Sept / Oct 2013

September/October 2013 • Volume 11 • Issue 5 EDITORIAL Continuing Medical Education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum

COSMETIC SCIENCE Is It Time to Revise CFR Title 21-Food Drugs & Cosmetics Act for Skin Care Products?

Epstein

Lambert and Parish

COMMENTARY Drug Reactions With Involvement of the Proximal Nail Fold Chang

ORIGINAL CONTRIBUTIONS Use of Granulocyte Colony-Stimulating Factor in the Treatment of Toxic Epidermal Necrolysis—Experience With 3 Patients Mahajan and Kanwar

Polypharmacy in Dermatology: Analysis of a Nationally Representative Sample of 46,273 Dermatology Patient Visits in the United States From 1995 to 2009 Gupta, Gupta, and Fink

REVIEW Aging and Facial Changes—Documenting Clinical Signs, Part 1: Clinical Changes of the Aging Face Nkengne and Bertin

CORE CURRICULUM Hair Biology and Its Comprehensive Sequence in Female Pattern Baldness: Treatment Modalities—Part III

case studies Multiple Cystic Disease: K17 Dysfunction?

Cabrera, Hermida, Griffa, Civitillo, and Porta

Multiple Giant Vulvar Syringoma: An Extraordinary Report Sadeghian and Ziaei

Epidermolysis Bullosa Pruriginosa Affecting 3 Successive Generations Kumar, Mondal, Lal, and Gharami

An Unusual Presentation and Distribution of Generalized Eruptive Syringomas Chow, Gharavi, Smart, Yashar, and Young

An Unusual Presentation of Perforating Metastatic Calcinosis Cutis Livingood and Newman

CORRESPONDENCE Acneiform Eruption and Pruritus in a Patient With Quetiapine Therapy Kansal and Sharma

Acquired Reactive Perforating Collagenosis Chhabra and Sharma

Sehgal, Srivastava, Aggarwal, and Midha

DEPARTMENTS perils of dermatopathology Atypia Without Pleomorphism and Atypia Without Atypia: When You Can’t Even See the Trees for the Trees Harmon, Lambert, Katava, and Lambert

new to the clinic Epiduo (Adapalene 0.1% and Benzoyl Peroxide 2.5%) Approval in Children 9 Years and Older Scheinfeld

Lebanese Dermatological Society

T A A G

™

Coming Soon

Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD

TABLE OF CONTENTS September/October 2013 • Volume 11 • Issue 5

EDITORIAL

Continuing Medical Education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum........................................................................................................ 262

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

COMMENTARy

Drug Reactions With Involvement of the Proximal Nail Fold....................................................................... 265

Patricia Chang, MD

ORIGINAL CONTRIBUTIONs

Use of Granulocyte Colony-Stimulating Factor in the Treatment of Toxic Epidermal Necrolysis—Experience With 3 Patients..................................................................................................... 269

Rahul Mahajan, MD; Amrinder J. Kanwar, MD

Polypharmacy in Dermatology: Analysis of a Nationally Representative Sample of 46,273 Dermatology Patient Visits in the United States From 1995 to 2009.......................................................... 273

Madhulika A. Gupta, MD, FRCPC; Aditya K. Gupta, MD, PhD, FRCPC; Naomi H. Fink, BMSc

REVIEW

Aging and Facial Changes—Documenting Clinical Signs, Part 1: Clinical Changes of the Aging Face......... 281

Alex Nkengne, PhD; Christiane Bertin, MS

Core curriculum

Virendra N. Sehgal, MD, Section Editor

Hair Biology and Its Comprehensive Sequence in Female Pattern Baldness: Treatment Modalities—Part III....... 287

Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Rashmi Midha, MBBS

Departments Perils of Dermatopathlogy

W. Clark Lambert, MD, PhD, Section Editor

Atypia Without Pleomorphism and Atypia Without Atypia: When You Can’t Even See the Trees for the Trees....... 291

Gretchen Harmon, MD; Peter C. Lambert, MA; Gordana L. Katava, DO, MS; W. Clark Lambert, MD, PhD

New to the Clinic

Noah Scheinfeld, MD, JD, Section Editor

Epiduo (Adapalene 0.1% and Benzoyl Peroxide 2.5%) Approval in Children 9 Years and Older.................. 295

Noah Scheinfeld, MD, JD

Cosmetic Science

Howard A. Epstein, PhD, Section Editor

Is It Time to Revise CFR Title 21-Food Drugs & Cosmetics Act for Skin Care Products?............................. 297

Howard A. Epstein, PhD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Multiple Cystic Disease: K17 Dysfunction?................................................................................................. 301

Hugo Néstor Cabrera; María Daniela Hermida, MD; Elba Griffa, MD; Claudia Civitillo, MD; José Porta, MD

Multiple Giant Vulvar Syringoma: An Extraordinary Report........................................................................ 305

Giti Sadeghian, MD; Hengameh Ziaei

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TABLE OF CONTENTS July/August 2013 • Volume 11 • Issue 4

Epidermolysis Bullosa Pruriginosa Affecting 3 Successive Generations..................................................... 308

Piyush Kumar, MD; Ashim Kumar Mondal, MD; Niharika Ranjan Lal, MD; Ramesh Chandra Gharami, MD

An Unusual Presentation and Distribution of Generalized Eruptive Syringomas......................................... 311

Conroy Chow, MD; Nima M. Gharavi, MD, PhD; Chandra N. Smart, MD; Sharona Yashar, MD; Lorraine C. Young, MD

An Unusual Presentation of Perforating Metastatic Calcinosis Cutis.......................................................... 314

Matthew Livingood, MD; Sabrina A. Newman, MD

CORRESPONDENCE

Acneiform Eruption and Pruritus in a Patient With Quetiapine Therapy...................................................... 317

Naveen Kumar Kansal, MD; Meghna Sharma, MD

Acquired Reactive Perforating Collagenosis............................................................................................... 318

Namrata Chhabra, MD; Sonal Sharma, MD

ABOUT OUR JOURNAL

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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.

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258

Finacea® (azelaic acid) Gel, 15% is a topical prescription medication used to treat inflammatory papules and pustules of mild to moderate rosacea.

Rosacea is with her wherever she goes.

So is Finacea . ®

It’s true. Rosacea is complex and it’s with them for life. Finacea® treats the papules and pustules with associated erythema of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

You have made Finacea® the #1 Dermatologist-prescribed topical brand.1 INDICATION & USAGE Finacea® (azelaic acid) Gel, 15% is indicated for topical treatment of inflammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

IMPORTANT SAFETY INFORMATION Skin irritation (e.g. pruritus, burning or stinging) may occur during use with Finacea®, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists during use with Finacea®, discontinue use and institute appropriate therapy. There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

Avoid contact with the eyes, mouth, and other mucous membranes. In case of eye exposure, wash eyes with large amounts of water. Wash hands immediately following application of Finacea®.

Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and peeling agents. Avoid the use of occlusive dressings or wrappings.

In clinical trials with Finacea®, the most common treatment-related adverse events (AE’s) were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). Contact dermatitis, edema and acne were observed at frequencies of 1% or less.

Finacea® is for topical use only. It is not for ophthalmic, oral or intravaginal use. Patients should be reassessed if no improvement is observed upon completing 12 weeks of therapy.

Please see Brief Summary of full Prescribing Information on adjacent page.

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.

1. According to IMS NPATM (National Prescription Audit) July 2010-August 2013 © 2013 Bayer HealthCare Pharmaceuticals. Bayer, the Bayer Cross and Finacea® are registered trademarks of Bayer. All rights reserved. FIN-10-0001-13b | AUGUST 2013

Skinmed 8 X 10.75 in (8 X 10 3/4 in)

6.2 Post-Marketing Experience The following adverse reactions have been identified post approval of FINACEA Gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure: Eyes: iridocyclitis upon accidental exposure of the eyes to FINACEA Gel

Finacea (azelaic acid) Gel,15% ®

7 DRUG INTERACTIONS There have been no formal studies of the interaction of FINACEA Gel with other drugs.

For Dermatologic Use Only–Not for Ophthalmic, Oral, or Intravaginal Use Rx only BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE FINACEA® Gel is indicated for topical treatment of the inflammatory papules and pustules of mild to moderate rosacea. Although some reduction of erythema which was present in patients with papules and pustules of rosacea occurred in clinical studies, efficacy for treatment of erythema in rosacea in the absence of papules and pustules has not been evaluated.

5 WARNINGS AND PRECAUTIONS 5.1 Skin Reactions Skin irritation (i.e. pruritus, burning or stinging) may occur during use of FINACEA Gel, usually during the first few weeks of treatment. If sensitivity or severe irritation develops and persists, discontinue treatment and institute appropriate therapy.

There have been isolated reports of hypopigmentation after use of azelaic acid. Since azelaic acid has not been well studied in patients with dark complexion, monitor these patients for early signs of hypopigmentation.

5.2 Eye and Mucous Membranes Irritation Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come in contact with the eyes, wash the eyes with large amounts of water and consult a physician if eye irritation persists [see Adverse Reactions (6.2)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two vehicle-controlled and one active-controlled U.S. clinical trials, treatment safety was monitored in 788 subjects who used twice-daily FINACEA Gel for 12 weeks (N=333) or 15 weeks (N=124), or the gel vehicle (N=331) for 12 weeks. In all three trials, the most common treatment-related adverse events were: burning/stinging/tingling (29%), pruritus (11%), scaling/dry skin/xerosis (8%) and erythema/irritation (4%). In the active-controlled trial, overall adverse reactions (including burning, stinging/tingling, dryness/tightness/ scaling, itching, and erythema/irritation/redness) were 19.4% (24/124) for FINACEA Gel compared to 7.1% (9/127) for the active comparator gel at 15 weeks.

Table 1: Adverse Events Occurring in ≥1% of Subjects in the Rosacea Trials by Treatment Group and Maximum Intensity*

Burning/ stinging/ tingling Pruritus Scaling/ dry skin/ xerosis Erythema/ irritation Contact dermatitis Edema Acne

FINACEA Gel, 15% N=457 (100%) Mild Moderate Severe n=99 n=61 n=27 (22%) (13%) (6%) 71 (16%) 42 (9%) 17 (4%)

Vehicle N=331 (100%) Mild Moderate Severe n=46 n=30 n=5 (14%) (9%) (2%) 8 (2%) 6 (2%) 2 (1%)

29 (6%) 21 (5%)

18 (4%) 10 (2%)

5 (1%) 5 (1%)

9 (3%) 31 (9%)

6 (2%) 14 (4%)

0 (0%) 1 (<1%)

6 (1%)

7 (2%)

2 (<1%)

8 (2%)

4 (1%)

2 (1%)

2 (<1%)

3 (1%)

0 (0%)

1 (<1%)

0 (0%)

0 (0%)

3 (1%) 3 (1%)

2 (<1%) 1 (<1%)

0 (0%) 0 (0%)

3 (1%) 1 (<1%)

0 (0%) 0 (0%)

0 (0%) 0 (0%)

* Subjects may have >1 cutaneous adverse event; thus, the sum of the frequencies of preferred terms may exceed the number of subjects with at least 1 cutaneous adverse event.

In patients using azelaic acid formulations, the following adverse events have been reported: worsening of asthma, vitiligo, depigmentation, small depigmented spots, hypertrichosis, reddening (signs of keratosis pilaris) and exacerbation of recurrent herpes labialis.

Local Tolerability Studies FINACEA Gel and its vehicle caused irritant reactions at the application site in human dermal safety studies. FINACEA Gel caused significantly more irritation than its vehicle in a cumulative irritation study. Some improvement in irritation was demonstrated over the course of the clinical trials, but this improvement might be attributed to subject dropouts. No phototoxicity or photoallergenicity were reported in human dermal safety studies.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Therefore, FINACEA Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been performed with azelaic acid, 15% gel. Oral embryofetal developmental studies were conducted with azelaic acid in rats, rabbits, and cynomolgus monkeys. Azelaic acid was administered during the period of organogenesis in all three animal species. Embryotoxicity was observed in rats, rabbits, and monkeys at oral doses of azelaic acid that generated some maternal toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162 times the maximum recommended human dose (MRHD) based on body surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times the MRHD based on BSA) and cynomolgus monkeys given 500 mg/kg/day (65 times the MRHD based on BSA) azelaic acid. No teratogenic effects were observed in the oral embryofetal developmental studies conducted in rats, rabbits and cynomolgus monkeys.

An oral peri- and post-natal developmental study was conducted in rats. Azelaic acid was administered from gestational day 15 through day 21 postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was observed in rats at an oral dose of 2500 mg/kg/day (162 times the MRHD based on BSA) that generated some maternal toxicity. In addition, slight disturbances in the post-natal development of fetuses was noted in rats at oral doses that generated some maternal toxicity (500 and 2500 mg/kg/day; 32 and 162 times the MRHD based on BSA). No effects on sexual maturation of the fetuses were noted in this study.

8.3 Nursing Mothers It is not known whether azelaic acid is excreted in human milk; however, in vitro studies using equilibrium dialysis were conducted to assess the potential for human milk partitioning. The studies demonstrated that, at an azelaic acid concentration of 25 µg/mL, the milk/plasma distribution coefficient was 0.7 and the milk/buffer distribution was 1.0. These data indicate that passage of drug into maternal milk may occur. Since less than 4% of a topically applied dose of 20% azelaic acid cream is systemically absorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant change from baseline azelaic acid levels in the milk. Nevertheless, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness of FINACEAGelin pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of FINACEA Gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

17 PATIENT COUNSELING INFORMATION Inform patients using FINACEA Gel of the following information and instructions: Use only as directed by your physician.

•For external use only.

•Before applying FINACEA Gel, cleanse affected area(s) with a very mild soap or a soapless cleansing lotion and pat dry with a soft towel.

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

•Avoid contact with the eyes, mouth and other mucous membranes. If FINACEA Gel does come in contact with the eyes, wash the eyes with large amounts of water and consult your physician if eye irritation persists.

