hypothesis ........................................................................................................... 424

Kirin Mian, BA; Muriel W. Lambert, PhD; Jun Kong, MS; Claude E. Gagna, PhD; Cindy Wassef, BA; Divya Sharma, BA; Chinmoy Bhate, MD; Awani Donthireddy, BS; W. Clark Lambert, MD, PhD

ORIGINAL CONTRIBUTIONS

Congenital Malalignment of the Great Toenail ........................................................................................... 433

Leonel Fierro-Arias, MD; André Morales-Martínez, MD; Rosa María Zazueta-López, MD; Silvia Ramírez-Dovala, MD; Alexandro Bonifaz, PhD; Rosa María Ponce-Olivera, MD, PhD

Use of an Interferon-γ Release Assay in the Detection of Latent Tuberculosis in Dermatology: A Descriptive Analysis ......................................................................................................... 439

Hazel H. Oon, MD; Hong-Liang Tey, MBBS; Wei-Sheng Chong, MBBS; Colin T.S. Theng, MBBS; Kar-Seng Lim, MBBS; Hiok-Hee Tan, MBBS; Benson Yeo, MBBS

B:11”

Abhijeet Kumar Jha, MBBS, MD; Piyush Kumar, MBBS, MD; Vikas Anand, MBBS, MD

T:10.75”

Topical Timolol: A Novel Approach in Infantile Hemangioma ..................................................................... 429

S:10.25”

Guidelines for the Topical Treatment of Psoriasis Vulgaris in the Levant and Iraq Area ............................. 445

Ossama Abbas, MD; Alfred Ammoury, MD; Mohammad Abbadi, MD; Medhat Abdel Malek, MBBCh; Laith Akkash, MD; Kamal Al-Chakharah, MD; Khalil Al-Hamdi, MBBCh; Firas Al-Qarqaz, MD; Abduljabbar Al-Soudani, MBBCh; Nameer Al-Soudani, MBBCh; Anwar Dandashle, MD; Fouad El-Sayed, MD; Yasser Ghafir, MD; Nazek Gargour, MD; Said Kabalan, MD; Abdul-Ghani Kibbi, MD; Isam Oumeish, MD; Zeina Tannous, MD; Roland Tomb, MD

Trichotillomania: Demographic and Clinical Features From a Nationally Representative US Sample ......... 455

Madhulika A. Gupta, MD, FRCPC; Aditya K. Gupta, MD, PhD, FRCPC; Katie Knapp, MSc

CORE CURRICULUM

Oral Mucosal Lesions: Oral Lichen Planus and Lichenoid Tissue Reaction/Interface Dermatitis––Part II .. 461

Virendra N. Sehgal, MD; Nazim Hussain Syed, MD (Iran); Ashok Aggarwal, MD; Shruti Sehgal, MDS

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

A Wolf in Fox’s Clothing: Aggressive Skin Cancers Posing as Less Aggressive Cancers ............................. 467

Ann M. John, BA; Vijay Vanchinathan, MD; Parmvir Singh, BS; Claude E. Gagna, PhD; W. Clark Lambert, MD, PhD

New Therapy Update

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

OPDIVO (Nivolumab) ................................................................................................................................ 471

Aditya K. Gupta, MD, PhD, FRCPC; Melissa A. MacLeod, MSc; William Abramovits, MD

417

TABLE OF CONTENTS November/December 2015 2015 •• Volume Volume 13 13 •• Issue Issue 66 November/December

The Heymann File

Warren R. Heymann, MD, Section Editor

Should Moderately Atypical Dysplastic Nevi Be Re-excised? Follow the Yellow Brick Road! ....................... 475

Warren R. Heymann, MD

Photo Capsule

Eruptive Syringomas in Pigmented Skin ................................................................................................... 477

Ajit Janagond, MD; Muthu Sendhil Kumaran, MD; Tarun Narang, MD; Uma Nahar Saikia, MD

Infectious Disease Capsule Jack M. Bernstein, MD, Section Editor

Here Chickie, Chickie: Chikungunya Has Arrived ...................................................................................... 479

Katelyn Booher, DO; Maryann Bernstein, BS; Jack M. Bernstein, MD

case study

Vesna Petronic-Rosic, MD, MSc, Section Editor

Posttraumatic Onychoheterotopia: A Report of Two Cases ........................................................................ 483

Reena Sharma, MD; Prashant Verma, MD; Archana Singal, MD, MNAMS; Pravesh Yadav, MD

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

Curative Electrochemotherapy in Lentigo Maligna Melanoma..................................................................... 486

Alessandro Gatti, MD; Giuseppe Stinco, MD; Nicola di Meo, MD; Serena Bergamo, MD; Giusto Trevisan, MD

Efficacy of a Single Daily Dose of Levofloxacin in Gram-Negative Folliculitis Complicating Acne Vulgaris ............................................................................................................................................ 488

Kabir Sardana, MD; Tanvi Gupta, MBBS, MD; Bipul Kumar, MSc; Hemant K. Gautam, PhD

Unusual Presentation of Acanthosis Nigricans Associated With Metabolic Syndrome ............................... 491

Namrata Chhabra, MD; Neel Prabha, MD; Nighat Hussain, MD; Sandeep Kulkarni, DNB, MNAMS

Hydroxychloroquine de Novo-Induced Psoriasis in a Patient With Lichen Planus Pigmentosus .................. 492

Lucia Seminario-Vidal, MD, PhD; Lauren S. Hughey, MD

BOOK REVIEW

Jennifer L. Parish, MD, Section Editor

Dermatopathology ..................................................................................................................................... 496

Jason B. Lee, MD

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INDICATION AND USAGE Taclonex® Topical Suspension is indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 18 years and older and for plaque psoriasis of the scalp in patients 12 to 17 years. Patients 18 years and older should not use more than 100 g per week and patients 12 to 17 years should not use more than 60 g per week. IMPORTANT SAFETY INFORMATION Taclonex® Topical Suspension is not for oral, ophthalmic, or intravaginal use and should not be applied to the face, axillae, or groin. Do not use if atrophy is present at the treatment site. Do not use with occlusive dressings unless directed by a physician. If hypercalcemia or hypercalciuria develop, discontinue until parameters of calcium metabolism normalize. Taclonex® can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent steroid. Cushing’s syndrome and hyperglycemia may also occur in adults. Pediatric patients are at a greater risk than adults of systemic toxicity, HPA axis suppression and adrenal insufficiency. The most common adverse reactions (≥1%) are folliculitis and burning sensation of skin. Patients who apply Taclonex® to exposed skin should avoid excessive exposure to either natural or artificial sunlight. There are no adequate and well-controlled studies of Taclonex® Topical Suspension in pregnant women. Safety and effectiveness of the use of Taclonex® Topical Suspension in pediatric patients under the age of 12 years have not been established. Please see Brief Summary of Prescribing Information on the following page. References: 1. Taclonex® Topical Suspension [package insert]. Parsippany, NJ: LEO Pharma Inc.; August 2014. 2. Segaert S, Ropke M. The biological rationale for use of vitamin D analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. J Drugs Dermatol. 2013;12(8):e129-e137.

November/December 2015

Volume 13 • Issue 6

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ

Meridian, MS

Philadelphia, PA

Aditya K. Gupta, MD, PhD, FRCPC

Vesna Petronic-Rosic, MD, MSc

Marcia Ramos-e-Silva, MD, PhD

London, Ontario, Canada

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Riccarda Serri, MD Milan, Italy

Robert L. Baran, MD Cannes, France

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

Ada Lo Schiavo, MD Naples, Italy

Charles Steffen, MD Oceanside, CA

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

Alexander J. Stratigos, MD Athens, Greece

George M. Martin, MD Kihei, HI

James S. Studdiford III, MD Philadelphia, PA

Marc S. Micozzi, MD, PhD Rockport, MA

Robert J. Thomsen, MD Los Alamos, NM

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

Julian Trevino, MD Dayton, OH

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

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

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

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

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

Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria

Joseph L. Pace, MD, FRCP Naxxar, Malta

Daniel Wallach, MD Paris, France

Art Papier, MD Rochester, NY

Michael A. Waugh, MB, FRCP Leeds, UK

María Daniela Hermida, MD Buenos Aires, Argentina

Johannes Ring, MD, DPhil Munich, Germany

Wm. Philip Werschler, MD Spokane, WA

Warren R. Heymann, MD Camden, NJ

Roy S. Rogers III, MD Rochester, MN

Joseph A. Witkowski, MD Philadelphia, PA

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Donald Rudikoff, MD New York, NY

Ronni Wolf, MD Rechovot, Israel

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Jianzhong Zhang, MD Beijing, China

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

Matthew J. Zirwas, MD Columbus, Ohio

Andrew P. Lazar, MD Washington, DC

Virendra N. Sehgal, MD Delhi, India

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

SKINmed. 2015;13:420

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Volume 13 • Issue 6

Editorial

Infantile Hemangioma: A Product of In Utero Implantation From the Placenta to the Skin: A Possible Door to the Future W. Clark Lambert, MD, PhD;1 Lawrence Charles Parish, MD, MD(Hon)2 “Be careful what you wish for; you may very well get it.”––Anonymous

nfantile hemangioma (IH) is widely considered to be the most common vascular neoplasm of infancy. It is characterized by an initial period of proliferation during infancy, which is typically followed by spontaneous involution over the ensuing 5 to 10 years, following which there may be no discernable residual lesion or a fibrofatty residuum.1,2

followed by involution appear to be that it is not really part of the patient at all; it originates from placental tissue that embolizes in amniotic fluid from it to the embryo. Current evidence suggests a placental chorionic mesenchymal core cell origin during the first trimester of pregnancy, following which there is a complex interplay between stem cells and certain cytokine receptors.2–4

Because it spontaneously involutes, there is a tendency not to treat IH despite its disfiguring appearance; however, this has changed in recent years, as it has become more widely recognized that sometimes the eventual outcome is not optimal and that the cosmetic/emotional burden of the active lesion is far from trivial.

Some authors, however, subclassify IH into congenital vs infantile lesions,3 and there are other subclassifications, as well. This begs the question: are all IH derived from the same tissue? By the same etiopathogenesis? What characteristics do IH share with pyogenic granulomas and other lesions that, spontaneously or intentionally, may (be made to) arise in adult tissues?5

A number of innovative treatments, most of them quite effective, have been introduced. These have been progressively more effective with fewer complications as time has progressed, and the present paper by Jha and colleagues in this issue of SKINmed1 using topical timolol is no exception. Embryologic Concept Attention to IH has quite naturally focused on treatment, cosmetic aspects, and other aspects of follow-up. We believe, however, that there is potentially an even more important facet of these interesting lesions. During the past two decades, driven primarily by molecular investigations, information regarding the etiopathogenesis of IH has exploded. The reason it is found on the skin, the reason why it is also found in other tissues exposed to amniotic fluid in utero, and the reason for the rapid growth,

Future Possibilities Finally, and most importantly, can cells from such lesions be used, or possibly stored and then used later, to generate artificial organs and/or other tissues? Are stored or cultured cells from these lesions (ie, IH) superior to other cells for this purpose, such as those that may be cultured from a granuloma pyogenicum (pyogenic granuloma), perhaps deliberately induced in a patient later in life? Should such tissues be harvested from placental or umbilical cord tissue at birth and saved for possible need by the patient or possibly a family member for such purposes later in life? Are there ethical issues involved or likely to become encountered? Might embryonic tissue from induced abortions end up playing a role as well?

From the Departments of Dermatology and of Pathology and Laboratory Medicine, Rutgers University-New Jersey Medical School, Newark, NJ;1 and the Department of Dermatology and Cutaneous Biology and Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA2 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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Conclusions The possibilities, and the questions, are endless for currently perceived applications of these tissues. But there is more: will such tissues have roles that are not yet even considered? Can they, independent of organ regeneration, prolong life or improve its quality? Or perhaps even control aging? Could they aid in survival of an environmental disaster, such as a nuclear incident? Can they be used to improve intelligence or athletic ability? To “improve” behavior? Alternatively, in future states and novel governments, can they be used to diminish such traits, as suggested in some dark futuristic visions such as Aldous Huxley’s Brave New World,6 or used as involuntary treatments of criminals or persons deemed as “inferior?”

1 Jha AK, Kumar P, Anand V. Topical timolol: a novel approach in infantile hemangioma. SKINmed. 2015;13:429– 431. 2 Itinteang T, Withers AH, Davis PF, Tan ST. Biology of infantile hemangioma. Front Surg. 2014;1:38. 3 Liang MG, Frieden IJ. Infantile and congenital hemangiomas. Semin Pediatr Surg. 2014;23:162–167. 4 Keller RG, Patel KG. Evidence-based medicine in the treatment of infantile hemangiomas. Facial Plast Surg Clin North Am. 2015;23:373–392. 5 Yazdanian S, Parish LC, Lambert PC, Lambert WC. Pyogenic granuloma: an enigma within a paradox or a solution in search of a problem. SKINmed. 2013;11:74– 77. 6 Huxley A. Brave New World. London, England: Harper Perennial Modern Classics; 2006, 288pp.

Again, the possibilities are endless!

Editorial

ABOUT OUR JOURNAL SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760. Printed in the USA. Disclaimer: The Publisher, Editors, and Editorial Board cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein do not necessarily reflect those of the Publisher, Editors, and Editorial Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products or services advertised. The Publisher, Editors, Editorial Board, Reviewers, Authors, and Affiliated Agents shall not be held responsible or in any way liable for the continued accuracy of the information or for any errors, inaccuracies, or omissions of any kind in this publication, whether arising from negligence or otherwise, or for any consequences arising thereafter.

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COPYEDITOR Elizabeth Holcomb eholcomb@skinmedjournal.com

MEDIA WEB DIRECTOR Joan Osgoodby joan@skinmedjournal.com

Composition Paul Bennett paul@skinmedjournal.com

Publishing PUBLISHER Art Kalaka

Corporate President Arthur Kalaka akalaka@skinmedjournal.com

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

Chinese Society of Dermatology

Lebanese Dermatological Society

SKINmed. 2015;13:421–422

Associate Publisher James R. Adams jadams@skinmedjournal.com

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Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

The Dermatologic & Aesthetic Surgery International League

Infantile Hemangioma: A Product of In Utero Implantation

November/December 2015

Volume 13 • Issue 6

COMMENTARY

Electroporation as a New Treatment Modality for Melanoma and Other Cancers: The “Guilty Bystander” Hypothesis Kirin Mian, BA;1 Muriel W. Lambert, PhD;2 Jun Kong, MS;3 Claude E. Gagna, PhD;2,4 Cindy Wassef, BA;3 Divya Sharma, BA;3 Chinmoy Bhate, MD;2 Awani Donthireddy, BS;3 W. Clark Lambert, MD, PhD2

kin cancer management has focused on removal of the cancer either by destructive or excisional means. Management of melanomas has been complicated by the tendency of both normal and cancerous melanocytes to migrate through normal tissues, requiring excision with wide local margins to ensure removal of lesional tissue.1–3 These treatments tend to leave behind a gap that must be closed and residual scarring. With the advent of Mohs surgery, the amount of necessary tissue removed, and therefore invasiveness and scarring, has been minimized for nonmelanoma skin cancers, although this is less so for melanomas, which still require wide margins. Chemotherapy and radiation are reserved for superficial cancers or cancers in locations in which it is difficult to perform surgery.

Electroporation (EPR), a well-established transfection method applied experimentally in cells in culture,4,5 can be used in the treatment of primary and metastatic cutaneous neoplasms as an alternative to surgical excision and/or radiation therapy. EPR is being used outside the United States for treatment of primary and metastatic cutaneous neoplasms and is a modality that should be considered in the United States. In this issue of SKINmed, Gatti and colleagues6 report a remarkable case of melanoma that was cured by administration of a drug via EPR. Definitions EPR begins with the application of electric pulses sent via electrodes into tissues to create an electric field (Figure 1). These pulses are of high intensity and short duration, allowing a brief transmembrane potential to occur across the cell membrane.

Once the potential exceeds a certain threshold, EPR occurs. During EPR, transient hydrophilic pores form within the cell membrane, allowing passage of various molecules into the cell (Figure 2). These molecules can range from ions to dyes, drugs, antibodies, and even DNA. This method of reversibly overcoming the barrier of the cell membrane has proved useful for various applications, such as increasing the immunogenicity of certain vaccines, as well as enhancing gene expression by allowing increased uptake of DNA. For example, in the United States, EPR has been applied to the HIV1 PENNVAX DNA vaccine, resulting in a superior immunogenic response compared with administering the vaccine alone.7 This concept has been taken further in Europe, where EPR has been used to enhance uptake of certain chemotherapy drugs into cells of lesional tissues. This application of EPR has proven to be an excellent treatment modality for cutaneous and even internal neoplasms.8 As of 2011, EPR had been performed in more than 100 clinics across Europe, successfully treating more than 1500 patients. This method of cancer treatment is an alternative to the surgical approach more commonly used in the United States and has been shown to have significant benefit for cancer patients. Electrochemotherapy (ECT) is the administration of chemotherapy drugs in combination with EPR. Certain chemotherapy drugs, such as cisplatin and bleomycin, are highly effective antimetabolites; yet they exhibit poor absorbability into cells because of their hydrophilic nature. With the application of an EPR device and subsequent increase in cell permeability, the uptake of these drugs is markedly improved, enhancing drug action and efficacy. This ECT modality was used in a 2010 German study on a 79-year-

From Rowan University, School of Osteopathic Medicine, Stratford, NJ;1 Departments of Dermatopathology, Dermatology, and Pathology and Laboratory Medicine,2 Rutgers University – New Jersey Medical School, Newark, NJ;3 and the Department of Life Sciences, New York Institute of Technology, Old Westbury, NY4 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers University – New Jersey Medical School, Departments of Pathology and Laboratory Medicine and Dermatology, Medical Science Building, Room C520, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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Figure 1. Scheme of electrochemotherapy (ECT) of tumors. A drug that is extremely slow to enter cells (i.e., to pass through cellular plasma membranes) is either introduced into a distant vein or injected directly into tumor tissue, following which, after allowing an interval sufficient for the drug to enter the tumor and surround the tumor cells, an electroporation pulse (very high voltage, very low amperage) electric current is passed through the tissue. This causes pores to form in the plasma membranes of tumor cells through which the drug may enter the cells. (The drug is transported into the nucleus by cellular processes.) This scheme may be modified in multiple ways; for example, the interval allowed for a drug to enter the tumor may be determined by injecting a label with the drug and monitoring by interventional radiology.

Figure 2. Conventional theory by which electrochemotherapy affects tumors. It is supposed that the drug enters each tumor cell (tumor cells shown as blue structures; drug as heterogeneous small red structures) and affects each tumor cell separately (effect shown as large red X within each tumor cell).

old patient with multiple cutaneous melanoma metastases.9 Intratumoral bleomycin with EPR was used on some lesions and surgical excision on others. The intraindividual study showed that EPR was a more advantageous method of treatment compared with surgical excision, as the wounds treated with EPR showed less bleeding, had a faster healing time, and required less wound care.9 A 2013 Irish study examined the use of ECT on ocular basal cell carcinoma. Ocular lesions often pose difficulty in treatment because of the paucity of local tissue and need for skin grafts and flaps post resection. Three patients with basal cell carcinoma in the periocular region were treated with EPR and intralesional bleomycin. All three cases of basal cell carcinoma showed complete resolution, with the patients reporting no side effects.10 The potential advantages of ECT coincide with its potential for use in a multitude of patient profiles. EPR is achieved when the induced transmembrane potential surpasses a certain threshold. Because the lipid bilayer membrane is a common feature for all eukaryotic cells, EPR is applicable to all histological cell types. A 2012 Italian study evaluated the use of ECT with bleomycin on 25 patients with basal cell and squamous cell carcinoma.11 A 100% objective response rate was achieved, with no reports of recurrence in the 72% complete responders. The subtype of skin cancer had no influence on the effectiveness of ECT. SKINmed. 2015;13:424–427

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Figure 3. Mechanism by which drug introduced by electrochemotherapy affects tumors according to the “Guilty Bystander Hypothesis (GBH)” introduced in this paper. Based on extensive data and the authors’ experience using electroporation in the research laboratory, the GBH proposes that not every tumor cell receives a dose of drug due to electroporation. Instead, some tumor cells (depicted as blue structures) indeed receive the drug (shown as small heterogeneous red structures) and others do not. Those tumor cells that receive a drug then undergo an effect due to the drug (shown as blue structures containing a large red X) whereas others (shown as blue structures containing a large black X) did not receive and are not directly affected by the drug but are affected by the fate of drug-affected tumor cells. Electroporation as a New Treatment Modality

November/December 2015

COMMENTARY

Vascular Effects of ECT Effects of EPR on the vascular system may also work to the advantage of its use as an anticancer agent. It has been shown that in vivo application of EPR causes transient hypoperfusion in the treated tissue. In an ongoing 2000 Danish study of ECT, one patient with hemorrhaging melanoma metastases was included. Nine bleeding skin lesions, of which seven were ulcerated, were treated with intratumoral bleomycin and EPR. Bleeding stopped immediately in all treated lesions after the administration of electric pulses and healing occurred within weeks. The patient reported minimal discomfort during treatment and no longterm side effects, suggesting ECT as a highly effective option for hemorrhaging cutaneous tumors.12 This effect of ECT was also seen in the treatment of recurrent cutaneous breast cancer metastases in a 2012 Danish study.13 Twelve patients were available for evaluation after ECT, of which four showed more than 50% reduction in tumor volume on computer-assisted tomography and two showed objective clinical response on clinical examination. All patients experienced symptomatic relief, including decreased bleeding, oozing, and odor. ECT Compared With Other Modalities Elimination of the need for surgery is a potentially revolutionary advantage of ECT as a treatment modality for skin cancer. Not only is there a decreased risk of post-treatment infection and bleeding, lesions treated with ECT have also exhibited faster healing times and less scarring compared with surgical excision.8 Furthermore, taking surgery out of the equation minimizes tissue loss, a consequence that can be critical for patients with diseases of multiple cutaneous neoplasm such as xeroderma pigmentosum or Gorlin-Goltz (basal cell nevus) syndrome. These patients may develop hundreds of neoplasms in the head and neck area and require multiple surgeries, often in the same sites, resulting in abundant tissue loss. Skin grafts and flaps can be used to cover the lesions at first, however, after multiple surgeries, the availability of healthy tissue is exhausted. EPR eliminates this problem, as this method does not require the removal of tissue. Whereas treatment modalities such as radiation can alter gene expression and affect metastatic potential of treated areas, EPR has no such affect. Little change is observed in the processes of transcription, translation, and apoptosis. Cellular proliferation, adhesion, and invasion are not affected by the utilization of EP. In fact, a downregulation of metastasis promoting genes LAMB3 and CD63 has been observed in treated cells.14 In addition, EPR is unlike other ablative methods in its effect on healthy tissue. A 2002 study compared the effects of EPR on cancer cells vs SKINmed. 2015;13:424–427

healthy tissue.15 The study showed that tumor cells were rapidly destroyed within 24 hours of treatment, whereas healthy skin, blood vessels, muscles, and nerves were minimally affected. This distinguishes EPR from other ablative methods such as cryotherapy, photodynamic, or radiation therapy, as these techniques damage both healthy and cancerous tissue. The “Guilty Bystander Hypothesis” ECT has been widely, and successfully, used for palliative treatment of advanced skin cancers; only in special circumstances has it been applied as a curative modality. In spite of this, however, there have now been sufficient reports of cures of even advanced malignancies using only ECT that we need to rethink what it all means and portends. Due to our extensive use of EPR as a laboratory modality by the three of us (MWL, CEG, WCL), we know that, even under ideal laboratory conditions, the electroporated substance is successfully introduced into no more than approximately 80% of target cells.4,5 We suspect that under clinical conditions, this fraction is less than 50%, perhaps much less. Because total clearing of a credible number of tumors has been reported, we conclude that at least one effect of ECT in these patients is to activate a host response, which then results in destruction of the remainder of the tumor. We term this idea the “Guilty Bystander Hypothesis (GBH)” (Figure 3). In this process, there may be a beneficial effect of, or even necessity for, preserving the tissue environment of the tumor, something that is absolutely not done using conventional methods such as surgery and radiation therapy. We do not know the mechanism for the GBH. Topical sensitizing treatments using 5-fluorouracil, a DNA synthesis antimetabolite, or imiquimod, an immune response modifier that activates the innate immune response via certain “toll-like receptors,” have been known for years to lead to destruction of early cancers and precancerous actinic keratoses in sun-damaged skin and in skin of patients with defective DNA repair of sun-induced damage in cellular DNA.16,17 The mechanisms responsible for this, however, are still poorly understood. One possibility is induction of pyroptosis, a newly described mechanism of programed cell death that is an alternative to apoptosis. Pyroptosis, unlike apoptosis, requires caspase-1 activation and induces an inflammatory reaction.18 Prospects for ECT as a Treatment for Skin Cancer We think that the prospects for ECT as a treatment for skin cancer are extremely promising. We note that successes have been documented even though ECT has been used as second- or

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COMMENTARY

third-line treatment in most cases. Also, little has been done to optimize the conditions under which ECT has been applied. The possibilities are endless and include development of new drugs specifically for ECT; modification of electrode design and pulse wavelength, amperage, duration, and frequency; and combinations with conventional methods, such as surgical placement of electrodes. Rather than drugs, informational molecules, such as RNA, DNA, or even prions or virons could be electroporated. Rather than depending on a set wait time, however determined, timing of the EPR pulses could be guided by interventional radiology, with a radio-opaque dye or other marker injected with the bolus of drug. We believe ECT may offer improved strategies for treatment of both primary and metastatic skin cancer, and may eventually replace a number of currently used modalities. Importantly for dermatologists, ECT can likely be applied as an office procedure in many cases. Prospects for ECT as a Treatment for Internal Cancer The prospects for treating internal cancers, including some currently considered incurable, are also endless.8,19 Because only one or a few treatment cycles may be necessary, it should be possible to place electrodes in the vicinity of internal cancers as an operative procedure; electrodes could then be left in place for future treatments or removed. Possibilities for electrode design are endless. For example, a slurry could serve as an electrode, or nanoparticles guided by a monoclonal antibody could be equipped with internal coils that could pick up charge from distantly placed, perhaps external sources. Alternatively, such nanoparticles could contain crystals that are sensitive to piezoelectric effects, so that a charge could be imparted from distant or external ultrasound sources. Such nanoparticles could be placed anywhere, even intrathecally. This has the potential to transform medical treatment of cancer and perhaps other disorders that are serious, perhaps life-threatening, but not malignant. Meningioma comes to mind but there are numerous other possibilities. The possible applications of this new technology are beyond our imagination. References

4 Tsongalis GJ, Lambert WC, Lambert MW. Correction of the ultraviolet light induced DNA repair defect in xeroderma pigmentosum cells by electroporation of a normal human endonuclease. Mutat Res. 1990;244:257–263. 5 Ramanathan M, Kuo HR, Lambert WC, Ingoglia NA. Introduction of macromolecules into synaptosomes using electroporation. J Neurosci Methods. 2000;96:19–23. 6 Gatti A, Stinco G, di Meo N, Bergamo S, Trevisan G. Curative electrochemotherapy in lentigo maligna melanoma. SKINmed. 2015;13:486–488 7 Kalams SA, Parker SD, Elizaga M, et al. Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery. J Infect Dis. 2013;208:818–829. 8 Miklavcic D, Serša G, Brecelj E, et al. Electrochemotherapy: technological advancements for efficient electroporation-based treatment of internal tumors. Med Biol Eng Comput. 2012;50:1213–1225. 9 Kaehler KC, Egberts F, Hauschild A. Electrochemotherapy in symptomatic melanoma skin metastases: intraindividual comparison with conventional surgery. Dermatol Surg. 2010;36:1200–1202. 10 Salwa SP, Bourke MG, Forde PF, et al. Electrochemotherapy for the treatment of ocular basal cell carcinoma; a novel adjunct in the disease management. J Plast Reconstr Aesthet Surg. 2014:67:403–406. 11 Gargiulo M, Papa A, Capasso P, et al. Electrochemotherapy for non-melanoma head and neck cancers: clinical outcomes in 25 patients. Ann Surg. 2012;255:1158–1164. 12 Gehl J, Geertsen PF. Efficient palliation of haemorrhaging malignant melanoma skin metastases by electrochemotherapy. Melanoma Res. 2000;10:585–589. 13 Matthiessen LW, Johannesen HH, Hendel HW, et al. Electrochemotherapy for large cutaneous recurrence of breast cancer: a phase II clinical trial. Acta Oncol. 2012;51:713–721. 14 Todorovic V, Sersa G, Mlakar V, et al. Metastatic potential of melanoma cells is not affected by electrochemotherapy. Melanoma Res. 2011;3:196–205. 15 Heller R, Coppola D, Pottinger C, Gilbert R, Jaroszeski MJ. Effect of ECT on muscle and skin. Technol Cancer Res Treat. 2002;1:385–392. 16 Moretti J, Blander JM. Insights into phagocytosis-coupled activation of pattern recognition receptors and inflammasomes. Curr Opin Immunol. 2014;26:100–110.

1 Lambert MW, Lambert WC, Schwartz RA, et al. Colonization of nonmelanocytic cutaneous lesions by dendritic melanocytic cells: a simulant of acral-lentiginous (palmar-plantar-subungual-mucosal) melanoma. J Surg Oncol. 1985;28:12–18.

17 Swanson N, Smith CC, Kaur M, Goldenberg G. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: two phase 3, multicenter, randomized, double-blind, placebo-controlled studies. J Drugs Dermatol. 2014;13:166–169.

2 Lambert WC, Lambert MW, Mesa ML, et al. Melanoacanthoma and related disorders: stimulants of aral-lentiginous (P-P-S-M) melanoma. Int J Dermatol. 1987;26:508–510.

18 Murphy JM, Silke J. Ars Moriendi; the art of dying well–– new insights into the molecular pathways of necroptotic cell death. EMBO Rep. 2014;15:155–164.

3 Rankin J, Gagna CE, Lambert MW, Lambert WC. Dendritic melanocytic pseudomelanomas. Skinmed. 2013;11:237–238.

19 Sersa G, Miklavcic D, Cemazar M, et al. Electrochemotherapy in treatment of tumours. Eur J Surg Oncol. 2008;34:232–240.

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November/December 2015

Volume 13 • Issue 5

Original contribution

Topical Timolol: A Novel Approach in Infantile Hemangioma Abhijeet Kumar Jha, MBBS, MD;1 Piyush Kumar, MBBS, MD;2 Vikas Anand, MBBS, MD2 Abstract Infantile hemangioma is the most common benign vascular tumor of childhood that has a tendency for spontaneous involution. The aim of this study was to evaluate the efficacy of topical timolol maleate in the treatment of superficial infantile hemangioma and associated side effects during the course of treatment. Four boys and five girls with a median age of 5 months were reviewed at 2-week intervals for a period of 16 weeks. A decrease in size, color, and consistency were noted. Adverse effects caused by timolol maleate were noted and managed. Of nine cases, two patients showed excellent response, five showed good response, one showed partial response, and one had poor response. Topical timolol maleate is safe and effective in the treatment of infantile hemangioma. (SKINmed. 2015;13:429–431)

nfantile hemangioma (IH) is the most common benign vascular tumor of childhood. It is composed of endothelial cells characterized by a proliferative phase and a lower involution phase.1 Glucose transporter 1 has been identified as the immunohistochemical marker of IH, regardless of stage, and in the microvasculature of the placenta. They also share vascular antigens, lewis Y antigen and merosin, and proliferating IH express CD31, CD34 markers for endothelial cells, and CD133 expressed in the primitive cell population.1 Within the first year, IH undergoes a phase of rapid and intermittent growth. Regression is complete in 60% of patients by the age of 4 and increases to 76% by the age of 7 years and to approximately 90% by the age of 9 years.2 A classification system by Mulliken and Glowacki1 was revised in 1996 by the International Society for the Study of Vascular Anomalies. Although there are no treatments approved by the Food and Drug Administration for IH, corticosteroids have been used for many decades as first-line systemic treatment. Oral propranolol, a nonselective β-blocker, has emerged as an alternative to corticosteroids for treatment of high-risk hemangiomas.3,4 Methods The aim of the study was to examine the efficacy and safety of topical timolol maleate in IH. The study was conducted at a tertiary care center in eastern India after obtaining clearance from the institution’s ethics committee. The diagnosis was made

clinically and patients, whose parents consented for them to be included in the study, were treated with a topical timolol maleate ophthalmic solution. Becasue IH has a tendency for spontaneous involution, a wait-and-watch approach was used for 1 month without any treatment, and, only when there was no decrease in the size or color of the lesion, the treatment was started. Our criteria for starting the treatment was parents’ anxiety regarding the disease and site of the lesion with fear of impending vital structures. Protocol Before starting topical timolol maleate, clinical evaluation and ultrasound examination were performed and photographs were taken. Blood pressure, heart rate, and blood glucose level were evaluated to rule out any complications that could affect treatment. Timolol maleate 0.5% ophthalmic solution was applied twice daily on the lesion for 10 weeks, reducing the dose to once daily, thereafter. Excellent response was defined as 100% resolution, good response as 60% to 90% resolution, partial response as 40% to 60% resolution, and poor response as <40% resolution. Clinical Evaluation The size, color, and consistency of the lesion was taken into account at the 2-week interval. Patients’ blood pressure, heart rate,

From the Department of Dermatology, STD and Leprosy, All India Institute of Medical Sciences, Patna, India;1 and the Department of Dermatology, Venereology and Leprosy, Katihar Medical College and Hospital, Katihar, India2 Address for Correspondence: Abhijeet Kumar Jha, MBBS, MD, All India Institute of Medical Sciences, Department of Dermatology, STD and Leprosy, Patna, Phulwari Sharif, Bihar, 801505, India • E-mail: drabhijeetjha@gmail.com

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Table. Site of Lesion, Response, and Side Effect of Timolol Maleate Case

Location of Hemangioma

Response to Treatment

Side Effect

Face

Good

None

Face

Excellent

None

Face

Good

Erythematous dermatitis

Face

Good

None

Nose

Excellent

None

Neck

Good

None

Upper extremity

Poor

None

Trunk

Good

None

Genitalia

Partial

None

blood glucose level, and complications, if any, were evaluated and managed accordingly. Photographic evaluation was performed at a subsequent follow-up visit. The response to treatment was evaluated based on criteria established by Garzon and colleagues5: (1) regression or cessation of growth, (2) shrinkage or flattening of the lesion, and (3) lightening of the surface color. Lesions demonstrating responses of two of the three criteria were judged to have good response, one criterion as partial response, and no improvement as no response. The success in reducing the size of the lesion after IH treatment in our case was confirmed clinically and supported by local ultrasonography and clinical photographs. Results The nine patients in our study were younger than 1 year, with a mean age of 5 months, and had a male to female ratio of 4:5. The size of the IHs ranged from 0.62 cm2 to 402 cm2. The anatomic locations of the superficial IHs were as follows: six (66.6%) in the head and neck region, one (11.1%) on the extremities, one (11.1%) in the genital region, and one (11.1%) on the trunk. The mean duration of treatment was 16 weeks (range, 8–13 weeks). Of nine patients, two (22.2%) showed excellent response, five (55.5%) showed good response, one (11.1%) showed partial response, and one (11.1%) showed poor response. One patient had erythematous scaly dermatitis during the treatment, but when inquired about the total number of applications, the patient’s parents revealed application of timolol maleate more than twice a day. The patient’s parents were counseled and timolol was stopped for a week, with administration of syrup prednisolone 1 mg/kg for a week that was gradually tapered and stopped. There was improvement in the erythema after which the patient was again put on timolol with significant reduction in the leSKINmed. 2015;13:429–431

sion color and size after appropriate application. The response to treatment is summarized in the Table. Discussion This study shows the efficacy of timolol in IHs associated with a side effect that occurred during the treatment period for which oral prednisolone was used and managed accordingly. This study is the first to report such a side effect with photographic documentation. The response to propranolol had been previously reported.6 Investigators serendipitously discovered that propranolol effectively treated hemangiomas in two infants, who had received the drug for cardiac complications while on corticosteroid therapy. Topical timolol has been used in IH.7 Long-term and widespread use of timolol and other topical β-blockers has yielded several case reports of drug-related wheezing, bradycardia, and respiratory depression, especially in infants and children treated with ocular timolol solution.8 Use of β-blockers causes vasoconstriction, change in color, and decreased expression of vascular endothelial growth factor and basic fibroblast growth factor genes through downregulation of the RAF/mitogen-activated protein kinase pathway.9 Although ophthalmic timolol solution resembles intravenous timolol in terms of systemic bioavailability, plasma kinetics, and cardiopulmonary effects,10 ophthalmic timolol gel has been shown to have less or insignificant systemic bioavailability than timolol ophthalmic solution. In adults, peak plasma concentrations after ocular administration of timolol 0.5% gel averaged <0.3 ng ⁄mL (lower limit of quantification of the assay), which suggests that there is minimal or no systemic bioavailability of timolol maleate gel.11 A study in 2002 demonstrated that approximately 80% of each drop (0.05 mL) of timolol 0.5% solution administered to an adult sample was systemically absorbed through the ocular and nasopharyngeal mucosa.10 Dif-

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ferent formulations are available in the form of ophthalmic solution including a gel forming solution (GFS). The absorption of timolol GFS through intact skin is unknown, but even less systemic absorption is expected, because timolol GFS is a more lipophobic vehicle than the polyethylene glycol mineral oil vehicle used for a transdermal patch.12 Side effects associated with timolol include urticaria, localized or generalized dermatitis, exacerbation of psoriasis, hair loss, and angioedema. During the start of our study, timolol ophthalmic solution was started due to lack of easy availability of the GFS. Conclusions We report this case series, because the use of topical timolol is a cost-effective and safe alternative drug for the treatment of IH; however, large-scale studies are needed to confirm these findings.13 The authors recommend application of topical timolol twice daily for 10 weeks, with a subsequent reduction to once daily. According to our study, significant improvement is clinically apparent after 8 weeks of application. References

4 Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics. 2009;124:e423–e431. 5 Garzon MC, Lucky AW, Hawrot A, Frieden IJ. Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol. 2005;52:281–286. 6 Jadhav VM, Tolat SN. Dramatic response of propranolol in hemangioma: report of two cases. Indian J Dermatol Venereol Leprol. 2010;76;691–694. 7 Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. 2010;146:564–565. 8 Burnstine RA, Felton JL, Ginther WH. Cardiorespiratory reaction to timolol maleate in a pediatric patient: a case report. Ann Ophthalmol. 1982;14:905–906. 9 D’Angelo G, Lee H, Weiner RI. cAMP‑dependent protein kinase inhibits the mitogenic action of vascular endothelial growth factor and fibroblast growth factor in capillary endothelial cells by blocking Raf activation. J Cell Biochem. 1997;67:353–366. 10 Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240:430–435.

1 Mathes EF, Frieden IJ. Vascular tumours. In: Goldsmith LA, Katz SI, Gilchrest BA, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw Hill; 2012:1456–1469.

11 Shedden AH, Laurence J, Barrish A, Olah TV. Plasma timolol concentrations of timolol maleate: timolol gelforming solution (TIMOPTIC-XE) once daily versus timolol maleate ophthalmic solution twice daily. Doc Ophthalmol. 2001;103:73–79.

2 Margileth AM, Museles M. Cutaneous hemangiomas in children. Diagnosis and conservative management. JAMA. 1965;194:523–526.

12 McMohan P, Oza V, Frieden IJ. Topical timolol for infantile hemangiomas: putting a note of caution in “cautiously optimistic.” Pediatr Dermatol. 2012;29:127–130.

3 Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651.

13 Jha A K, Mallik S K, Raihan M. Topical ophthalmic solution in infantile hemangioma. J Postgrad Med. 2012;58:163–165.

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吀栀攀渀攀眀攀猀琀愀渀搀洀漀猀琀攀砀挀椀椀渀最攀搀甀挀愀愀漀渀愀氀猀礀洀瀀漀猀椀愀椀猀栀愀瀀瀀攀渀椀渀最愀最愀椀渀愀琀漀渀攀漀昀琀栀攀最爀攀愀琀爀攀猀漀爀琀猀漀昀琀栀攀戀攀愀甀甀昀甀氀一漀爀琀栀眀攀猀琀☠吀栀攀䌀漀攀甀爀搀ᤠ䄀氀攀渀攀⸀ 䄀⬀䴀䐀椀猀搀攀猀椀最渀攀搀昀漀爀瀀栀礀猀椀挀椀愀渀猀Ⰰ 渀甀爀猀攀瀀爀愀挀挀挀漀渀攀爀猀Ⰰ 瀀栀礀猀椀挀椀愀渀愀猀猀椀猀琀愀渀琀猀Ⰰ 漀ϻ挀攀洀愀渀愀最攀爀猀Ⰰ 挀漀猀洀攀攀挀挀漀渀猀甀氀琀愀渀琀猀Ⰰ 愀渀搀琀栀漀猀攀椀渀琀攀爀攀猀琀攀搀椀渀氀攀愀爀渀椀渀最愀戀漀甀琀琀栀攀椀渀琀攀爀猀攀挀挀漀渀漀昀搀椀猀攀愀猀攀愀渀搀搀攀猀椀爀攀搀攀爀洀愀琀漀氀漀最礀愀渀搀琀栀攀瀀猀礀挀栀漀氀漀最椀挀愀氀椀洀瀀愀挀琀漀昀愀攀猀琀栀攀攀挀椀洀瀀爀漀瘀攀洀攀渀琀⸀ 伀甀爀搀椀猀猀渀最甀椀猀栀攀搀昀愀挀甀氀琀礀椀猀栀攀愀搀攀搀戀礀圀洀⸀ 倀栀椀氀椀瀀圀攀爀猀挀栀氀攀爀Ⰰ 䴀䐀Ⰰ 愀渀搀漀甀爀匀挀椀攀渀渀ǻ挀䄀搀瘀椀猀漀爀礀䈀漀愀爀搀椀猀挀漀洀瀀爀椀猀攀搀漀昀䜀攀漀爀最攀䴀愀爀爀渀Ⰰ 䴀䐀愀渀搀嘀椀挀䄀⸀ 一愀爀甀欀甀爀Ⰰ 䴀䐀⸀ 倀刀䔀ⴀ䌀伀一䘀䔀刀䔀一䌀䔀圀伀刀䬀匀䠀伀倀匀漀渀䘀椀氀氀攀爀猀 ☀ 吀漀砀椀渀猀䔀猀猀攀渀渀愀氀猀愀渀搀䄀搀瘀愀渀挀攀搀吀攀挀栀渀椀焀甀攀猀眀椀琀栀倀刀䔀ⴀ 䔀渀攀爀最礀䐀攀瘀椀挀攀猀⸀ 䴀䄀䤀一倀刀伀䜀刀䄀䴀䠀䤀䜀䠀䰀䤀䜀䠀吀匀䤀一䌀䰀唀䐀䔀㨀吀栀攀洀愀渀礀昀甀渀搀愀洀攀渀琀愀氀猀漀昀䄀攀猀琀栀攀攀挀䴀攀搀椀挀椀渀攀 ☀ 倀爀愀挀挀挀攀 ∠ 匀瀀攀挀椀愀氀挀漀渀猀椀搀攀爀愀愀漀渀猀漀昀猀欀椀渀漀昀挀漀氀漀爀 ∠ 一攀甀爀漀琀漀砀椀渀猀愀渀搀搀攀爀洀愀氀 ǻ氀氀攀爀猀 ∠ 䔀渀攀爀最礀ⴀ戀愀猀攀搀猀欀椀渀挀愀爀攀 ∠ 倀猀漀爀椀愀猀椀猀洀愀渀愀最攀洀攀渀琀 ∠ 刀漀猀愀挀攀愀Ⰰ 愀挀渀攀愀渀搀挀漀洀瀀氀攀砀椀漀渀搀椀猀漀爀搀攀爀猀 ∠ 䄀挀挀渀椀挀䬀攀爀愀琀漀猀椀猀洀愀渀愀最攀洀攀渀琀 ∠ 一漀渀洀攀氀愀渀漀洀愀猀欀椀渀挀愀渀挀攀爀琀爀攀愀琀洀攀渀琀 ∠ 倀椀最洀攀渀琀攀搀氀攀猀椀漀渀洀愀渀愀最攀洀攀渀琀 ∠ 倀椀最洀攀渀琀愀愀漀渀搀椀猀漀爀搀攀爀猀 ∠ 倀爀愀挀挀挀攀洀愀渀愀最攀洀攀渀琀 ∠ 䐀攀瘀攀氀漀瀀洀攀渀琀漀昀琀栀攀䌀漀猀洀攀攀挀伀ϻ挀攀倀爀愀挀挀挀攀琀攀愀洀 ∠ 䄀搀瘀愀渀挀攀搀挀漀猀洀攀攀挀猀甀爀最椀挀愀氀瀀爀漀挀攀搀甀爀攀猀昀漀爀琀栀攀漀ϻ挀攀 ∠ 䄀最攀洀愀渀愀最攀洀攀渀琀洀攀搀椀挀椀渀攀昀漀爀搀攀爀洀愀琀漀氀漀最礀 ∠ ∠ 䌀漀渀挀椀攀爀最攀瀀爀愀挀挀挀攀 ∠ 䌀氀椀渀椀挀愀氀爀攀猀攀愀爀挀栀 ∠ 倀氀甀猀洀愀渀礀洀漀爀攀 ᰠ一攀攀搀琀漀䬀渀漀眀ᴠ 琀漀瀀椀挀猀⸀

刀䔀䜀䤀匀吀䔀刀一伀圀戀礀瘀椀猀椀椀渀最䄀䴀䐀猀礀洀⸀挀漀洀

November/December 2015

Volume 13 • Issue 5

Original contribution

Congenital Malalignment of the Great Toenail Leonel Fierro-Arias, MD;1 André Morales-Martínez, MD;3 Rosa María Zazueta-López, MD;4 Silvia Ramírez-Dovala, MD;5 Alexandro Bonifaz, PhD;2 Rosa María Ponce-Olivera, MD, PhD1 Abstract Congenital malalignment of the great toenail (CMA) is a disorder of the anatomic orientation of the ungual apparatus, in which the longitudinal axis of the nail plate is not parallel with the axis of the distal phalanx but is deflected sideways. This disorder is understood to arise from multiple factors. Although many theories have been proposed about its origin, its pathogenesis is not fully known. Besides the cosmetic impact, this disorder causes such problems in the medium and long term as onychocryptosis and difficulty in motion. Some cases may regress spontaneously, although persistent cases may require a specialized surgical approach. Congenital malalignment of the great toenail is poorly understood and described medical condition that is often treated incorrectly; thus, reviewing the subject is important. A symptombased clinical classification system is proposed to guide diagnosis and treatment modality decisions. (SKINmed. 2015;13:433–437)

tructural disorders of the nail are poorly understood due to lack of clinical inquiry by the physician or failure to assess the problem on behalf of the patient. Delayed treatment, whether caused by patient embarrassment or unawareness that nail disorders are actual health issues that require attention, increases the number of complications and comorbidities associated with these disorders. Congenital malalignment of the great toenail (CMA) is likely underdiagnosed. The lack of information on this disease exposes the patient to unnecessary procedures and treatments such as antifungals, antibiotics, steroids and nail splints, and partial or total nail plate avulsion, which may cause greater comorbidities.1 We review this issue in an effort to raise awareness of this chronic medical condition (temporary or permanent) that may lead to local problems, such as cosmetic deterioration, onychogryphosis, onychomycosis, onychocryptosis, or even postural and walking disorders that progress with age and may be avoided with prompt treatment. Background CMA was first described in 1978 as “great toe nail dystrophy” at the St. John’s Hospital Dermatological Society Congress in patients who had nail dystrophy limited to the first toe on one or both feet. A number of case reports were later published.2 It

was not until 1979 that the “congenital malalignment of the big toenail” was noted, emphasizing its main feature: lateral deviation of the ungueal lamina from the longitudinal axis.3 Over the years, the disorder has been referred to by a variety of terms, such as nail dystrophy of the first toe, inherited dystrophy of the nails of the first toe, congenital digital lateralization, nail malalignment, and hallux nail dystrophy.4 To date, very few case reports have been published, including events in homozygous and dizygotic twins and coexistence with other clinical entities, plus various theories regarding pathogenesis and treatment have been proposed. Epidemiology Due to the small number of case reports, international CMA statistics are unknown. A similar scenario is apparent in Mexico, despite the existence of treatment centers specializing in nails. No incidence rate data exist for CMA. One hundred cases of nail disorders in children were reported in a study from the National Institute of Pediatrics in Mexico City, with none involving CMA.5 In the Dermatology Department of the General Hospital of Mexico, we estimate a frequency of two CMA cases per year, which constitutes 0.5% of the total investigations of nail disorders.

From the Departments of Dermatology1 and Micology,2 Hospital General de México “Dr. Eduardo Liceaga,” Mexico City, Mexico; Pediatric Dermatologist, Unidad Médica de Alta Especialidad (UMAE) Gineco-Pediatría 48, Instituto Mexicano del Seguro Social, Leon, Guanajuato, Mexico;3 and Dermatologist in Private Practice, Hermosillo, Sonora,4 and Leon, Guanajuato,5 Mexico. Address for Correspondence: Leonel Fierro-Arias, MD, Perpetua 40-3 piso, San José Insurgentes 03900, Mexico City, Mexico. • E-mail: leofierro@yahoo.com

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Pathogenesis Until now, the pathogenesis of CMA has been unknown, but several theories have been proposed. One of the most commonly referenced theories cites a hereditary etiology first published in 1979, describing two families in which several members were affected, demonstrating the association of an autosomal dominant mode of inheritance with variable expression occurring from birth.6–9 Cases have been reported of as many as three generations of monozygotic and dizygotic twins with congenital nail dystrophy of the first toes.10–12 Supported by this theory, CMA has been defined as “congenital” or familial.12 Note that the genetic background of CMA is unknown; however, it has been correlated with some genetic syndromes that have other nail or ectodermal conformation changes.13 The clinical features observed in some of these conditions may result in an altered allometry of structures adjacent to the nail.9,12 The second theory proposes the acquired pathogenesis of CMA, suggesting that in the absence of a family history, intrauterine conditions, such as excessive pressure or vascular constriction, may interfere with the normal growth of the nail, leading to aberrant digital and nail architecture. These intrauterine conditions may also interfere with proper development of the first toes, resulting in congenital bilateral encryption. Other possible causes of nail malalignment include iatrogenic factors.10,14–16 In addition, the matrix may have a secondary deviation caused by the increased tension of the hallux extensor tendon, which tracks the lateral matrix portion, switching the axis and vectors during nail growth. This hypothesis has been corroborated by several imaging studies.10 The existence of a ligamentous structure that corresponds to a dorsal expansion of the lateral liga-

ment of the distal interphalangeal joint was later demonstrated, indicating a clear association between this enlargement and injury to the nail matrix;17 furthermore, it was argued that CMA is caused by a misalignment of the nailbed, adhered to the distal phalanx, which consequently diverts the matrical projection.12 Recent references suggest an orthopedic background for the development process and reveal a clear association of CMA with an underlying bone malformation of the distal phalanx of the first toe, which is suggested to be the primary cause of this disorder.18 The development of CMA may be a multifactorial process involving orthopedic conditions or genetic influences with some hereditary pattern, but it may also be caused by exogenous influences, such as compromised fetal development (vascular or pressure), bone formation, or ligamentous structure and function. Clinical Features Congenital malalignment is an alteration of the angle of projection and direction of nail growth that affects one—or sometimes both—great toes and can occasionally appear in thumbs (Figure 1). The nail plate is offset on a lateral angle with regard to the longitudinal axis of the distal phalanx and the midsagittal plane (Figures 2 and 3). In contrast, the shift to the medial region is extremely rare, although possible. Transversal single or multiple rows and ridges, also called Beau’s lines, are one of the earliest appearing abnormalities and may be found on the entire surface of the nail plate in regular, progressive waves.19,20 Numerous lines and rows, often caused by recurrent episodes of damage to the matrix, may lead to an oystershell appearance, onychomadesis, or a condition, in which a large portion of the nail plate surface is lost.1–4,6,9,18

Figure 1. Bilateral congenital nail malalignment in a 3-year-old child. SKINmed. 2015;13:433–437

Figure 2. Lateral deviation from the matrix axis.

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ORIGINAL CONTRIBUTION ment misalignment (which corresponds to a lateral ligament dorsal extension of the interphalangeal joint in its distal portion that is connected to the nail matrix), changes in the physical properties of these elements during postnatal growth, accomplished by pulling the nail plate and adhering it to perfect anatomical position, may be an effective treatment. The second hypothesis states that the nail matrix is misaligned with regard to the underlying structure. A realignment of the phalanx growth may occur with age. This, however, does not explain the cause of the problem. Both hypotheses suggest that CMA generates an alteration in the alignment of the nail matrix. Although nail plate size, form, and orientation are the main problems, underlying dermis adhered to the periosteum contributes to the anatomic stability and orientation of the plate.12,15,22

Figure 3. Unilateral congenital nail malalignment in an 8-year-old girl.

The nail plate may be thickened (pachyonychia), with thickness decreasing progressively toward the distal portion, which alters strength of adhesion to the nail bed, generating secondary onycholysis. Color changes in shades of gray, brown, or green may be observed and are usually secondary to bleeding, infection with Pseudomonas, and other signs. The possibility of complications that may appear during childhood, such as onychocryptosis or onychogryphosis, should be considered, as well as permanent adult nail dystrophy.21 CMA appears to be the main factor causing nail embedding and prevention of normal growth. Nail development in these patients is lateralized; therefore, limited longitudinal growth impairs the normal growth of the nail plate by rendering it unable to attach to the soft tissue accumulated distally (even when childhood koilonychia is present). This situation favors dystrophy and may affect proper gait mechanics. At this stage, the possibility of surgical intervention must be assessed to realign the nail apparatus completely. The best results are obtained when performing procedures before the age of 2 in patients.1,4,10 Cases of spontaneous resolution of CMA between 2 and 10 years of age have been reported. Less than 50% of patients reporting spontaneous resolution did so after the first 2 years of age; as a result, there is no way to know which cases are permanent. The best surgical results are obtained in younger patients; however, delaying surgery is currently preferred.10,12,16 Regarding the possibility of involution, two hypotheses have been considered. The first proposes that, due to structural ligaSKINmed. 2015;13:433â&#x20AC;&#x201C;437

The most significant pediatric complication by frequency and disability is an ingrown nail (onychocryptosis). This condition causes painful inflammation and infection in the surrounding soft tissue. During this process, a clinical examination may show a short nail pressing the lateral nail fold to form a raised edge and secondary reagent granuloma.1,10,12,23 In the event of this occurrence, we agree with some authors, who recommend conservative treatment, simple monitoring, and maneuvers to release the ingrown spike.22 Surgery should be deferred until needed, due to complications, such as distal enclosing in patients younger than 2 years and for patients older than 10 years who fail to show improvement. The clinical course is variable, depending upon the degree of severity presented at birth and evolution during the first 2 years of age. The degree of onycholysis from the early stages of the disease and clinical severity at birth appear to be crucial indicators for prognosis and evolution.12,18 There is no way to categorize cases based on their presentation. Under our criteria and as proposed by the qualitative ordinal clinical classification, we consider CMA: (1) mild, including cases of indolent course and only lateral deviation of the matrix and the plate; (2) moderate including the above, with ondulations, dystrophy, and discoloration; and (3) severe, including cases with evident onychogryphosis, onycholysis, and complications such as surface fracture or some added complications such as angular onychocryptosis (Table). This classification can be used as a guide to clinical diagnosis and to select an appropriate monitoring or proper treatment approach for each case. Diagnosis Diagnosis of CMA is clinical and depends on adequate knowledge of the entity. The presence of this disorder at birth is important to rule out other options.12 Several conditions must be excluded with mycologic potassium hydroxide (KOH) prepa-

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Table. Congenital Malalignment of the Great Toenail: Proposal for Clinical Classification Grade

Designation

Clinical Aspects

Mild

Indolent course, involving only plate and nail matrix deviation

Moderate

Additional dystrophy with ripples and chromonychia

III

Severe

Evident onychogryphosis and onycholysis Nail fracture and secondary onychocryptosis

rations, bacterial and mycologic cultures, and/or comparative foot radiographs.1,4,10,24 Histopathologically, no alterations are described. The plate adhesion characteristics and the matrix conformation, as well the remaining nail apparatus, do not differ from the normal microscopic conformation. In this respect, the matrix and the nail bed dermis are firmly attached to the periosteum of the distal phalanx.12 Differential Diagnosis In the early stages of CMA, bacterial infections should be ruled out. Noninfectious paronychia, pustulation, onychocryptosis, and hypertrophy of the lateral folds of the fingers not only resemble CMA, but may be ongoing conditions that also require treatment.20 Other diseases that cause nail dystrophy at birth, such as congenital pachyonychia, an autosomal dominant disorder of keratins 16 and 17, or ectodermal dysplasia, should be discarded.25 Infant nail psoriasis and lichen planus may generate pachyonychia resembling CMA, causing confusion in primary stages. Nail biting and thumb sucking may also cause onychodystrophy and paronychia and should be considered.1,12,23 Because fungal nail diseases such as dermatophytes, yeast, and mold fungi (onychomycosis) are rare in infants, these diseases should be considered.24 In adults, especially when the nail plate is thickened and onycholysis or distal pulverization is present, fungal infection should be ruled out by direct examination with KOH or culture. One must distinguish true onychogryphosis, in which lateral and longitudinal deviation occurs, with only lateral deviation occurring in hemionychogryphosis.15 At older ages, other onychopathies may simulate this entity, as the processes that generate malalignment and pachyonychia may be frictional, iatrogenic, or traumatic.16 Treatment The therapeutic approach to CMA depends on the degree of clinical presentation and the associated secondary changes. A functional nail plate requires at least 5 mm of healthy nail bed beyond the lunula to have an adequate adhesion, which promotes the harmonious development from the matrix to the distal edge. SKINmed. 2015;13:433â&#x20AC;&#x201C;437

Any alteration in the rate growth can lead to dystrophy.10,16 Radiologic assessment of the status of the phalangeal conformation is suggested, because identification of bone alteration and orthopedic treatment may improve the course of the disorder.18 When no complications exist in mild to moderate deviation, over time, the nail becomes stiff and may prevent distal ingrowth favored by childhood flexibility. Conservative management is indicated with the application of soaks, topical antibiotics, or keratolytics, such as 30% to 40% urea cream, and massage maneuvers that promote nail channel opening.19 In the postnatal stage, the rapid growth of the phalanx may improve spontaneous realignment; therefore, a large number of cases are self-limiting, and observing the patient for the first 10 years of life is appropriate. If the severity of the complications is imminent from an early age, the choice of surgery must be immediately considered, as the best results are seen with treatment before the age of 2 years.9,12,16 Trauma caused by repeated percussion against shoes accelerates the progression of CMA and its complications; therefore, the use of soft shoes suitable for children should be advised.23 If the deviation is severe and the nail penetrates the adjacent soft tissue, the patient will develop secondary angle ingrowth. At this stage, the surgical correction of misaligned matrix is critical to prevent recurrence and permanent dystrophy interlock at the side edges. The surgical approach is to redirect the matrix by installing it on a new axis consistent with the longitudinal axis. This is a specialized procedure that involves substantial risk of complication at early ages. There is a risk of developing epidermoid inclusion cysts in the surgical incision line or below the free edge of the nail.15,16,26â&#x20AC;&#x201C;27 Some of the recommended surgical procedures to correct this entity include nail plasty, unguodermal flap, and simple section of the dorsal expansion of the lateral ligament.28,29 The process of reorientation of the matrix and digital reconstruction are procedures that should be limited to widely trained personnel and performed in centers with optimal conditions to reduce the possibility of complications.