•Wash hands immediately following application of FINACEA Gel. •Cosmetics may be applied after the application of FINACEA Gel has dried.

•Avoid the use of occlusive dressings or wrappings.

•Skin irritation (e.g., pruritus, burning, or stinging) may occur during use of FINACEA Gel, usually during the first few weeks of treatment. If irritation is excessive or persists, discontinue use and consult your physician.

•Report abnormal changes in skin color to your physician.

•To help manage rosacea, avoid any triggers that may provoke erythema, flushing, and blushing.

These triggers can include spicy and thermally hot food and drinks such as hot coffee, tea, or alcoholic beverages. © 2012, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470

Manufactured in Italy 6706805BS

September/October 2013

EDITORIAL BOARD

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 Vesna Petronic-Rosic, MD, MSc

Meridian, MS Marcia Ramos-e-Silva, MD, PhD

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

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

Virendra N. Sehgal, MD Delhi, India

Robert L. Baran, MD Cannes, France

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

George M. Martin, MD Kihei, HI

Riccarda Serri, MD Milan, Italy

Anthony V. Benedetto, DO Philadelphia, PA

Anthony A. Gaspari, MD Baltimore, MD

Marc S. Micozzi, MD, PhD Rockport, MA

Charles Steffen, MD Oceanside, CA

Brian Berman, MD, PhD Miami, FL

Michael Geiges, MD Zurich, Switzerland

George F. Murphy, MD Boston, MA

Alexander J. Stratigos, MD Athens, Greece

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

James S. Studdiford III, MD Philadelphia, PA

Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Joaquin Calap Calatayud, MD Cadiz, Spain Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Noah Craft, MD, PhD, DTMH Torrance, CA Natalie Curcio, MD Nashville, TN Ncoza C. Dlova, MBChB, FCDerm Durban, South Africa Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Boni E. Elewski, MD Birmingham, AL Charles N. Ellis, MD Ann Arbor, MI

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Pittsburgh, PA

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Aditya K. Gupta, MD, PhD, FRCP(C) London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK Tanya R. Humphreys, MD Philadelphia, PA

Joseph L. Pace, MD, FRCP Naxxar, Malta Art Papier, MD Rochester, NY Johannes Ring, MD, DPhil Munich, Germany Roy S. Rogers III, MD Rochester, MN Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Vincenzo Ruocco, MD Naples, Italy

Andrew P. Lazar, MD Washington, DC

Noah Scheinfeld, MD, JD New York, NY

Jasna Lipozencic, MD, PhD Zagreb, Croatia

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Robert J. Thomsen, MD Los Alamos, NM Julian Trevino, MD Dayton, OH Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Joseph A. Witkowski, MD Philadelphia, PA Ronni Wolf, MD Rechovot, Israel

September/October 2013

Volume 11 • Issue 5

EDITORIAL

Continuing Medical Education II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, Etcetera et Ad Nauseum W. Clark Lambert, MD, PhD;1 Lawrence Charles Parish, MD, MD(Hon)2 “If you have ten thousand regulations, you destroy all respect for the law.”

Winston Churchill (1874–1965)

C

ontinuing medical education (CME) has morphed into a complex grid of interconnecting bureaucracies and organizations and has spun a mind-boggling array of “alphabet soup” terms and eponyms that would make any New Dealer proud. Many of these new edicts are associated with numerous regulations and requirements, which were unknown to medicine just a few decades ago. This is in the context of a misguided zeal for new regulatory control in the United States that has been recognized in the press1 and recently prompted the influential British periodical, The Economist, to title an entire issue “Over-regulated America.”2 The administrators and dignitaries responsible for this loquacious medical CME monstrosity may be said to have simply been participating in a national paroxysm of obfuscatory regulatory innovation. It has been difficult for dermatologists to keep track of all this, even in our relatively small field. We are therefore grateful (as are no doubt numerous dermatologists) to our colleagues, Erik Stratman, Robert S. Kirsner, and Thomas D. Horn, for their recent contributions in the Journal of the American Journal of Dermatology, explaining their concept of how we arrived at the current dilemma and what is required of us now and in the future.3,4 Whether their contributions, which lack disclosures of conflicts of interest and impart no medical knowledge, warrant “CME” status is open to question, but we shall allow that to pass. The above eponyms are taken from these essays.

ble, advisable, appropriate, or even sane. Even if the tenants put forward by these and other authors advocating more stringent CME requirements, which essentially boil down to claims that physicians do not keep up-to-date in their fields unless forced to do so by proctored examinations, eventually turn out to be true.

This is by no means certain or even likely, and so we question the need or appropriateness of adopting such draconian, intrusive, and expensive measures, particularly when they will inevitably drain numerous physician man hours from an already overtaxed system. They should be recognized as an unfunded mandate against physicians, which are certain to elevate medical costs and contribute to physician burnout. As Churchill correctly noted, such measures will “destroy all respect for” all regulation on the part of physicians and, eventually, their patients.

Our Observations We have a different concept of how the current situation arose.

At the heart of our analysis are our two observations:

Regulations We do not, however, accept that the massive regulatory structure, which has been proposed to be added to our specialty, is inevita-

1. These increases in regulatise benefit one group, the regulators, members of the regulatory boards, and their appeasers, who derive incremental money and power from these increases.

2. This benefit, an obvious and odious conflict of interest, is virtually never acknowledged in the numerous publications advocating these increases, mostly written by board members and others who stand to benefit from them. (This is a special annoyance to those of us who regularly give presentations at which we are required to meticulously list all potential conflicts.)

From the Departments of Medicine (Dermatology) and Pathology, Rutgers University – New Jersey Medical School, Newark, NJ;1 and the Department of Dermatology and Cutaneous Biology, Jefferson Center for International Dermatology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: W. Clark Lambert, MD, PhD, Rutgers University – New Jersey Medical School, Departments of Medicine (Dermatology) and Pathology, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lambertwc@njms.rutgers.edu

SKINmed. 2013;11:262–263

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© 2013 Pulse Marketing & Communications, LLC

September/October 2013

EDITORIAL

These observations lead to the logical conclusion that the proposed regulations are actually not written to solve the problems the proponents claim to exist, many of which are not yet proven, or any other problems, but rather to enhance the monetary income and power of the proponents or their organizations at the considerable and unnecessary expense and inconvenience of others. This is not new; we have all seen instances where industries fail as a result of burdens imposed by unions, which do not benefit rank and file union members, but rather the union bosses. One example is the recent Hostess (maker of “Twinkies”) bankruptcy.5

This should be all there is to recertification and/or maintenance of certification. We see no sense or merit to the remaining requirements that have been promelgated by the American Board of Dermatology (ABD). If the ABD refuses to change its ways, we propose that one of two solutions be adopted: 1. The recertification process be taken over by the American Academy of Dermatology (AAD), which already has an MOC committee and could take over this process, and the bylaws of the AAD be modified to allow successful candidates of this recertification process to be fellows of the AAD.

Our Proposal We propose a much simpler solution to the anticipated problems, assuming that they even exist: For each year or group of years since a diplomate’s last board examination, a book of essential innovations and new discoveries shall be prepared by a body approved by the appropriate powers (these may even include one or more of the regulatory boards). These books should be readily available, of reasonable length, and written in plain English that physicians can readily understand. Then, a separate committee shall be charged with writing examination questions that must be answerable solely based on reading the above text. These test questions shall then constitute an examination, which shall be given in a proctored format to applicants for recertification. In this way, the examination can be tailored for each applicant, depending on the length of time since his or her last certification examination.

2. Alternatively, a new American Board of Recertification in Dermatology be established to take over the process altogether. The AAD should then recognize these successful candidates as fellows.

The Final Questions Whether the AAD adopts either approach will be an interesting test of whether it indeed represents its members, as it claims, or whether its real priorities are to represent the interests of a clique of insiders, including ABD members and even AAD hired staff members, as so many AAD fellows strongly maintain.

References

This approach leaves us with the issue of relevance in individual cases; for example, is it fair to test a diplomate on cosmetic procedures if he or she does no cosmetic dermatology? Fortunately or unfortunately, these issues are already with us. A set of other examination questions may also be added to assure that the candidate has retained essential skills at recognizing basic dermatologic diseases, prepared by an appropriately constituted committee. Finally, the examination preparation and the exam itself should be available at reasonable cost and should not have an artificial “fail rate.”

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1 Ferguson N. The regulated states of America. The Wall Street Journal. June 19, 2013:A15.

2 United States’ Economy: over-regulated America. The Economist. February 18, 2012. http://www.economist. com/printedition/2012-02-18. Accessed September 24, 2013.

3 Stratman E, Kirsner RS, Horn TD. Maintenance of certification in dermatology: what we know, what we don’t. J Am Acad Dermatol. 2013;69:1.e1–1.e11.

4 Stratman E, Kirsner RS, Horn TD. Maintenance of certification in dermatology: requirements for diplomates. J Am Acad Dermatol. 2013;69:13.e1–13.e16.

5 Protess B. Hostess, maker of Twinkies, files for bankruptcy. The New York Times. January 11, 2012. http:// nytimes.com/2012/01/11/imagining-a-world-withouttwinkies/. Accessed September 24, 2013.

Continuing Medical Education II

September/October 2013

Volume 11 • Issue 5

COMMENTARY

Drug Reactions With Involvement of the Proximal Nail Fold Patricia Chang, MD

T

he proximal nail fold is an important part of the nail apparatus that contributes to the formation of the nail plate and that, through the cuticle, acts as an impermeable barrier that protects it from any cause. It is also called the vallum unguis, or nail wall, and is a continuation of the dorsal part of the skin of the digits.

The proximal fold can be affected by dermatologic, systemic, infectious (viruses, bacteria, fungi, and parasites), benign and malignant tumors, reactive, traumatic, drug-derived, and other diseases.1

Perionyxis, or paronychia, is one of the most frequent lesions found in the proximal fold.2,3 Investigators studied 93 patients with dermatoses of the proximal nail fold predominating in the proximal nail fold of the hands, with the causes established as traumatic (45.16%), dyschromiacs (11.82%), cytostatics (6.45%), dermatologic (7.52%), systemic (2.15%), and other (6.45%) diseases.

At the proximal nail folds of the feet, predominant disturbance by microtrauma proximal nail fold in 15.05% of cases and other causes such as dyschromias in 5.37%, cytostatics in 1.07% associated with systemic diseases in 3.22%, and tumor and infections in 1.07%. The drug effect provoked by cytostatics at the level of the proximal fold in this study was the blackish pigmentation in 7 cases: 6 affecting the proximal fold in the hands and 1 in the feet.1 Drug reactions can affect different organs. They can be defined as “an unintended effect that develops at doses normally prescribed to patients for prophylaxis, diagnosis, or treatment of their illnesses.”4 Drug reactions can be observed in various organs or systems, and when they involve a skin condition, they are referred to as farmacodermia, drug eruptions, drug skin reactions and toxicoderma, or drug dermatoses. The skin is the organ

Figure 1. Erythema multiform lesions secondary to penicillin affecting the proximal nail fold.

most frequently involved along with the mucosa and adnexal structures.5–7 The nail apparatus can become compromised by different drug reactions such as fixed-drug eruptions, Steven Johnson syndrome, Lyell syndrome, and dyschromia, which can affect the proximal nail fold itself. It may be associated with the remains of the drug pathology of the nail apparatus and the body.8 Drug reactions can affect each of the components of the nail apparatus. At the proximal nail fold level, it appears as erythema,

From the Department of Dermatology, Hospital Ángeles y General de Enfermedades IGSS, Guatemala Address for Correspondence: 2a av 14-74 zona 1, Hospital Ángeles, Guatemala 01001 • E-mail: pchang2622@gmail.com

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Figure 2. Drug exanthema secondary to amoxicillin with periungual erythema on the hands.

Figure 3. Lyell syndrome caused by tetracycline affecting the proximal nail fold on the hands and feet of a 76-year-old patient with acquired immunodeficiency syndrome.

bleeding, necrosis, painful desquamation, edema,10,11 vesicles or bullae, and dyschromy.8 Thirteen cases that affected the proximal nail fold have been reported, secondary to drug reactions on the feet in 6 patients (46.1%), the hands in 4 patients (30.7%), and both the feet and the hands in 3 patients (23.0%). The drug reactions that affected the proximal fold included Stevensâ&#x20AC;&#x201C;Johnson disease in 5 cases (38.4%), fixed drug eruption in 4 cases (30.7%), melanoderma by cytostatics in 2 cases (15.3%), periungual erythema in 1 case (7.69%), and photosensitivity in 1 case (7.69%).8 ObSKINmed. 2013;11:265â&#x20AC;&#x201C;268

served drug reactions that affect the proximal fold also include erythema multiforme caused by penicillin (Figure 1), exanthema secondary to amoxicillin (Figure 2), Lyell syndrome secondary to tetracycline in a patient with acquired immunodeficiency syndrome (Figure 3), and magnesium glutamate hydrobromide (Figure 4) and ciprofloxacin (Figure 5).

Conclusions Drugs reactions can affect the nail apparatus, making it important to examine the area to complement a suspected diagnosis.

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Figure 4. Lyell syndrome caused by magnesium glutamate hydrobromide affecting the proximal fold of a 5-year-old child.

Figure 5. Lyell syndrome secondary to ciprofloxacin affecting the proximal fold on the toes of a 24-year-old woman.

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References 1 Chang P, Haneke E. Dermatosis del pliegue proximal ungueal. Dermatologia CMQ. 2011;9:96–101.

2 Dawber RPR, De Berker D, Baran R Science of the nail apparatus. In: Diseases of the Nails and their Management. Oxford, England: Blackwell Scientific Publications; 1994:1,15,17,18.

3 Tosti A, Piraccini BM, Le Unghie Peluso AM. Guida pratica alle piú comuni affezioni. Biochimsi. 1996;10:41.

4 Alonzo L, López L. Diagnóstico diferencial de reacciones medicamentosas adversas. Rev Cent Dermatol Pascua.

2000;9:120–124.