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ORIGINAL CONTRIBUTION

Conclusions One of the first reasons for consultation in CMA cases is the parents’ concern over a dysmorphic appearance in the infant’s nails. CMA may cause brachyonychia, compression pain in the nail bed, onycholysis, or paronychia with periungual pustulation, which further hinders the diagnosis.20 It is also appropriate to suggest the prevention of unnecessary interventions that may compromise the functional integrity and podalic dynamics. This condition is relevant due to of its chronicity, risk of disability, and comorbidities. These implications could be prevented with an optimal and timely diagnosis, staging, and management, which cannot be achieved without proper knowledge of the disorder. References 1 Cohen P. Congenital malalignment of the great toenails: case report and literature review. Pediatr Dermatol. 1991;8:43–45. 2 Samman PD. Great toenail dystrophy. Clin Exp Dermatol. 1978;3:81–82. 3 Baran R, Bureau H, Sayag J. Congenital malalignment of the big toenail. Clin Exp Dermatol. 1979;4:359–360. 4 Iglesias-Zamora ME, Casado-Redondo MF. Desviación ungueal congénita del primer dedo del pie. Presentación de dos casos. Actas Dermosifiliogr. 1999;90:439–442. 5 Iglesias A, Tamayo L, Sosa-de-Martínez C, et al. Prevalence and nature of nail alterations in pediatric patients. Pediatr Dermatol. 2001;18:107–109. 6 Dawson TA. An inherited nail dystrophy principally affecting the great toenails. Clin Exp Dermatol. 1979;4:309– 313. 7 Dawson TA. An inherited nail dystrophy principally affecting the great toenails: further observations. Clin Exp Dermatol. 1982;7:455–456. 8 Harper KJ, Beer WE. Congenital malalignment of the great toe-nails––an inherited condition. Clin Exp Dermatol. 1986;11:514–516. 9 Wagner G, Sachse MM. Congenital malalignment of the big toe nail. J Dtsch Dermatol Ges. 2012;10:326–330. 10 Baran R, Bureau H. Congenital malalignment of the big toe-nail as a cause of ingrowing toe-nail in infancy. Pathology and treatment (a study of thirty cases). Clin Exp Dermatol. 1983;8:619–623. 11 Kus S, Tahmaz E, Gurunluoglu R, et al. Congenital malalignment of the great toenails in dizygotic twins. Pediatr Dermatol. 2005;22:434–435. 12 Chaniotakis I, Bonitsis N, Stergiopoulou C, et al. Dizygotic twins with congenital malalignment of the great toenails: reappraisal of the pathogenesis. J Am Acad Dermatol. 2007;57:711–715.

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13 Balci S, Bostanci S, Ekmekci P, et al. A 15-year-old boy with Rubinstein-Taybi syndrome associated with severe congenital malalignment of the toenails. Pediatr Dermatol. 2004;21:44–47. 14 Hendricks WM. Congenital ingrown toenails. Cutis. 1979;24:393–394. 15 Dyall-Smith D. Congenital malalignment of the great toenails. Australas J Dermatol. 1996;37:54. 16 Baran R, Haneke E. Etiology and treatment of nail malalignment. Dermatol Surg. 1998;24:719–721. 17 Guéro S, Guichard S, Fraitag SR. Ligamentary structure of the base of the nail. Surg Radiol Anat. 1994;16:47–52. 18 Kernland Lang K, Haneke E. Congenital malalignment of the big toe nail (CMAL)––the result of an orthopedic malformation? Poster: Congress of the Swiss Society for Dermatology and Venereology. November 2, 2010. 19 Rich P, Scher R. Age associated nail disorders. In: Rich P, ed. An Atlas of Diseases of the Nail. 2nd ed. New York, NY: Parthenon Publishing; 2005:115, 125. 20 Baran R, Dawber R, Haneke E, et al. A text Atlas of Nail Disorders. Technique in Investigation and Diagnosis. 3rd ed. London, England: Martin Dunitz; 2003:32, 68, 92, 153, 260. 21 Cohen JL, Scher RK, Pappert AS. Congenital malalignment of the great toenails. Pediatr Dermatol. 1991;8:40– 42. 22 Handfields-Jones SE, Harman RR. Spontaneous improvement of the congenital malalignment of the great toe nails. Br J Dermatol. 1988;118:305–306. 23 Barth JH, Dawber RP. Diseases of the nails in children. Pediatr Dermatol. 1987;4:275–290. 24 Perlis CS, Telang GH. Congenital malalignment of the great toenails mimicking onychomycosis. J Pediatr. 2005;146:575. 25 Terrinoni A, Smith FJ, Didona B, et al. Novel and recurrent mutations in the genes encoding keratins K6a, K16 and K17 in 13 cases of pachyonychia congenita. J Invest Dermatol. 2001;117:1391–1396. 26 Baran R, Dawber RP. The nail in childhood and old age. In: Baran R, ed. Diseases of the Nails and their Management. 2nd ed. London, England: Blackwell Scientific Publications; 1994:88–89. 27 Richert B, Choffray A, de la Brassinne M. Cosmetic surgery for congenital nail deformities. J Cosmet Dermatol. 2008;7:304–308. 28 Baran R, Grognard C, Duhard E, et al. Congenital malalignment of the great toenail: an enigma resolved by a new surgical treatment. A new concept about congenital malalignment of the big toenail. Br J Dermatol. 1998;139:72. 29 Jellinek NJ. Flaps in nail surgery. Dermatol Ther. 2012;25:535–544.

Congenital Malalignment of the Great Toenail

MEDIA PARTNER

November/December 2015

Volume 13 • Issue 6

Original contribution

Use of an Interferon-γ Release Assay in the Detection of Latent Tuberculosis in Dermatology: A Descriptive Analysis Hazel H. Oon, MD;1 Hong-Liang Tey, MBBS;1 Wei-Sheng Chong, MBBS;1 Colin T.S. Theng, MBBS;1 Kar-Seng Lim, MBBS;1,2 Hiok-Hee Tan, MBBS;1,3 Benson Yeo, MBBS1 Abstract With the increasing use of biologic therapy in psoriasis, it is becoming more important to identify and treat latent tuberculosis (TB) infection (LTBI). Tuberculin skin test (TST) has been traditionally used to detect LTBI, but interferon-γ release assays (IGRAs), such as the T-SPOT.TB test (T-Spot), are increasingly being used in its place. The indications and results of 51 T-Spot tests performed at the National Skin Centre in Singapore between 2008 and 2010 were analyzed and compared with TST results, decision on LTBI treatment, and previous use of immunosuppressants. T-Spot was most commonly performed as part of a prebiologic workup in patients with psoriasis. A total of 14 (27.5%) results were positive, and no patients had features of active TB. Ten of these patients also underwent TST, five of whom had negative TST results. Six patients (11.8%) had equivocal results with T-Spot test. This study shows poor concordance between T-Spot test and TST. A high incidence of equivocal results in IGRA may limit the utility of the T-Spot test. (SKINmed. 2015;13:439–442)

nterferon-γ release assays (IGRAs) have been shown in various studies to be reliable in detecting tuberculosis (TB) infection.1,2 They have been approved by the US Centers for Disease Control and Prevention for use in all circumstances in which the tuberculin skin test (TST) is currently used, as an aid in diagnosing latent and active TB infection.3 They work on the principle that T cells of previously exposed individuals produce interferon-γ on exposure to the mycobacterial antigen. The two commercially available assays in the market are the TSPOT.TB test (T-Spot; Oxford Immunotec Ltd, Oxford, England) and the QuantiFERON-TB Gold test (QFT-G; Cellestis Ltd, Chadstone, Australia). The T-Spot test uses an enzymelinked immunospot assay to count the number of T lymphocytes that secrete interferon-γ in response to the test antigens, while QFT-G test detects the whole blood production of interferon-γ. A comparison between these two commercially available tests showed significantly higher sensitivity in the T-Spot test but a lower (although statistically insignificant) specificity as compared with the QFT-G test.4

Since the QuantiFERON-TB test was first approved by the US Food and Drug Administration as an aid in detecting latent TB infection (LTBI) in 2001, IGRAs have been increasingly adopted by dermatologists. They are mainly used as a screening tool for LTBI in patients with psoriasis scheduled for biologic therapies. Our study aims to describe the utility of the T-Spot test in the National Skin Centre, the main tertiary dermatology center in Singapore, and to determine its rate of concordance with the TST. Materials and Methods We performed a retrospective review of all patients (both inpatients and outpatients) in the National Skin Centre, Singapore, who underwent the T-Spot test between January 1, 2008, and June 9, 2010. Extracted data included the dermatological diagnosis, the results of T-Spot test and TST (when performed), and whether anti-TB medicine was started. The study was approved by the National Healthcare Group Domain Specific Review Board in Singapore.

From the National Skin Centre,1 The Dermatology Practice,2 and the Thomson Specialist Skin Centre,3 Singapore Address for Correspondence: Benson Yeo, MBBS, National Skin Centre, 1 Mandalay Road, Singapore 308205 • E-mail: yeobenson@gmail.com

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ORIGINAL CONTRIBUTION All 51 patients with positive results on T-Spot test did not have symptoms of active TB, such as chronic cough, night sweats, and loss of weight. Chest radiography was performed in all patients, in whom five showed radiographic changes suggestive of previous TB infection, while the rest had normal radiography findings. Among these five patients, two had positive T-Spot test results, two had indeterminate results, and one had a negative T-Spot test result.

Figure. T-SPOT.TB (Oxford Immunotec Ltd, Oxford, England) test results. LTBI indicates latent tuberculosis infection; TB, tuberculosis.

All T-Spot tests were performed at the laboratory in Tan Tock Seng Hospital, Singapore. The T-Spot test reports the result as positive, negative, indeterminate, or borderline. An indeterminate result is defined as a mitogen positive control spot count <20 and/or negative well count >10 spots.5 A borderline result was defined as a final test panel spot count (number of spots in the panel subtracted by the number in the nil control) of 5, 6, or 7 spots.5 TSTs were performed by injecting 0.1 mm of purified protein derivative intradermally into the forearm and reading the diameter of induration 72 hours later. An induration diameter >10 mm was recorded as a positive result.6 Results T-Spot test was performed in 51 patients during the study period. Thirty-one patients had psoriasis prior to initiating biologic therapy, five had suspected tuberculids and tuberculosis verrucosa cutis, three had presumptive erythema nodosum, three were staff of the institution who were screened for LTBI, and nine had miscellaneous conditions, including Crohn’s disease, acropustulosis, and suspected Kimura disease (Table). Fourteen patients had positive results on T-Spot test. Ten of them eventually received treatment for LTBI or TB infection (Figure). Of the four patients who were not treated, two had psoriasis with no symptoms of TB and biologic therapy was no longer required with improvement of psoriasis, one patient underwent previous treatment for TB, and one patient defaulted follow-up. Among the 14 patients tested positive with T-Spot, 10 also had TST performed during the same period. Five had concordant results, while the remaining five had no reaction on TST (Table). Of these 5 patients with discordant negative results, two had histology-confirmed tuberculid and tuberculosis verrucosa. SKINmed. 2015;13:439–442

Thirty-one patients had negative T-Spot test results and did not receive any TB treatment. Twenty-one of these patients were tested as part of a prebiologic workup and 16 went on to receive biologic treatment without reactivation of TB. Of the remaining five patients, four did not receive biologics, as their condition was controlled with other treatment, while one patient defaulted follow-up. Of the patients with negative T-Spot results, three also had TST performed, with one positive result. This patient was diagnosed with idiopathic recurrent erythema nodosum, with lesions resolving after treatment with dapsone and colchicine for 1 year. Six T-Spot tests returned equivocal results––four borderline, one indeterminate, and one could not be interpreted because of insufficient lymphocytes. None of them were treated for LTBI. Of these six patients, four had psoriasis, one had severe endogenous dermatitis, and one was a staff member who had screening for LTBI. All of these patients except the staff member had current or prior exposure to immunosuppressants (methotrexate, cyclosporine, or prednisolone) and did not develop reactivation of TB. In particular, one patient had two T-Spot tests performed but both returned as uninterpretable because of insufficient lymphocyte yield. This patient was taking multiple immunosuppressive medications for erythrodermic psoriasis and arthropathy, including prednisolone and leflunomide. He went on to receive four doses of adalimumab and subsequently, infliximab with no reactivation of TB; a repeat T-Spot test performed 1 year later was negative. Discussion LTBI, unlike active TB infection, does not have a gold standard of diagnosis. LTBI has been traditionally diagnosed by combining information from medical history, physical examination, chest radiography and results of TST or IGRA. The reported sensitivities and specificities of the T-Spot test and TST refer only to their accuracy in diagnosing active TB infection that is proven by culture and not for LTBI. As shown in our study, in dermatology practice, the large bulk of T-Spot tests are ordered to detect LTBI as part of a prebiologic workup in patients with psoriasis. T-Spot test is gaining favor over TST among local der-

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Table. Indications for Performing and Results of T-SPOT.TB Test Compared With Results of Tuberculin Skin Test Condition

Patients, No.

Positive T-SPOT.TB Results

Positive Tuberculin Skin Test/Tuberculin Skin Tests Performed, No.

Abnormal Findings on Chest Radiography

Patients Treated for Tuberculosis Infection, No.

Psoriasis

1/3

1 (scarring in right upper zone)

4 (monotherapy with isoniazid)

Tuberculid/erythema nodosum/tuberculosis verrucosa cutis

3/6

1 (scarring in bilateral upper zone and pleural thickening)

5 (combination of isoniazid, rifampicin, ethambutol, pyrazinamide)

Miscellaneous conditions

1/1

1 (monotherapy with isoniazid)

Screening in healthcare workers

0/0

Total

5/10

matologists for this indication because of its convenience and sensitivity in detecting active TB infection. In addition, it is not affected by prior Bacillus Calmette-Guérin (BCG) vaccination, which is routinely performed in all children born in Singapore. In our study, as in previous studies,7,8 the concordance between TST and IGRA was poor. With either a positive IGRA but negative TST or a negative IGRA but positive TST, the physician will have to decide whether treatment is to be recommended based on the patient’s risk profile and the history of past BCG vaccination. Without a gold standard of diagnosis for LTBI, dermatologists need to decide whether to perform IGRA only or both IGRA and TST to aid in detecting LTBI. Prospective studies that examine at the incidence of reactivation of TB after starting biologics in patients with discordant IGRA/TST results can help set guidelines on the appropriate test to order. Autoimmune conditions including psoriasis were shown to be an independent risk factor for LTBI, with an 18% prevalence rate among patient with psoriasis, possibly related to a dysregulated immune system.9 Because patients chosen to be tested with T-Spot in the dermatologic clinic are usually those with psoriasis or suspected tuberculids, the relatively high rate of positive T-Spot test results in our study population was expected (14 of 51, 27.5%).

was to increase the sensitivity and specificity of T-Spot by eliminating results near a dichotomous cutoff point. There have been no previous studies reporting the rate of borderline rates of TSpot test and, in our study, this was found to be 7.84% (4 of 51). The US Centers for Disease Control and Prevention recommends that repeating the IGRA or performing a TST might be useful when the initial IGRA result is indeterminate, borderline, or invalid.5 One of our patients was retested with T-Spot, but the result remained uninterpretable due to insufficient lymphocytes. Further studies will be useful to shed light on the best approach to such ambiguous results and will be especially helpful for dermatologists deciding on TB treatment before prescribing biologic therapy for psoriasis. Conclusions T-Spot test was most frequently used to screen for LTBI prior to initiation of biologic therapy. There was poor concordance between T-Spot test and TST, and TST lacked sensitivity in two of the cases (tuberculid and tuberculosis verrucosa cutis) in this study. A high incidence of equivocal results may limit the utility of the T-Spot test. References

IGRAs have shown high sensitivity (94%) and specificity (88%) in the detection of culture-proven active TB infection.5 Indeterminate results do occur, however, and this rate in T-Spot tests was reported to be 3.4% in a large study involving 1429 samples.10 The rate of indeterminate results in our study was comparable, at 2.0% (1 of 51). Borderline T-Spot test was introduced in 2008 by the US Food and Drug Administration.5 Its purpose SKINmed. 2015;13:439–442

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1 Mazurek GH, LoBue PA, Daley CL, et al. Comparison of a whole-blood interferon gamma assay with tuberculin skin testing for detecting latent Mycobacterium tuberculosis infection. JAMA. 2001;286:1740–1747. 2 Meier T, Eulenbruch HP, Wrighton-Smith P, Enders G, Regnath T. Sensitivity of a new commercial enzymelinked immunospot assay (T SPOT-TB) for diagnosis of tuberculosis in clinical practice. Eur J Clin Microbiol Infect Dis. 2005;24;529–536.

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ORIGINAL CONTRIBUTION

3 Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobaterium tuberculosis infection, United States. MMWR Recomm Rep. 2005;54(RR-15):49–55.

titumour necrosis factor therapy: comparison of an interferon-γ release assay vs. tuberculin skin test. Br J Dermatol. 2009;161:797–800.

4 Lee JY, Choi HJ, Park IN, et al. Comparison of two commercial interferon-gamma assays for diagnosing Mycobaterium tuberculosis infection. Eur Respir J. 2006;28:24–30.

8 Kang YA, Lee HW, Yoon HI, et al. Discrepancy between the tuberculin skin test and the whole-blood interferon gamma assay for the diagnosis of latent tuberculosis infection in an intermediate tuberculosis-burden country. JAMA. 2005;293:2756–2761.

5 Mazurek GH, Jereb J, Vernon A; Centers for Disease Control and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection––United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1–25.

9 Bordignon V, Bultrini S, Prignano G, et al. High prevalence of latent tuberculosis infection in autoimmune disorders such as psoriasis and in chronic respiratory diseases, including lung cancer. J Biol Regul Homeost Agents. 2011;25:213–220.

6 Jensen PA, Lambert LA, Iademarco MF, Ridzon R; Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care setting, 2005. MMWR Recomm Rep. 2005;54(RR-17);1–141

10 Beffa P, Zellweger A, Janssens JP, et al. Indeterminate test results of T-SPOT.TB performed under routine field conditions. Eur Respir J. 2008;31:842–846.

7 Laffitte E, Janssens JP, Roux-Lombard P, et al. Tuberculosis screening in patients with psoriasis before an-

11 Obashi Y, Sugiu T, Shimizu H, et al. Clinical evaluation of the T-SPOT.TB test for patients with indeterminate results on the QuantiFERON TB-2G test. Intern Med. 2009;48:137–142.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

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AdvertoriAl

CleAn lAundry & Gentle on Skin Educate Patients: Who believe they must sacrifice cleaning power for a detergent that is non-irritating Sponsored by Procter & Gamble Researchers have found that nearly 45 percent of people report having “sensitive” or “very sensitive” skin.1 Many dermatologists recommend sensitive-skin patients use a dye- and perfume-free laundry detergent because dyes and fragrances are considered to be one of the most common causes of detergent skin allergies. Each one of us approaches our laundry with the same goal: to clean it. However, to those with sensitive skin, achieving “clean” has not always been a straightforward task. “A lot of my patients feel they are sacrificing cleaning power when using some dye-free and perfume-free laundry products,” said Dr. Marnie Nussbaum. “As a result, many of my patients compensate by using scented stain removers or even abandon dye-free and perfumefree products in order to get their clothes truly clean.” In fact, surveys of patients with sensitive skin show:

Marnie nussbaum, MD Dr. Nussbaum specializes in general and cosmetic dermatology. She is also Clinical Instructor of Dermatology at Weill Cornell Medical Center. Among her numerous awards are the Outstanding House Staff Award and the Women in Science Award. Dr. Nussbaum is a member of the American Academy of Dermatology, the American Society of Dermatologic Surgery and the Women’s Dermatologic Society.

• 80 percent say they are dissatisfied with their current fragrance-free laundry products and believe they must sacrifice cleaning power for a detergent that is non-irritating. • More than four out of five use a pre-treatment to compensate for a lack of cleaning power.2 More and more dermatologists are now recommending Tide Free & Gentle. New data show it provides a better clean while being mild on sensitive skin in multiple dermatologist supervised studies or tests.

How Does Tide Free & Gentle Clean Better?

In tests, Tide Free & Gentle removes more residue from stains than the leading free detergent. In fact, Tide Pods Free & Gentle outperform the leading free detergent on 10 different stains, including blood, coffee and grass stains, and is mild on sensitive skin. Tide Free & Gentle’s unique “Lift and Block” technology removes stains and soils to keep clothes clean while being gentle to skin.

Fig. 1 The fabric washed in Tide Free & Gentle is clean down to the fiber level, demonstrating superior clean ability; not only removing or lifting stains, dirt and odor particles, but preventing them from reattaching or redepositing to the fabrics, wash after wash. Original image in B&W. Soil has been colorized to show contrast.

Step 1: Lift

• Deep Clean System: Enzymes break up hard-to-remove stains and surfactants lift out stains, dirt and odor particles down to the fiber level. See Fig. 1.

Fig. 2 Soil residues left on fibers attract dirt from the wash water.

Step 2: Block

• Anti-Redeposition Technology: Concentrated polymers sweep in to trap the dirt in the wash water, to prevent it from reattaching to the fabric fibers. Our bodies produce up to 50 grams of body soil per day, including mucus, dead skin, sweat, sebum and bacteria. Clothing may look clean, but in a given laundry load, all that soil combines in the water to create a very dirty environment. This is important because even if a stain appears to have been removed from clothing the first trip through the washing machine, dirt attracts dirt, so any soil residues left on clothing fibers will cause dirt in the wash water to redeposit on clothes over time. See Fig. 2. Dirt redeposition is a primary reason why whites tend to appear dingy after numerous washings – not just dye transfer as is commonly believed. As larger high eﬃciency washers continue to become the norm in American households, this issue becomes more pronounced. High eﬃciency washers use three times less water so soil is more concentrated in the wash water, increasing the likelihood of redeposition of dirt on clothing. However, Tide Free & Gentle’s unique “Lift and Block” technology provides a superior clean from wash to wash. Patients benefit from the gentleness of a dye- and perfume-free detergent without having to sacrifice superior cleaning power.

The Importance of Patient Compliance in a Laundry Regimen

“I recommend Tide Free & Gentle to my patients because it drives compliance since it is not only gentle, but provides a better clean,” says Dr. Nussbaum.

Fig. 3 Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets. But it’s also very important to remind patients with sensitive skin issues that the entire laundry regimen needs to be free of dyes and perfumes. Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets. See Fig. 3. For this reason, it is critical to remind patients that caring for sensitive skin doesn’t stop with detergent; the entire laundry regimen needs to be dye-free and perfumefree. In fact, fabric softeners that do not contain dyes or fragrance, such as Downy Free & Gentle, may have sensitive skin benefits, such as reducing friction between clothes and skin and, therefore, skin irritation.

Dermatologists Play an Important Role

Dermatologists can help patients ensure they are achieving the best results for their laundry and their skin. Talk with your patients, particularly those with sensitive skin, about their current laundry detergent choices and help them understand the benefits of following a Free & Gentle regimen. Be sure to recommend products that complement your patient’s skin health needs while also helping them achieve the optimal result of clean laundry.

References

1 Misery, L., Sibaud, V., Merial-Kieny, C., & Taieb, C. Sensitive skin in the American population: Prevalence, clinical data, and role of the dermatologist. Int J Dermatol. 2011;50:961–967. 2 2010 Habits, Practices and Attitudes conducted by P&G.

CMY

November/December 2015

Volume 13 • Issue 6

Original contribution

Guidelines for the Topical Treatment of Psoriasis Vulgaris in the Levant and Iraq Area Ossama Abbas, MD;1 Alfred Ammoury, MD;2 Mohammad Abbadi, MD;3 Medhat Abdel Malek, MBBCh;4 Laith Akkash, MD;5 Kamal Al-Chakharah, MD;6 Khalil Al-Hamdi, MBBCh;7 Firas Al-Qarqaz, MD;8 Abduljabbar Al-Soudani, MBBCh;9 Nameer Al-Soudani, MBBCh;10 Anwar Dandashle, MD;11 Fouad El-Sayed, MD;12 Yasser Ghafir, MD;13 Nazek Gargour, MD;14 Said Kabalan, MD;15 Abdul-Ghani Kibbi, MD;16 Isam Oumeish, MD;17 Zeina Tannous, MD;18 Roland Tomb, MD19* Abstract Psoriasis vulgaris is a common chronic, inflammatory, multisystem disorder that affects approximately 1.5% to 3.4% of the population in the Middle East. The disease has an impact on the quality of life in a significant number of affected patients. The majority of patients (approximately 70%) have mild to moderate psoriasis that is manageable with topical agents, which generally show a high efficacy to safety ratio. Topical agents can be used alone when treating patients with limited disease or may be used as adjunctive therapy for patients with more extensive psoriasis undergoing systemic treatment. Treatment should also be customized to meet individual patients’ needs. To optimize the topical treatment of psoriasis in the Levant and Iraq area, dermatology experts from Iraq, Jordan, Lebanon, Palestine, and Syria met and initiated a project to develop guidelines and recommendations for the topical management of psoriasis. The guidelines are based on literature evidence and experts’ opinions. We present recommendations for the use of topical corticosteroids, vitamin D analogues, calcineurin inhibitors, tazarotene, salicylic acid, anthralin, and coal tar, as well as combination therapy, based on their efficacy and safety profiles. (SKINmed. 2015;13:445–453)

soriasis vulgaris is a common chronic, immune-mediated, inflammatory, multisystem disease that affects approximately 1.5% to 3.4% of patients in the Middle Eastern population.1–3 Although inadequate studies exist, psoriasis in our area appears to be similar to other parts of the world based on our experience; however, environmental, psychosocial, cultural, and other factors have to be accounted for in the delivery of care for psoriatic patients. The disease tends to significantly influence patients’ quality of life.4,5 To standardize psoriasis manage-

ment, psoriasis severity can be defined as follows: mild disease (manageable with topical treatment) is defined by the rule of 10 (body surface area [BSA] ≤10 or Psoriasis Area and Severity Index [PASI] ≤10 and Dermatology Life Quality Index [DLQI] ≤10), while moderate to severe psoriasis (candidates for UV and/ or systemic treatment) is defined as BSA >10 or PASI >10 and DLQI >10.6 Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement.

*The authors represent the expert members of the Levant & Iraq Guideline Group who were involved in developing the guideline, reviewing the pertinent literature, and giving their opinions in voting. Their listing is presented in alphabetical order, except for the first two authors, who drafted the manuscript. All authors contributed equally to the work. From the American University of Beirut, Beirut, Lebanon;1 Balamand University, Beirut, Lebanon;2 Ministry of Health Hospital, Amman Jordan;3 Private Practice, Amman, Jordan;4 University of Jordan, Amman, Jordan;5 Private Practice, Ramallah, Palestinian Authority;6 Basra Medical College, Basra, Iraq;7 Jordan University of Science and Technology, Irbid, Jordan;8 Hawler Medical University, Erbil, Iraq;9 Al-Mustansiriya University, Iraq;10 German Hospital, Dubai, United Arab Emirates;11 Lebanese University, Beirut, Lebanon;12 Private Practice, Damascus, Syria;13 Private Practice, Lattkia, Syria;14 Damascus University, Syria;15 American University of Beirut, Beirut, Lebanon;16 King Hussein Medical Center, Amman, Jordan;17 Lebanese American University, Beirut, Lebanon;18 and Saint Joseph University, Beirut, Lebanon19 Address for Correspondence: Abdul-Ghani Kibbi, MD, Professor and Chair, Department of Dermatology, American University of Beirut Medical Center, PO Box 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon • E-mail: agkibbi@aub.edu.lb

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Topical agents are the mainstay of psoriasis treatment due to their generally high efficacy to safety ratio. Becasue the majority of psoriasis patients present with limited disease (<10% of BSA involvement), topical agents alone are sufficient to achieve good control. Topical agents are typically used as adjunctive therapy with systemic agents in cases of more extensive disease. Care should be taken, however, so that treatment is customized to meet the individual needs of patients. This is important in order to increase patient compliance and satisfaction, as the noncompliance rate may be as high as 40%.4,7 Multiple factors contribute to low treatment adherence rates, including specific aspects of the topical treatments themselves, such as physical properties, ease of use, and the vehicle in which the active ingredients are dissolved, as well as the long-term use of ineffective topical treatment.5–11

of existing published guidelines that extensively reviewed the literature on the topical treatment of psoriasis,12–15 team expert opinion in a Delphi consensus was used to generate our clinical recommendations, when evidence-based data were not available.