5 Mayorga C, Torres M, Fernández J, et al. Cutaneous symptoms in drug allergy: what have we learnt? Curr Opin Allergy Clin Immunol. 2009;9:431–436.

6 Gruchalla R. Understanding drug allergies. J Allergy Clin Immunol. 2000;105(S1):637–644.

7 Martín R, Marcano M, Sardi J, Ball, Giansante E. Síndrome de hipersensibilidad inducido por fármacos. Revisión de 3 años en el Servicio de Dermatología del Hospital Universitario de Caracas, Venezuela”. Dermatología Venezolana. 2008;46:18–23.

8 Chang P, Galvez D. Reacciones medicamentosas con afección del pliegue proximal. Dermatologia CMQ. 2012;3:172–177.

9 Dawber RP, Berker D, Baran R. Science of the nail apparatus. In: Baran R, Dawber RP, De Berker D, et al. Diseases of the Nails and their Management. Oxford, England: Blackwell Science Publications; 2001:11–21.

10 Tosti A, Baran R, Dawber R. The nail in systemic diseases and drug-induced changes. In: Baran R, Dawber RP, De Berker D, et al. Diseases of the Nails and their Management. Oxford, England: Blackwell Science Publications; 2001:302–329.

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ORIGINAL CONTRIBUTION

Use of Granulocyte Colony-Stimulating Factor in the Treatment of Toxic Epidermal Necrolysis—Experience With 3 Patients Rahul Mahajan, MD; Amrinder J. Kanwar, MD Abstract The use of recombinant granulocyte colony-stimulating factor has recently been advocated in the treatment of toxic epidermal necrolysis as it may help in faster regeneration of detached skin. Three patients who presented with toxic epidermal necrolysis were managed as per the protocol followed at our department. In addition, they received recombinant granulocyte colony-stimulating factor in a dose of 300 µg/d (5µg/ kg/d) for 5 days. Severity of Illness Score for Toxic Epidermal Necrolysis was calculated on day 1 and the lesions were observed for re-epithelialization. The 3 patients were aged 16 years, 20 years, and 65 years, with the latter showing leucopenia at presentation. All 3 patients showed a significant rise in total leukocyte count (reaching up to 45,000/mm3) after administering recombinant granulocyte colony-stimulating factor, with the rise being comparatively less in the third patient (maximum of 12,000/mm3). A similar pattern was seen in re-epithelialization of skin, with rapid re-epithelialization occurring in the first 2 patients and much slower re-epithelialization in the third. The first two survived but the third died from refractory sepsis. Recombinant granulocyte colony-stimulating factor improves epithelialization of skin and should be used for treating toxic epidermal necrolysis irrespective of the leucopenic status of the patient. (SKINmed. 2013;11:269–271)

T

oxic epidermal necrolysis (TEN) is a rare dermatologic emergency that presents as widespread peeling of the skin with severe mucosal involvement and carries a significant mortality risk. Recently, investigators presented the Chelsea and Westminster protocol for the management of TEN, and the usefulness of recombinant granulocyte colony-stimulating factor (rG-CSF) as an agent for accelerating wound regeneration in TEN.1 We describe our experience with the use of rG-CSF in managing severe TEN in 3 patients, only 1 of whom had leucopenia at presentation.

Case Reports

Case 1 A 20-year-old woman with a history of poorly controlled seizures presented with generalized dusky red erythema and blisters all over her body of 5 days’ duration. Ten days previously, she

had been started on lamotrigine (50 mg/d), following which she developed high-grade fever with swelling of the hands and feet, painful oral ulcers, redness in the eyes, and blistering and peeling of the skin. At the time of presentation, nearly 60% of her total body surface was involved with severe conjunctival, oral, and genital mucositis (Figure 1). Severity of Illness Score for TEN (SCORTEN) on day 1 was 4. She was started on intravenous immunoglobulins (1 g/kg/d) but was discontinued due to sudden onset of chest pain. The treatment was changed to intravenous methyl prednisolone 64 mg/d and intravenous antibiotics (initially intravenous piperacillin/tazobactum 4.5 g 3 times daily, which was later changed to vancomycin 1 g twice daily and colistin after 72 hours due to worsening clinical status). On day 3, she had an episode of aspiration that led to right lung upper lobe collapse and pneumonitis. On day 6 of admission, she showed altered consciousness as a result of hypernatremia. During this time there was no evidence of regeneration of skin. On day 7

From the Departments of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Address for Correspondence: Amrinder J. Kanwar, MD, Professor and Head, Department of Dermatology, Venereology, and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India • E-mail: ajkanwar1948@gmail.com

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she was started on rG-CSF at a dose of 300 µg/d (body weight 55 kg) for sepsis-induced leucopenia for 5 days. Her leukocyte count rose to a maximum of 48,000 cells/mm3. At the end of day 5 her skin lesions were observed to be drying up with evidence of re-epithelialization. Steroids were tapered off rapidly and the patient was discharged from the hospital after 3 weeks.

Case 2 A 16-year-old woman with a seizure disorder was started on lamotrigine (100 mg/d). Three weeks after starting the medication, she developed high-grade fever along with generalized erythema, formation of fluid-filled flaccid blisters, and peeling of the skin. There were associated oral ulcers and conjunctivitis.

Examination revealed involvement of 50% of her body surface area, with large sheets of necrotic skin and few atypical target lesions. SCORTEN on day 1 was 3. She was started on oral cyclosporine 5 mg/kg/d along with parenteral antibiotics. Simultaneously, rG-CSF 300 µg/d (body weight 54 kg) was started on day 1 and continued for 5 days. Her leukocyte count rose to a maximum of 35,000 cells/mm3 on day 5. A rapid recovery in her general condition and cutaneous re-epithelialization was observed and she was discharged from the hospital after 9 days.

Case 3

Figure 1. Sheets of detached skin with few erosions and fluid filled bulla over the back in patient 1.

A 65-year-old woman presented with extensive areas of denuded skin, generalized erythema all over her body, and painful oral ulcers.

Three weeks previously, she had taken some analgesics and antibiotics, following which she developed generalized erythema with extensive peeling of the skin with involvement of oral and genital mucosae. Examination revealed involvement of 70% of body surface area with large areas of necrotic and denuded skin and mild to moderate erythema (Figure 2). Her baseline investigations showed a leucopenia value of 3000/mm3. SCORTEN on day 1 was 4. She was started on parenteral antibiotics (intravenous piperacillin/tazobactum 4.5 g 3 times daily plus vancomycin 500 mg twice daily) and rG-CSF in a dose of 300 µg/d (body weight 60 kg on day 1).

No immunosuppressive medications were added due to the long duration between onset of disease and time of presentation and involvement of no new skin lesions for the past 1 week. Despite introduction of rG-CSF from day 1, however, only a moderate increase in leucocyte count was seen (maximum of 12,000 cells/mm3 at day 4) with relatively slow re-epithelialization. On day 5, the patient underwent a sudden episode of severe hypoglycemia followed by cardiac arrest, from which she could not be revived.

Discussion TEN is associated with an overall mortality rate of approximately 30%. In addition, it may be associated with devastating SKINmed. 2013;11:269–271

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Figure 2. Large areas of necrotic and denuded skin over the back with mild to moderate erythema in patient 3.

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ORIGINAL CONTRIBUTION

long-term sequelae in survivors.2 The most important aspects of managing TEN are prompt diagnosis and early withdrawal of all suspect drug(s), supportive therapy, specialized nursing care, multidisciplinary teamwork, prevention of complications, and specific therapy with intravenous immunoglobulins, cyclosporine, or corticosteroids. There have been few case reports of the use of rG-CSF in the treatment of TEN.3,4 Most of these earlier reports described using rG-CSF as an adjunct in the setting of neutropenia and aplastic anaemia.

its usefulness in managing TEN and also to establish appropriate dosage and duration of therapy.

References

Because TEN is characterized by acute skin failure, any agent that induces rapid healing of denuded skin should theoretically reduce the risk of secondary bacterial infection and hence mortality. Investigators have noted that rG-CSF not only accelerates re-epithelialization but also has immune tolerance–inducing properties and therefore have advocated its role in managing TEN irrespective of the presence of neotropenia.1 Researchers have also reported successful use of rG-CSF (5 µg/kg/d for 5 days) in the treatment of nonhealing skin ulcers in systemic sclerosis.5 Topical rG-CSF has been used for the treatment of oral and genital ulcers in Behcet’s disease.6 That rG-CSF is important in wound healing is reinforced by the observation that neovasularization is impaired during healing in granulocytemacrophage colony-stimulating factor absent mice.7 In animal models, a combination of rG-CSF, recombinant macrophage colony-stimulating factor, and inhibitor of transforming growth factor β1 has been shown to improve post-radiotherapy wound strength.8 Investigators found basic fibroblast growth factor and recombinant granulocyte macrophage colony-stimulating factor to be useful options for the treatment of skin injury caused by vinorelbine extravasation.9 In addition to mobilizing regulatory T cells from bone marrow, rG-CSF induces immune tolerance and avoids further tissue damage.10 The first two patients in the present case series had a SCORTEN of 4 and 3, implying a predictive mortality of 58.3% and 36.2%, respectively. The observed mortality was 33%, suggesting that there was no significant improvement in mortality risk; however, in the two surviving patients, the skin lesions healed rapidly after instituting rG-CSF therapy. The third patient in whom fatality was observed had several other poor prognostic factors such as older age, leucopenia at presentation, delay in admission to the hospital, and prior treatment with steroids. No adverse effect secondary to rG-CSF use was seen.

Granulocyte colony-stimulating factor in toxic epidermal necrolysis (TEN) and Chelsea & Westminster TEN protocol. Br J Dermatol. 2010;162:860–865.

2 Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol. 2007;56:181– 200.

3 Robak E, Robak T, Góra-Tybor J, et al. Toxic epidermal necrolysis in a patient with severe aplastic anemia treated with cyclosporin A and G-CSF. J Med. 2001;32:31–39.

4 Goulden V, Goodfield MJ. Recombinant granulocyte colony stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol. 1996;135:305–306.

5 Giuggioli D, Magistro R, Colaci M, et al. The treatment of skin ulcers in systemic sclerosis: use of granulocytecolony stimulating factor (G-CSF) in 26 patients. Reumatismo. 2006;58:26–30.

6 Bacanli A, Yerebakan Dicle O, Parmaksizoglu B, et al. Topical granulocyte colony-stimulating factor for the treatment of oral and genital ulcers of patients with Behçet’s disease. J Eur Acad Dermatol Venereol.

2006;20:931–935.

7 Fang Y, Gong SJ, Wang Y, et al. Effect of GMCSF-absence on neovascularization during wound healing. Zhonghua Zheng Xing Wai Ke Za Zhi. 2007;23:233–235.

8 Sugiyama K, Ishii G, Ochiai A, Esumi H. Improvement of the breaking strength of wound by combined treatment with recombinant human G-CSF, recombinant human MCSF, and a TGF-beta 1 receptor kinase inhibitor in rat skin. Cancer Sci. 2008;99:1021–1028.

9 Yu C, Wang J, Fu Y, et al. Treatment of skin injury due to vinorelbine extravasation using bFGF and rhGM-CSF: an experimental study in a murine model. Biol Res Nurs.

2011;13:32–37.

10 Vela-Ojeda J, Esparza MA, Reyes-Maldonado E, et al.

Conclusions

CD4+ CD25+ lymphocyte and dendritic cell mobiliza-

rG-CSF is a useful adjunct in the treatment of TEN for improving the skin barrier function; however, further prospective randomized studies should be conducted to conclusively prove SKINmed. 2013;11:269–271

1 De Sica-Chapman A, Williams G, Soni N, Bunker CB.

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tion with intermediate doses of recombinant human granulocyte colony-stimulating factor in healthy donors.

Stem Cells Dev. 2005;14:310–316.

Use of Granulocyte Colony-Stimulating Factor

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September/October 2013

Volume 11 • Issue 5

Original contribution

Polypharmacy in Dermatology: Analysis of a Nationally Representative Sample of 46,273 Dermatology Patient Visits in the United States From 1995 to 2009 Madhulika A. Gupta, MD, FRCPC;1 Aditya K. Gupta, MD, PhD, FRCPC;2 Naomi H. Fink, BMSc1 Abstract There are no large-scale studies of polypharmacy (PP) in dermatology. The authors examined trends in PP (simultaneous use of ≥4 medications in our study) and associated clinical factors among a nationally representative sample of 46,273 (weighted count±standard error [SE]: 617,970,596±25,187,959) dermatology-related (International Classification of Diseases, Ninth Revision, Clinical Modification codes 680-709) patient visits from 1995 to 2009.

Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Care Survey were examined. The overall frequency (±SE) of PP was 8.9%±0.4%. There was almost a doubling in the frequency of PP in dermatology from 1995 to 2009 (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.67–2.44, after controlling for comorbidities and sex). This increase was noted among patients with ≥1 diagnoses, and all age groups including the younger than 25 age category (PP frequency±SE, 7.4%±0.4%; OR, 1.45; 95% CI, 1.12–1.88), and not just among patients in the geriatric age range with multiple complex dermatologic problems. Some of the most frequent conditions in the PP group included acne, psoriasis, atopic dermatitis, and infections of the skin and subcutaneous tissue, conditions that are known to be affected by psychodermatologic factors. PP among these patients may in part be an indication of their complex presentation caused by psychosocial vs dermatopathologic factors. (SKINmed.