In daily practice, traditional concepts are more widely used than evidence-based data in selecting treatments for psoriasis patients, especially in our area. Based on that and in order to optimize and improve the standard of care provided to psoriasis patients in the Levant and Iraq, dermatology experts initiated a project to develop guidelines for psoriasis management. The guidelines are derived from the literature evidence, which has already been extensively reviewed by several guidelines,12–15 as well as from opinions of experts from our area. The first step is the development of guidelines for the topical treatment of psoriasis. The scalp and nails will be addressed separately. We present recommendations for the use of topical corticosteroids, vitamin D analogues, calcineurin inhibitors, tazarotene, salicylic acid, anthralin, coal tar, as well as combination therapy, based on their efficacy and safety profiles. These guidelines should complement rather than duplicate those that have been published regionally and internationally by organizations and working groups and may serve as a proof of seal that management of chronic skin diseases including psoriasis in our part of the world follows clinical pathways and trends of practice widely recognized in other parts of the world. In addition, it will allow expatriates from many countries who are subscribers to international insurance companies to receive reimbursements on their health bills in a smooth and timely fashion. Such guidelines provide a practice framework for visiting dermatologists in our part of the world, where cultural, social, environmental, and other factors should be considered, when providing appropriate and quality care to patients with psoriasis.

General Considerations of Topical Treatment

Methods A working group of expert dermatologists from Iraq, Jordan, Lebanon, Palestine, and Syria met and initiated a project to develop guidelines for the management of psoriasis based on evidence from the literature and team experience. After evaluation SKINmed. 2015;13:445–453

These guidelines are intended for dermatologists and other physicians involved in the treatment of psoriasis to optimize the standard of care provided to patients in our area. They do not, however, represent a guarantee for successful treatment and reimbursement. Eventually, it is the agreement of the physician and the patient, based on the circumstances presented by each individual patient, that dictates the decision of any specific therapy. We agreed that our first step would be to develop guidelines on topical management of psoriasis.

Several factors dictate the appropriate topical treatment, chosen to the needs of the individual patient. These include the body site affected, patient preferences, characteristics of the psoriatic lesions being treated, and the vehicle in which it is presented.12,16–18 Topical Treatments for Psoriasis Table I summarizes and compares, based on the Delphi consensus among the members of the panel of experts from our region, the characteristics of the different topical treatments for psoriasis including efficacy, evidence level, use in induction therapy and/or maintenance therapy, ease of use, and cost-effectiveness. Tables II and III summarize the recommendations for pregnant/ nursing patients and the pediatric population. Table IV describes the side effects of the different topical agents. Topical Corticosteroids

Background Among the various topical agents used for the treatment of psoriasis, topical corticosteroids remain the cornerstone of therapy.12–15,19 Topical steroids are available in different strengths and formulations. Their potency is based on their ability to cause vasoconstriction19; however, the same molecule could present with different strengths depending on the concentration and vehicle. They generally range in strength from weakly potent to midpotent, potent, or superpotent. Table V lists the potency classes of the different topical steroids that are available in the Levant area. Corticosteroids are characterized by anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive functions. These are mediated by their binding to intracellular receptors

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Table I. Comparison of Characteristics of the Different Topical Agents Used in the Treatment of Psoriasis: Efficacy, Level of Evidence, Use in Induction vs Maintenance Therapy, Ease of Use, and Cost-Effectiveness Therapy

Steroids (Potent)a

Vitamin D Analoguesb

Calcipotriene and Betamethasone Propionate

Calcineurin Inhibitorsc

Tazarotene

Dithranol

Coal Tar

Efficacy

+4d

+2e

+3f

Induction therapy

+3f

Maintenance therapy

+1g

+3h

Not applicablei

+2e

Not preferablej

Ease of usek

+2g

+3g

Cost-effectiveness

Team expert opinion in a Delphi consensus was used to generate the scoring, which was based on a scale of 0 (poor) to +5 (excellent). For comparison purposes, potent steroids are used in this column to better compare steroids with the other topical agents, especially the combination of calcipotriene and betamethasone propionate. b Currently not available in the region but scoring is based on past experience with calcipotriol. c Off-label use in psoriasis, mainly used to treat psoriasis on the face and intertriginous sites. d There was consensus that superpotent steroids have an efficacy of +5 but with more side effects than potent steroids. e Agreement on a regional level (no consensus due to lack of experience) and consensus on a country level (Lebanon). f Disagreement on a regional level (lack of experience) and consensus on a country level (Jordan). g Agreement on a regional level. hIntermittent rather than continuous use. i Lack of safety data. j Not preferable for cosmetic reasons/poor acceptance. k Based on tolerability and cosmetic appearance. a

Table II. Summary of Recommendations on the Use of Topical Agents in Pregnancy/Nursing Topical Agent

Use During Pregnancy/Nursing

Topical corticosteroids

Pregnancy category Ca Safety unknown during nursing

Vitamin D analogues

Pregnancy category C Safety unknown during nursing

Calcineurin inhibitors

Pregnancy category C They are not recommended for nursing mothers, as they have been found in human milk

Tazarotene

Absolutely contraindicated

Coal tar

Contraindicated

Salicylic acid

Appears to be safe for control of localized lesions

Dithranol

Pregnancy category C

Emollients

Safe

a Although topical corticosteroids are generally considered to be in pregnancy category C, recent evidence indicates that the risk to the fetus is considerable with potent and superpotent formulations and should be avoided, while less risk is evident with weak and midpotent compounds. Physicians should restrict prescription of steroids during pregnancy to the less potent compounds and in special cases where treatment is needed.

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Table III. Recommendations on the Use of Topical Agents in the Pediatric Population Topical Agent

Pediatric Use

Topical corticosteroids

Care should be taken due to a higher risk of side effects given the increased skin surface/body mass ratio

Vitamin D analogues

Appear to be safe in children older than 2 years with a maximum of 50 g/wk

Calcineurin inhibitors

Approved for the treatment of atopic dermatitis for patients 2 years and older; if necessary, they may be used off-label for the same age group Care should be taken due to a higher risk of side effects given the increased skin surface/body mass ratio

Tazarotene

Relatively contraindicated in patients younger than 18 years

Coal tar

If needed and if there is no other alternative, it may be used with caution

Salicylic acid

Should be avoided due to the higher risk of systemic absorption and toxicity

Dithranol

If necessary, use with caution

Table IV. Side Effects of the Different Topical Agents Used in the Treatment of Psoriasis Agents

Adverse Effects

Topical corticosteroids

Local: skin atrophy, telangiectasia, hypertrichosis, acne, folliculitis, rosacea, striae, purpura, tachyphylaxis, and contact dermatitis Systemic: occur infrequently but more often when using more potent topical corticosteroids for prolonged durations, especially when applied to the face, genital region, and intertriginous areas

Vitamin D analogues

Transient irritation, itching, redness, burning in lesional, and perilesional skin, especially when applied to the face and intertriginous areas May cause photosensitivity with risk of postinflammatory hypopigmentation or hyperpigmentation Reversible serum calcium elevation, especially when used in excess of 100 g/wk

Calcineurin inhibitors

Burning, itching, increased rate of skin infections Phototherapy should be avoided in the same day of their use Given the potential risk for developing cutaneous lymphoma, the US Food and Drug Administration implemented a black box warning in 2005 due to the lack of long-term safety data

Tazarotene

Irritation, burning, pruritus, erythema, photosensitivity, irritant contact dermatitis It is preferable to use tazarotene in combination with a potent steroid gel in order to improve tolerance and increase efficacy

Coal tar

Folliculitis, irritant contact dermatitis, and photosensitivity Poorly tolerated due to cosmetic issues, especially staining of clothes and odor While shown to be carcinogenic in animals, there are yet no convincing data proving carcinogenicity in humans

Calcipotriene and betamethasone combination

Better tolerability profile when compared with either of its constituents alone Vitamin D analogue may reduce steroid-associated atrophy and tachyphylaxis/rebound effect while the steroid component reduces the irritation associated with the vitamin D analogue

Efficacy

erate psoriasis, especially during the induction phase.12â&#x20AC;&#x201C;14 Their efficacy as monotherapy has the highest evidence level (evidence level I: intervention supported by meta-analysis or randomized, double-blind, high-quality clinical comparative studies).

Although some concerns regarding adverse effects may exist (particularly when used on a long-term basis), topical corticosteroids have proven to be clinically effective in mild to mod-

Based on different studies, efficacy rates of topical corticosteroids with different potencies in mild to moderate psoriasis vary widely, even within the same category. Efficacy rates, based on

that affect transcription of many genes, especially those encoding proinflammatory cytokines.1,12,13

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Table V. Potency Class of the Different Topical Corticosteroids Available in the Levant Area Potency

Generics

Class 1—superpotent

Clobetasol propionate 0.05%

Class 2—potent

Betamethasone valerate 0.05% and 0.1%, triamcinolone acetonide 0.1%, fluticasone propionate, betamethasone propionate 0.05% and 0.064%, fluocinolone acetonide 0.025%

Class 3—midpotent

Betamethasone valerate 0.025%, mometasone furoate, triamcinolone acetonide, fluocinolone acetonide 0.00625%, methylprednisolone, hydrocortisone 0.1%

Class 4—weakly potent

Hydrocortisone 0.25% and 0.1%, desonide

a mean PASI recovery rate of >75% used in most studies, range from 41% to 83% in the case of weakly potent steroids, 68% to 72% in the case of midpotent steroids, 68% to 74% in the case of potent steroids, and 58% to 92% in the case of superpotent steroids.20–31 In addition to potency, other factors also influence efficacy rates, including the area of application, vehicle, presence or absence of occlusion, and patient age. The duration of treatment in most studies is 2 to 4 weeks, concluding that there is enough evidence to support the use of topical steroids in the induction phase, while their role as maintenance therapy needs further investigation.

Dose and usage Several factors influence the choice of the appropriate potency of corticosteroids and its vehicle.12,14,15 These include patient age, disease severity, localization of lesions, and patient preference. In our opinion, we agreed that lower-potency steroids should generally be used for limited periods on certain skin areas (face, intertriginous areas, areas with thin skin) and in infants, while mid- or high-potency agents are generally recommended as initial therapy in other areas and in adults. The highest-potency steroids are often required to treat chronic thick psoriatic plaques for short periods, not exceeding 2 to 4 weeks. While diluting topical steroids (by mixing it with an emollient to decrease potency) is common in our region, this practice is not recommended, given the lack of evidence to support it. During induction therapy, application once per day to the affected site for 2 to 4 weeks is sufficient.21 Once improvement occurs, we recommend that a gradual reduction in the frequency of topical corticosteroid use be instituted. Generally, we suggest tapering the applications to once every other day for 1 week, then once every third day for 1 week, followed by discontinuation of therapy. SKINmed. 2015;13:445–453

Recommendation We strongly recommend the use of topical corticosteroids once per day as induction therapy for 2 to 4 weeks for patients with mild to moderate psoriasis, especially when appropriate potency and vehicle are used. Following clinical response, a gradual reduction in the frequency of use should be instituted or a switch to a lower-potency steroid or calcineurin inhibitors. Topical steroids can also be used as intermittent therapy but are not recommended for maintenance therapy. Upon discontinuation, patients should be advised of the risk of using self-prescribed topical steroids for the long term without medical supervision, especially given the relatively free access to medications in our region. Vitamin D3 Analogues

Background Calcipotriol, a synthetic vitamin D analogue, was the first vitamin D3 analogue to be approved for the topical treatment of mild to moderate plaque psoriasis in 1992, followed by tacalcitol and calcitriol.12–14 Calcipotriol has currently been withdrawn and is no longer available in the Levant area and Iraq. In addition, tacalcitol and calcitriol are not available in our markets. The mechanism of action of the vitamin D analogues in psoriasis involves inhibition of keratinocyte proliferation while enhancing their differentiation.12,13 This effect is likely mediated by binding of vitamin D analogues to intracellular receptors, which then bind to regulatory sections of DNA, leading to changes in target gene expression; furthermore, vitamin D analogues have immunomodulatory effects on T lymphocytes, Langerhans cells, and monocytes.32

Efficacy Topical vitamin D analogues have proven to be clinically effective in mild to moderate psoriasis and are classified as having a level of evidence I as monotherapy. A recent Cochrane review

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reported that vitamin D analogue monotherapy, along with corticosteroid monotherapy, showed the greatest efficacy overall, when compared with other topical monotherapies for psoriasis.20 The majority of evidence is on calcipotriol. Studies have shown that within a few weeks, 30% to 50% of patients treated with topical calcipotriol for their mild to moderate psoriasis achieve complete clearance or significant improvement,20,33–35 with a mean PASI recovery rate of >75%. Significant improvement is usually seen after 1 to 2 weeks, while maximum effect is typically reached after 12 weeks of daily application.

Dose and usage The recommended dose for vitamin D analogues is usually twice daily. Twice-daily application of calcipotriol has been shown to be more effective than once-daily dosing.12,13,20 Dose recommendations in the initial 12-week phase of treatment is no application to more than 30% of the BSA, not exceeding a total of 100 g/wk for up to 1 year in the maintenance phase.12,13,20

Efficacy Calcineurin inhibitors are currently used off-label in the treatment of psoriasis. Initial clinical studies in the late 1990s showed that both pimecrolimus and tacrolimus 0.1% can be highly effective against plaque psoriasis but only when used under occlusion.37 More recent studies have reported complete clearance or significant diminution of lesions (mean PASI recovery rate >75%) in 40% to 50% of patients with daily application of tacrolimus 0.1% or pimecrolimus for 6 to 12 weeks, especially in certain areas including the face, anogenital region, and intertriginous region.20,38,39

Dose and usage Topical tacrolimus 0.1% ointment or pimecrolimus cream applied once a day on sun-exposed areas and twice a day on intertriginous areas may be considered for psoriasis treatment especially on the face, intertriginous regions, and anogenital area. Their use is not advised on other areas of the body.12,13,20

Recommendation

When reavailable in the region, the topical use of vitamin D3 derivatives once or twice daily is recommended for both induction and maintenance phases in the treatment of mild to moderate psoriasis. Calcipotriol is more effective, when applied twice daily.

Calcineurin inhibitors are used off-label for treating psoriasis. They have limited efficacy in plaque psoriasis; however, we recommend their use on the face or intertriginous or anogenital regions as once- or twice-daily application. Their use on other body sites is not advised due to limited efficacy and insufficient data on their long-term use.

Calcineurin Inhibitors

Tazarotene

Background Topical calcineurin inhibitors were approved for the treatment of atopic dermatitis in 2002. Ever since, numerous off-label indications for their use have been advocated, including that for psoriasis treatment.12–15 Currently available topical calcineurin inhibitors are tacrolimus (Protopic; Astellas Pharma, Toyama, Japan) and pimecrolimus (Elidel; Valeant Pharmaceuticals, Canada). Tacrolimus is marketed in two concentrations, 0.03% and 0.1%, and is available as an ointment in only a few of the Levant countries, namely Jordan, while pimecrolimus as a 1% cream can be found in parts of the Levant area. The mechanism of action is similar to that of cyclosporine. It involves blocking the synthesis of numerous inflammatory cytokines important in the pathogenesis of psoriasis by inhibiting calcineurin phosphatase.12,13,36 This leads to reducing the production of interleukin 2 and other proinflammatory cytokines such as tumor necrosis factor α and interferon γ.36 SKINmed. 2015;13:445–453

Background Tazarotene, a potent third-generation retinoid, was first approved for mild to moderate psoriasis vulgaris in 1997.12 It is available as 0.05% and 0.1% tazarotene gel. Its mechanism of action is not fully understood, but it is believed to act by diminishing hyperproliferation, normalizing abnormal keratinocytes differentiation, and decreasing expression of inflammatory markers.12,13

Efficacy The level of evidence for tazarotene use in psoriasis treatment is II (evidence based on predominantly consistent results from high-quality, randomized, double-blind comparative clinical studies or a randomized clinical study of lesser quality or other comparative studies).12,13,40 Tazarotene gel 0.1% shows at least 50% improvement in approximately half of psoriasis patients with mild disease after 12 weeks of treatment. The effect persists for up to 12 weeks after stopping therapy. 12,13,40

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Dose and usage

Recommendation

Tazarotene is recommended as a once-daily dose in the evening.

Dithranol is effective for treatment in the induction phase especially as short-contact therapy; however, it is less effective than potent topical corticosteroids or vitamin D3 analogues. It is not recommended for treatment in the maintenance phase. It is difficult to use and can cause local irritation, especially if used on the face or intertriginous skin.

Recommendation The topical use of tazarotene as a once-daily evening dose may be considered in the induction phase; however, it should not be used on the face, scalp, or intertriginous regions, due to its high rate of local irritation, which also limits its use in the maintenance phase. Coal Tar

Background Coal tar, a distillation product from coal, contains more than 400 different ingredients, including benzols, naphthaline, and phenols.41 Various forms of tar have been used for many decades. Its effectiveness was increased by adding ultraviolet (UV) light (Goeckerman therapy, introduced in 1925).42 Its mechanism of action is uncertain. Commercially available preparations containing coal tar include shampoos and lotions that are commonly used in our area, especially in Iraq.

Other Topical Monotherapies Salicylic acid is a keratolytic agent that may be used in 2% to 10% concentrations for treating psoriasis in order to soften scaly layers. There are limited data on its use as monotherapy, and it is not recommended as monotherapy, except in the initial phase to enhance the penetration of other subsequent topical agents on limited BSA <10%.12,13,20 Emollients are generally used as standard adjunctive therapy in psoriasis treatment in our area. Application of moisturizers can reduce erythema, flaking, and lichenification, as well as improve hydration. Emollients can be applied once to several times per day.12 Combination Formulations

Efficacy There is not enough evidence on the use of coal tar as monotherapy. The level of evidence for the use of coal tar in psoriasis is low (level IV, with little or no systematic empirical evidence).12,13,20,43,44 Experience has shown, however, that coal tar may be effective for psoriasis only after taking into account alternative therapies with lower risk and cautiously weighing the therapeutic benefit against a theoretical cancer risk.

Recommendation Use of coal tar is not recommended for induction and maintenance phase treatment, especially in the presence of more effective, safer, and practical alternatives. In certain situations, coal tar may be used with UV-B for the treatment of refractory plaque psoriasis on a short-term basis. Dithranol Dithranol was first approved for psoriasis treatment in our areas in 1983. Studies have shown that once-daily application, as short contact therapy, results in total remission in 30% to 70% of patients over a period of 5 to 8 weeks (level of evidence II).12â&#x20AC;&#x201C; 14,20 It can be used only during induction therapy. Common side effects include burning and redness of the skin. It is not available in any of the Levant countries except Jordan. SKINmed. 2015;13:445â&#x20AC;&#x201C;453

The concept of topical combination therapies is usually based on increasing the efficacy over that of single constituents, while attempting to decrease the adverse effects associated with each. Several combination therapies have been studied in the topical treatment of psoriasis, and only two are available in our area. The available agents are calcipotriene 0.005% and betamethasone propionate 0.064% ointment, and salicylic acid with different corticosteroids including mometasone, dexamethasone, or betamethasone. Combined Formulation of Calcipotriene and Betamethasone Propionate Evidence shows that combination therapy with calcipotriene and betamethasone propionate is superior in the first 4 weeks, when compared with either agent as monotherapy (level of evidence I).20,45,46 Once-daily application of combination therapy was shown to be successful in 55% to 63% of patients, and twicedaily use was shown to be successful in 68% to 76% of patients (mean PASI recovery rate used was >75%).46,47 The gel seems to be more acceptable to patients, with better overall adherence, and is more pharmacoeconomically favorable, when compared with the ointment formulation. 11

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Recommendation Combined formulation of calcipotriene and betamethasone propionate is highly recommended as induction therapy for mild to moderate psoriasis in the first 4 weeks. It is also highly recommended for maintenance therapy when used intermittently. Topical Steroids With Salicylic Acid Evidence exists that salicylic acid increases the effectiveness of topical steroid therapy,48,49 which is probably due to increased skin penetration that occurs as a result of salicylic acid keratolytic effects. Conclusions

9 Thorneloe RJ, Bundy C, Griffiths CE, et al. Adherence to medication in patients with psoriasis: a systematic literature review. Br J Dermatol. 2013;168:20–31. 10 Feldman SR. Approaching psoriasis differently: patientphysician relationships, patient education and choosing the right topical vehicle. J Drugs Dermatol. 2010;9:908– 911. 11 Colombo GL, Di Matteo S, Bruno G, et al. Calcipotriol and betamethasone dipropionate in the treatment of mild-to-moderate psoriasis: a cost-effectiveness analysis of the ointment versus gel formulation. Clinicoecon Outcomes Res. 2012;4:261–268. 12 Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2009;60:643–659.

The current guidelines present the level of evidence for efficacy of the available topical therapies for psoriasis and provide recommendations for their use in daily practice. Optimal management of psoriasis cannot be achieved, however, without considering several important factors, including patients’ quality of life.

13 Nast A, Boehncke WH, Mrowietz U, et al. S3 - Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges. 2012;10:S1–S95.

Acknowledgment and disclosure

15 Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol. 2002;146:351–364.

Drs Abbas and Ammouri contributed equally as the main writers of this manuscript. The authors acknowledge LEO Pharma for their educational grant and also acknowledge Dr Diamant Thaci for his role in facilitating the development of the guidelines. References 1 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496–509. 2 Abdulghani M, Al Sheik A, Alkhawajah M, et al. Management of psoriasis in Africa and the Middle East: a review of current opinion, practice and opportunities for improvement. J Int Med Res. 2011;39:1573–1588. 3 Raychaudhuri SP, Farber EM. The prevalence of psoriasis in the world. J Eur Acad Dermatol Venereol. 2001;15:16– 17. 4 Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence, severity and patients’ beliefs and attitudes towards the disease. Br J Dermatol. 1996;135:533–537.

14 Paul C, Gallini A, Archier E, et al. Evidence-based recommendations on topical treatment and phototherapy of psoriasis: systematic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2012;26:1–10.

16 Brown KK, Rehmus WE, Kimball AB. Determining the relative importance of patient motivations for nonadherence to topical corticosteroid therapy in psoriasis. J Am Acad Dermatol. 2006;55:607–613. 17 Feldman SR, Horn EJ, Balkrishnan R, et al. Psoriasis: improving adherence to topical therapy. J Am Acad Dermatol. 2008;59:1009–1016. 18 Devaux S, Castela A, Archier E, et al. Adherence to topical treatment in psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26:61–67. 19 Castela E, Archier E, Devaux S, et al. Topical corticosteroids in plaque psoriasis: a systematic review of efficacy and treatment modalities. J Eur Acad Dermatol Venereol. 2012;26:36–46. 20 Mason AR, Mason J, Cork M, et al. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev. 2009;2:CD005028.

5 Rapp SR, Feldman SR, Exum ML, et al. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41:401–407.

21 Sears H, Bailer JW, Yeadon A. A double-blind, randomized placebo-controlled evaluation of the efficacy and safety of hydrocortisone butyrate 0.1% cream in the treatment of psoriasis. Adv Ther. 1997;14:140–149.

6 Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303:1–10.

22 Pauporte M, Maibach H, Lowe N, et al. Fluocinolone acetonide topical oil for scalp psoriasis. J Dermatolog Treat. 2004;15:360–364.

7 Richards HL, Fortune DG, O’Sullivan TM, et al. Patients with psoriasis and their compliance with medication. J Am Acad Dermatol. 1999;41:581–583.

23 Olsen EA. Efficacy and safety of fluticasone propionate 0.005% ointment in the treatment of psoriasis. Cutis. 1996;57:57–61.

8 Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis treatment. Arch Dermatol. 2004;140:408–414.

24 Franz TJ, Parsell DA, Halualani RM, et al. Betamethasone valerate foam 0.12%: a novel vehicle with enhanced delivery and efficacy. Int J Dermatol. 1999;38:628–632.

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25 Stein LF, Sherr A, Solodkina G, et al. Betamethasone valerate foam for treatment of nonscalp psoriasis. J Cutan Med Surg. 2001;5:303–307. 26 Savin RC. Desoximetasone—a new topical corticosteroid: short- and long-term experiences. Cutis. 1978;21:403– 407. 27 Lepaw MI. Double-blind comparison of halcinonide solution and placebo control in treatment of psoriasis of the scalp. Cutis. 1978;21:571–573. 28 Bernhard J, Whitmore C, Guzzo C, et al. Evaluation of halobetasol propionate ointment in the treatment of plaque psoriasis: report on two double-blind, vehiclecontrolled studies. J Am Acad Dermatol. 1991;25:1170– 1174. 29 Lebwohl M, Sherer D, Washenik K, et al. A randomized, double-blind, placebo-controlled study of clobetasol propionate 0.05% foam in the treatment of nonscalp psoriasis. Int J Dermatol. 2002;41:269–274. 30 Gottlieb AB, Ford RO, Spellman MC. The efficacy and tolerability of clobetasol propionate foam 0.05% in the treatment of mild to moderate plaque-type psoriasis of nonscalp regions. J Cutan Med Surg. 2003;7:185–192. 31 Olsen EA, Cram DL, Ellis CN, et al. A double-blind, vehicle-controlled study of clobetasol propionate 0.05% (Temovate) scalp application in the treatment of moderate to severe scalp psoriasis. J Am Acad Dermatol. 1991;24:443–447. 32 Boonstra A, Barrat FJ, Crain C, et al. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001;167:4974–4980. 33 Kragballe K, Gjertsen BT, De Hoop D, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet. 1991;337:193–196. 34 Guenther LC, Poulin YP, Pariser DM. A comparison of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream once daily versus calcipotriene 0.005% ointment twice daily in the treatment of plaque psoriasis. Clin Ther. 2000;22:1225–1238. 35 Korver JE, Vissers WH, van Rens DW, et al. A doubleblind, randomized quantitative comparison of calcitriol ointment and calcipotriol ointment on epidermal cell populations, proliferation and differentiation. Br J Dermatol. 2007;156:130–137. 36 O’Keefe SJ, Tamura J, Kincaid RL, et al. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992;357:692–694. 37 Zonneveld IM, Rubins A, Jablonska S, et al. Topical tacrolimus is not effective in chronic plaque psoriasis. A pilot study. Arch Dermatol. 1998;134:1101–1102.

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38 Gribetz C, Ling M, Lebwohl M, et al. Pimecrolimus cream 1% in the treatment of intertriginous psoriasis: a double-blind, randomized study. J Am Acad Dermatol. 2004;51:731–738. 39 Liao YH, Chiu HC, Tseng YS, Tsai TF. Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(1) ointment and tacrolimus 0.3 mg g(-1) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol. 2007;157:1005–1012. 40 Weinstein GD, Koo JY, Krueger GG, et al. Tazarotene cream in the treatment of psoriasis: two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and efficacy of tazarotene creams 0.05% and 0.1% applied once daily for 12 weeks. J Am Acad Dermatol. 2003;48:760–767. 41 Grupper C. The chemistry, pharmacology and use of tar in treatment of psoriasis. In: Farber EM, Cox AJ, eds. Psoriasis: Proceedings of the International Symposium, Stanford University, Stanford, CA; 1971:347–356. 42 Belsito DV, Kechijian P. The role of tar in Goeckerman therapy. Arch Dermatol. 1982;118:319–321. 43 Kanzler MH, Gorsulowsky DC. Efficacy of topical 5% liquor carbonis detergens vs. its emollient base in the treatment of psoriasis. Br J Dermatol. 1993;129:310–314. 44 Goodfield M, Kownacki S, Berth-Jones J. Double-blind, randomised, multicentre, parallel group study comparing a 1% coal tar preparation (Exorex) with a 5% coal tar preparation (Alphosyl) in chronic plaque psoriasis. J Dermatolog Treat. 2004;15:14–22. 45 Devaux S, Castela A, Archier E, et al. Topical vitamin D analogues alone or in association with topical steroids for psoriasis: a systematic review. J Eur Acad Dermatol Venereol. 2012;26:52–60. 46 Papp KA, Guenther L, Boyden B, et al. Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. J Am Acad Dermatol. 2003;48:48–54. 47 Ortonne JP, Kaufmann R, Lecha M, et al. Efficacy of treatment with calcipotriol/betamethasone dipropionate followed by calcipotriol alone compared with tacalcitol for the treatment of psoriasis vulgaris: a randomised, double-blind trial. Dermatology. 2004;209:308–313. 48 Katz HI, Tanner DJ, Cuffie CA, et al. A comparison of the efficacy and safety of the combination mometasone furoate 0.1%/salicylic acid 5% ointment with each of its components in psoriasis. J Derm Treat. 1998;9:151–156. 49 Koo J, Cuffie CA, Tanner DJ, et al. Mometasone furoate 0.1%-salicylic acid 5% ointment versus mometasone furoate 0.1% ointment in the treatment of moderateto-severe psoriasis: a multicenter study. Clin Ther. 1998;20:283–291.