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P

olypharmacy (PP), a term used to describe simultaneous use of multiple medications in the same patient, commonly refers to patients taking ≥4 medications, even though there is no standard definition of PP.1 PP has been implicated2,3,4 in cases of adverse drug events and increased risk of unexpected drug-drug interactions and poses potentially serious clinical dilemmas as the information available on a drug typically originates only from randomized placebo-controlled trials and medications are almost never tested in conjunction with multiple other medications. Multiple medication regimens may be the result of changes in diagnostic patterns including patients presenting with more complex or ill-defined symptoms, copious prescribing by physicians, increasing expectations by patients for treatment outcomes, available medications, and a growing number of US Food and Drug Administration–approved as well as off-label uses of medications. It is also important to be aware of the potential benefits of multiple drug therapy in some patients

and not to condemn PP in general.5 PP has tended to be considered a problem among older adults in the geriatric age range, and only one recent study examined the use of ≥2 prescription medications in adults aged 25 to 60 years, and found that medication-related adverse reactions such as falls were more common in this age group who were taking ≥2 more prescription drugs.6 Examination of PP in adults who are not in the geriatric age range is a relatively unexplored topic. The skin as an active immune organ is a major target of allergic reactions to a wide range of medications, and the skin can play an important role in metabolism of both oral and topical drugs.7 The impact of PP on the skin, caused by the use of multiple topical and/or oral agents, can therefore affect the metabolism of both topical and systemic medications.7 There are no studies that have systematically examined the trends and demographic and clinical aspects of PP in dermatology patients.

From the Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada;1 and the Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada2 Address for Correspondence: Madhulika A. Gupta, MD, FRCPC, 585 Springbank Drive, Suite 101, London, Ontario, Canada, N6J 1H3 • E-mail: magupta@uwo.ca

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We examined trends in PP, defined in our study as the simultaneous use of ≥4 medications, and associated demographic and clinical features in a nationally representative sample of 46,273 patient visits (weighted count 617,970,596[±standard error (SE)]±25,187,959) in the United States from 1995 to 2009 with only a dermatologic diagnosis. Secondly, we examined PP in dermatology patients representing all age groups and not just among older adults. To our knowledge, there are no reported studies of PP in dermatology patients from an epidemiologically representative sample.

Materials and Methods Data collected between 1995 and 2009 by the National Ambulatory Medical Care Survey (NAMCS)8 and National Hospital Ambulatory Care Survey (NHAMCS),8 which are both nationally representative samples of healthcare visits in the United States, were studied.

The details of the sampling methods used in these 2 databases are described elsewhere9 and on the NAMCS8 and NHAMCS8 websites. The US Bureau of the Census acts as the field data collection agent for the NAMCS and NHAMCS. They are both national surveys conducted by the National Center for Health Statistics at the Centers for Disease Control and Prevention (CDC).8 The NAMCS8 collects information on care provided by officebased physicians, and the data collection is carried out by the physician aided by his or her office staff when possible. The basic sampling unit for the NAMCS is the physician-patient encounter or visit, and the final stage of the sampling process involves the random selection of patient visits by the physician during a 1-week period. The sampling procedure for the NAMCS is designed so that about 30 patient record forms are completed during the assigned reporting week. Physicians record up to 3 diagnoses for each visit. The NHAMCS8 uses similar methods to obtain a national probability sample of visits to the emergency departments and outpatient departments of noninstitutional general and short-stay hospitals, exclusive of federal, military, and Veterans Administration hospitals, located in the 50 States and the District of Columbia. The basic sampling unit for the NHAMCS is the patient visit or encounter, and up to 3 diagnoses are recorded for each visit. All diagnoses are coded using International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes.10 In order to preserve the confidentiality of participating patients and physicians, all survey data in the databases are masked through the inclusion of variables containing stratification, sampling unit, and patient weighting variables. Up to 6 drugs per patient visit were coded in the NAMCS and NHAMCS from 1995 to 2002; from 2003 to 2009 up to 8 drugs per patient visit were coded, using the original CDC’s Ambulatory Care Drug Database System (ACDDS)11 which was based on the Food and Drug Administration’s National Drug Code Directory.

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Study Variables

Patients Only patient visits with a dermatology-related diagnosis (ICD-9CM codes 680 to709 for diseases of the skin and subcutaneous tissue10) were studied to ensure that the medications prescribed were primarily for a dermatologic diagnosis. As up to 3 possible diagnoses were coded for each patient visit, all patients had a dermatologyrelated diagnosis for their primary diagnosis and also their second and third diagnoses where applicable. A dichotomous comorbidity variable was created to compare patient visits with 2 or 3 dermatologic diagnoses vs one dermatology diagnosis only. In order to minimize the contribution of nondermatologic comorbidities toward PP, patient visits with dermatologic diagnoses only were studied.

Year of Visit Patient visits from 1995 to 2009 were studied. A dichotomous (after vs before 2002) variable categorized the 15 years of patient visits represented in the database into visits from (July 2002 to 2009) vs (1995 to June 2002) for some of the analyses.

Demographic Factors Patients representing all age groups and both sexes were studied.

Age was categorized into the following 3 major groups for our analyses: 0 to 24 years, 25 to 65 years, and older than 65 years.

Medications Used in Dermatology Medications classified by the original ACDDS as drugs for the skin/mucous membrane11 (National Drug Code or class category 12) were coded. Table I summarizes the ACDDS dermatology medication groups that were included in our medication variable.

Polypharmacy Variable This variable categorized patients receiving ≥4 medications (maximum of 6 drugs coded from 1995 to 2002 and maximum of 8 drugs coded from 2003 to 2009) vs those receiving 0 to 3 medications. These medications included all possible medications associated with each dermatology patient visit and were not limited to any specific agents. Use of ≥4 medications has been previously used to define PP,1 and it has been reported that, in general, patients taking 2 or 3 drugs do not tend to report medication problems; however, medication-related problems increase when the treatment load exceeds 4 medications.12

Statistical Analysis The data from both the NAMCS and NHAMCS were merged into one dataset. A chi-square test was used to compare categori-

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Table I. Frequencya of Commonly Used Dermatology Medications in the PP vs non-PP Patient Groups Medications (ACDDS Classification and NDC Specific Category)

Frequency±SE (%) of Use in PP vs Non-PP Groups

Topical steroids (code 1268)

22.0%±1.2% vs 11.8%±0.3%

Topical anti-infectives (code 1271)

11.1%±0.8% vs 5.7%±0.2%

Topical acne products (code 1270)

12.0%±1.0% vs 5.4%±0.3%

Dermatitis/antipruritic agents (code 1274)

3.6%±0.5% vs 1.1%±0.1%

Topical analgesics (code 1275)

3.8%±0.5% vs 1.6%±0.1%

Keratolytics (code 1266)

2.4% ±0.3% vs 0.3%±0.0%

Burn/sunburn product (code 1269)

2.3%±0.7% vs 0.9%±0.1%

Antiseptics/disinfectives (code 1264; 99 items)

1.4%±0.3% vs 0.5%±0.1%

Oral acne products (code 1270; acitretin, metronidazole, and isotretinoin)

1.4%±0.3% vs 2.1%±0.1%

a

Abbreviations: ACDDS, Ambulatory Care Drug Database System; NDC, National Drug Code; SE, standard error.

All medications used significantly (P<.01, chi-square test) more frequently in the polypharmacy (PP) group except for the oral acne products, where the frequency of use did not differ significantly (P>.05) between the PP vs non-PP groups. a

Table II. Demographic Characteristics of the Dermatology Patient Sample Dermatology Patients Only (ICD-9-CM Codes 680-709) All patient visits

Total Patient Visits (Weighted±SE Count) 46,273 (617,970,596 [±25,187,959])

Polypharmacy (≥4 medications) patient visits

4,689 (54,945,670 [±3,326,857])

Nonpolypharmacy (<4 medications) patient visits

41,584 (563,024,926 [±22,942,656])

Sex Distribution±SE, %

Racea Distribution±SE, %

38.43±0.11

Men 44.3%±0.4% Women 55.7%±0.4%

White 79.5%±0.8% Black 10.0%±0.5%

40.64±0.351

Men 39.7%±1.2% Women 60.3%±1.2%

White 74.3%±1.6% Black 12.9%±1.4%

38.18±0.118

Men 44.8%±0.4% Women 55.2%±0.4%

White 80.0%±0.8% Black 9.7%±0.4%

Mean Age±SE, Years

Abbreviations: ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; SE, standard error.

The other categories of race include the following: Asian/Native Hawaiian/Pacific Islander/American Indian/Alaska Native/more than 1 race reported/race not coded. a

cal variables and a 2-sample t test was used to compare continuous variables. Logistic regression analysis was used to examine the possible confounding effect of comorbidity, sex, and year of visit on PP. All analyses, including descriptive statistics and calculation of odds ratios, were conducted using the Complex Samples module of SPSS version 15.0 (SPSS Inc, Chicago, IL) in order to account for the multi-stage probability sampling design used by the NAMCS8 and the NHAMCS.8 In order to provide national estimates for the United States, all analyses incorporated sampling weights that account for differential probability of selection and nonresponse.

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Results Table II summarizes the major demographic features of our study sample in patients with and without PP. The overall frequency of PP among dermatology patients representing all age groups increased from 5.6%±0.7% in 1995 to 18.5%±1.9% in 2009 (Figure 1). Figure 1 summarizes the frequencies of PP for each year from 1995 to 2009 among patients representing all age groups. Among the PP group, 43.7%±1.6% of patients used at least 1 dermatology drug listed in Table I.

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Figure 1. Frequency of polypharmacy (PP) by age categories in dermatology patient visits from 1995 to 2009. SE indicates standard error.

Figure 2. Frequency of polypharmacy (PP) by number of dermatologic diagnoses for patient visits from 1995 to 2009. SE indicates standard error.

We examined the relationship between comorbidities and PP. Among patients with 2 or 3 dermatologic diagnoses, the overall frequency of PP was 13.0%±0.7%; among patient visits with only 1 dermatologic diagnosis, the overall frequency of PP was 7.6%±0.4%. Figure 2 summarizes the frequency of PP among SKINmed. 2013;11:273–280

patient visits with 1 vs 2 or 3 dermatologic diagnoses for each year from 1995 to 2009. Table III describes the associations of PP with sex and dermatologic comorbidity across the age groups.

The frequency of PP was significantly higher among women and in patient visits with comorbidities (Table III).

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Table III. OR for PP by Age Group, Sex, Dermatologic Comorbidities, and Year of Patient Visit

OR (95% CI) for PP in Women vs Men

OR (95% CI) for PP With Dermatologic Comorbidities (≥2 Diagnoses vs 1 Diagnosis)

ORa (95% CI) for PP After vs Before 2002, Controlling for Sex and Comorbidities

8.9±0.4

1.23 (1.10–1.38)

1.81 (1.57–2.09)

2.02 (1.67–2.44)

0 to 24 y (26.5%±1.1%)

7.4±0.4

1.06 (0.86–1.31)

3.21 (2.42–4.27)

1.45 (1.12–1.88)

25 to 65 y (50.2%±1.3%)

9.0±0.5

1.27 (1.08–1.48)

1.50 (1.25–1.81)

2.30 (1.85–2.87)

>65 y (23.2%±1.2%)

11.1±0.8

1.36 (1.10–1.68)

1.40 (1.04–1.87)

2.17 (1.58–2.98)

Frequency of PP%±SE% Within Each Age Group

All patient visits

Dermatology Patients by Age Group, %

Abbreviations: CI, confidence interval; PP, polypharmacy; SE, standard error.

Odds ratio (OR) obtained after controlling for (i) year of visit from 1995 to 2009 with dichotomous variable representing patient visits from July 2002 to 2009 (after 2002) vs 1995 to June 2002 (before 2002), (ii) sex (women vs men), and (iii) comorbidities (≥2 dermatologic diagnoses vs 1 dermatologic diagnosis) using logistic regression analysis.

a

Figure 3. Ten most frequent primary dermatologic diagnoses among polypharmacy (PP) patient visits in the 0 to 24 years age category. SE indicates standard error; oth, other; d/t, due to; unsp, unspecified; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

We examined the trends in PP from 1995 to 2009 using the dichotomous “after vs before 2002” variable across all age categories. Table III summarizes the results of the logistic regression analysis, which controlled for the possible confounding effect of sex and comorbidities.

The results (Table III) indicate a consistent and significant increase in the frequency of PP across all age categories during this period.

Figures 3, 4, and 5 show the frequencies of the most common 10 primary dermatologic diagnoses in PP patients representing the SKINmed. 2013;11:273–280

3 age categories of 0 to 24 years, 25 to 65 years, and older than 65 years, respectively.

Discussion We examined the trends in PP, defined as the simultaneous use of ≥4 medications and associated clinical factors such as comorbidities, sex, and age among an epidemiologically representative sample of more than 617 million patient visits (unweighted count, 46,273) from 1995 to 2009. To our knowledge, there are

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Figure 4. Ten most frequent primary dermatologic diagnoses among polypharmacy (PP) patient visits in the 25 to 65 years age category. SE indicates standard error; oth, other; d/t, due to; unsp, unspecified; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

Figure 5. Ten most frequent primary dermatologic diagnoses among polypharmacy (PP) patient visits in the older than 65 years age category. SE indicates standard error; oth, other; d/t, due to; unsp, unspecified; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

no published studies of PP in dermatology from an epidemiologically representative sample and across all age categories. In fact, to our knowledge, the studies of PP have mainly involved patients in the geriatric age range, and there are no large-scale studies of PP among younger adults and youth.

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Our findings indicate a significant and steady increase in the frequency of PP in dermatology patients from 1995 to 2009 (Figure 1), with the most remarkable increase from 2003 to 2009.

The average rate of PP has at least doubled over this time period (Table III), with an increase from 5.6%Âą0.7% in 1995 to

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18.5%Âą1.9%, when one considers the extreme time points. This increase was greater among women vs men (Table III) and was the greatest in the older than 65 years age group, a finding that is consistent with earlier studies. The significant increase in PP also observed in the younger than 25 and 25 to 65 age groups, where the overall rate of increase was not much different from the older than 65 age category (Table II), has not been previously reported. Most studies to date have tended to attribute PP to multiple health problems associated with increasing age and largely focused on the geriatric age group, and to our knowledge there are no published studies of PP in the younger than 25 age group. This increase cannot be explained by a larger number of cutaneous reactions as a result of PP, as the increase in PP persisted (Table III) after the possible confounding effect of other dermatologic comorbidities was controlled for in the logistic regression model.

We considered the possible reasons for the steady increase in the frequency of PP from 1995 to 2009 (Figures 1 and 2, Table III).

We considered the explanation that during this period, especially with the aging of the population, patients were presenting with more medically complex dermatologic conditions that required multiple medications; the 10 most frequent diagnoses in PP for each age category (Figures 3, 4, and 5) do not support this as they do not represent complex dermatologic conditions. The results from Figures 3, 4, and 5 indicate that dermatologic diagnoses that would be expected to occur frequently in a particular age category, eg, acne in the 0 to 24 age category (Figure 3), and actinic keratosis in the older than 65 age category (Figure 5), were the most frequent diagnoses in the PP group for the respective age categories. This also suggests that most of the diagnoses in Figures 3, 4, and 5 most likely represent a primary dermatologic diagnosis vs a cutaneous reaction to medications in the PP group. Some of the dermatologic conditions, eg, contact dermatitis and eczema (Figures 3, 4, and 5) may represent a reaction to the medications in the PP group. It is also noteworthy that several dermatologic conditions listed for the different age categories in Figures 3, 4, and 5 (eg, cellulitis and abscess affecting various body regions involve infection of the skin and subcutaneous tissue) can be a feature of neglect of self-care that is encountered in psychiatric conditions such as depressive disease, psychotic illness, and dissociative disorders; furthermore, most of the other diagnostic groups (Figures 3, 4, and 5) such as acne, eczema due to unspecified cause, atopic dermatitis, psoriasis, urticarial, and rosacea can all be exacerbated by psychological stress and other psychodermatologic factors.13 The representation of these diagnoses in the PP group may be an indication that these patients are more likely to have a complex presentation caused by psychodermatologic rather than primary dermatopathologic SKINmed. 2013;11:273â&#x20AC;&#x201C;280

factors, and the clinician is therefore more likely to employ more complex medical regimens, including PP, for their management.

This has to be examined further by evaluating, for example, the use of psychotropic agents in the dermatology PP population.

Limitations Some of the weaknesses of our study include the fact that the results are based on cross-sectional data from patient visits. First, it is helpful to have data from multiple time points across the years from 1995 to 2009; however, only clinical prospective data can help differentiate between whether a dermatologic condition represents a reaction to medications or the primary dermatologic diagnosis. The basic sampling unit in the NAMCS and NHAMCS is the patient visit, and therefore it is possible that some of the datapoints represent the same patient seen for more than 1 visit during the data collection period. Second, we examined only medications from ACDDS11 classified drugs for skin/mucous membrane, which include largely topical medications. In future analyses we expect to examine in greater detail the various classes of medications included in the PP group. A study of psoriasis patients14 has reported PP in psoriasis as a result of other medical comorbidities. While we have attempted to exclude nondermatologic comorbidities by including only patients who were assigned an ICD-9-CM10 dermatology diagnosis, it is quite possible that PP among some of our patients represent medical comorbidities that were perhaps not coded as one of the 3 primary diagnoses.

Conclusions Our findings overall suggest that the basis for the marked increase in PP in dermatology patients is likely multifactorial. Our findings from this first-reported epidemiologic study of PP in dermatology patients have to be followed up with prospective clinical studies. Our findings do not support the notion that PP is on the rise only among geriatric patients due to multiple health problems that increase with age, as the rate of increase in PP was similar among all age categories including the younger than 25 age group, and the increase was present even after the potential confounding effect of sex and comorbid diagnoses were controlled for statistically (Table III). Our findings suggest that some of the cutaneous reactions observed with PP, eg, contact dermatitis and eczema due to unspecified cause and urticaria, may represent dermatologic reactions to multiple medications; however, the preponderance of conditions that are also affected by psychodermatologic factors,13 eg, acne, psoriasis, eczema, urticaria, atopic dermatitis, and infection of the skin and subcutaneous tissue (Figures 3, 4, and 5), suggests that patients receiving PP may have presented with complex symptoms to the clinician as a result of associated psychodermatologic and not necessarily

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primary dermatopathologic factors, which, in turn, predisposed the clinician to prescribe more complex medical regimens including PP. Finally, the increasing trend in PP, especially since 2003, across all age categories (Figure 1) and among patients with both 1 vs 2 or 3 dermatologic diagnoses (Figure 2) may also be an indication of a general trend for copious prescribing by physicians and increasing expectations by patients for treatment outcomes.

References 1 Milton JC, Jackson SH. Inappropriate polypharmacy: reducing the burden of multiple medication. Clin Med. 2007;7:514–517.

2 Colley CA, Lucas LM. Polypharmacy: the cure becomes the disease. J Gen Intern Med. 1993;8:278–283.

7 Merk HF. Drug skin metabolites and allergic drug reactions. Curr Opin Allergy Clin Immunol. 2009;9:311–315.

8 Centers for Disease Control and Prevention: National Center for Health Statistics. Ambulatory Health Care Data. http://www.cdc.gov/nchs/about.htm. Accessed June 24, 2012.

9 Gupta MA, Gupta AK, Chen SJ, et al. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey-Outpatient Department data collected by the U.S. National Center for Health Statistics from 1995 to 2002. Br J Dermatol. 2005;153:1176– 1181.

10 International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). 2004, volumes 1 and 2.

Chicago, IL: AMA Press; 2003.

3 Preskorn SH, Lacey LR. Polypharmacy: when is it rational? J Psychiatr Pract. 2007;13:97–105.

11 Ambulatory Care Drug Database System. Centers for Disease Control and Prevention: National Center for Health Statistics. http://www2.cdc.gov/drugs/index. asp. Accessed June 24, 2011.

4 Fialova D, Onder G. Medication errors in elderly people: contributing factors and future perspectives. Br J Clin Pharmacol. 2009;67:641–645.

12 Bjerrum L, Sogard J, Hallas J, et al. Polypharmacy: correlations with sex, age and drug regimen. A prescription database study. Eur J Clin Pharmacol. 1998;54:197–202.

5 Steinman MA. Polypharmacy and the balance of medication benefits and risks. Am J Geriatr Pharmacother.

2007;5:314–316.

13 Gupta MA, Gupta AK. Psychodermatology: An update. J Am Acad Dermatol. 1996;34:1030–1046.

6 Slomski A. Falls from taking multiple medications may be a risk for both young and old. JAMA. 2012;307:1127– 1128.

14 Gerdes S, Zahl VA, Knopf H, et al. Comedication related to comorbidities: a study in 1203 hospitalized patients with severe psoriasis. Br J Dermatol. 2008;159:1116– 1123.

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Aging and Facial Changes—Documenting Clinical Signs, Part 1: Clinical Changes of the Aging Face Alex Nkengne, PhD; Christiane Bertin, MS Abstract The process of aging induces the transformation of the face with changes that are usually classified as either chronological or photo-induced and that affect the shape, the texture, and the color of the face. Facial shape is mainly transformed by the evolution of bones and soft tissues (muscles, fat, and skin) in addition to noticeable effects of gravity. Skin texture is mainly determined by wrinkles, which arise from atrophy of the skin layers, elastosis, and facial expressions. Skin color is related to the distribution of skin chromophores and the structure of the dermis, which affects light scattering. All facial changes are dependant on sex, ethnicity, and lifestyle. They affect self-perception and social interactions and can sometimes be slowed down or reversed using appropriate clinical procedures (eg, dermatological, surgical, cosmetic interventions). (SKINmed. 2013;11:281–286)

S

agging, wrinkling, and changes in pigmentation are typical characteristics of advancing facial aging that progressively transform the youthful appearance with smooth lines and surfaces and clear facial contours (Figure). The first visually perceptible alterations in facial skin attributed to aging occur as early as in the third decade of life; however, these alterations are subject to sex- and ethnicity-specific variations and are influenced by environmental factors, in particular sun exposure and lifestyle and social factors.

Bones and cartilage provide the structural support and define the contours of the face. These structures undergo age-dependant changes that impact the firmness and smoothness of the skin. The individual characteristics of the face are, furthermore, shaped by soft tissues, ie, facial muscles and fat, which give the face soft and rounded contours. Facial expressions, speech, and mastication depend on the activation of specific muscle combinations. Prominent wrinkles and folds, such as forehead lines, crow’s feet in the corner of the eyes ,and the nasolabial folds appear and/or deepen through repeated muscular activation. Both chronological age and extrinsic factors influence the surface texture (soft vs dry, rough), topography (smooth vs wrinkled), and pigmentation of the skin (even vs blotched).

Clinical Changes of the Aging Face

Factors Influencing Facial Aging The skin’s aging process is influenced by intrinsic and extrinsic factors. In sun-exposed areas such as the face, skin aging is most obvi-

ous. An estimated 80% of facial aging is attributed to UV exposure1; photoaging (ie, the deleterious effects of chronic UV light exposure on skin2) is thus synonymous with extrinsic aging. Patients with long-term sun exposure accumulate more extensive signs of aging such as wrinkling and hyperpigmentation than those with less exposure. Cellular damage and tissue breakdown evoked by reactive oxygen species (ROS) is a molecular mechanism central to both chronological aging and photoaging. ROS production arises from endogenous activity (mitochondrial respiration) as well as UV radiation. ROS activity induces mitochondrial DNA damage, inhibits procollagen expression, and leads to accumulation of partially degraded collagen. The latter is due to the upregulation of collagen-degrading matrix metalloproteinases in keratinocytes and fibroblasts.3 Next to UV exposure, exposure to tobacco smoke is the best documented factor decisive in premature skin aging. Smokers have a higher extent of skin elastosis4,5 and more wrinkling of the face than nonsmokers.6–8 One study found that smoking 20 cigarettes daily corresponds to almost 10 years of chronological aging.9 Impairment of collagen synthesis and induction of matrix metalloproteinases are among the molecular mechanisms that explain the effect of tobacco smoke on skin.10 The high intake of certain food groups, including vegetables, olive oil, and fish, was found to be related to less skin wrinkling compared with other foods, including dairy products, butter, margarine, and sugar products, the intake of which reportedly correlated with more wrinkling.11

From Johnson & Johnson Santé Beauté France, Issy les Moulineaux, France Address for Correspondence: Alex Nkengne, PhD, Johnson & Johnson Santé Beauté France, 1, rue Camille Desmoulins, 92787 Issy-les-Moulineaux, France • E-mail: ANKENGNE@its.jnj.com

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Figure. Differences between the facial appearance of a 23-year-old Caucasian woman vs a 61-year-old Caucasian woman. Shape: Sagging of the jaw line, lips thickness, cheek fullness, orbital rim. Texture: Expression and solar elastosis wrinkles. Color: Dull and uneven skin tone.

Gravity was evoked as a force that contributed to the shift in subcutaneous tissues and drooping of the eyelids, brows, nose, lips, and cheeks seen in people of advanced age.12 Its effect on the shape of the jaw line was demonstrated in silico.13 Among the intrinsic factors influencing skin aging are genetic traits14 and hormone homeostasis.15 Sex-specific, age-related skin deterioration is attributed to a shift in sex-hormone balance as estrogen production declines with the onset of menopause in women. The resulting hypoestrogenism triggers a reduction of the content in collagen and hydrophilic glycoaminoglycans.16 The consequence is thinner skin, deeper and more numerous wrinkles, increased skin dryness, and decreased skin firmness and elasticity.17 In postmenopausal women, the rate of collagen loss is 2% annually.18 Hormone replacement therapy can mitigate the deterioration of skin quality that accompanies the decline in estrogen during and after menopause19; however, it does not modify increased wrinkling caused by smoking.7 Adding to the cutaneous changes due to reduced estrogen production is bone SKINmed. 2013;11:281–286

Ethnicity was also documented to have a marked impact on facial aging. The most obvious difference in skin quality between different ethnic groups is skin pigmentation due to differences in melanin content, a pigment that is supposed to play a photo-protective role by absorbing UV radiation from sunlight.20 Light-pigmented skin types of European, Chinese, or Mexican origin have less epidermal melanin and smaller melanosomes than dark-pigmented skin types of African and Indian origin.21 Individuals with low constitutive pigmentation burn more and tan less readily than those who have higher pigmentation;22 furthermore, skin aging appears later in darker-skinned individuals and with signs predominantly including mottled pigmentation and uneven skin tone compared with lighter-skinned individuals who feature wrinkling and sagging as major skin problems.21 Facial wrinkles were reported to appear about 10 years later in Chinese women compared with French women, but the former experienced a fast-progressing aging process between age 40 and 50, while the wrinkling rate in French women remained constant.23 Age pigmentation on the other hand was more severe in Chinese women compared with their French counterparts; however, the chronology of wrinkle appearance, first crow’s feet, then glabellar wrinkles, followed by perioral wrinkles, was the same in both populations. Caucasian women living in Cincinnati showed more wrinkling (in particular in the lower parts of the face) and sagging compared with Japanese woman living in Tokyo.24 Among Asian women living in Bangkok, Tokyo, and Shanghai, facial wrinkling was more pronounced in those living in Bangkok.25 In a cohort of women of different ethnic background (Caucasian, Asian Indian, African American, Latino, East Asian) living in Los Angeles, Caucasian women had more wrinkles than any other ethnic group and East Asians had the least, while African American women had more hyperpigmented spots and East Asians the least.26 The drawback of studies such as these is that confounding factors such as differences in melanosome density and size, climatic conditions, sun exposure, nutrition, and lifestyle are difficult to control and conclusions as to the source of the observed differences remain speculative.