Guidelines for the Topical Treatment of Psoriasis Vulgaris

MEDIA PARTNER

November/December 2015

Volume 13 • Issue 6

Original contribution

Trichotillomania: Demographic and Clinical Features From a Nationally Representative US Sample Madhulika A. Gupta, MD, FRCPC;1,2 Aditya K. Gupta, MD, PhD, FRCPC;3 Katie Knapp, MSc1,2 Abstract Trichotillomania (TTM) is a psychodermatologic disorder that is typically first seen in the dermatology clinic. There are no reported studies of TTM from nationally representative samples. The authors examined epidemiologic and clinical characteristics of an estimated 695,588±136,456 (unweighted count=89) patient visits with physician-diagnosed TTM (using International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 312.39) from a nationally representative US sample. An estimated 20.6%±7.4% visits for TTM were by patients 12 years and younger and demonstrated no sex difference (P=.52). Overall, TTM patients were younger (mean age: 24.01±3.09 years) (P<.001) and more likely to be female (80.3%±6.2%) (P=.003). These demographic findings are consistent with standard diagnostic criteria for TTM (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). There were no racial (white vs nonwhite) differences in TTM frequency. Psychiatric disorders were seen in 75.5%±9.1% of TTM patient visits, with depressive disorder being the most common comorbidity (37.8%±9.5%) and selective serotonin reuptake inhibitor antidepressants the most commonly (50.6%±9.7%) used medication. These findings highlight the importance of psychiatric comorbidity in TTM. (SKINmed. 2015;13:455–460)

richotillomania (TTM) is a psychodermatologic condition1 that is typically first encountered in a dermatology setting.2 TTM is characterized by recurrent pulling of one’s own hair resulting in hair loss.2 In addition to psychosocial and occupational impairment, TTM can be associated with significant medical morbidity, eg, secondary to the loss of eyebrows and eyelashes or gastrointestinal complications from trichobezoars.2 In the earlier psychiatric nosology (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IVTR]),3 TTM was grouped with disorders such as pyromania and kleptomania and classified as an “Impulse-Control Disorder Not Elsewhere Classified.”3,4 In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5),2 TTM has a more dermatology-focused classification under “ObsessiveCompulsive and Related Disorders” and is recognized as a bodyfocused repetitive behavior along with skin-picking disorder.5 There is a relative lack of epidemiologic studies of TTM from

nationally representative samples.6,7 Most studies have either examined: (1) the prevalence rates and characteristics of TTM in special groups, or (2) psychiatric comorbidity in samples of TTM patients.8–10 The smaller-scale studies of TTM in special groups involve university students11–23 or multiple patient groups with specific psychiatric disorders including obsessive-compulsive disorder (OCD),24 major depressive disorder,25 bipolar disorder,26 alcohol dependence,27 and eating disorders.28 Studies on patients presenting to dermatology clinics29,30 have found that among patients suspected of having a psychocutaneous problem, 12.4% were subsequently diagnosed with TTM,29 and 7% of children presenting to dermatologists’ offices with hair loss and scalp issues were diagnosed with TTM.30 We identified three epidemiologic studies of TTM.31–33 One community-based study of 218 participants31 from a city mar-

From the Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada;1 Psychmed Research, London, Ontario, Canada;2 and the Division of Dermatology, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario,3 Canada Address for Correspondence: Madhulika A. Gupta, MD, 585 Springbank Drive, Suite 101, London, Ontario, N6J 1H3 Canada • E-mail: magupta@uwo.ca

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ket and urban shopping center in the United States reported a 4% prevalence rate of TTM using an 11-item questionnaire that addressed noncosmetic hair-plucking; TTM cases were initially identified if an affirmative answer was provided to the question “Have you ever pulled or plucked your hair other than to improve your looks?”31 A second study of a community sample of 794 adolescents reported that 1% of their sample (eight participants: five male and three female) reported past or current hair-pulling and 0.5% (four participants) reported current hairpulling.32 This study32 of 17-year-old Israeli adolescents undergoing preinduction screening for universal military service obtained both participant self-ratings and clinician ratings of TTM using the following item: “Have you ever or do you now pull out hair from your, scalp, eyebrows, or elsewhere?” This same item was used in the clinical screening interview by a child psychiatrist who was blind to the participants’ responses on the written questionnaire. Another community-based study33 of 830 participants in a Southeastern college city in the United States reported a TTM prevalence rate of 0.6% with five of 830 participants meeting inclusion criteria for TTM. The TTM diagnosis was based primarily on participant-rated responses to the Florida Hair Pulling Scale-Revised.33 The literature indicates that the prevalence rates reported for TTM from the smaller-scale epidemiologic samples vary from 0.5% to 4%. In each of these studies,31–33 fewer than nine patients were diagnosed with TTM. Among studies that examined psychiatric comorbidities, one investigation33 reported that hair pullers scored higher than nonpullers on the Beck Anxiety Inventory and the Beck Depression Inventory-II. Another investigation32 reported that two hair pullers had OCD, two experienced generalized anxiety disorder, and two experienced attention deficit hyperactivity disorder. We examined demographic features and comorbidities of physician-diagnosed TTM using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9CM)34 criteria in a nationally representative sample of patient visits from the National Ambulatory Medical Care Survey (NAMCS)35 and National Hospital Ambulatory Medical Care Survey (NHAMCS).35 A recent study has independently demonstrated that the NAMCS provides a sample that is generalizable to dermatology outpatients.36 To our knowledge, this is the largest study of physician-diagnosed TTM from a nationally representative sample of patient visits in the United States. Methods Data collected from 1995–2010 by the NAMCS and NHAMCS were examined using a retrospective cross-sectional design.35 SKINmed. 2015;13:455–460

The University of Western Ontario Office of Research Ethics determined that ethics approval was not required for research involving publicly accessible data such as those provided by the NAMCS/NHAMCS. The databases studied35 have been described elsewhere.37 Variables studied Trichotillomania. Represented patient visits coded using ICD-9CM code 312.39 denoting “Disorders of Impulse Control, not elsewhere classified – Other – Trichotillomania.” Demographic factors. TTM has been reported in early childhood where it runs a self-limited course and a more chronic waxing and waning course postpuberty2; therefore, we examined the age group of 12 years and younger separately. Race was categorized as white, black, and other in the databases; the black and other categories were combined to denote a nonwhite category. Comorbidities. Associations of the TTM variable with all other ICD-9-CM diagnostic groups (representing ICD-9-CM codes 001 to 999.9) and all reasons for visit (RFV) were examined. Medications. We examined all major groups of medications coded in the NAMCS/NHAMCS using the Ambulatory Care Drug Database System38 that were used with TTM. Statistical Analysis The Complex Samples module of SPSS version 20.0 (IBM, Armonk, NY) was used in order to account for the multistage probability sampling design used by the NAMCS/NHAMCS. Two-sample t tests and chi-square tests were conducted to examine differences between continuous variables and categorical variables, respectively. According to the National Center for Health Statistics (NCHS) standards for reliability of estimates, estimates that were based on <30 unweighted cases were considered as not reliable.39 Results There were an estimated (±standard error [SE]) 695,588 (±136,456) (unweighted count=89) patient visits associated with TTM from an estimated (±SE) 17,110,750,400 (±680,573,007) (unweighted count=1,442,259) patient visits (age±SE: 42.95±0.19 years; 58.7%±0.2% female and 41.3%±0.2% male) from 1995–2010 to physicians’ offices (NAMCS) (unweighted TTM visits=28) and hospital outpatient departments (NHAMCS-OPD) (unweighted TTM visits=57) and emergency departments (NHAMCS-ED) (unweighted TTM visits=4) in the United States. In our nationally representative sample for all

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conditions, an estimated (frequency±SE) 0.0041%±0.0008% of all patient visits were associated with TTM. The demographics of the TTM patient visits are shown in Table I. Overall, TTM patients were younger (P<.001) and more likely to be female (P=.003) (Table I). An estimated 20.6%±7.4% patients who had TTM visits were 12 years and younger (unweighted count=19); the percentage of females (58.1%±17.4%) vs males (41.9%±17.4%) was not significantly (P=.52) different in the age group of patients 12 years and younger. Among comorbidities, an estimated 75.5%±9.1% (unweighted count=69) of TTM patient visits had another comorbid psychiatric disorder (coded using ICD-9-CM codes 290–319 or an RFV mental disorder-related complaint). An estimated 7.8%±7.2% of TTM patient visits (unweighted count=3) also had a comorbid dermatologic diagnosis (representing ICD-9-CM codes 680–709). Table II summarizes the major psychiatric disorders that were associated with TTM. Among medications,38 an estimated 53.9%±9.9% of all TTM patient visits were associated with the use of antidepressants38 (unweighted count=45) and 50.6%±9.7% of TTM visits were associated with selective serotonin reuptake inhibitor (SSRI) antidepressants38 (unweighted count=33). No other comorbidities or medications overall met the NCHS criteria39 for the reliability of estimates. Discussion We have examined demographic and clinical characteristics of an estimated 700,000 patient visits (unweighted count=89) for TTM from a nationally representative sample of an estimated 17 billion patient visits (unweighted count=1,442,259) in the United States for all disorders from 1995–2010. To our knowledge, this is the first epidemiologic study of physician-diagnosed

TTM using standard ICD-9-CM criteria and the largest sample of TTM patients studied from a nationally representative sample. Previous studies of TTM from smaller epidemiologic studies identified fewer than nine cases of TTM.31–33 The lower frequency of TTM visits (an estimated 0.0041%±0.0008%) in our sample vs the generally accepted 1% to 2% prevalence of TTM2,3 is likely a reflection of several factors, including: (1) the fact that definitions of TTM have varied across studies and none31–33 have used all the core diagnostic criteria,2,3 such as noticeable hair loss as a result of hair-pulling in their diagnostic criteria; (2) previous epidemiologic studies31–33 on the prevalence of TTM involve select patient populations, and to our knowledge there are no previously reported studies of TTM from randomly selected nationally representative samples of patient visits for all disorders; and (3) previous epidemiologic studies31–33 have used study samples that were younger in comparison to our sample (mean±SE age: 42.95±0.19 years), with a median age of 20 years in one study (nine in the teens, 10 in the 20s, and one in the 30s),31 a sample of 17-year-old patients,32 and participants aged 17 to 43 years,33 with a mean±SD age of 20.28±2.11 years in the various studies. This could have led to a bias towards reporting of higher prevalence rates, as TTM is more common among children and young adults.2,3 In our sample, patient visits with TTM were more likely to be female, a finding that is consistent with the standard diagnostic criteria for TTM.2 Our findings are consistent with previous findings from studies of nonclinical hair-pulling13,16–18,22 and also coincide with the only other epidemiological study conducted in a community sample that found cases of TTM meeting most of the standard diagnostic criteria;33 however, our results are in contrast to most studies in college samples that have looked at

Table I. Demographic Characteristics of Patient Visits Associated With TTM vs All Other Visits Demographic Factor

TTM-Associated Visits (Unweighted Count=89)

All Other Visits Excluding TTM (Unweighted Count=1,442,170)

Difference Between TTM vs All Other Visits (P Value)

Age (mean±SE), y

24.01±3.09

42.95±0.19

<.001

Frequency of patient visits in children 12 years and younger, %

20.6±7.4

16.0±0.2

.50

Female

80.3±6.2

58.7±0.2

.003

Male

19.7±6.2

41.3±0.2

Sex (±SE), %

Race (±SE), %

.81

White

85.2±7.6

83.3±0.5

Nonwhite

14.8±7.6

16.7±0.5

Abbreviations: SE, standard error; TTM, trichotillomania. SKINmed. 2015;13:455–460

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Table II. Psychiatric Comorbidities in Patient Visits With vs Without TTM for All Ages and for Children Aged 12 Years and Younger Psychiatric Disorder

Visits With TTM (All Ages)

Visits With TTM (Age ≤12 y)

Depressive disorder (ICD-9-CM codes 296.2, 296.3, 296.82, 296.20–296.36, 300.4, 311, or RFV)

Prevalence (%±SE) Odds ratioa Unweighted count

37.8%±9.5%b 17.95 (8.09–39.83) 31

10.8%±7.9% 22.86 (4.58–114.12) 2

Obsessive-compulsive disorders (ICD-9-CM code 300.3 or RFV)

Prevalence (%±SE) Odds ratioa Unweighted count

35.1%±10.4% 407.20 (164.40–1008.58) 17

14.6%±12.9% 171.11 (22.36–1309.76) 2

Anxiety states and phobic disorders (all ICD-9-CM codes beginning with 300.0 or 300.2 or RFV)

Prevalence (%±SE) Odds ratioa Unweighted count

21.0%±8.4% 12.06 (4.47–32.53) 16

12.0%±8.7% 36.86 (7.26–187.26) 2

Attention deficit disorder (all ICD-9-CM codes beginning with 314.0)

Prevalence (%±SE) Odds ratioa Unweighted count

15.4%±6.1% 22.86 (9.23–56.59) 10

42.4%±17.5% 29.75 (7.26–121.83) 7

Drug or alcohol dependence (all ICD-9-CM codes beginning with 303 or 304 or RFV)

Prevalence (%±SE) Odds ratioa Unweighted count

2.0%±1.4% 6.38 (1.51–26.91) 9

– – 0

Abbreviations: ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; RFV, reason for visit; SE, standard error. The odds ratio reflects trichotillomania (TTM) visits vs all other visits in the database (excluding TTM). b Only estimates with an unweighted count ≥30 meet the National Center for Health Statistics criteria for reliability of estimates.40 Estimates with unweighted counts of <30 should be considered provisional. a

TTM using standard diagnostic criteria.11,15,19 Studies that found a more equal sex preponderance in TTM involved random college samples not seeking health care or assistance for hairpulling.11,15 They suggested that increased prevalence of TTM in females, usually found in clinical samples, may be the result of the higher odds of females seeking mental health treatment15 and the reluctance of men to seek assistance for their health.11 In the subgroup of patients 12 years and younger with TTM in our study, there was no significant sex difference, which is consistent with previously reported findings.2 Patient visits with TTM were more likely to be younger (P<.001), with a mean age of 24.01±3.09 years (Table I). This value coincides with previous findings from community samples that have reported the median age of hair pullers to be 20 years31 and the mean age at onset of hair-pulling to be 15.92 years (SD=7.68).33 These findings are consistent with current diagnostic criteria for TTM.2,3 There was no difference in TTM frequency between white and nonwhite patients in our sample (Table I). Race as a demographic variable has not been addressed in the existing epidemiologic studies31–33 on TTM or in the standard diagnostic criteria.2,3 The majority of comorbidities associated with TTM and the only group fulfilling the NCHS criteria for the reliability of esSKINmed. 2015;13:455–460

timates39 were psychiatric disorders, with 75.5%±9.1% of TTM patient visits also having an additional psychiatric diagnosis. The most prevalent psychiatric disorder (an estimated 37.8%±9.5%) comorbid with TTM was depressive disorder, and this was the only disorder with ≥30 unweighted patient visits.39 OCD was the next most frequent diagnosis (an estimated 35.1%±10.4% patient visits) (unweighted count=17) (Table II). These findings are consistent with the current description of TTM in the DSM-5 where TTM is classified as an “Obsessive-Compulsive and Related Disorder,” with the most common mental disorder associated with TTM being major depressive disorder.2 Finally, the only group of medications that were significantly associated with TTM were the SSRI antidepressants. This is entirely consistent with the first-line psychopharmacologic therapies that are typically prescribed in TTM.40 Study Limitations There are several limitations to our study. Firstly, the basic sampling unit used in our analyses was the patient visit, and some patients may have been included more than once due to a repeat visit during the data collection period. Secondly, the design of the study is cross-sectional, thus the directionality of results is unclear. Finally, while this study does offer the largest number of

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diagnosed TTM cases from an epidemiologically representative sample, the unweighted number of cases is still low given the size of the database. In many of the analyses assessing psychiatric comorbidity (Table II), the unweighted number of patient visits was <30 and did not meet the criteria for reliability39; therefore, the results of such analyses had to be considered provisional. Conclusions Our findings from an epidemiologically representative sample underline the importance of psychiatric comorbidity in TTM. It is important for the dermatologist to have a high index of suspicion for comorbid psychiatric disorders in the TTM patient, as untreated psychiatric disorders especially starting during childhood, can have an adverse impact on the long-term psychosocial and vocational functioning of the patient. References

12 Hajcak G, Franklin ME, Simons RF, Keuthen NJ. Hairpulling and skin picking in relation to affective distress and obsessive-compulsive symptoms. J Psychopathol Behav. 2006;28:179–187. 13 Mansueto CS, Thomas AM, Brice AL. Hair pulling and its affective correlates in an African-American university sample. J Anxiety Disord. 2007;21:590–599. 14 Mazhari S. Association between problematic Internet use and impulse control disorders among Iranian university students. Cyberpsychol Behav Soc Netw. 2012;15:270– 273. 15 Odlaug BL, Grant JE. Impulse-control disorders in a college sample: results from the self-administered Minnesota Impulse Disorders Interview (MIDI). Prim Care Companion J Clin Psychiatry. 2010;12. 16 Siddiqui EU, Naeem SS, Naqvi H, Ahmed B. Prevalence of body-focused repetitive behaviors in three large medical colleges of Karachi: a cross-sectional study. BMC Res Notes. 2012;5:614.

1 Lee CS, Koo JYM. Psychocutaneous Diseases. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. Vol 1. 3rd ed. Amsterdam, Netherlands: Elsevier; 2012:127–134.

17 Stanley MA, Borden JW, Mouton SG, Breckenridge JK. Nonclinical hair-pulling: affective correlates and comparison with clinical samples. Behav Res Ther. 1995;33:179–186.

2 American Psychiatric Association. Diagnostic and Statical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.

18 Stanley MA, Borden JW, Bell GE, Wagner AL. Nonclinical hair pulling––phenomenology and related psychopathology. J Anxiety Disord. 1994;8:119–130.

3 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.

19 Sulkowski ML, Mariaskin A, Storch EA. Obsessive-compulsive spectrum disorder symptoms in college students. J Am Coll Health. 2011;59:342–348.

4 Gupta MA. Emotional regulation, dissociation, and the self-induced dermatoses: clinical features and implications for treatment with mood stabilizers. Clin Dermatol. 2013;31:110–117. 5 Gupta MA, Gupta AK. Current concepts in psychodermatology. Curr Psychiatry Rep. 2014;16:449. 6 Duke DC, Keeley ML, Geffken GR, Storch EA. Trichotillomania: a current review. Clin Psychol Rev. 2010;30:181– 193. 7 Wong JW, Nguyen TV, Koo JY. Primary psychiatric conditions: dermatitis artefacta, trichotillomania and neurotic excoriations. Indian J Dermatol. 2013;58:44–48. 8 Christenson GA, Mackenzie TB, Mitchell JE, Callies AL. A placebo-controlled, double-blind crossover study of fluoxetine in trichotillomania. Am J Psychiatry. 1991;148:1566–1571. 9 Odlaug BL, Grant JE. Trichotillomania and pathologic skin picking: clinical comparison with an examination of comorbidity. Ann Clin Psychiatry. 2008;20:57–63. 10 Walther MR, Snorrason I, Flessner CA, et al. The trichotillomania impact project in young children (TIP-YC): clinical characteristics, comorbidity, functional impairment and treatment utilization. Child Psychiatry Hum Dev. 2013;45:24–31. 11 Christenson GA, Pyle RL, Mitchell JE. Estimated lifetime prevalence of trichotillomania in college students. J Clin Psychiatry. 1991;52:415–417.

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20 Woods DW, Miltenberger RG, Flach AD. Habits, tics, and stuttering. Prevalence and relation to anxiety and somatic awareness. Behav Modif. 1996;20:216–225. 21 Bohne A. Impulse-control disorders in college students. Psychiatry Res. 2010;176:91–92. 22 Duke DC, Keeley ML, Ricketts EJ, Geffken GR, Storch EA. The phenomenology of hairpulling in college students. J Psychopathol Behav. 2010;32:281–292. 23 Rothbaum BO, Shaw L, Morris R, Ninan PT. Prevalence of trichotillomania in a college freshman population. J Clin Psychiatry. 1993;54:72–73. 24 Torresan RC, Ramos-Cerqueira AT, Shavitt RG, et al. Symptom dimensions, clinical course and comorbidity in men and women with obsessive-compulsive disorder. Psychiatry Res. 2013;209:186–195. 25 Lejoyeux M, Arbaretaz M, McLoughlin M, Ades J. Impulse control disorders and depression. J Nerv Ment Dis. 2002;190:310–314. 26 Karakus G, Tamam L. Impulse control disorder comorbidity among patients with bipolar I disorder. Compr Psychiatry. 2011;52:378–385. 27 Lejoyeux M, Feuché N, Loi S, Solomon J, Adès J. Study of impulse-control disorders among alcohol-dependent patients. J Clin Psychiatry. 1999;60:302–305. 28 Zucker N, Von Holle A, Thornton LM, et al. The significance of repetitive hair-pulling behaviors in eating disorders. J Clin Psychol. 2011;67:391–403.

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29 Ehsani AH, Toosi S, Mirshams Shahshahani M, Arbabi M, Noormohammadpour P. Psycho-cutaneous disorders: an epidemiologic study. J Eur Acad Dermatol Venereol. 2009;23:945–947. 30 Al-Refu K. Hair loss in children: common and uncommon causes; clinical and epidemiological study in Jordan. Int J Trichology. 2013;5:185–189.

36 Ahn CS, Allen MM, Davis SA, et al. The National Ambulatory Medical Care Survey: a resource for understanding the outpatient dermatology treatment. J Dermatolog Treat. 2014;25:453–458.

31 Graber J, Arndt WB. Trichotillomania. Compr Psychiatry. 1993;34:340–346.

37 Gupta MA, Gupta AK, Fink NH. Polypharmacy in dermatology: analysis of a nationally representative sample of 46,273 dermatology patient visits in the United States from 1995 to 2009. Skinmed. 2013;11:273–280.

32 King RA, Zohar AH, Ratzoni G, et al. An epidemiological study of trichotillomania in Israeli adolescents. J Am Acad Child Adolesc Psychiatry. 1995;34:1212–1215.

38 Centers for Disease Control and Prevention. The New Ambulatory Care Drug Database. http://www2.cdc.gov/ drugs/applicationnav1.asp. Accessed May 1, 2014.

33 Duke DC, Bodzin DK, Tavares P, Geffken GR, Storch EA. The phenomenology of hairpulling in a community sample. J Anxiety Disord. 2009;23:1118–1125.

39 Centers for Disease Control and Prevention. Ambulatory Health Care Data: Reliability of Estimates. http://www. cdc.gov/nchs/ahcd/ahcd_estimation_reliability.htm. Accessed May 1, 2014.

34 American Medical Association. International Classification of Diseases, Ninth Revision, Clinical Modification. Salt Lake City, UT: Ingenix, Inc; 2003. 35 Centers for Disease Control and Prevention. Ambulatory Health Care Data. http://www.cdc.gov/nchs/ahcd.htm. Accessed May 1, 2014.

40 McGuire JF, Ung D, Selles RR, et al. Treating trichotillomania: a meta-analysis of treatment effects and moderators for behavior therapy and serotonin reuptake inhibitors. J Psychiatr Res. 2014;58:76–83.

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 474)

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Volume 13 • Issue 6

Core curriculum Virendra N. Sehgal, MD, Section Editor

Oral Mucosal Lesions: Oral Lichen Planus and Lichenoid Tissue Reaction/Interface Dermatitis––Part II Virendra N. Sehgal, MD;1 Nazim Hussain Syed, MD (Iran);1 Ashok Aggarwal, MD;1 Shruti Sehgal, MDS2

In order to succinctly interpret the clinical undertones of oral lichen planus and lichenoid tissue reaction/interface dermatitis, the well-recognized oral mucosal lesions, it is mandatory to comprehend oral cavity biology in the right perspective, the clinical connotations of which have been highlighted in perspective to facilitate diagnosis. In addition, a focus is formed on systemic association. Additionally, the imperative of salient histopathology in the diagnosis is emphasized for instant reference. (SKINmed. 2015;13:461–466)

ral lichen planus (OLP), a relatively common disorder, is associated with lesions having a distinctive clinical morphology and a characteristic distribution. It may also present with a wide range of clinical forms and patterns that mimick other diseases. The mean age of onset of OLP is the fifth to sixth decade of life, with a female to male ratio of 2:1. Two thirds of lesions are symptomatic. Up to 20% of women display genital involvement. There is also an increased risk of malignant transformation.1 The reticular form of OLP is the predominant presentation, and symptoms are present in the majority of patients with the erosive form of the disease. Foods, dental procedures, systemic illness, and poor oral hygiene are found to be precipitating factors. South authors even implicate stress. Oral squamous cell carcinoma may develop at the site of erosive or erythematous forms of lichen planus.2 Lichen planus is a common, idiopathic skin disorder affecting approximately 2% of the adult population.3,4 The exact incidence of the disease is speculative, as it has many clinical forms and may involve one or more sites. Lichen planus may affect the skin alone, both the skin and the oral cavity simultaneously, one or more mucosal and nonmucosal sites, or may not have

skin or oral involvement.1 Over a third of patients who present with cutaneous lichen planus have oral lesions, with only 15% of patients with predominantly OLP developing cutaneous lesions.5 In most instances, cutaneous lichen planus typically develops within several months after the appearance of the oral lesions; moreover, the severity of the oral manifestations usually does not correlate with the extent of cutaneous involvement. The highlights of oral cavity biology were reviewed in part I.6 Causes of OLP Lichen planus may also involve the scalp, nails, esophagus, eyes, and genital mucosa. Patients often present with multiple sites of involvement, with more than 5% developing the disease in three or more sites simultaneously.5 The most commonly implicated drugs are nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors.7,8 A variety of drugs, topical and systemic, have been shown to induce lichenoid lesions/ lichenoid tissue reactions or interface dermatitis through antigenic mechanisms.9,10 Among them are allopurinol, furosemide, hydralazine, naproxen, penicillamine, quinidine, thiazides, chloroquine, gold, isoniazid, palladium, propranolol, spironolactone, tolbutamide, chlorpropamide, griseofulvin, mercury,

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India, Skin Institute, and School of Dermatology, Greater Kailash, New Delhi,1 and the Department of Conservative Dentistry and Endodontics, Government Dental College, Raipur, India2 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

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Dental Materials Known to Cause Oral Lichen Planus Dental Resins for Restorative Dentistry

Miscellaneous Dental Materials

Dental Gold and Gold Alloys

General

Calcium hydroxide

General

Acrylic resins

Root canal filling materials

Administrative control

Composite resins

Gutta-percha points

Fineness, carat, and weighing

Acid etch technique

Silver root canal points

Annealing and tempering

Pit and fissure sealants

Cavity lining varnish

Gold foil

Intermediate restorative material

Dental porcelain

Casting gold alloy

Polishing materials

Gold alloy solder Wrought gold Gold plate Nonprecious alloys

phenytoin, streptomycin, triprolidine, dapsone, hydroxychloroquine, methyldopa, penicillin, phenothiazine, and tetracycline. Dental amalgams and dental plaques can act as antigens to induce OLP;11 moreover, dental material comprising dental resins for restorative dentistry, miscellaneous dental material, and dental gold and gold alloys are implicated in OLP lesions (Table). Amalgam or its components are known to cause type IV hypersensitivity reactions on oral mucosa. A delayed hypersensitivity to mercury and bilateral oral lichenoid reaction to amalgam restorations are well-known. Histopathologic features are compatible with lichenoid mucositis. Results from patch testing may be positive with pulverized amalgam and tin. The lesions heal after replacement of restorations with an intermediate restorative material.12 Unlike skin lesions of lichen planus, OLP lesions are chronic, sometimes lasting for 20 years or more.13

terlacing white keratotic lines, Wickham striae. The buccal mucosa, mucobuccal fold, and gingiva (Figure 1) are frequent sites of presentation, while the tongue (Figure 2), palate, and lips are infrequently affected.18 There is a preponderance of this type in men compared with women.19

Erythematous pattern Half of the affected mucosa may show a diffuse background of mild to intense erythema, which may invariably extend beyond the white lines merging into the surrounding normal mucosa, representing epithelial atrophy. Occasionally, the lesions are primarily erythematous, with very few white streaks. Erythroplakia, erythroleukoplakia, and oral psoriasis need to be excluded. The lesions may also present with severe ulceration or blistering of the mucosa.

Clinical connotation

Erosive pattern

The plaque form of OLP is more often seen in smokers.14 OLP is common in children, but when it develops in this age group,d it is frequently erosive and painful. Children with OLP often have concomitant cutaneous disease,15,16 and those of Asian descent may be predisposed to the development of the disease.17 OLP can manifest in one of the three forms: (1) reticular, papular, plaque-type, and lacy; (2) erythematous atrophic; and (3) erosive, ulcerated, or bullous.1

The erosive pattern often presents as erythematous and ulcerative areas surrounded by keratotic striae (Figure 3). Gingival involvement with this form produces desquamative gingivitis.