Skin wrinkling and hyperpigmentation were found to have a stronger correlation with perceived facial age (ie, the estimated age of a person derived from visual cues) than with chronological age.27 The facial features that appear to influence most of the perception of someone’s age are lip volume, upper lip wrinkles, crow’s feet, wrinkles and bags under the eyes, dark circles under the eyes, brown spots, and skin color uniformity.28 Even isolated skin images of the cheek that reveal no other information but skin color

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distribution permit a fairly accurate estimate of a personâ&#x20AC;&#x2122;s age.29 Sun exposure, smoking, and a low body mass index were found to negatively influence perceived facial age, while a high social status, a low depression score, and being married were associated with a younger perceived age;30 furthermore, perceived age was inversely correlated with physical and cognitive function and a predictor of survival, as indicated in a study of pairs of twins wherein the olderlooking twin was found to be more likely to die first.31 Clinical Changes With Age

Facial Shape The bony and cartilaginous structures of the craniofacial skeleton function as scaffolding for the overlying soft tissue and skin and define the facial anatomy. The facial bones comprise 14 bones of the anterior and lower skull. They function as attachment for the facial muscles, support the teeth, maintain the nasal airway, and support organs for the main senses. Not all structures of the face are determined by the shape of the skull, such as the shape of the eyes and eyelids, the tip of the nose, and the lips. On the other hand, the overall face shape, the forehead, margins of the eyes, cheeks, bridge of the nose, and chin are closely related to the contours of the facial bones.32 The facial bones are subject to noticeable transformations as we age.33â&#x20AC;&#x201C;36 There is an apparent rotation of the facial skeleton, as the frontal bone moves anteriorly and inferiorly, while the maxillae move posteriorly and superiorly.33 The superior and inferior orbital rims recede, thereby significantly changing the orbital aperture.35 Bony prominences coarsen, facial height diminishes especially in the maxillae and mandible, and strongly correlate with loss of teeth, while facial width and depth increase with age.37 Some skeletal changes are more dramatic in the female population, such as mandible resorption,38 and are probably related to increasing osteoporosis with age through bone demineralization. The remodeling of the bony structures and cartilage affects the position of overlying soft tissues and results in the face losing the softer curves of youth and a shift in facial proportions.

The facial muscles are a group of striated muscles that form layers over the cranium, facial bones, cartilage, fat, and other tissues of the head. They are localized subcutaneously where they originate on bone and insert on the skin of the face. Through isolated or combined activity, they control facial expressions, speech, mastication, and opening/closing of the eyes. With advancing age, muscle tissue progressively diminishes, causing the loss of muscle mass and strength (sarcopenia).39 Weakening of the facial mimetic muscles contributes to sagging, which is the case in brow ptosis (drooping) through weakening of the lateral SKINmed. 2013;11:281â&#x20AC;&#x201C;286

frontalis muscle (outer forehead). Repeated downward contraction of the orbicularis oculi muscle (around the eye) and glabellar muscles (between eyebrows) also plays a role in this process.

The young face has an even distribution of fat, conferring a homogenous appearance without compartmentalization. Major arcs define the 3-dimensional topography of the face: in front view, the jawline from ear to ear and the convexity of the temples; in side view, the arc that constitutes the forehead and the brows, the convexity of the cheeks, and the arcs that define the lips in profile and front view.40 The aging face undergoes atrophy and hypertrophy of subcutaneous fat that largely contribute to the changes in the 3-dimensional topography. Fat atrophy is observed in the forehead and periorbital, temporal, perioral and buccal areas, while fat hypertrophy occurs submentally, in the jowl, lateral nasolabial folds, lateral labiomental creases, and lateral malar areas. The nasolabial fold can appear at all ages, but similar to expression wrinkles, its depth increases with age.41 With age, the orbital septum weakens, causing pseudoherniation of orbital fat and contributing to lower eyelid prominence.12 Shifts in the subcutaneous fat also impacts muscles, as seen in the nose where subcutaneous fat infiltration of muscle tissue contributes to nose ptosis.42 Lips become thinner and the lip vermilion area (red area) becomes smaller.12 Thus, the aging face appears more compartmentalized and looses the convex outlines of the youthful arcs that are replaced by straighter (eg, the cheeks, lips) or wavy lines (eg, the jawline).

Skin anatomy exhibits three layers: the epidermis, the outer layer, which is in direct contact with the environment; the underlying dermis, which supports and sustains the epidermis; and the hypodermis. The dermis is a network of connective tissue, largely consisting of collagen fibers that confer tensile strength and resistance to shear and other mechanical forces. Type I collagen is secreted by fibroblasts and forms more than 90% of the dry weight of the dermis. Elastin fibers, which make up a small part of the dermal weight, give skin its elasticity. The subcutaneous fat layer, the hypodermis, provides the skin with nutrients and contains blood vessels and nerves. Underneath the dermis lies the superficial musculoaponeurotic system, which connects the facial muscles with the dermis and consists of collagen, elastic fibers, and fat cells.43 Photoaging is considered to amplify and increase the molecular changes that are associated with chronological/intrinsic skin aging.44 Regardless of the overlap in molecular changes in aged, sun-protected skin and photoaged skin (connective tissue damage, elevated levels of collagen-degrading matrix metalloproteinase, and reduced collagen production45), both processes display microscopic and macroscopic differences. With age, the skin becomes increasingly lax and accumulates fine wrinkles. Pho-

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todamaged skin on the other hand exhibits variable epidermal thickness and solar elastosis, ie, accumulation of degraded and disorganized elastic fibers. The amount of mature collagen and its overall density decrease, and partially degraded collagen accumulates, resulting in the fibrous network becoming coarser.46,47

visible scars (“solar scars”), which, upon accumulating damage, eventually turn into wrinkles.55 Deep, coarse wrinkles; dryness; and leathery appearance are tell tale signs of photodamaged skin.

Individuals with lighter skin color are more prone to accumulate photo damage than others.

Fat hypertrophy and resorption of mandibular and maxillary bones together with muscle weakness and decreasing skin elasticity and firmness due to changes in the collagen and elastin network affect facial shape, which is obvious in the jaw line with chin ptosis and a weak mandibular line and in the orbital area with eyelid sagging and bulging fat under the eyes.12

The decline in epidermal cell turnover56 and changes in Stratum corneum lipid content with increasing age57 translate to a compromised skin barrier function and increased skin dryness.58 Skin of very old persons typically appears scaly and parchment-like.

Facial Skin Texture The primary change in facial skin texture with age includes excessive wrinkling on the forehead, periorbital area, perioral area, and on the cheeks and neck brought about by epidermal atrophy, atrophy of skin components (such as collagen), and elastosis related to sun exposure, facial expressions, and gravity.48,49 Three major groups of wrinkles are distinguished50: crinkling-type wrinkles that form from folded skin and may be caused by sun damage; glyphic wrinkles with a crisscross pattern frequently seen on the neck and cheeks; and deep wrinkles that form long and straight major lines or deep grooves such as forehead wrinkles and crow’s feet.

Repeated activation of facial mimetic muscles causes the appearance of permanent crease lines such as frown lines and furrows on the forehead that eventually remain obvious even in a relaxed state.12 These lines appear perpendicular to the long axis of the muscle activity: the frontalis muscle works in a vertical plane to lift the eyebrows and creates horizontal frown lines; the lips are surrounded by the horizontally running orbicularis oris muscles, which create vertical lines.51 The cohesion of the dermis and epidermis is ensured by fingerlike structures, the rete ridges, which are at the dermal-epidermal junction that interlock these two skin layers and support the transfer of nutrients from dermal blood vessels to the epidermis.

The epidermis of chronologically aged skin is atrophic and the dermal-epidermal junction is flattening with a loss of rete ridges.52 Underneath wrinkles, the collagen content of the dermalepidermal junction is deminished and the epidermal thickness is smaller than in the surrounding areas.53 Atrophy of the dermis with a decrease in fibroblasts and collagen combined with the disorganization of the elastic fibers also contribute to skin wrinkling;45,54 furthermore, the orientation and depth of microrelief structures is affected by age-related changes in collagen. As discussed above, the majority of changes in aging skin are attributed to photodamage. Solar damage leaves inSKINmed. 2013;11:281–286

Facial Skin Color Visual perception of skin color is due to light absorption by the chromophores melanin, oxy-hemoglobin and deoxy-hemoglobin, and light scattering by collagen fibers and melanosomes.

Age-related changes in skin color are caused by modifications in the distribution of chromophores and by alterations in the dermis structure that affect scattering. Photoaging involves the appearance of hyperpigmented spots (solar lentigo), irregular pigmentation (due to uneven distribution of pigment cells, loss of melanocytes, and a modification in the interactions between melanocytes and keratinocytes59), and solar elastosis manifested as the thickened, coarse, and yellowish appearance of skin.60 Blood microcirculation in the dermis changes with age and thus the contribution of hemoglobin to skin color.61 Discussion Facial aging is a progressive process involving the combined effect of changes in the soft tissue and bony structures, collagen network, skin texture, elasticity, firmness, and pigmentation. These changes together give the following overall picture of the anatomy and surface structure of the aging face. In the upper third of the face, brow ptosis, crow’s feet, bulging of fat in the lower lid, wrinkling of forehead, and glabella are observed. In the midface, the bone and cartilage elements that underlie the nose may protrude through the thinning skin and subcutaneous tissue and the tip of the nose droops. The nasojugal fold deepens and the cheeks loose their juvenile round appearance due to shifting soft tissue. Typical features of the aging lower third of the face include the weakening of a well-defined mandibular line with chin ptosis and jowl formation from excess skin and sagging of fat and soft tissue in the mandibular region. Laxity of the platysma (a superficial muscle in the neck) causes the appearance of vertical bands in the neck. Earlobe elongation due to skin laxity is also a prominent characteristic. In the perioral area, thinning of the upper lip vermillion area and an increase in height of the white upper lip are noticeable along with the appearance of lines and wrinkles around the mouth. This goes hand in hand with overall face wrinkling and uneven pigmenta-

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tion. All these changes influence the apparent age of an individual, hence the pursuit of solutions to prevent and reverse them.

11 Purba MB, Kouris-Blazos A, Wattanapenpaiboon N, et al. Skin wrinkling: can food make a difference? J Am Coll Nutr. 2001;20:71-80.

Conclusions

12 Friedman O. Changes associated with the aging face. Facial Plast Surg Clin North Am. 2005;13:371-380.

While the contributing sources to skin aging are multifactorial, photodamage is by far the main player in the process. Sun protection/avoidance is thus a key player to prevent aging. Once aged skin is apparent, the challenge to reduce or reverse this is to attack the different levels of the facial anatomy that are concerned. If desired, multidisciplinary approaches are available to this end: cosmetic products to improve skin elasticity, correct wrinkles, dry and rough skin; chemical peels and laser therapy for skin regeneration and correction of discoloration; botulinum toxin injections to relax hyperfunctional facial muscles; dermal fillers to compensate for volume loss; and plastic surgery to rebalance facial proportions.

13 Barbarino GG, Jabareen M, Trzewik J, et al. Development and validation of a three-dimensional finite element model of the face. J Biomech Eng. 2009;131:041006.

Disclosures and acknowledgement: All of the authors are full time employees of Johnson & Johnson Santé Beauté France. We would like to thank Beate Gerstbrein for her considerable help for editing and reviewing this manuscript.

References 1 Uitto J. Understanding premature skin aging. N Engl J Med. 1997;337:1463-1465.

2 Kligman LH. Photoaging. Manifestations, prevention, and treatment. Dermatol Clin. 1986;4(3):517-528.

3 Kohl E, Steinbauer J, Landthaler M, Szeimies RM. Skin ageing. J Eur Acad Dermatol Venereol. 2011;25:873-884.

4 Boyd AS, Stasko T, King LE, Jr, et al. Cigarette smokingassociated elastotic changes in the skin. J Am Acad Dermatol. 1999;41:23-26.

5 Kennedy C, Bastiaens MT, Bajdik CD, et al. Effect of smoking and sun on the aging skin. J Invest Dermatol.

Apr 2003;120:548-554.

6 Koh JS, Kang H, Choi SW, Kim HO. Cigarette smoking associated with premature facial wrinkling: image analysis of facial skin replicas. Int J Dermatol. 2002;41:21-27.

7 Castelo-Branco C, Figueras F, Martinez de Osaba MJ, Vanrell JA. Facial wrinkling in postmenopausal women.

Effects of smoking status and hormone replacement therapy. Maturitas. 1998;29:75-86.

8 Asakura K, Nishiwaki Y, Milojevic A, et al. Lifestyle factors and visible skin aging in a population of Japanese elders. J Epidemiol. 2009;19:251-259.

9 Leung WC, Harvey I. Is skin ageing in the elderly caused by sun exposure or smoking? Br J Dermatol.

2002;147:1187-1191.

10 Morita A, Torii K, Maeda A, Yamaguchi Y. Molecular basis of tobacco smoke-induced premature skin aging. J Investig Dermatol Symp Proc. 2009;14:53-55.

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14 Guinot C, Malvy DJ, Ambroisine L, et al. Relative contribution of intrinsic vs extrinsic factors to skin aging as determined by a validated skin age score. Arch Dermatol.

2002;138:1454-1460.

15 Verdier-Sevrain S, Bonte F, Gilchrest B. Biology of estrogens in skin: implications for skin aging. Exp Dermatol.

2006;15:83-94.

16 Raine-Fenning NJ, Brincat MP, Muscat-Baron Y. Skin aging and menopause: implications for treatment. Am J Clin Dermatol. 2003;4:371-378.

17 Stevenson S, Thornton J. Effect of estrogens on skin aging and the potential role of SERMs. Clin Interv Aging.

2007;2:283-297.

18 Brincat M, Kabalan S, Studd JW, et al. A study of the decrease of skin collagen content, skin thickness, and bone mass in the postmenopausal woman. Obstet Gynecol. 1987;70:840-845.

19 Brincat MP. Hormone replacement therapy and the skin.

Maturitas. 2000;35:107-117.

20 Brenner M, Hearing VJ. The protective role of melanin against UV damage in human skin. Photochem Photobiol.

2008;84:539-549.

21 Rawlings AV. Ethnic skin types: are there differences in skin structure and function? Int J Cosmet Sci. 2006;28:7993.

22 Wagner JK, Parra EJ, Norton HL, Jovel C, Shriver MD. Skin responses to ultraviolet radiation: effects of constitutive pigmentation, sex, and ancestry. Pigment Cell Res. 2002;15:385-390.

23 Nouveau-Richard S, Yang Z, Mac-Mary S, et al. Skin ageing: a comparison between Chinese and European populations. A pilot study. J Dermatol Sci. 2005;40:187193.

24 Tsukahara K, Fujimura T, Yoshida Y, et al. Comparison of age-related changes in wrinkling and sagging of the skin in Caucasian females and in Japanese females. J Cosmet Sci. 2004;55:351-371.

25 Tsukahara K, Sugata K, Osanai O, et al. Comparison of age-related changes in facial wrinkles and sagging in the skin of Japanese, Chinese and Thai women. J Dermatol Sci. 2007;47:19-28.

26 Hillebrand GG, Levine MJ, Miyamoto K. The age dependent changes in skin condition in African-Americans, Asian Indians, Caucasians, East Asians & Latino’s. IFSCC Mag. 2001:259-266.

27 Mayes AE, Murray PG, Gunn DA, et al. Ageing appearance in China: biophysical profile of facial skin and its relationship to perceived age. J Eur Acad Dermatol Venereol. 2010;24:341-348.

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28 Nkengne A, Bertin C, Stamatas GN, et al. Influence of facial skin attributes on the perceived age of Caucasian women. J Eur Acad Dermatol Venereol. 2008;22:982-991.

29 Matts PJ, Fink B, Grammer K, Burquest M. Color homogeneity and visual perception of age, health, and attractiveness of female facial skin. J Am Acad Dermatol.

2007;57:977-984.

30 Rexbye H, Petersen I, Johansens M, et al. Influence of environmental factors on facial ageing. Age Ageing.

2006;35:110-115.

31 Christensen K, Thinggaard M, McGue M, et al. Perceived age as clinically useful biomarker of ageing: cohort study. BMJ. 2009;339:b5262.

32 Evison MP. Modeling age, obesity, and ethnicity in a computerized 3-D facial reconstruction. 9th Biennial Meeting of the International Association for Craniofacial Identification, FBI; 2000; Washington, DC. 33 Richard MJ, Morris C, Deen BF, Gray L, Woodward JA. Analysis of the anatomic changes of the aging facial skeleton using computer-assisted tomography. Ophthal Plast Reconstr Surg. 2009;25:382-386.

34 Mendelson BC, Hartley W, Scott M, McNab A, Granzow JW. Age-related changes of the orbit and midcheek and the implications for facial rejuvenation. Aesthetic Plast Surg. 2007;31:419-423.

35 Kahn DM, Shaw RB, Jr. Aging of the bony orbit: a threedimensional computed tomographic study. Aesthet Surg J. 2008;28:258-264.

36 Shaw RB, Jr, Kahn DM. Aging of the midface bony elements: a three-dimensional computed tomographic study. Plast Reconstr Surg. 2007;119:675-681; discussion 682-673.

37 Bartlett SP, Grossman R, Whitaker LA. Age-related changes of the craniofacial skeleton: an anthropometric and histologic analysis. Plast Reconstr Surg. 1992;90:592600.

38 Soikkonen K, Ainamo A, Xie Q. Height of the residual ridge and radiographic appearance of bony structure in the jaws of clinically edentulous elderly people. J Oral Rehabil. 1996;23:470-475.

45 Varani J, Warner RL, Gharaee-Kermani M, et al. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol. 2000;114:480-486.

46 Yaar M, Gilchrest BA. Photoageing: mechanism, prevention and therapy. Br J Dermatol. 2007;157:874-887.

47 Bernstein EF, Chen YQ, Kopp JB, et al. Long-term sun exposure alters the collagen of the papillary dermis.

Comparison of sun-protected and photoaged skin by northern analysis, immunohistochemical staining, and confocal laser scanning microscopy. J Am Acad Dermatol. 1996;34(2 pt 1):209-218.

48 Quatresooz P, Thirion L, Pierard-Franchimont C, Pierard GE. The riddle of genuine skin microrelief and wrinkles.

Int J Cosmet Sci. 2006;28:389-395.

49 Callaghan TM, Wilhelm KP. A review of ageing and an examination of clinical methods in the assessment of ageing skin. Part 2: Clinical perspectives and clinical methods in the evaluation of ageing skin. Int J Cosmet Sci. 2008;30:323-332.

50 Kligman AM, Zheng P, Lavker RM. The anatomy and pathogenesis of wrinkles. Br J Dermatol. 1985;113:3742.

51 Wray D, Stenhouse D, Lee D, Clark AJE, eds. Textbook of General and Oral Surgery. Churchill Livingstone; 2003.

52 Kurban RS, Bhawan J. Histologic changes in skin associated with aging. J Dermatol Surg Oncol. 1990;16:908914.

53 Contet-Audonneau JL, Jeanmaire C, Pauly G. A histological study of human wrinkle structures: comparison between sun-exposed areas of the face, with or without wrinkles, and sun-protected areas. Br J Dermatol. Jun 1999;140:1038-1047.

54 Lapiere CM. The ageing dermis: the main cause for the appearance of ‘old’ skin. Br J Dermatol. 1990;122 suppl 35:5-11.

55 Kang S, Fisher GJ, Voorhees JJ. Photoaging: pathogenesis, prevention, and treatment. Clin Geriatr Med. 2001;17:643-659, v-vi.

39 Marcell TJ. Sarcopenia: causes, consequences, and preventions. J Gerontol A Biol Sci Med Sci. 2003;58:M911916.

56 Grove GL, Kligman AM. Age-associated changes in human epidermal cell renewal. J Gerontol. 1983;38:137142.

40 Donofrio LM. Fat distribution: a morphologic study of the aging face. Dermatol Surg. 2000;26:1107-1112.

57 Rogers J, Harding C, Mayo A, Banks J, Rawlings A. Stratum corneum lipids: the effect of ageing and the seasons. Arch Dermatol Res. 1996;288:765-770.

41 Yousif NJ, Gosain A, Sanger JR, Larson DL, Matloub HS. The nasolabial fold: a photogrammetric analysis. Plast Reconstr Surg. 1994;93:70-77.

42 Vacher C, Accioli J, Lezy JP. Surgical anatomy of the nose in the elderly: value of conservative rhinoplasty by transoral route. Surg Radiol Anat. 2002;24:140-146.

43 Ghassemi A, Prescher A, Riediger D, Axer H. Anatomy of the SMAS revisited. Aesthetic Plast Surg. 2003;27:258264.

44 Fisher GJ, Kang S, Varani J, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol.

2002;138:1462-1470.

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58 Engelke M, Jensen JM, Ekanayake-Mudiyanselage S, Proksch E. Effects of xerosis and ageing on epidermal proliferation and differentiation. Br J Dermatol.

1997;137:219-225.

59 Ortonne JP. Pigmentary changes of the ageing skin. Br J Dermatol. 1990;122 suppl 35:21-28.

60 Gilchrest BA. Skin aging and photoaging. Dermatol Nurs.

1990;2:79-82.

61 Li L, Mac-Mary S, Sainthillier JM, et al. Age-related changes of the cutaneous microcirculation in vivo. Gerontology. 2006;52:142-153.

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Core curriculum Virendra N. Sehgal, MD, Section Editor

Hair Biology and Its Comprehensive Sequence in Female Pattern Baldness: Treatment Modalities—Part III Virendra N. Sehgal, MD; Govind Srivastava, MD; Ashok K. Aggarwal, MD; Rashmi Midha, MBBS

Female pattern baldness is a major social concern for many women afflicted with hair loss. Parts I and II of this review discussed the types, sequence, and diagnosis of this condition. Part III will conclude the discussion by presenting treatment options for female pattern baldness.

Treatment Modalities

Medical Treatments Minoxidil Minoxidil is an ideal effective topical treatment for female pattern baldness (FPB), because it fulfills other requirements: (1) it stimulates a telogen to anagen transition, (2) it retards the onset of catagen/telogen, and/or (3) it enlarges the dermal papillae/matrix in order to produce a thicker diameter hair.1 Although there are many compounds that purport to do one or more of the preceding functions, the only compound that has been found effective in the treatment of female pattern hair loss (FPHL) in multicenter controlled trials is topical minoxidil. It is a piperidylpyrimidine derivative that causes hypertrichosis when given systemically for the treatment of hypertension.2,3 It also causes vasodilation through the potassium channel opening activity of its active metabolite, minoxidil sulfate. Although its precise mechanism of action in inducing hair growth is debatable, it appears to directly increase follicular proliferation.4 Topical minoxidil has been found to promote anagen growth and leads to an increase in the size of the affected hair follicle in both studies of the stump tail macaque and humans.4,5 It has a few side effects, including contact dermatitis. Its frequency is less than 8% and is more often used with 5% than 2% solution due to the higher concentration of propylene glycol, a frequent irritant.4 A newer

formulation of 5% topical minoxidil in a foam vehicle without propylene glycol has recently been approved by the US Food and Drug Administration and may lower the incidence of this potential side effect. Hypertrichosis may occur in 3% to 5% of women using 2% topical minoxidil solution, while it is likely to be higher in those using 5% solution.6

Anti-Androgens There are three anti-androgens that may be used in FPHL. They are approved for use in different countries for various indications. Spironolactone is an approved diuretic for treatment of hypertension in the United States,7 whereas it is recommended for use in hirsutism in Australia. Flutamide is approved as a treatment for prostate cancer in combination with luteinizing hormone. Releasing hormone and cyperoterone acetate are unavailable in the United States. Each has their own advantages and disadvantages in the treatment of FPB. All these drugs can cause feminization of a male fetus in pregnant women; therefore, they are contraindicated in pregnancy.8

Spironolactone Spironolactone, an anti-androgen, not only blocks the production of testosterone in the adrenal gland by decreasing the activity of cytochrome P450-dependent enzymes, but it is also a competitive inhibitor of the dihydrotestosterone receptor and

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

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nuclear translocations. Canrenone and potassium-canrenone, with half-lives of about 20 hours, are its major metabolites and are eliminated through the biliary route.9 Its effective minimal dose is 100 mg per day, based more on the treatment of hirsutism than alopecia; however, its usual dose is 100 to 200 mg per day. The drug is used regularly in the treatment of FPB in women, particularly in those with documented hyperandrogenism.10,11 Hyperkalemia is its potential side effect, related to its aldosterone antagonist/potassium-sparing effect on the kidney. Potassium level, therefore, should be checked after starting the drug. It may cause breast tenderness, irregular menses, and mood swings. It is worthwhile that women of child-bearing potential use oral contraceptives prior to instituting spironolactone.

Flutamide Flutamide’s metabolite 2-hydroxy flutamide is a nonsteroidal, pure antiandrogen with hardly any intrinsic androgenic activity.

It inhibits the binding of testosterone to an androgen receptor, the negative feedback of gonadal steroids at the hypothalamicpituitary level, and adrenal12,13 desmolase, with a resulting decrease in dehydroepiandrosterone DHEA and DHEAS.7,9 It is primarily excreted through the kidneys.

The drug has been evaluated only in women with hair loss accompanied by hyperandrogenism. A combined administration of 250 mg of flutamide twice a day along with oral contraceptive agents has yielded cosmetically acceptable growth in 6 of 7 women in one study and may have superior efficacy in alopecia compared with spironolactone. Gastrointestinal disturbances including diarrhea are its major side effects. Hepatotoxity is its major limitation for use as a therapeutic agent.7

Cyproterone Acetate Cyproterone acetate blocks dihydrotestone (DHT) androgen receptor binding, and given its steroid structure, it has progestogenic and antigonadotropic properties. In women of childbearing potential, estrogens are usually given with cyproterone acetate in order to reinforce the latter effect and to ensure regular menses. Two combinations of cyproterone acetate with 50 μg ethinyl-estradiol are utilized for their anti-androgenic effect in premenopausal women.14 Either of the following schedules may be adopted: (1) 100 mg of cyproterone acetate along with estrogen on days 5 to 15 and estrogen alone on days 16 to 25 (cyclic antiandrogen therapy) for hirsuitism, or (2) 2 mg of cyproterone acetate in combination with estrogen on days 5 to 25.

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In postmenopausal women, 50 mg of cyproterone acetate daily may be used alone. Menstrual irregularity, weight gain, breast tenderness, decreased libido, depression, and nausea are its major dose-related potential side effects. There have been only a few controlled clinical trials of cyproterone acetate in FPHL.8

Other Anti-Androgens Cimetidine Cimetidine is an H2 receptor blocker (antihistamine) that inhibits DHT binding. One uncontrolled study of 300 mg 5 times a day suggests that it has some efficacy in FPHL.15

5α-Reductase Inhibitors In a large controlled multicenter trial of postmenopausal women with FPHL, the results with finasteride 1 mg daily were not found to be significantly different from placebo at the end of one year.16 There were individual patients in this trial who did have hair growth, and there have since been anecdotal reports of finasteride being effective in postmenopausal women without hyperandrgenism at 1 or 2.5 mg and in women with hyperandrogenism at 2.5 mg. There is no placebo or active-controlled studies of finasteride in premenopausal women with early-onset FPHL, but there is now a controlled open-label study of 37 premenopausal women with FPHL and no hyperandrogenemia or signs of hyperandrogenism.17 These women were given 2.5 mg of finasteride daily in conjugation with the oral contraceptive Yasmin®. At the conclusion of 12 months, 60% of the women had increased hair growth as documented by global photographs (11 of 37) had moderate or greater hair growth and 12 of 37 (32%) had an increase in hair density. There were no adverse reactions. Finasteride was reported to be effective in doses of 2.5 mg in 41 women and FPB and seborrhea, acne, hirsutism, and androgenetic alopecia.

Dutasteride is a dual type I and type II 5α-reductase inhibitor currently approved in a 0.5 mg dose form for prostatic hyperplasia.17 In a comparative study of men with male pattern baldness, serum DHT was suppressed by 92% vs 73% and scalp DHT by 51% vs 41% in men treated with 0.5 mg dutasteride vs 5 mg finasteride, respectively. Dutasteride has a much longer half-life than finasteride (4 weeks vs 6–8 hours) with prolonged suppression of DHT and has not been subjected to any clinical trials in women.