Reticular pattern The reticular pattern of OLP is the most common variant, presenting either as papules and/or plaques. The lesions have inSKINmed. 2015;13:461â&#x20AC;&#x201C;466

Lichenoid tissue reaction/interface dermatitis Lichenoid tissue reaction/interface dermatitis is a well-established clinical and/or histopathological entity identified by lichnoid/papular lesions of certain skin diseases, of which lichen planus and its variants are the prototype.20 The term interface dermatitis is characterized by the presence of lymphohistiocytic infiltrate that abuts or obscures the dermoepidermal junction. Lupus erythematosus,21 fixed-drug eruptions,22 potentially life-

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Figure 2. Reticular pattern over the buccal mucosa and the tongue.

Figure 1. Reticular pattern over the buccal mucosa and the tongue.

threatening disorders such as graft-versus-host disease,23 StevenJohnson syndrome and toxic epidermal necrolysis,24 and paraneoplastic pemphigus25 are known to exhibit this pattern.9 The posterior buccal mucosa is the most frequent site of presentation (Figure 4), followed by the tongue, gingiva, labial mucosa, and vermilion of the lower lip. About 10% of OLP patients have the disease confined to the gingiva only, while the lesions on the palate, floor of the mouth, and upper lip are uncommon.

Figure 3. Erosive pattern over the labial mucosa.

Histopathologic Features Although histopathologic assessment of OLP is required, it is subjective and insufficiently reproducible.26 Superficial bandlike lymphohistiocytic infiltrates and vacuolar and/or basal cell liquefaction degeneration are diagnostic features in addition to focal hyperparakeatosis, irregular acanthosis, and an amorphous eosinophilic band at the basement membrane (Figure 5).27 Gingival lichen planus may be more difficult to diagnose, because the clinical appearance shares clinical features with the vesiculo-erosive diseases. Direct immunofluorescence of perilesional mucosa is an effective and accurate diagnostic technique that is especially useful in excluding other causes.28 Immunofluorescence reveals fibrin and shaggy fibrinogen in a linear pattern at the basement membrane zone. Cytoids in the absence of SKINmed. 2015;13:461â&#x20AC;&#x201C;466

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Figure 4. Lichenoid dermatitis following mercury amalgam. Oral Mucosal Lesions: Part II

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Core Curriculum seem to correlate with the severity of OLP.35 The association of OLP with both HCV infection and liver disease, however, may be dependent on geographic factors. Research studies on OLP patients in the United States, United Kingdom, France, and Germany failed to confirm an association between lichen planus and liver abnormalities.36 In a study consisting of 723 patients with OLP, none had detectable antibodies to HCV or abnormal liver function tests.2 OLP may be an early marker or manifestation of hepatitis in select populations; however, routine serologic screening in Western European and American OLP patients may not be warranted.1 The incidence of other systemic diseases, such as hypertension, arthritis, and diabetes, is lower than that compared with the incidence reported in the general population.1 The development of squamous cell carcinoma is a complication of OLP, with a reported frequency of 0.4% to more than 5% over a period of 0.5 to more than 20 years.37 The lack of reliable, well-defined, objective clinical criteria of epithelial dysplasia emphasizes the need to confirm by biopsy the diagnosis of patients with suspected OLP. Exceptions include patients with classic bilateral white reticulated lesions on the buccal mucosa and those with concomitant, easily recognizable skin lesions. Given the uncertainty of the premalignant nature of OLP, and the fact that early detection of oral cancer results in improved survival, it is prudent to carefully monitor patients with OLP for a long period;1 patients with OLP exhibit higher levels of anxiety, depression, and vulnerability to psychic disorders.38,39

Figure 5. Vacuolar and/or liquefactive degeneration of the basal cell layer (hematoxylin and eosin stain, original magnification Ă&#x2014;10).

deposition of fibrinogen are commonly detected through immunofluorescence.29 The value of direct immunofluorescence for confirmation of the disease is well accepted, especially with nondiagnostic histopathologic features, and for the desquamative gingival form of lichen planus. Systemic Associations Systemic associations of OLP with liver diseases, Wilsonâ&#x20AC;&#x2122;s disease, hemochromatosis, primary biliary cirrhosis, and a1-antitrypsin deficiency with lichen planus have been shown.31,32 Several controlled studies have demonstrated a strong association between chronic hepatitis disease and hepatitis C virus (HCV) infection with OLP.4,33 Reported prevalence rates of HCV infection in OLP patients range from 20% in Spain to as high as 62% in Japan.34 Elevated liver function tests have also been detected most often in patients with oral erosive disease, and 30

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The Koebner phenomenon, characteristic of cutaneous lichen planus, may also be observed in the oral cavity. Mechanical trauma from dental procedures, heat and irritation from tobacco products, friction from sharp cusps, rough dental restorations and poorly fitting dental prostheses, and oral habits such as lip and cheek chewing are exacerbating factors. The Koebner phenomenon may explain why erosive lesions develop most commonly in areas subjected to trauma.1 The association of oral cavity sarcoidosis and OLP is interesting, for it is recognized by the firm, asymptomatic, submucosal masses of the tongue and/or buccal mucosa. It is, therefore, important to palpate the tongue for any suspected irregularity of the oral cavity.40 Conclusions A total recall of clinical features of oral lichen planus, and lichenoid tissue reaction/interface dermatitis along with interpretive histopathology forms the mainstay for the future.

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References 1 Eisen D. The clinical manifestations and treatment of oral lichen planus. Dermatol Clin. 2003;21:79–89. 2 Eisen D. The clinical features, malignant potential and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol. 2002;46:207– 214. 3 Finne K, Goransson K, Winckler L. Oral lichen planus and contact allergy to mercury. Int J Oral Surg. 1982;11:236– 239. 4 Bagan JV, Ramon C, Gonzalez L, et al. Preliminary investigation of the association of oral lichen planus and hepatitis C. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85:532–536. 5 Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:431–436. 6 Sehgal VN, Syed NH, Aggarwal A, Sehgal S. Oral mucosal lesions: oral cavity biology––Part I. Skinmed. 2015;13:121–126. 7 Potts AJ, Hamburger J, Scully C. The medications of patients with oral lichen planus and the association of nonsteroidal anti-inflammatory drugs with erosive lesions. Oral Surg Oral Med Oral Pathol. 1987;64:541–543. 8 Robertson WD, Wray D. Ingestion of medication among patients with oral keratosis including lichen planus. Oral Surg Oral Med Oral Pathol. 1992;74:183–185. 9 Sehgal VN, Srivastava G, Sharma S, Sehgal S, Verma P. Lichenoid tissue reaction/interface dermatitis: Recognition, classification, etiology, and clinicopathological overtones. Indian J Dermatol Venereol Leprol. 2011;77:418–429; quiz 430. 10 Eversole LR. Disease of oral mucosa. In: Millard HD, Mason DK, eds. Perspectives on 1988 World Workshop on Oral Medicine: 1988. Chicago, IL: Year Book Medical Publishers; 1989:54–65. 11 Bolewska J, Hansen HJ, Holmstrup P, Pindborg JJ, Stangerup M. Oral mucosal lesions related to silver amalgam restorations. Oral Surg Oral Med Oral Pathol. 1990;70:55– 58.

18 Edwards PC, Kelsch R. Oral lichen planus: clinical presentation and management. J Can Dent Assoc. 2002;68:494–499. 19 Chainani-Wu N, Silverman S Jr, Lozada-Nur F, Mayer P, Watson JJ. Oral lichen planus: patient profile, disease progression and treatment responses. J Am Dent Assoc. 2001;132:901–909. 20 Sehgal VN, Aggarwal A, Syed NH, et al. Palmoplantar keratoderma an exquisite variant of lichen planus. Skinmed. In Press. 21 Jacobs MI, Schned ES, Bystryn JC. Variability of the lupus band test. Results in 18 patients with systemic lupus erythematosus. Arch Dermatol. 1983;119:883– 889. 22 Sehgal VN, Srivastava G. Fixed drug eruption (FDE): changing scenario of incriminating drugs. Int J Dermtol. 2006;45:897–908. 23 Saijo S, Honda M, Sasahara Y, Konno T, Tagami H. Columnar epidermal necrosis: a unique manifestation of transfusion-associated cutaneous graft-vs-host disease. Arch Dermatol. 2000;136:743–746. 24 Sehgal VN, Srivastava G. Toxic epidermal necrolysis (TEN) Lyell’s syndrome. J Dermatol Treat. 2005;16:278– 286. 25 Sehgal VN, Srivastava G. Paraneoplastic pemphigus/ paraneoplastic autoimmune multiorgan syndrome. Int J Dermatol. 2009;48:162–169. 26 Van der Meij EH, Reibel J, Slootweg PJ, et al. Interobserver and intraobserver variability in the histologic assessment of oral lichen planus. J Oral Pathol Med. 1999;28:274–277. 27 Scully C, Beyli M, Ferreiro MC, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med. 1998;9:86–122. 28 Firth NA, Rich AM, Radden BG, Reade PC. Assessment of the value of immunofluorescence microscopy in the diagnosis of oral mucosal lichen planus. J Oral Pathol Med. 1990;19:295–297. 29 Helander SD, Rogers RS 3rd. The sensitivity and the specificity of direct immunofluorescence testing in disorders of mucous membranes. J Am Acad Dermatol. 1994;30:65–75.

12 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.

30 Rebora A. Lichen planus and the liver. Int J Dermatol. 1992;31:392–395.

13 Miles DA, Howard MM. Diagnosis and management of oral lichen planus. Dermatol Clin. 1996;14:281–290.

31 Boyd AS, Neldner KH. Lichen planus. J Am Acad Dermatol. 1991;25:593–619.

14 Silverman S Jr, Gorsky M, Lozada-Nur F, Giannotti K. A prospective study of findings and management in 214 patients with oral lichen planus. Oral Surg Oral Med Oral Pathol. 1991;72:665–670.

32 Porter SR. Oral lichen planus and chronic liver disease. Oral Surg Oral Med Oral Pathol Radiol Endod. 1995;79:267–268.

15 Nanda A, Al-Ajmi HS, Al-Sabah H, Al-Hasawi F, Alsaleh QA. Childhood lichen planus: a report of 23 cases. Pediatr Dermatol. 2001;18:1–4. 16 Sharma R, Maheshwari V. Childhood lichen planus: a report of fifty cases. Pediatr Dermatol. 1999;16:345–348. 17 Alam F, Hamburger J. Oral mucosal lichen planus in children. Int J Paediatr Dent. 2001;11:209–214.

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33 Sánchez-Pérez J, De Castro M, Buezo GF, et al. Lichen planus and hepatitis C virus: prevalence and clinical presentation of patients with lichen planus and hepatitis C virus infection. Br J Dermatol. 1996;134:715–719. 34 Carrozzo M, Gandolfo S, Lodi G, et al. Oral lichen planus in patients infected or noninfected with hepatitis C virus: the role of autoimmunity. J Oral Pathol Med. 1999;28:16–19.

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Core Curriculum

35 Bagán JV, Aguirre JM, del Olmo JA, et al. Oral lichen planus and chronic liver disease: a clinical and morphometric study of the oral lesions in relation to transaminase elevation. Oral Surg Oral Med Oral Pathol. 1994;78:337– 342. 36 Scully C, Eisen D, Carrozzo M. Management of oral lichen planus. Am J Clin Dermatol. 2000;1:287–306. 37 van der Meij EH, Schepman KP, Smeele LE, et al. A review of the recent literature regarding malignant transformation of oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:307–310.

38 Allen CM, Beck FM, Rossie KM, Kaul TJ. Relation of stress and anxiety to oral lichen planus. Oral Surg Oral Med Oral Pathol. 1986;61:44–46. 39 Roja-Morena JL, Bagan JV, Rojo-Moreno J, et al. Psychologic factors and oral lichen planus. A psychometric evaluation of 100 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86:687–691. 40 Batal H, Chou LL, Cottral DA. Sarcoidosis: medical and dental implications. Oral Surg Oral Med Oral Pathol Oral Radiol Oral Endod. 1999;88:386–390.

Smallpox (Vaiolo umano florido all’apice dell’eruzione pustolosa): Courtesy of Museo delle Cere Anatomiche L. Cattaneo, University of Bologna, Italy. Photo by Cristian Mancini. Submitted by Diana Garrisi, London, UK.

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Volume 13 • Issue 6

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

A Wolf in Fox’s Clothing: Aggressive Skin Cancers Posing as Less Aggressive Cancers Ann M. John, BA;1 Vijay Vanchinathan, MD;1 Parmvir Singh, BS;1 Claude E. Gagna, PhD;2 W. Clark Lambert, MD, PhD1 “They come to you in sheep’s clothing, but inwardly they are ferocious wolves.”––Matthew 7:15b (New International Version)

orrect clinical diagnosis is paramount for determination of treatment, prognosis, and impact of patient quality of life. It is sometimes difficult to distinguish between different types of skin cancer, as several conditions have similar clinical and histologic findings.1 Because the aggressiveness of a cancer varies based on the etiology, it is essential that the correct diagnosis is made and that alternate, more dangerous entities requiring more aggressive treatment are excluded by the clinician. This problem has been reported with several other types of cancer, including synovial sarcoma, giant cell tumors of bone, thyroid carcinoma, endometrial carcinoma, musculoskeletal tumors, pancreatic neoplasms, and ophthalmologic cancers.1 In dermatology, there have been several reports of common mimics of melanoma and squamous cell carcinoma.2,3 Usually, diagnostic challenges arise from histopathologic nuances or taking small biopsies that only sample a small part of the lesion;1 therefore, confirmatory studies, including immunohistochemistry and polariscopic examination, should be performed to exclude differential diagnoses. In addition, clinical correlation with results of diagnostic studies, particularly special histochemical stains, immunohistochemical studies, or molecular hybridization studies of the sections, is important to avoid overlooking dangerous diagnoses. We present two cases of aggressive cancers posing as basal cell carcinomas: Merkel cell carcinoma (MCC) and eccrine porocarcinoma. Case 1 A 67-year-old woman developed a 2.2-cm lesion on her right buccal region (cheek) 2 centimeters infraorbitally. Excision re-

vealed a poorly circumscribed intradermal basophilophilic mass initially diagnosed elsewhere as a basal cell carcinoma, but subsequently diagnosed at this center as MCC (Figures 1 and 2), a diagnosis confirmed by immunopathologic markers. Following additional surgery to assure clear margins, she is alive and well 4 years later. Case 2 A 78-year-old man developed a nodule on his brow (forehead) that was excised and diagnosed by a routine histopathologist as basal cell carcinoma (Figure 3). A subsequent reading by one of us (WCL) led to a diagnosis of eccrine porocarcinoma, confirmed by immunohistochemistry, including a Ki67 immunohistochemical stain, which measures cell proliferation. Results from Ki67 staining revealed that most of the cells were proliferating (Figure 4). Following wider excision and excision of a cervical lymph node, which contained tumor, the patient is alive and well 3 years later. Discussion MCC requires early detection and diagnosis for the best prognosis. It is usually diagnosed using histopathological examination with hematoxylin and eosin staining. There have been previous reports of MCC histologically resembling lymphoma, acute myeloid leukemia, cutaneous lymphoid hyperplasia, squamous cell carcinoma, sweat gland carcinoma, undifferentiated carcinoma, small cell melanoma, metastatic neuroendocrine carcinoma, and basal cell carcinoma. One report of a misdiagnosis of MCC as basal cell carcinoma noted that the histopathology showed irreg-

From the Departments of Dermatopathology, Dermatology, and Pathology and Laboratory Medicine, Rutgers University – New Jersey Medical School, Newark, NJ;1 and the Department of Life Sciences, New York Institute of Technology, Old Westbury, NY2 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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Figure 1. Case 1: section showing “murky” basaloid cells characteristic of Merkel cell carcinoma. Note also fibrous trabeculae within the lesion characteristic of this tumor and necrosis (hematoxylin and eosin stain, original magnification ×387).

Figure 3. Case 2: section showing atypical cells replacing the epidermis, well demarcated at the edges from normal epidermis and showing lack of normal epidermal maturation, all characteristic of eccrine porocarcinoma (hematoxylin and eosin stain, original magnification ×387).

Figure 2. Case 1: section showing a more bluish area of “murky” basaloid cells characteristic of Merkel cell carcinoma (hematoxylin and eosin stain, original magnification ×387).

Figure 4. Case 2: a Ki67 immunostain showing that most of the tumor cells are proliferating (original magnification ×387).

ular lobules of basaloid cells, and immunohistochemistry results were negative for cytokeratin 20. Positive staining for synaptophysin and clinical-pathological correlation assisted dermatopathologists in making the diagnosis of MCC.4 Confirmatory immunohistochemistry with cytokeratin 20 is recommended to avoid misdiagnosis,5 but, as this case demonstrated, this is not foolproof. MCC is also positive for chromogranin A, synpatophysin, and neuron-specific enolase, and special staining to de-

tect these compounds should be considered in ambiguous cases. Histologic features found in MCC but not basal cell carcinoma include relatively sparse cytoplasm, nuclear molding, necrosis, and absence of peripheral palisading and clefting, but these differences may be subtle or even absent.4,5

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Eccrine porocarcinoma is a rare adnexal malignancy with an ambiguous presentation. As an aggressive cancer with fre-

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quent metastasis, eccrine porocarcinoma requires early diagnosis and prompt treatment.6 Clinical presentation can include ulcers, plaques, nodules, and papules. Because eccrine porocarcinoma is usually confused clinically with squamous cell carcinoma, biopsy is necessary for diagnosis. Immunohistochemistry can confuse pathologists, since staining for BerEP4, which is mostly specific for basal cell carcinoma, is occasionally positive in eccrine porocarcinoma.7 In such cases, clinical-pathological correlation is essential to determine the correct diagnosis.

Conclusions The only reliable solution is for clinicians and pathologists to recognize important histologic mimics of benign or less aggressive cancers. In addition, other methods of minimizing misdiagnoses include being aware of various differential diagnoses; performing multiple studies, especially immunohistochemistry; and seeking another opinion in challenging cases. References

Other cutaneous neoplasms can also pose as less malignant tumors. For example, sebaceous carcinoma is a rare tumor that often presents in periocular or extraocular sites. It has a high rate of recurrence and tendency to spread locally or to distant areas and therefore should be ruled out with any eyelid lesion.8 Since basal cell carcinomas often occur in similar locations, it is essential to differentiate sebaceous carcinoma from basal cell carcinoma. In addition, sebaceous carcinoma may mimic a benign tumor or even an inflammatory lesion, thus causing a delay in diagnosis and treatment. Diagnosis consists of histopathological examination and staining, where possible, with Oil Red O and Sudan IV stains. These stains, however, require careful special fixation to optimize results. In addition, a panel of antibodies may be used to differentiate sebaceous carcinoma from basal cell and other carcinomas. Sebaceous carcinoma is positive for cytokeratin 5 and cytokeratin 14; epithelial membrane antigen, a glycoprotein found in normal epithelia; and NR3C4, a nuclear receptor. It is usually negative for Ber-EP4, which is positive in basal cell carcinoma. In addition, the p53 and ki67 indices are usually higher in sebaceous carcinoma than in basal cell carcinoma.8

1 Samsudin EZ, Kamarul T, Mansor A. Avoiding diagnostic pitfalls in mimics of neoplasia: the importance of a comprehensive diagnostic approach. Singapore Med J. 2015;56:e92–e95. 2 Bhawan J. Non-melanocytic mimics of melanocytic neoplasms. Histopathology. 2012;60:715–730. 3 Tan KB, Tan SH, Aw DC, et al. Simulators of squamous cell carcinoma of the skin: diagnostic challenges on small biopsies and clinicopathological correlation. J Skin Cancer. 2013;2013:752–864. 4 Ball NJ, Tanhuanco-Kho G. Merkel cell carcinoma frequently shows histologic features of basal cell carcinoma: a study of 30 cases. J Cutan Pathol. 2007;34:612–629. 5 Succaria F, Radfar A, Bhawan J. Merkel cell carcinoma (primary neuroendocrine carcinoma of skin) mimicking basal cell carcinoma with review of different histopathologic features. Am J Dermatopathol. 2014;36:160–166. 6 Riera-Leal L, Guevara-Gutierrez E, Barrientos-Garcia JG, et al. Eccrine porocarcinoma: epidemiologic and histopathologic characteristics. Int J Dermatol. 2015;54:580–586. 7 Afshar M, Deroide F, Robson A. BerEP4 is widely expressed in tumors of the sweat apparatus: a source of potential diagnostic error. J Cutan Pathol. 2013;40:259–264. 8 Mulay K, White VA, Shah SJ, Honavar SG. Sebaceous carcinoma: clinicopathologic features and diagnostic role of immunohistochemistry (including androgen receptor). Can J Ophthalmol. 2014;49:326–332.

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Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2015;13:467–469

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Edward L. Keyes Resident Contest for Outstanding Case Reports 11th World Congress of the International Academy of Cosmetic Dermatology June 23–25, 2016 Panama City, Panama Abstract deadline: April 15, 2016 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 11th World Congress of the International Academy of Cosmetic Dermatology in Panama City, Panama, June 23–25, 2016. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, or cosmetic (or combined) in nature. The author, whose abstract receives the highest score during the review process, will be awarded a scholarship by the IACD to present the full paper at the 11th World Congress of the International Academy of Cosmetic Dermatology in Panama City, Panama, June 23–25, 2016. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend. Abstracts should be submitted via email to vrosic@medicine.bsd.uchicago.edu before noon, CDT, April 15, 2016, and should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thought-out, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been or is in consideration for publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31st, 2016. 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 1st, 2016. Vesna Petronic-Rosic, MD, MSc Chair, Resident Contest Committee Associate Professor The University of Chicago Pritzker School of Medicine, Section of Dermatology Tel: +1.773.702.6559 vrosic@medicine.bsd.uchicago.edu

November/December 2015

Volume 13 • Issue 6

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

OPDIVO (Nivolumab) Aditya K. Gupta, MD, PhD, FRCPC;1,2 Melissa A. MacLeod, MSc;2 William Abramovits, MD3

PDIVO (nivolumab) is a registered trademark of Bristol-Meyers Squibb, New York, NY. Nivolumab is a fully human IgG4 programmed death receptor-1 (PD1)–blocking antibody that disrupts PD-1–mediated signaling to restore tumor immunity.1,2 Blocking this pathway prevents the tumor from inhibiting T-cell activation and proliferation and allows the tumor to be recognized by the immune system.1 Approved in December 2014 by the US Food and Drug Administration, nivolumab is indicated for use in unresectable or metastatic melanoma.2 Although melanoma represents less than 5% of skin cancers, it accounts for about 80% of skin cancer deaths, with survival for metastatic melanoma ranging from 6 to 10 months.3 Despite the availability of treatment options such as ipilimumab, dacarbazine, and BRAF inhibitors, there remains an unmet need for treatment that can prolong survival.4 Four phase II/III randomized clinical trials assessing the efficacy of nivolumab in treating melanoma have shown nivolumab to demonstrate greater efficacy than comparator treatments (Table I).4–7 Nivolumab offers an alternative to existing first-line therapies for metastatic melanoma. In all studies, nivolumab doses were given by intravenous (IV) infusion over 60 minutes. Phase II Clinical Trials A phase II double-blind trial examined tumor response with nivolumab-ipilimumab combination therapy (n=94) vs ipilimumab monotherapy (n=47) among patients with untreated, unresectable metastatic melanoma.6 Combination therapy included 1 mg/kg of nivolumab given every 3 weeks with 3 mg/ kg of ipilimumab by IV infusion over 90 minutes for four doses. This schedule was followed by 3 mg/kg of nivolumab every 2 weeks as long as clinical benefit was observed or until unacceptable side effects occurred. The same dosing schedule was used for patients receiving monotherapy, with nivolumab replaced by a

matched placebo. Among patients with BRAF wild-type tumors, 61% (95% confidence interval [CI], 49–72) had an objective tumor response with combination therapy compared with 11% (95% CI, 3–25) with ipilimumab monotherapy (P<.001). The median progression-free survival was not reached with combination therapy and was 4.4 months (95% CI, 2.8–5.7) with ipilimumab monotherapy (P<.001). Among patients with BRAF mutation–positive tumors, 52% (95% CI, 31–73) had an objective response with combination therapy compared with 10% (95% CI, 0–45) with ipilimumab monotherapy. The median progression-free survival was 8.5 months (95% CI, 2.8–not estimable) with combination therapy compared with 2.7 months (95% CI, 1.0–5.4) with ipilimumab therapy. Phase III Clinical Trials A phase III, multicenter, double-blind trial examined overall survival with nivolumab compared with dacarbazine among patients with untreated metastatic melanoma without a BRAF mutation.4 The first drug arm was assigned to receive 3 mg/kg of nivolumab every 2 weeks with a dacarbazine-matched placebo every 3 weeks (n=210). The second arm was assigned to receive 1000 mg/m2 IV infusion dacarbazine every 3 weeks with a nivolumab-matched placebo every 2 weeks (n=208). Nivolumab was statistically superior to dacarbazine in terms of survival at 1 year, median progression-free survival, and objective tumor response. The 1-year survival rate with nivolumab was 72.9% (95% CI, 65.5–78.9) compared with 42.1% (95% CI, 33.0– 50.9; P<.001) with dacarbazine. Median progression-free survival was 5.1 months (95% CI, 3.5–10.8) with nivolumab vs 2.2 months (95% CI, 2.1–2.4; P<.001) with dacarbazine and the objective tumor response rate was 40.0% (95% CI, 33.3–47.0) with nivolumab compared with 13.9% (95% CI, 9.5–19.4; P<.001) with dacarbazine.

From the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center, Dallas, TX;3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School, Dallas, TX;4 and the Dermatology Treatment and Research Center, Dallas, TX5 Address for Correspondence: Aditya K. Gupta, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Objective Tumor Response and Median Progression-Free Survival for Nivolumab Phase II/III Melanoma Clinical Trials Objective Tumor Response, % (95% CI)

Median Progression-Free Survival, mo (95% CI)

40.0 (33.3–47.0)

5.1 (3.5–10.8)

13.9 (9.5–19.4)

2.2 (2.1–2.4)

Nivolumab

43.7 (38.1–49.3)

6.9 (4.3–9.5)

Nivolumab-ipilimumab

57.6 (52.0–63.2)

11.5 (8.9–16.7)

Ipilimumab

19.0 (14.9–23.8)

2.9 (2.8–3.4)

Nivolumab

31.1 (23.1–40.2)

4.7 (2.3–6.5)

ICC

8.3 (2.8–18.4)

4.2 (2.1–6.3)

Nivolumab-ipilimumab

61 (49–72)

Not reached

Ipilimumab

11 (3–25)

4.4 (2.8–5.7)

Clinical Trial CheckMate 0664 Nivolumab Dacarbazine CheckMate 067

CheckMate 0377

CheckMate 0696a

Abbreviations: CI, confidence interval; ICC, investigator’s choice of chemotherapy. Percentages were not reported with decimal places by the authors.6

Another double-blind, multicenter trial compared nivolumab monotherapy and nivolumab-ipilimumab combination therapy with ipilimumab monotherapy for unresectable or metastatic melanoma with no prior systemic treatment.5 A total of 945 patients were randomly assigned (1:1:1) to the three treatment arms. Patients were assigned to receive 3 mg/ kg IV nivolumab every 2 weeks with an ipilimumab-matched placebo (n=316), 3 mg/kg IV ipilimumab every 3 weeks for four doses with a nivolumab-matched placebo (n=315), or a combination of nivolumab and ipilimumab (n=314), 1 mg/ kg nivolumab every 3 weeks plus 3 mg/kg ipilimumab every 3 weeks for 4 doses, followed by 3 mg/kg nivolumab every 2 weeks. Median progression-free survival time was longer for both the combination therapy (11.5 months; 95% CI, 8.9– 16.7) and the nivolumab monotherapy (6.9 months; 95% CI, 4.3–9.5) groups compared with the ipilimumab monotherapy group (2.9 months; 95% CI, 2.8–3.4; P<.001 for both). In patients with PD-L1–positive tumors, combination therapy and nivolumab monotherapy had similar median progressionfree survival (about 14.0 months); however, for patients with PD-L1–negative tumors, combination therapy appeared to SKINmed. 2015;13:471–474

have longer median progression-free survival than nivolumab monotherapy (11.2 months vs 5.3 months, respectively). The objective tumor response rate was 57.6% (95% CI, 52.0–63.2) for combination therapy, 43.7% (95% CI, 38.1–49.3) for nivolumab monotherapy, and 19.0% (95% CI, 14.9–23.8) for ipilimumab monotherapy. No statistical tests were conducted for these comparisons. A multicenter, open-label trial examined tumor response and survival with nivolumab compared with the investigator’s choice of chemotherapy (ICC) among patients with melanoma that had progressed after ipilimumab or ipilimumab and BRAF inhibitor therapy.7 A total of 405 patients were randomized (2:1) to receive either 3 mg/kg nivolumab every 2 weeks (n=272) or ICC (either dacarbazine or paclitaxel; n=133). Although this study was open-label, tumor assessments were masked. No difference was found in median progression-free survival between nivolumab (4.7 months; 95% CI, 2.3–6.5) and ICC (4.2 months; 95% CI, 2.1–6.3); however, the objective tumor response was numerically higher with nivolumab (31.1%; 95% CI, 23.1–40.2) compared with ICC (8.3%; 95% CI, 2.8–18.4).

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Table II. Pooled Adverse Events (Any Grade) From Phase II/III Melanoma Clinical Trials for Nivolumaba Adverse Event

Nivolumab (N=787), No. (%)

Ipilimumab (N=357), No. (%)

Nivolumab Plus Ipilimumab (N=407), No. (%)

Chemotherapyb (N=307), No. (%)

Any treatment-related adverse event

591 (75.1)

268 (75.1)

385 (94.6)

236 (76.9)

Fatigue

215 (27.3)

107 (30.0)

147 (36.1)

65 (21.2)

Pruritus

137 (17.4)

123 (34.5)

137 (33.7)

13 (4.2)

Diarrhea

123 (15.6)

120 (33.6)

180 (44.2)

47 (15.3)

Dermatitis

112 (14.2)

114 (31.9)

165 (40.5)

6 (2.0)

Nausea

100 (12.7)

61 (17.1)

102 (25.1)

123 (40.1)

Decreased appetite

48 (6.1)

43 (12.0)

70 (17.2)

16 (5.2)

Vomiting

42 (5.3)

28 (7.8)

61 (15.0)

63 (20.5)

Arthralgia

38 (4.8)

23 (6.4)

43 (10.6)

12 (3.9)

Constipation

28 (3.6)

4 (1.1)

10 (2.5)

25 (8.1)

Hypothyroidism

27 (3.4)

20 (5.6)

62 (15.2)

Headache

23 (2.9)

29 (8.1)

45 (11.1)

Vitiligo

22 (2.8)

4 (1.1)

10 (2.5)

1 (0.003)

Asthenia

21 (2.8)

5 (1.4)

8 (2.0)

25 (8.1)

Pyrexia

18 (2.3)

28 (7.8)

77 (18.9)

Dyspnea

14 (1.8)

18 (5.0)

41 (10.1)

14 (3.2)

Anemia

12 (1.5)

23 (4.6)

Increased ALT level

12 (1.5)

14 (3.9)

76 (18.7)

Increased AST level

12 (1.5)

13 (3.6)

68 (16.7)

Colitis

4 (0.1)

42 (11.8)

59 (14.5)

Alopecia

1 (0.001)

28 (9.1)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 3 mg/kg intravenously over 60 minutes every 2 weeks.4â&#x20AC;&#x201C;7 b Chemotherapy includes pooled adverse events for dacarbazine and paclitaxel drug arms. N includes the patients who received treatment. a

Safety Nivolumab appears to be well-tolerated and safe for use in patients with metastatic melanoma. Pooled across the four phase II/III clinical trials, the proportion of patients who experienced any adverse treatment-related event was 75.1% with nivolumab, 75.1% with ipilimumab, 94.6% with nivolumab-ipilimumab, and 76.9% with chemotherapy (Table II). The most common adverse events among patients receiving nivolumab were fatigue (27.3%), pruritus (17.4%), diarrhea (15.6%), dermatitis (14.2%), and nausea (12.7%). The majority of treatment discontinuations were the result of disease progression; however, 3% to 8% of patients withdrew because of adverse events (diarrhea, colitis).4,5,7 There was one death in the nivolumab treatment SKINmed. 2015;13:471â&#x20AC;&#x201C;474

group attributed to neutropenia.5 Patients should be monitored for abnormal liver test results, elevated serum creatinine, and thyroid dysfunction prior to and periodically during treatment.2 Conclusions Across clinical trials, nivolumab appears to be superior to ipilimumab monotherapy and chemotherapy in regards to objective tumor response and median progression-free survival. Among melanoma patients with PD-L1â&#x20AC;&#x201C;negative tumors, median progression-free survival was found to be longer when nivolumab was combined with ipilimumab compared with nivolumab alone.5 With primarily minor adverse events, nivolumab seems to be a promising first- or second-line treatment for unresect-

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New Therapy Update

able or metastatic melanoma. The recommended dose is 3 mg/ kg as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.2 Nivolumab is also indicated for use with squamous non-small cell lung cancer that has progressed during or after chemotherapy.2 However, this new therapy update focused on clinical trials using nivolumab for metastatic melanoma only. Ongoing clinical trials are examining the use of nivolumab with other types of cancer, such as leukemia, renal cell carcinoma, pancreatic, and breast cancer. In the future, we may see nivolumab indicated for several different forms of cancer. References 1 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–135.

2 OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 3 Deeks ED. Nivolumab: a review of its use in patients with malignant melanoma. Drugs. 2014;74:1233–1239. 4 Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–330. 5 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. 6 Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–2017. 7 Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–384.

Historical Diagnosis and treatment: epithelioma

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November/December 2015

Volume 13 • Issue 6

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

Should Moderately Atypical Dysplastic Nevi Be Re-excised? Follow the Yellow Brick Road! Warren R. Heymann, MD

linically atypical nevi (also known as dysplastic nevi, nevi with architectural disorder, Clark nevi, B-K moles) are common lesions that are assessed on a daily basis by practicing dermatologists. With increasing patient awareness and concern for melanoma, clinically atypical nevi that are worrisome to the dermatologist or patient are biopsied to rule out the possibility of a melanoma. Optimally, these lesions may be completely excised by the biopsy procedure itself; frequently, however, the histologic report will be that of a moderately dysplastic nevus extending to the margins of the specimen. Is it in the patient’s best interest to have these lesions re-excised? Dysplastic nevi (DN) are a risk factor for melanoma. Although approximately 20% of melanomas may arise from a dysplastic nevus, their role as “precursors” is small, because an individual dysplastic nevus itself rarely progresses to melanoma. Overall, the presence of DN confers a 10-fold increased risk for melanoma. Patients with DN and familial melanomas, independent of CDKN2A mutations, are at greater risk for development of melanoma.1 Clinical decisions are not made in a vacuum. Patient preference (which may be based on real or imagined fear), economic factors (fee for service reimbursement), and defensive medicine (to avoid a malpractice claim of missing a melanoma) often results in re-excising moderately DN. We have all seen patients who have had dozens of re-excisions of such nevi, leaving innumerable scars––both physical and emotional. Every dermatologist has to choose whether or not to perform this procedure. What is the best guide for the clinician? Follow the yellow brick road! On her way to Oz, Dorothy Gale in The Wonderful Wizard of Oz encountered the scarecrow who desired a brain, the tin man who

longed for a heart, and the lion who craved courage. Dermatologists displaying all three attributes can manage their DN patients optimally. Brain Ever since the original description of DN in 1978, controversy has enveloped the concept as to how to manage these lesions. Recently, there have been several studies allowing clinicians to make rational decisions. A study of 115 histologically confirmed DN (66 mildly dysplastic, 42 moderately dysplastic, and 7 severely dysplastic), either incompletely excised or with no greater than a 0.2 mm margin, were followed for a mean of 17.4 years. No patient developed melanoma at the site of an incompletely or narrowly removed DN.2 A report of 580 biopsied DN lesions demonstrated 196 with positive margins, with 127 of the 196 excised. Of these, two (1.6%) resulted in a clinically significant change in diagnosis, from moderate to severe DN to melanoma in situ.3 In a study of 393 histologically proven DN (from 380 patients), 134 (34%) were excised because of the presence of moderate to severe atypia, a history of melanoma, or both. None of the excised lesions showed evidence of melanoma; only 14% of excised lesions were found to have residual lesions, with 4.4% showing residual nevi.4 Another report evaluated 1809 mildly and moderately atypical DN. Of these, 765 (42.3%) involved the margins and 495 of the 765 (64.7%) were re-excised. Melanocytic residuum was present in 90 (18.2%), with the remaining 405 (81.8%) being scars. Of the re-excised lesions, one patient had the diagnosis changed to a severely dysplastic nevus (0.2%). These data confirm that there is only the remotest possibility of either mild or moderately atypical nevi that have been biopsied becoming melanoma. Indeed, the most recent consensus confer-

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

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ence addressing the management of clinically atypical nevi state that: “based on the current data and our collective experience, we agree that mildly DN with positive histologic margins following biopsy, without evidence of clinical residual pigmentation, may be safely observed rather than reexcised. Observation may be a reasonable option for management of moderate DN with positive histologic margins without clinical residual pigmentation; however, more data are needed to make a definitive recommendation.”6 Heart I understand the emotions associated with being diagnosed with melanoma, having been diagnosed myself 4 years ago. Patients are worried about their prognosis, especially if they have a family member who has succumbed to the disease. It is our responsibility to treat these patients with compassion and explain that having clinically atypical nevi may place them at an increased risk for melanoma, but a risk is not a guarantee that they will develop melanoma. By careful monitoring, by both patient and physician, we should be able to keep the risk minimal. Fewer biopsies and a greater understanding of their disorder would better serve patients.

Conclusions Even without high-tech scans, we should be able to assess melanoma risk with family history and physical examination, routine follow-up using dermatoscopy, medical photography for those with clinically significant atypical nevi, and biopsy of changing or suspicious nevi. A shave excisional biopsy with a small margin should suffice in most cases. Where there is significant severe histologic atypia (architectural and/or cytologic) and the lesion extends to the margin, re-excision should be performed. This should be in concert with encouraging sun avoidance and selfexamination (with the help of a significant other, if possible). I can only imagine what the healthcare costs are for re-excision of lesions that are unnecessary, let alone the cost to the patient (financial and emotional). If we do not institute a rational approach to these patients, I have every confidence that Centers for Medicare & Medicaid Services and other insurers will. References

Courage Dermatopathologists need to have the courage not to recommend re-excision of moderately atypical nevi that extend to the margin of the specimen. That comment concerning re-excision puts the clinician in a precarious position of having to perform another procedure that realistically only protects the dermatopathologist from potential litigation for the small possibility that a melanoma might develop at that site. Re-excisions foster undue anxiety for the patient, produce scars, and increase their economic burden (and that of the healthcare system). Dermatopathologists should recommend re-excisions of severely atypical nevi that extend to the margin due to documented interpreter variability in categorizing lesions as severely atypical nevi vs melanoma in situ. It will also take courage to trust noninvasive novel molecular techniques, such as mRNA molecular signatures that differentiate nevi from melanoma, thereby decreasing the number of unnecessary biopsies.7

1 Goldstein AM, Tucker MA. Dysplastic nevi and melanoma. Cancer Epidemiol Biomarkers Prev. 2013;22:528– 532. 2 Hocker TL, Alikhan A, Comfere NI, Peters MS. Favorable long-term outcomes in patients with histologically dysplastic nevi that approach a specimen border. J Am Acad Dermatol. 2013;68:545–551. 3 Reddy KK, Farber MJ, Bhawan J, et al. Atypical (dysplastic) nevi: outcomes of surgical excision and association with melanoma. JAMA Dermatol. 2013;149:928–934. 4 Abello-Poblete MV, Correa-Selm LM, Giambrone D, et al. Histologic outcomes of moderate and severe dysplastic nevi. Dermatol Surg. 2014;40:40–45. 5 Strazzula L, Vedak P, Hoang MP, et al. The utility of re-excising moderately dysplastic nevi: A retrospective analysis. J Am Acad Dermatol. 2014;71:1071–1076. 6 Kim CC, Swetter SM, Curiel-Lewandrowski C, et al. Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: Pigmented Lesion Subcommittee consensus statment. JAMA Dermatol. 2015;151:212–218. 7 Gerami P, Alsobrook JP 2nd, Palmer TJ, Robin HS. Development of a novel noninvasive adhesive patch test for the evaluation of pigmented lesions of the skin. J Am Acad Dermatol. 2014;71:237–244.

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Volume 13 • Issue 6

PHOTO CAPSULE

Eruptive Syringomas in Pigmented Skin Ajit Janagond, MD;1 Muthu Sendhil Kumaran, MD;1 Tarun Narang, MD;1 Uma Nahar Saikia, MD2

23-year-old woman presented with a 10-year history of multiple, asymptomatic, papular lesions over the body that appeared in successive crops. Clinical examination revealed numerous dark brown to skin-colored, flat, soft, discrete papules (Figures 1 and 2) in a nonfollicular distribution. Histopathologic study showed multiple tubular ducts lined by two rows of epithelial cells and filled with homogenous, eosinophilic amorphous material in the dermis. A few ducts showed comma-like epithelial cells, giving a tadpole-like appearance (Figure 3). All findings were consistent with syringoma. The patient was treated with electrofulguration.

Figure 2. Multiple discrete skin-colored to brown-colored soft papules over fingers.

Syringomas are benign tumors of eccrine glands, characterized by multiple firm, yellow-brown papules commonly located around the lower lids and less commonly seen over other areas.1 Syringomas have been classified into a localized form; a familial form, associated with Down syndrome; and a generalized form that comprises multiple and eruptive syringomas.2 Eruptive syringomas are rare and often misdiagnosed as plane warts, milia, lichen planus, acne, or xanthomas in dark-skinned patients, and histopathology is essential for making the diagnsosis.

Figure 3. H&E 40×, dermis showing tubular ducts lined by 2 rows of epithelium and giving a tadpole appearance.

References 1 Kumaran MS, Kanwar AJ. Multiple syringomas of the forehead and scalp: an unusual presentation. Indian J Dermatol. 2005;50:171–172.

Figure 1. Multiple discrete brown-colored soft fleshy papules over the abdomen.

2 Friedman SJ, Butler DF. Syringoma presenting as milia. J Am Acad Dermatol. 1987;16:310–314.

From the Department of Dermatology, Venereology and Leprology,1 and Department of Pathology,2 Postgraduate Institute of Medical Education and Research, Chandigarh, India Address for Correspondence: Muthu Sendhil Kumaran, MD, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India • E-mail: drsen_2000@yahoo.com

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November/December 2015

Volume 13 • Issue 6

INFECTIOUS DISEASE CAPSULE Jack M. Bernstein, MD, Section Editor

Here Chickie, Chickie: Chikungunya Has Arrived Katelyn Booher, DO;1,2 Maryann Bernstein, BS; Jack M. Bernstein, MD1,2

62-year-old Caucasian woman was scuba diving in rural Indonesia in March 2013. She transited Bali and Seoul, Korea, on the way home to Ohio. In Seoul, she noted a mosquito bite, which she assumed she acquired while eating at an ocean-side restaurant in Bali. Approximately 96 hours after leaving Bali she developed a fever of 103°F associated with a debilitating headache and severe muscle aches. She assumed that she had developed influenza because it was prevalent in her community at that time. Oseltamivir was initiated but had no effect. Seventy-two hours later, a diffuse maculopapular eruption appeared (Figure 1 and Figure 2). In addition to the dermatitis, she developed severe joint pain in her knees, ankles, and hands with associated joint swelling. The eruption and fever slowly abated by the seventh day, although the joint pain persisted for almost 6 months. A year later, in another hemisphere, a 50-year-old man of African descent residing in Dominica, an island in the eastern Caribbean, reported the acute onset of diffuse body aches most prominent in the knees and chest. Symptoms began the morning of May 3, 2014, and peaked by noon that day. The patient recorded an oral temperature of 106°F by 1 PM. He described his knees first, then elbows, feeling like they were being “ripped apart from inside.” The second day into his illness, severe joint pains continued and the patient noticed an eruption on his right arm at 6:30 AM. By 11 AM the dermatitis had spread to his elbow and resembled raised individual welts. The patient then attempted self-treatment with an Indian homeopathic remedy consisting of an extract of papaya leaves, which seemed to ameliorate his joint pains. By the third day, joint pains persisted, although they had improved. One month later, significant edema remained in the proximal and distal interphalangeal joints of the index and middle finger of the patient’s left hand.

Epidemiology These patients’ clinical manifestations and courses were consistent with those experienced by patients during outbreaks of Chikungunya, a viral disease that has recently appeared and spread throughout the Caribbean. Global awareness and prevention of this disease are imperative, given the ongoing but early invasion into the Americas.1,2 CHIKV is an RNA virus in the Alphavirus genus of the Togaviridae family.1 The name chikungunya translates to “that which bends up” or “to be contorted.”1 The virus was initially identified in Africa during an outbreak in Tanzania in the early 1950s and had since been confined to Africa and Asia until recently.2 Since December 2013, CHIKV has affected more than 580,000 people in the Caribbean.2 As of December 2, 2014, the Centers for Disease Control and Prevention has reported 11 laboratory-confirmed infections with CHIKV acquired via local transmission in Florida.3,4 Multiple factors fueled this global epidemic, including increasing travel, expanding geographic distribution of CHIKV mosquito vectors, and adaptation of the endemic strain to Aedes albopictus.5 The current outbreak is caused by the Asian genotype of CHIKV and favors the Aedes aegypti mosquito species.1 CHIKV can be divided into three genetic lineages: West African, East/Central/South African (ECSA), and Asian.6 The West African genotype was responsible for outbreaks in Nigeria, the Ivory Coast, and Senegal more than 30 years ago. The ECSA genotype virus was implicated in the 2005–2006 epidemic involving more than 1 million cases in Kenya, adjacent southeastern African islands, and India.6 Aedes aegypti and Aedes albopictus are the responsible vectors for CHIKV transmission; however, the latter species is a less efficient vector for the Asian genotype. Both species of Aedes are distributed widely in the United States,1 and the role of Aedes albopictus in viral transmission in more temperate areas remains to be seen.7

From the Department of Internal Medicine, Wright State University, Dayton, OH;1 and the Department of Veterans Affairs Medical Center, Dayton, OH2 Address for Correspondence: Katelyn Booher, DO, 825 Gainsborough Road, Dayton, OH 45419 E-mail: katebooher@gmail.com

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The primary amplifying hosts for CHIKV are humans, and during the first week of illness there is adequate viremia to transmit CHIKV to mosquitoes.6 If infected, there is a high likelihood of developing disease, reportedly between 72% to 97%.6 Clinical Presentation Following an incubation period of approximately 3 to 7 days, persons infected with CHIKV experience sudden onset of high fever, along with headache, back pain, myalgia, and polyarthralgias.1 Arthralgia is often symmetrical, severe in some cases, and targets phalanges, ankles, and wrists, although large joints can be affected. Our patients’ cases demonstrate classic features of CHIKV infection, including temperature of 106°F and multijoint involvement, which was severe. Dermatitis is commonly reported and is thought to affect about 50% of those infected, although reports are variable.8 The eruption typically evolves after the onset of fever, is most commonly maculopapular, and involves the trunk and extremities, consistent with our patients’ presentations. The eruption can affect the palms, soles, and face and can have unusual presentations, such as vesiculobullous lesions with desquamation, aphthous-like ulcers, or vasculitic lesions.8 Acute symptoms of chikungunya often subside within 7 to 10 days, although some patients develop prolonged symptoms lasting several weeks to months.7,8 Persistent sequelae can include fatigue, incapacitating joint pain, and tenosynovitis or edematous polyarthritis of the digits. Long-term follow-up studies have demonstrated that up to 64% of patients with CHIKV infection report joint stiffness and/or pain >1 year following initial infection. Three to five years later, 12% still reported symptoms.8 This prolonged polyarthritis is consistent with our cases, as well. Severe and atypical disease is unusual but more likely to occur in adults older than 65 years, neonates exposed intrapartum, and patients with comorbid conditions such as diabetes or cardiovascular disease.1,7 Death caused by CHIKV infection is rare and estimated to affect <1% of infected persons, primarily elderly adults.7

Figure 1. Maculopapular eruptions involving both legs..

Diagnosis Although no testing was completed or confirmatory in our patients’ cases, the diagnosis is usually based on clinical presentation and epidemiologic factors with diagnostic testing, confirming the association of the virus with an ongoing clinical outbreak. Real-time polymerase chain reaction during the acute infection phase (days 1–8), IgM, or acute and convalescent IgG from the sera can confirm CHIKV infection.1 Based on exposure history, testing for other entities such as dengue and malaria should be considered, as there is significant overlap in clinical presentation.7 SKINmed. 2015;13:479–481

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Figure 2. Maculopapular eruptions involving the left part of the upper extremity. Here Chickie, Chickie: Chikungunya Has Arrived

November/December 2015

INFECTIOUS DISEASE CAPSULE

Treatment

Acknowledgment

Treatment of CHIKV infection remains supportive, as no antiviral medications are licensed to treat chikungunya. Anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs or acetaminophen, have been recommended for symptomatic relief.1,2 Our latter patient and his cohort have reported benefits of the Indian bush remedy of papaya. Leaf extracts from Carica papaya are commonly prescribed for dengue fever.9 Studies are limited regarding papaya as a treatment option for CHIKV infection, but there have been reports of the use of papaya for infection with the dengue virus.9 Anti-dengue activities of Carica papaya compounds have been noted, where the flavonoid quercetin from Carica papaya inhibited the NS2B-NS3 protease, preventing viral assembly of dengue.9 Preventive measures including insect repellents, mosquito nets, and environmental mosquito control remain imperative in regions with CHIKV transmission. Efforts to develop a chikungunya vaccine remain ongoing.1

Arun Madisetti contributed his personal experience with the Caribbean outbreak of the Chikungunya virus. References

Conclusions The ensuing reign of chikungunya into the Americas has potential for severe implications. Clinicians should be aware of the active penetration of this virus into the Americas, including the continental United States. With an immunologically naive human population in its grip, two potential broadly distributed insect vectors, and regular human transcontinental travel, CHIKV has the potential for an ongoing epidemic with a high rate of outbreak.1

1 Hamer DH, Chen LH. Chikungunya: establishing a new home in the Western hemisphere. Ann Intern Med. 2014;161:827–828. 2 Stamm LV. Chikungunya: emerging threat to the United States. JAMA Dermatol. 2015;151:257–258. 3 Centers for Disease Control and Prevention. Chikungunya virus in the United States. http://www.cdc.gov/chikungunya/geo/united-states.html. Accessed December 10, 2014. 4 Kendrick K, Stanek D, Blackmore C. Notes from the field: Transmission of chikungunya virus in the continental United States––Florida, 2014. MMWR Morb Mortal Wkly Rep. 2014;63:1137. 5 Rougeron V, Sam IC, Caron M, et al. Chikungunya, a paradigm of neglected tropical disease that emerged to be a new health global risk. J Clin Virol. 2015;64:144–152. 6 Lanciotti RS, Valadere AM. Transcontinental movement of Asian genotype chikungunya virus. Emerg Infect Dis. 2014; 20:1400–1402. 7 Staples JE, Fischer M. Chikungunya virus in the Americas––what a vectorborne pathogen can do. N Engl J Med. 2014; 371:887–889. 8 Staples JE, Breiman RF, Powers AM. Chikungunya fever: an epidemiological review of a re-emerging infectious disease. Clin Infect Dis. 2009;49:942–948. 9 Senthilvel P, Lavanya P, Kumar KM. Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly. Bioinformation. 2013;9:889–895.

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Volume 13 • Issue 6

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

Posttraumatic Onychoheterotopia: A Report of Two Cases Reena Sharma, MD; Prashant Verma, MD; Archana Singal, MD, MNAMS; Pravesh Yadav, MD Case 1: A 35-year-old otherwise healthy man presented to us with ectopic nail growth over the palmar aspect of the middle finger of the right hand for the past 9 to 10 months. His history was conspicuous for trauma to the right hand in which his index finger was amputated along with avulsion of the nail plate and laceration of the middle finger. Two months later, the nail grew back normally, together with an asymptomatic, ectopic nail on the palmar aspect of the same finger 1 cm proximal to the fingertip (Figure 1). The ectopic nail lacked the luster of a normal nail and was oriented vertically. The patient had to clip it regularly like the other nails. X-ray findings of the hand were normal. The quality of life of the patient was assessed using the Dermatology Life Quality Index (DLQI), with a score of 0. The patient refused surgical excision of the ectopic nail because it was asymptomatic. (SKINmed. 2015;13:483–484)

ase 2: 14-year-old boy presented with ectopic nail growth over the dorsal aspect of the middle finger of the left hand for the past 9 months. He attributed the injury he had sustained, when his finger was caught in a door jam.One to two months after the trauma, he noticed an asymptomatic, ectopic nail growth over the left middle finger. Examination revealed the ectopic nail just parallel to the normal nail, proximal to the proximal nail fold on the dorsal aspect of the middle finger of the left hand. X-ray findings of the hand were unremarkable. DLQI score of the patient was 0. The parents of the patient refused surgical excision. Discussion Ectopic nail, or onychoheterotopia, is rare.1 It is classified as congenital (genetic predisposition) or acquired.2 Most of the earlier reported cases are congenital;2 herein, we report two cases of acquired posttraumatic onychoheterotopia. The pathogenesis of ectopic nail is a matter of debate. Posttraumatic onychoheterotopia may occur following an acute injury (single overwhelming injury) or a chronic, repetitive injury.2 It has been postulated that germinal matrix implanted into the site of injury gives rise to an ectopic nail, which occurs inevitably over the distal phalanx.1,2 Palmar, as well as the dorsal aspects of the digits, may be afflicted, as illustrated in the present report.3–6 Onychoheteroto-

Figure 1. Vertically oriented ectopic nail on the palmar aspect of the terminal phalanx of the right middle finger.

From the Department of Dermatology & STD, University College of Medical Sciences & Guru Teg Bahadur Hospital, University of Delhi, Delhi-110095, India Address for Correspondence: Reena Sharma, MD, C-304, Shri Sai Baba Apartment, Sector-9, Rohini, Delhi, 110085 India • E-mail: reenalhmc@yahoo.co.in

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CASE STUDY pia may appear different from normal nails due to the abnormal direction of their matrices and, hence, the angle of nail growth.2 Horizontal, vertical, and circumferential patterns of growth have been described.2 Vertical growth of the ectopic nail in case 1 may be explained by the lack of proximal nail fold at this site,2 while horizontal growth in case 2 could be the result of resistance by the proximal nail fold.2 A meticulous search on PubMed/Medline revealed five reports of posttraumatic ectopic nail (Table). Surgical resection of the ectopic nail, including the entire nail matrix, has been recommended to remove it completely.2 In the present report, both patients refused surgery. Conclusions Acquired onychoheterotopia should be considered in the differential diagnosis of ectopic nail presentations. Assessment of the quality of life of these patients can be useful in the management of these cases.

Figure 2. Horizontally oriented ectopic nail, proximal to the proximal nail fold on the dorsal aspect of the middle finger of the left hand.

Table. Characteristics of Reported Posttraumatic Onychoheterotopia Authors

Year

Age, y/Sex

Site

Palmar/ Dorsal Surface

Direction of Growth

X-Ray Findings

Mahdi and Beardsmore1

1997

5/boy

Left ring finger

Dorsoulnar

Horizontal

Normal

Sasmaz et al5

2004

32/man

Middle phalanx of the right middle finger

Dorsal

Vertical

Small fissure at the tip of the distal phalanx

Abood and Grobbelaar6

2005

60/woman

Middle phalanx of the right middle finger

Palmar

Horizontal (60% from plane of skin)

Normal

Goikoetxea et al4

2006

8/boy

Distal interphalangeal joint of the right little finger

Dorsal

Not mentioned

Normal

Rajashekar et al3

2006

19/man

Distal phalanx of the left thumb

Dorsal

Horizontal

–

Sharma et al (present report)

2015

50/man

Distal phalanx of the right middle finger

Palmar

Vertical

Normal

Sharma et al (present report)

2015

14/boy

Distal phalanx of the left middle finger

Dorsal

Horizontal

Normal

References 1 Mahdi S, Beardsmore J. Post-traumatic double fingernail deformity. J Hand Surg Br. 1997;22:752–753.

4 Goikoetxea X, Etxebarria I, Careaga M. Posttraumatic ectopic nail: case report. J Hand Surg Am. 2006;31:819– 821.

2 Riaz F, Rashid RM, Khachemoune A. Onychoheterotopia: pathogenesis, presentation, and management of ectopic nail. J Am Acad Dermatol. 2011;64:161–166.

5 Sasmaz S, Coban YK, Gumusalan Y, Boran C. Posttraumatic ectopic nail. J Am Acad Dermatol. 2004;50:323– 324.

3 Rajashekar M, Bhandary S, Henoy M, Sali AR. Post traumatic ectopic nail. J Postgrad Med. 2006;52:218.

6 Abood A, Grobbelaar AO. Ectopic nail formation in the hand. J Hand Surg Br. 2005;30:488–489.

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November/December 2015

Volume 13 • Issue 6

correspondence Snejina Vassileva, MD, PhD, Section Editor

Curative Electrochemotherapy in Lentigo Maligna Melanoma Alessandro Gatti, MD;¹ Giuseppe Stinco, MD;² Nicola di Meo, MD;¹ Serena Bergamo, MD;² Giusto Trevisan, MD¹ To the Editor: The term electrochemotherapy (ECT) describes a local treatment in which electroporation is used in order to potentiate the cytotoxicity of a usually poorly permeating chemotherapeutic drug, such as bleomicin or cisplatin, by increasing tumor cell permeability with the application of electric pulses.1 In clinical practice, ECT is used mainly as a palliative treatment for melanoma, including cutaneous metastasis. It is also used to treat head and neck tumors, as well as primary basal cell carcinoma, Kaposi sarcoma, breast tumors, and metastatic cancers including hypernephroma and chondrosarcoma.2,3 Clinical Findings We present the case of an 84-year-old woman who came to our outpatient clinic for the appearance of a bleeding nodule on her right cheek, arising on a preexisting brown-black pigmented macule present for almost 3 years, which she reported to be in slow but constant growth (Figure 1a). The whole lesion was approximately 5×3 cm in its major axes, and it occupied a huge portion of her right cheek. The appearance of the nodular, easily bleeding mass triggered her to consult us. The clinical impression was a lentigo maligna melanoma with satellite metastases. Both the patient and her relatives declined any form of surgical therapy, and they also refused even a small incisional biopsy in order to obtain a histologic diagnosis for staging. As a result, we proposed ECT as an alternative to traditional surgery, and the patient accepted this option. She also had diabetes mellitus, hypertension, and vascular encephalopathy. The patient was eli-

gible for ECT because she did not have pulmonary fibrosis, coagulation disorders, an allergic reaction to bleomycin, epilepsy, peripheral neuropathy, chronic renal failure, or an arrhythmia, nor did she have a pacemaker. Treatment We decided to treat both the primary lesion and the satellite metastasis simultaneously with ECT, with 1 cm of perilesional clinically healthy skin, using a bolus of bleomycin and a pulse generator under general anesthesia. Bleomycin was injected intravenously at a dose of 22,500 UI (15 mg/m2 body surface area) 8 minutes before electric pulses delivery, with a hexagonal array of electrodes of 20 mm (Cliniporator, type III electrodes) (as specified by the manufacturer, IGEA, Carpi, Italy). The duration of the treatment was less than 20 minutes. The patient was monitored for 1 day after the treatment in our inpatient clinic, with intravenous paracetamol 1 g every 6 hours as postsurgical analgesia. Side effects included only local edema with a transudate, occurring within a few days after the ECT session. At 6 months, there remained a scar and three areas of blue regressive pigmentation (Figure b). At 12 and 18 months, the pigmented portion was reduced to two salt and pepper pattern areas (Figure c and d). No metastatic disease was seen on positron emission tomography/computed tomographic scan at 24-month follow-up. In treating melanoma, wide surgical excision remains the therapy of choice. Recently, ECT has been proposed as a new treatment modality for widespread cutaneous and subcutaneous metastases

From the Dermatology Department, University of Trieste, Italy;¹ and the Department of Experimental and Clinical Medicine, Institute of Dermatology, University of Udine, Italy2 Address for Correspondence: Nicola di Meo, MD, University of Trieste, Dermatology Department,Ospedale Maggiore di Trieste, Clinica Dermatologica, Universita’ Degli Studi di Trieste, IV piano Palazzina Infettivi, Piazza Ospedale 1, 34100, Trieste, Italia • E-mail: nickdimeo@libero.it

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Figure. The clinical presentation of the primary lesion (a). Follow-up after 6 (b), 18 (c), and 24 (d) months.

of advanced melanoma.4 The cases of primary melanoma treated with ECT are surely less frequent and anecdotal, because surgical therapy is known to be the gold standard. In our case, ECT had to be considered as an alternative to surgery, which could grant the smallest impact on a noncompliant patient. In particular, we had to manage the patient’s and her relatives’ absolute refusal of both destructive and incisional surgery. Other nonsurgical options in treatment melanoma metastases SKINmed. 2015;13:486–494

are chemotherapy or chemoimmunotherapy, isolated limb perfusion/isolated limb infusion, and radiotherapy.5 In the context of the low compliance of our patient, we chose to perform ECT with curative proposal because of the few reported side effects of the procedure, the ease of application, the repeatability, the absence of hematologic toxicity caused by bleomycin, and the possible efficacy independent of the histologic type of the tumor. ECT allowed the simultaneous treatment of the satellite metastasis and the control of apparently healthy margins.

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The efficacy of ECT has also been described in the treatment of previously irradiated masses and in areas operated on with classical surgery.6

References 1 Jarm T, Cemazar M, Miklavcic D, Sersa G. Antivascular effects of electrochemotherapy: implications in treatment of bleeding metastases. Expert Rev Anticancer Ther. 2010;10:729–746

Conclusions

2 Sersa G, Miklavcic D, Cemazar M, et al. Electrochemotherapy in treatment of tumours. Eur J Surg Oncol. 2008;34:232–240.

In our case, although it is a single patient experience, the interesting aspect of using ECT was the very good clinical local control of the disease. Our patient overcame, with no particular side effects, the postsurgical period and at follow-up showed the efficacy of this approach within 18 months. No metastatic spread had been detected during this interval. Unfortunately, this report is limited by the lack of histologic analysis for diagnosis, prognosis, and healing confirmation: all of our data are completely based on clinical evaluation. The apparent good outcome achieved in this patient suggests that, in very select cases, ECT may be considered as an alternative treatment in primary melanoma.

3 Reinhold U. Electrochemotherapy for primary skin cancer and skin metastasis related to other malignancies. Anticancer Drugs. 2011;22:711–718. 4 Kubota Y, Tomita Y, Tsukigi M, et al. A case of perineal malignant melanoma successfully treated with electochemotherapy. Melanoma Res. 2005;15:133–134. 5 Quaglino P, Mortera C, Osella-Abate S, et al. Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases. Ann Surg Oncol. 2008;15:2215–2222. 6 Escoffre JM, Rols MP. Electrochemotherapy: progress and prospects. Curr Pharm Des. 2012;18:3406–3415.

Efficacy of a Single Daily Dose of Levofloxacin in Gram-Negative Folliculitis Complicating Acne Vulgaris Kabir Sardana, MD;1 Tanvi Gupta, MBBS, MD;1 Bipul Kumar, MSc;2 Hemant K. Gautam, PhD2

To the Editor: Gram-negative folliculitis (GNF) is an underdiagnosed disorder and is one of the causes of recalcitrant acne vulgaris, which also includes hormonal causes and antimicrobial resistance.1,2 A study of recalcitrant acne found that of 65% of nonresponders, 16% had GNF.2 Although isotretinoin is often the drug of choice in GNF, it is slow-acting, and an antimicrobial may be needed. For this reason, bacterial culture and sensitivity may be indicated.3–5 Case Report A 29-year-old man with significant acne for 7 years presented with multiple and recurrent pustules of 1 month’s duration, which proved to be nonresponsive to a 6-week course of isotreti-

noin (1 mg/kg/d) (Figure 1). Previous treatment included multiple courses of tetracycline, azithromycin, and topical agents such as clindamycin, benzoyl peroxide, and adapalene. The lack of response to isotretinoin raised the possibility of resistant Propionbacterium acnes, and the lesions were sampled to confirm resistance.3 The pustules were cultured in brain-heart infusion medium at 37°C for 3 to 4 days using gas-pak for P acnes and Mueller-Hinton agar aerobically at 37°C for 48 hours. Escherichia coli ATCC*25922 was used as the quality control. Results from Gram staining revealed gram-negative rods, and 16S RNA polymerase chain reaction was used to confirm the organism as Klebsiella pneumoniae (http://www.ncbi.nlm.nih.gov/nuccore/ KJ741255).

From Maulana Azad Medical College and Lok Nayak Hospital,1 and the Institute of Genomics and Integrative Biology, Sukhdev Vihar,2 New Delhi, India Address for Correspondence: Kabir Sardana, MD, 466, Sector 28, NOIDA, UP, India 201303 • E-mail: kabirijdvl@gmail.com

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Figure 2. A patient with multiple pustules admixed with erythematous papules and acne scars. The patient was taking isotretinoin (1 mg/kg/d) and applying topical benzoyl peroxide.

Figure 2. After 14 days of levofloxacin 750 mg, complete resolution of lesions with residual erythema and acne scars was seen in the patient.

The standardized disk diffusion method was performed,3 and the minimum inhibitory concentration (MIC) values showed that the organism was resistant to ampicillin, trimethoprimsulfamethoxazole, and tetracycline. The MIC to levofloxacin was 0.56 (0.25–1 µg/mL) and was considered sensitive.3 On this basis, the patient was given levofloxacin 750 mg at night for 14 days, which resulted in complete resolution of the lesions (Figure 2). The patient was asked to continue topical benzoyl peroxide 2.5%/adapalene 0.1% and oral isotretinoin (0.5 mg/kg/d) and to apply intranasal neomycin ointment. He had a similar relapse after 1 month, which again promptly responded to levofloxacin. Discussion Unresponsiveness to antimicrobials in acne patients is one of the reasons to suspect antibiotic resistance,2 although our case was SKINmed. 2015;13:486–494

clinically suggestive of GNF. While the choice of therapy may be isotretinoin,4 this regimen may take up to 3 to 6 months to work,5 possibly because GNF is an infection, unlike acne vulgaris, where isotretinoin is consistently effective. The mode of action of isotretinoin is by reduction of moist skin conditions, which encourage the growth of gram-negative organisms,4,5 but isotretinoin does not directly inhibit the growth of gram-negative organisms.6 In addition, isotretinoin decreases sebaceous gland size and seborrhea as early as 2 weeks,7 which does not explain the long time required for the amelioration of GNF.4,5 Of the 62% of patients with recurrences after isotretinoin therapy, 57% had gram-negative bacteria in the lesions.8 Even after 43 months of isotretinoin, 9 of the 13 patients still had recurrences.8 GNF ideally responds to an appropriate antimicrobial,8 which depends on in vitro antibiotic sensitivity.3,9

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Table. Antibiotic Sensitivity Results of the Index Case Antimicrobial Agent

Minimum Inhibitory Concentration/Interpretive Criteria, µg/mL3

Results

Sensitive

Intermediate

Resistant

Ampicillin

≤8

≥32

Intermediate resistant

Doxycycline

≤4

≥16

Resistant

Ciprofloxacin

≤1

≥4

Sensitive

Levofloxacin

≤0.12

0.25–1

≥2

Sensitive

Trimethoprim-sulfamethoxazole

≤2/38

–

≥4/76

Resistant

Of all the enterobacteriacae, E coli, Klebsiella species, and Proteus species cause the majority of the cases of GNF.10 While trimethoprim, cotrimoxazole, and ampicillin have been used in the treatment of GNF,10 the present MIC values2 (Table) do not favor their use. All strains of Klebsiella express a chromosomally encoded β-lactamase that confers resistance to ampicillin, while Proteus vulgaris, Enterobacter, and Serratia frequently harbor plasmids.11 For these organisms, quinolones are an ideal drug class.11 Levoﬂoxacin is two-fold more potent than other quinolones, is as active as ciproﬂoxacin, and its convenient dosages (once a day) make it the ideal quinolone for enterobacteriaceae infections.11 Conclusions Many patients have ordinary acne vulgaris in addition to GNF. Once the folliculitis has responded, the residual acne should be treated by other means.10 In GNF, an initial targeted antimicrobial for a short duration makes microbiologic sense,10 compared with giving only isotretinoin, which has no in vitro activity against gram-negative organisms.8 Our case demonstrates that levofloxacin with its convenient dosages can be a useful therapy for GNF. The rapid response with levofloxacin (Figure 2) suggests its use as a “bridge therapy” in GNF for unresponsive cases.9 References 1 Eady EA, Cove JH, Blake J, et al. Recalcitrant acne vulgaris. Clinical, biochemical and microbiological investigation of patients not responding to antibiotic treatment. Br J Dermatol. 1988;118:415–423.

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2 Sardana K, Gupta T, Garg VK, et al. Antibiotic resistance to Propionibacterium acnes: worldwide scenario, diagnosis and management. Expert Rev Anti Infect Ther. 2015;13:883–896. 3 Patel JB, Cockerill III FR, Alder J, et al. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fourth Informational Supplement (M100-S24). Clinical and Laboratory Standards Institute antimicrobial susceptibility testing. 2014;34:1–230. 4 James WD, Leyden JJ. Treatment of gram-negative folliculitis with isotretinoin: positive clinical and microbiologic response. J Am Acad Dermatol. 1985;12:319–324. 5 Böni, Nehrhoff B. Treatment of gram-negative folliculitis in patients with acne. Am J Clin Dermatol. 2003;4:273– 276. 6 Simjee S, Sahm DF, Soltani K, Morello JA. Organisms associated with gram-negative folliculitis: in vitro growth in the presence of isotretinoin. Arch Dermatol Res. 1986;278:314–316. 7 Hughes BR, Cunliffe WJ. A prospective study of the effect of isotretinoin on the follicular reservoir and sustainable sebum excretion rate in patients with acne. Arch Dermatol. 1994;130:315–318. 8 Neubert U, Plewig G, Ruhfus A. Treatment of gramnegative folliculitis with isotretinoin. Arch Dermatol Res. 1986;278:307–313. 9 Poli F, Prost C, Revuz J. Gram-negative bacteria folliculitis. Ann Dermatol Venereol. 1988;115:797–800. 10 Leyden JJ, Marples RR, Mills Jr OH, et al. Gram-negative folliculitis––a complication of antibiotic therapy in acne vulgaris. Br J Dermatol. 1973;88:533–538. 11 Hauser AL, Enterobacteriaceae. In: Hauser AL, ed. The ABCs of Choosing the Right Antibacterial Agent. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:121– 139.

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Unusual Presentation of Acanthosis Nigricans Associated With Metabolic Syndrome Namrata Chhabra, MD;1 Neel Prabha, MD;1 Nighat Hussain, MD;2 Sandeep Kulkarni, DNB, MNAMS1 To the Editor: Acanthosis nigricans (AN) is the most common dermatologic manifestation of obesity.1 Common locations in order of frequency include the axillae, posterolateral aspect of the neck, external genitalia, groin, face, inner aspect of the thighs, antecubital fossae, popliteal fossae, umbilicus, and the perianal area. In addition, the mucosal surfaces of the oral cavity, esophagus, pharynx, larynx, conjunctiva, and anogenital region may also be involved.2 Case Report A 52-year-old man presented with thick, velvety, hyperpigmented lesions over the periorbital area (Figure 1), pinnae (Figure 2), nuchae (Figure 3), axillae, and groin. The lesions appeared 2 years previously and had gradually progressed and darkened since then. In addition, multiple acrochordons were present over these plaques. The patient was hypertensive but well controlled on medication. There was no history of diabetes or any other chronic illness. Family history for similar lesions was negative. The patient had a body mass index of 31 and abdominal obesity, with a waist-to-hip ratio of 1.0. There were no symptoms or signs suggestive of malignancy. Laboratory evaluations, including complete blood cell count and urinalysis, showed normal findings. Results from blood chemistry revealed elevated fasting blood sugar (113 mg/dL; normal range, 70–105 mg/dL), raised serum creatinine (1.40 mg/dL; normal range, 0.90–1.30 mg/dL), low high-density lipoprotein cholesterol (30 mg/dL, normal range, 35–60 mg/dL), and raised serum insulin (66.92 mU/L, normal range 3–25 mU/L). Results from a biopsy specimen from a pinna revealed papillomatosis, hyperkeratosis, and focal parakeratosis. Based on clinical and laboratory evaluation, a diagnosis of AN with metabolic syndrome was made. The patient was advised to maintain diet control and to exercise for weight reduction. Topical retinoids were prescribed for AN with some lessening of the lesions.

Figure 1. Thick, velvety, hyperpigmented lesions over the periorbital area.

Figure 2. Thick, velvety, hyperpigmented lesions over the pinnae.

From the Departments of Dermatology,1 and Pathology and Laboratory Medicine,2 All India Institute of Medical Science, Raipur, Chhattisgarh, India Address for Correspondence: Namrata Chhabra, MD, Maple-212, Parthivi Pacific Apartment Tatibandh, Raipur-492099, Chhattisgarh, India • E-mail: chhabra.namrata@gmail.com

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CORRESPONDENCE AN is commonly observed in the flexural areas, including the neck, axillae, and groin, with only one reported case of obesity-associated AN involving the auricles.5 Eyelid involvement in AN is also rare and is seen in patients with insulin resistance6 and malignancy. Our patient had an unusual presentation of AN involving both pinnae as well as the eyelids associated with obesity. We report a rare and interesting case of metabolic syndrome–associated AN. References 1 Yosipovitch G, DeVore A, Dawn A. Obesity and the skin: skin physiology and skin manifestations of obesity. J Am Acad Dermatol. 2007;56:901–916. 2 Kalus AA, Chien AJ, Olerud JE. Skin manifestations of internal organ disorders. In: Wolff K, Goldsmith LA, Katz SI, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2008:1460.

Figure 3. Thick, velvety, hyperpigmented lesions over the nuchae.

Discussion

3 Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol. 1994;31:1–19.

AN may be divided into benign AN, obesity-associated AN, syndromic AN, malignant AN, acral AN, unilateral AN, medication-induced AN, and mixed-type AN.3 Among these, obesityassociated AN is the most common. Our patient had abdominal obesity, hyperinsulinemia, impaired fasting blood sugar, low high-density lipoprotein cholesterol, and hypertension consistent with metabolic syndrome (based on World Health Organization Clinical Criteria for Metabolic Syndrome4). AN and acrochordons have been associated with insulin resistance and may therefore represent an easily identifiable sign of insulin resistance and noninsulin-dependent diabetes.

4 World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO Consultation. Part 1: diagnosis and classification of diabetes mellitus. Geneva, Switzerland: World Health Organization; 1999. http://whqlibdoc. who.int/hq/1999/WHO_NCD_NCS_99.2.pdf. Accessed December 12, 2003. 5 Lee YB, Lee JD, Cho SH. Unusual presentation of obesity-associated dermatoses: acanthosis nigricans involving both auricles. Ann Dermatol. 2010;22:463–464. 6 Endocrine diseases. In: James WD, Elston DM, Berger TG, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, PA: Elsevier; 2011:494–495.

Hydroxychloroquine de Novo-Induced Psoriasis in a Patient With Lichen Planus Pigmentosus Lucia Seminario-Vidal, MD, PhD;1 Lauren S. Hughey, MD2 To the Editor: Antimalarials have been used by dermatologists for more than 50 years to treat diverse inflammatory cutaneous conditions. Their pharmacologic properties and adverse side effects are well understood. It has been demonstrated that antimalarials exacerbate psoriasis; however, only a few cases have reported de novo-induced

psoriasis. To our knowledge, the patient described herein represents the first reported case of hydroxychloroquine-induced psoriasis in the setting of lichen planus pigmentosus. Clinical Case A woman in her 50s presented for a follow-up appointment of lichen planus pigmentosus (Figure 1). She complained about a new,

From the Department of Dermatology and Cutaneous Surgery, University of South Florida College of Medicine, Tampa, Florida,1 and the Department of Dermatology University of Alabama at Birmingham School of Medicine, Birmingham, Alabama2 Address for Correspondence: Lucia Seminario-Vidal, MD, PhD, University of South Florida College of Medicine, Department of Dermatology and Cutaneous Surgery, 12901 Bruce B. Downs Boulevard, MDC 28, Tampa, FL 33612 • E-mail: luciasem@health.usf.edu

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Figure 1. Lichen planus pigmentosus. Blue-gray patches on the face and upper chest.

Figure 3. Psoriasiform hyperplasia with attenuation of the granular cell layer and neutrophils microabscesses within the stratum corneum (top). Mild superficial perivascular infiltrate with scattered accompanying eosinophils (bottom). Hematoxylin and eosin staining at low power (×40, top) and high power (×200, bottom).

Figure 2. Lichen planus pigmentosus with superimposed psoriasis. Erythematous scaly plaques over blue-gray ill-defined patches on the forehead (top) and upper chest (bottom). SKINmed. 2015;13:486–494

red, scaly, pruritic eruption that began 4 weeks after initiation of hydroxychloroquine therapy. Lesions appeared on the dorsum of her hands and feet, and rapidly spread to the rest of her body. The patient denied joint pain, recent infection, or new medications, as well as personal or family history of psoriasis. Skin examination demonstrated multiple, thick, erythematous, and scaly papules confluent into plaques involving 80% of her body surface area, including the scalp, ears, neck, back, chest, abdomen, bilateral upper and lower extremities, and dorsal surfaces of the hands and feet. In addition, there were blue-gray ill-defined patches on her face, neck, upper portion of the chest, lower part of the back, and upper aspect of the abdomen (Figure 2). No fingernail changes were identified. Results from biopsy specimens displayed psoriasiform hyperplasia with attenuation of the granular cell layer. There

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was overlying confluent parakeratosis with neutrophil microabscesses within the stratum corneum. Within the reticular dermis, there was a mild superficial perivascular infiltrate with scattered accompanying eosinophils. Biopsy results indicated drug-induced psoriasis (Figure 3). Hydroxychloroquine was stopped and the patient was treated with 12.5 mg of methotrexate weekly and topical triamcinolone 0.05% cream, with 90% clearance of her psoriatic lesions at 3-month follow-up.

Conclusions Our patient is the first case reported where psoriasis occurred de novo in the setting of hydroxychloroquine therapy for lichen planus pigmentosus. Dermatologists should monitor for psoriasis development in the setting of antimalarial therapy for cutaneous conditions. References

Discussion Psoriasis is a common chronic skin disorder with a profound impact on quality of life. Drugs may result in exacerbation of preexisting psoriasis, induction of new psoriatic lesions in patients with psoriasis, or precipitation of the disease in susceptible individuals. It is well recognized that antimalarials may exacerbate preexisting psoriasis in up to 30 to 50% of patients; however, it has been suggested that antimalarials do not induce psoriasis de novo.1 Five cases have been described of psoriasis induced by antimalarials in patients who did not have the disease previously.2–6 Two of the reported patients had a family history of psoriasis, suggesting that genetic susceptibility may play a role in these individuals. Most of the patients received antimalarials for malaria prophylaxis, except one who was being treated for lichen planus pilaris.5

1 Wolf R, Lo Schiavo A. Is transglutaminase the mediator between antimalarial drugs and psoriasis? Int J Dermatol. 1997;36:10–13. 2 Baker H. The influence of chloroquine and related drugs on psoriasis and keratoderma blenorrhagicum. Br J Dermatol. 1966;78:161–168. 3 Gray RG. Hydroxychloroquine provocation of psoriasis. Rheumatol. 1985;12:391. 4 Nicolas JF, Mauduit G, Haond J, et al. Severe psoriasis induced by chloroquine (Nivaquine). Ann Dermatol Venereol. 1988;115:289–293. 5 Gravani A, Gaitanis G, Zioga A, et al. Synthetic antimalarial drugs and the triggering of psoriasis––do we need disease-specific guidelines for the management of patients with psoriasis at risk of malaria? Int J Dermatol. 2014;53:327–330. 6 Kirschenbaum MB. Psoriasis following administration of antimalarial drugs. JAMA. 1963;28;185:1044.

“Perforating basalioma”. Moulage No. 961, made by Lotte Volger in 1940 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Volume 13 • Issue 6

Book Review Jennifer L. Parish, MD, Section Editor

Dermatopathology Jason B. Lee, MD

his second edition, simply titled Dermatopathology (Elston DM, Ferringer T, Ko CJ, et al. Dermatopathology. 2nd edition. Philadelphia, PA: Saunders; 2014: 452 pp. $154) and written by the same authors as the first edition, is physically a larger book, with an increase of approximately 30% in size, although the thickness of the book remains the same. What this means for this popular book among students and residents is that not only are many of the images larger, but there are more images as a result of the increase in real estate for each page. Despite its large size, the latest edition still has a small form feel, making it attractive for those who do not want to lug around a cumbersome reference book (one of the big reasons for its popularity). The new edition continues to be complemented by online access to enumerable images and insightful lectures. This is not a comprehensive reference textbook of dermatopathology nor does it pretend to be, but it packs in all the core dermatopathology material and more. The new edition has the same number of chapters as the previous edition, some of which have been expanded. For example, the immunohistochemistry section in chapter 1 includes many more images, and one additional appendix has been added—Appendix 3: External Agents and Artifacts. Another new feature of the new addition is its online-only material—Chapter 20a: Key Diagnostic Features of Additional Soft Tissue Neoplasms. All of these are welcome updates in the new edition. The organization of the book is clear, with chapter titles that are succinct. The table of contents highlights the additional material that is online, making it easier for readers to navigate through the material. My only advice for the next edition is to consistently arrange all the chapters into broad categories, such as inflammatory, neoplastic, and infectious, although I realize this is a difficult task as many of the skin diseases do not neatly fit into any broad categories. The new edition contains many of the images that were used in the previous edition, but many are larger and often with pointers

that highlight the diagnostic histopathologic findings. The new edition continues the tradition of having nearly every page filled with multiple images that are well laid out with clear explanation of the histopathologic findings. The authors have carefully chosen cases that represent outstanding examples of the diseases that are being illustrated. It is clear that the intent of the authors was to have the pertinent histopathologic changes “pop” as the reader turns the pages, a feat that is clearly achieved. The attraction for this book is that the authors have made the daunting subject of dermatopathology easier to approach, especially by novices, by dissecting out the subject and presenting it in a way that is easier to comprehend and retain. In that spirit, the new edition does an even better job. The latest edition will continue to be popular among students, residents, fellows, and seasoned dermatopathologists, and it is sure to attract new followers of the book.

Reviewed by Jason B. Lee, MD, Professor of Dermatology and Cutaneous Biology and Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA • E-mail: jason.lee@jefferson.edu

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IMPORTANT INFORMATION ABOUT

SOOLANTRA®

(ivermectin) Cream, 1% BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea. WHO IS SOOLANTRA CREAM FOR? SOOLANTRA Cream is indicated for people with inflammatory lesions of rosacea. It is not known if SOOLANTRA Cream is safe and effective for children. Advise your patients to not use SOOLANTRA Cream for a condition for which it was not prescribed and remind them to not give SOOLANTRA Cream to other people, even if they have the same symptoms as it may harm them. WHAT SHOULD I ASK MY PATIENTS BEFORE PRESCRIBING SOOLANTRA CREAM? Before you prescribe SOOLANTRA Cream, ask your patients if they: • have any other medical conditions. • are pregnant or planning to become pregnant. It is not known if SOOLANTRA Cream can harm an unborn baby. • are breastfeeding or plan to breastfeed. It is not known if SOOLANTRA Cream passes into breast milk and if it can harm a baby.

SOOLANTRA Cream is supplied in a child-resistant capped tube. • To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing. • To close, gently press down on the child resistant cap and twist clockwise. WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM? Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol. WHERE SHOULD I GO FOR MORE INFORMATION ABOUT SOOLANTRA CREAM? • This Brief Summary summarizes the most important information about SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert. • Go to www.soolantra.com or call 1-866-735-4137

Trademarks are the property of their respective owners. GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USA Revised: December 2014

WHAT ARE THE MOST COMMON SIDE EFFECTS OF SOOLANTRA CREAM? The most commonly reported side effects when using SOOLANTRA Cream include skin burning sensation and skin irritation. Remind your patients to tell you if they have any side effect that bothers them or that does not go away. These are not all of the possible side effects of SOOLANTRA Cream. For more information, see the full Prescribing Information. You are encouraged to report negative side effects of prescription drugs to the FDA at www.fda.gov/medwatch or call 1-800-FDA-1088. You may also contact GALDERMA LABORATORIES, L.P. AT 1-866-735-4137. HOW SHOULD PATIENTS USE SOOLANTRA CREAM? • SOOLANTRA Cream is for use on the face only and should not be used in the eyes, mouth, or vagina. • SOOLANTRA Cream should be applied to the affected areas of the face once a day. APPLYING SOOLANTRA CREAM: • A pea-sized amount of SOOLANTRA Cream should be applied to each area of the face (forehead, chin, nose, each cheek) that is affected. Avoid contact with the lips and eyes.

References: 1. Stein Gold L, Kircik L, Fowler J, et al; Ivermectin Phase III Study Group. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316-323. 2. Data on file. Galderma Laboratories, L.P. 3. Taieb A, Ortonne JP, Ruzicka T, et al; Ivermectin Phase III Study Group. Superiority of ivermectin 1% cream over metronidazole 0.75% cream in treating inflammatory lesions of rosacea: a randomized, investigator-blinded trial. Br J Dermatol. 2015;172(4):1103-1110.

TREATING INFLAMMATORY LESIONS OF ROSACEA CAN BE TOUGH…

PRESCRIBE

A TOUGH TOPICAL SOOLANTRA® (ivermectin) CREAM, 1%—POWERFUL AND RAPID RESULTS FROM A ONCE-DAILY TOPICAL1,2*† • –20.5 (–64.9%) mean inflammatory lesion count reduction at week 122*† • Better efficacy from once-daily Soolantra Cream, 1% vs twice-daily metronidazole 0.75% cream as early as 3 weeks3‡ • Specifically formulated for patients with inflammatory lesions of rosacea—Cetaphil® Moisturizing Cream was the basis for the vehicle2

www.soola n t ra .com/h cp Important Safety Information Indication: SOOLANTRA® (ivermectin) Cream, 1% is indicated for the treatment of inflammatory lesions of rosacea. Adverse Events: In clinical trials with SOOLANTRA® Cream, the most common adverse reactions (incidence ≤1%) included skin burning sensation and skin irritation. Warnings/Precautions: Not for oral, ophthalmic, or intravaginal use. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see brief summary of Prescribing Information on adjacent page. * The efficacy and safety of SOOLANTRA® Cream, 1% once daily was evaluated in subjects aged ≥18 years in 2 identically designed phase 3 clinical trials (N=1371). Final results were comparable between the 2 studies, with the least favorable results presented here. † A phase 3, multicenter, randomized, double-blind, 12-week, vehicle-controlled, parallel-group study assessing the efficacy and safety of SOOLANTRA® Cream, 1% once daily in 683 subjects with moderate to severe papulopustular rosacea (Investigator Global Assessment [IGA] score of 3 or 4). ‡ An investigator-blinded, multicenter, randomized, parallel-group study comparing the efficacy and safety of SOOLANTRA® Cream, 1% once daily with metronidazole 0.75% cream twice daily in 962 subjects with moderate to severe papulopustular rosacea (IGA score of 3 or 4) over a 16-week treatment period.