One postmenopausal woman with FPB responded to dutasteride and not finasteride.18 Women of child-bearing potential should be taking an effective form of contraception prior to beginning any 5α-reductase inhibitor. Since 5α-reductase inhibitors have

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the potential to cause feminization of a male fetus, an oral contraceptive pill is the contraceptive of choice for the additional reason that it will decrease production of circulating androgens.

Given its longer half-life, women of child-bearing age should not take dutasteride.

Estrogens Systemic administration of estrogens increases the production of sex hormone-binding gloubin leading to a decrease in free testosterone. Topical 0.025% 17-alpha estradiol preparations appeared to stabilize hair loss when applied by 7 women with androgenetic alopecia for 6 months and/or increased telogen hair shedding compared with 2 female controls. Interestingly, hair loss has not been one of the common side effects reported with systemic inhibitors.19,20

Estrogen Receptor Antagonist Largely based on the anagen-promoting activity of an estrogen receptor antagonist in mice, a proof-of-concept study was performed in 70 postmenopausal women with Ludwig class I or II FPB treated with either fulvostatin (an estrogen receptor antagonist) or placebo for 16 weeks.17 There was no statistically significant difference between groups in hair density, cumulative hair thickness, or growth rate. In clinical practice, hair loss or growth has not been a common side effect of estrogen receptor inhibitors.21

of some viable terminal hair when preparing the recipient hole.

The advent of follicular unit hair transplant18 in which 1 to 2 unit grafts are placed into the recipient area by a hypodermic needle, holes or slits made by a scalpel has eliminated this. Grafts are generated from elliptical donor strip harvesting. It is the same in women as in men, except that the donor area may be more restricted in women than men; therefore, the temporal and inferior parietal/occipital areas are not used for donor areas in women in order to present future limitations in hairstyles.23,24 In the focal atrichia areas, either larger follicular units are placed or the bald skin is removed by trephine and a larger graft is placed into these new recipient sites. Realistic goals for transplant should be established. An increase in hair density in strategic areas seems feasible in most women with further goals dependent on the donor site and number of sessions. Postoperatively there may be a temporary loss of hair in both the donor and recipient areas.

This effect may be mitigated by the use of topical minoxidil.23,25 Conclusions Although FPB is a unique entity, it has received little attention.

Future studies on the subject are needed.

References

Melatonin Melatonin has been shown to promote anagen induction in animals. In a double-blind, randomized, placebo-controlled study, women aged 20 to 70 years with diffuse alopecia (n=28) or androgenetic alopecia (n=12) were treated with 1 mL daily of 0.1% melatonin alcohol solution vs vehicle topically for a period of 6 months. Efficacy was determined by trichograms in the frontal and occipital areas. At the conclusion of the study of women with FPB, there was a statistically significant increase from baseline in anagen hairs in the occiput in the topical melatonin group (mean, 76.3 to 85.2 hairs) compared with placebo (mean, 78 to 82 hairs), but no difference from placebo in the frontal area.19,22

Surgical Treatment Hair transplant may be extremely useful in FPB, the limitation being adequate donor hair, reasonable expectation, and cost-effectiveness. Before the development of follicular unit transplantation, slit round trephines were used to remove grafting donor tissue and the grafts were placed into holes made by marginally smaller trephines. Because the recipient site in FPB was not bald, but only less dense than normal, this led to unnecessary removal SKINmed. 2013;11:287–290

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

2 Olsen EA, Weiner MS, DeLong ER, Pinnel S. Topical minoxidil in early pattern baldness. J Am Acad Dermatol.

1985;13:185–192.

3 DeVillez RL, Jacobs JP, Szpunar CA, Warner ML. Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution. Arch Dermatol. 1994;130:303– 307.

4 Lucky AW, Placquadio DJ, Ditre CM, et al. A randomized, placebo controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004;50:541–553.

5 Uno H, Cappas A, Brigham P. Increased DNA synthesis of the hair follicular and parafollicular cells by topical minoxidil in the macaque scalp. J Invest Dermatol.

1985;84;358 6 Scirra F, Toscano V, Concolino G, Di Silverio F. Antiandrogens: Clinical applications. J Steroid Biochem Mol Biol.

1990;37:349–362.

7 Cusan L, Dupont A, Gomez JL, Tremblay RR, Labrie F. Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial.

Fertile Steril. 1994;61:281–287.

8 Dawber RPR, Sonnex T, Ralfs I. Oral antiandrogen treatment of common baldness in women. Br J Dermatol.

1982;107:20 9 Sinclair R, Wererinke M, Jolley D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol.

2005;152:466–473.

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10 Burke BM, Cunliffe WJ. Oral spironolactone therapy for female patients with acne, hirsutism or androgenic alopecia. Br J Dermatol. 1985;112:124–125.

11 Drake ID, Hordinsky M, Fiedler V, et al. The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol.

1999;41:550–554.

12 Rebora A, Guarrere M. Kenogen. A new phase of the hair cycle? Dermatology. 2002;205:108–110.

13 Norwood OT, Lehr B. Female androgenetic alopecia: a separate entity. Dermatol Surg. 2000;26:679–682.

14 Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol. 2005;52:301–311.

15 Kossard S. Postmenopausal frontal fibrosing alopecia.

Scarring alopecia in a pattern distribution. Arch Dermatol. 1994;130:770–774.

16 Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol.

2008;59:547–566.

17 Oh HS, Smart RC. An estrogen receptor pathway regulates the telogen-anagen hair follicle transition and influences epidermal cell proliferation. Proc Natl Acad Sci. 1996;93:12525–12530.

18 Price VH, Roberts JL, Hordinsky M, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol. 2000;43:768– 776 19 Simpson N. The management of androgenetic alopecia in women. J Dermatol. 1989;1:107–11 20 Thornton MP. The biological actions of estrogens on skin. Exp Dermatol. 2002;11:487–502.

21 Kuster W, Happle R. The inheritance of common baldness: two B or or not two B? J Am Acad Dermatol.

1984;11:921–926.

22 Olsen EA. Current and novel methods for assessing efficacy of hair growth promoters in pattern hair loss. J Am Acad Dermatol. 2003;48:253–262.

23 Unger WP, Unger RF. Hair transplanting an important but often forgotten treatment for female pattern hair loss. J Am Acad Dermatol. 2003:49:853–860.

24 Marwah HS. Follicular unit hair transplant. Sehgal VN, ed. Dermatologic Surgery Made Easy. 1st ed. Jaypee: New Delhi; 2006:222–227.

25 Avram MR, Cole IP, Gandelman M, et al. The potential role of minoxidil in hair transplanting setting. Dermatol Surg. 2002;10:894–900.

Wax Moulage

“Sycosis staphylogenis”, Folliculitis barbae because of an infection with Staphylococcus. Moulage No. 722, made by Lotte Volger in 1935 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich. www.moulagen.ch Courtesy of Michael Geiges, MD

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Volume 11 • Issue 5

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

Atypia Without Pleomorphism and Atypia Without Atypia: When You Can’t Even See the Trees for the Trees Gretchen Harmon, MD;1 Peter C. Lambert, MA;2 Gordana L. Katava, DO, MS;3 W. Clark Lambert, MD, PhD4 “The range of what we think and do is limited by what we fail to notice. And because we fail to notice that we fail to notice there is little we can do to change until we notice how failing to notice shapes our thoughts and deeds.”—Daniel Goleman, Vital Lies Simple Truths: The Psychology of Self-Deception (1985)

D

ermatopathology training comprises about a quarter of the dermatology residency curriculum, and continuing education in this area is prevalent.1 The majority of resident dermatopathology training is provided by dermatologytrained dermatopathologists.2 In 1 year, approximately 33% of American Academy of Dermatology members reported contributing to at least one final histologic diagnosis.3 Despite this emphasis, pathologists have argued that nonpathologists are not adequately trained to evaluate slides.1 There are of course, differences between dermatology-trained and pathology-trained dermatopathologists, with the former having much more clinical expertise, but does the pathologist have expertise lacked by the dermatologist?

The most frequently used dermatopathology textbooks in dermatology training are those by Lever and Weedon,4 and neither book has a section on cytology. The Accreditation Council for Graduate Medical Education (ACGME), however, lists cytopathology as a mandatory area of learning within a pathology residency,5 whereas the dermatology residency curriculum specifies immunofluorescence, immunohistochemistry, electron microscopy, and “routinely stained histologic sections,”6 but not cytopathology, as requirements. Cytopathology is a requirement for dermatopathology fellows,7 but many dermatologists read their own slides without having any fellowship training.

General practitioners typically send skin biopsies to a pathologist rather than a dermatopathologist for interpretation. The rate of clinically important errors is about 1.4% in this set. The types of

specimens, however, are generally noncomplicated, single, noninflamed lesions.8 More complex lesions, such as suspected melanomas, have a much higher rate of discordance.9 Differences in diagnostic opinion may be partly due to differences in experience, but differences in training may also be an issue.

One of us (WCL) became aware of this difference many years ago when he personally consulted with a prominent pathologist and also a prominent dermatopathologist, trained in dermatology, regarding several challenging melanocytic lesions. The pathologist, in examining the sections, went immediately to high power on his microscope, where he spent much time and attention, whereas the dermatopathologist went immediately to low power and only much later to high power, where relatively little time was spent.

Why should a dermatologist, or even a dermatopathologist, who is unlikely to ever use cytopathology pay attention to high power? The value of cytopathology becomes evident when examining cases that show atypia without pleomorphism. Atypia, though sometimes used to describe size, refers primarily to abnormal nuclear morphology of individual cells. Anisotropy describes variation in size and pleomorphism variability in the shape of nuclei and cells of the same type. In practice, anisotropy is almost always accompanied by pleomorphism, and so the term pleomorphism has come to indicate variation in both size and shape of cells and nuclei. Dysplasia is the nontypical arrangement of cells within a lesion.

From New York Medical College, Valhalla, NY;1 St. Georges University School of Medicine, St. Georges, Grenada, W.I.;2 Department of Pathology, Rutgers University–New Jersey Medical School, Newark, NJ;3 and the Departments of Dermatology and Pathology, Rutgers University–New Jersey Medical School, Newark, NJ4 Address for Correspondence: W. Clark Lambert, MD, PhD, Professor of Dermatology and Pathology, Rutgers University–New Jersey Medical School, Newark, NJ • E-mail: lamberwc@njms.rutgers.edu

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Figure 2. Pleomorphism without atypia: Darier-White disease. Premature and aberrant keratinization within keratinocytes causes displacement and distortion of nuclei within individual cells, as well as distortion of the keratinocytes themselves, but no atypia is present. (Hematoxylin and eosin, original magnification ×281.)

important part of the diagnostic process include sebaceous carcinoma and granular cell tumor. A common pathologic finding of sebaceous carcinoma is atypia without pleomorphism.11 Granular cell tumors with pleomorphism alone are more likely to be benign than malignant.2 Personal experience (WCL) would also add superficial spreading melanoma to the list; rarely, melanoma can be associated with atypia occurring with little or no pleomorphism (Figure 1). Pleomorphism can also occur in special circumstances without atypia, as in Darier-White disease (Figure 2).

Figure 1. Atypia without pleomorphism: Superficial spreading melanoma. Atypia is present in the melanocytes, but they are each atypical in the same way, making recognition of this challenging. This banal appearing lesion metastasized and killed its 57-year-old man host 2 years later. (Hematoxylin and eosin, original magnification ×310.)

These distinctions would appear to be straightforward. Problems arise, however, when one of these phenomena is used to designate another.

Atypia Without Pleomorphism In one author’s (WCL) experience, dermatologists tend to use pleomorphism as a substitute for atypia in the diagnosis of malignancy. Pleomorphism tends to be much easier to recognize, and frequently the two phenomena are found together, making it an understandable cognitive shortcut. The development of malignancy, however, is a multi-step, complex process in which atypia can be found at a point prior to the development of pleomorphism.10 For this reason, atypia must be recognizable alone. Examples where cytopathology is an SKINmed. 2013;11:291–293

Atypia Without Atypia The term atypia may be used in several different ways, as follows: (1) To describe the overall architecture of a lesion. We have not seen the term atypia used in this way in the literature, although the adjective form, “atypical,” is used in general pathology to denote several entities, such as “atypical lobular dysplasia.”12 (2) To describe a portion of the architecture of a lesion. (Again, we have not seen this usage in the literature.) (3) To describe an individual cell, sometimes in isolation, as in a cytology preparation. (4) To describe a portion of the cells in a lesion. (5) To describe all cells in a lesion.

In the latter 3 instances atypia usually denotes changes indicative of progression toward cancer, but it may indicate any appearance that is not “typical,” including changes caused by such entities as

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herpesviruses or other viral infections. Used without a modifier, the former definition is conventionally denoted.

Thus, a lesion may show atypia, describing its cells, but not atypia, describing its overall architecture: atypia without atypia.

What is one to make then, of a diagnosis of “nevus with mild/ moderate/severe atypia?” If “atypia” is being used to denote overall lesional architecture, this diagnosis may justify an excision, or at least a return visit, as prophylaxis against melanoma; alternatively, if it applies individually to some cells, a further office visit may not be indicated. We recommend that “atypia” not be used in a diagnosis without a modifier indicating, at the very least, whether cytological or architectural atypia is indicated. In most instances, the term dysplasia or dysplastic is more accurate and useful to describe architectural atypia and not cytologic atypia.

Whatever the term, if it is used to describe only a part of the lesion, this should be clearly indicated.

When You Can’t Even See the Trees for the Trees When recognizing one attribute, such as pleomorphism, to diagnose another, such as cytological atypia, or noting the presence of an attribute, such as atypia, which may have more than one meaning, physicians reading slides run the risk of missing a diagnosis or having their diagnosis misinterpreted. Physicians who depend on these reports need to be aware of these limitations as well, and not hesitate to question diagnoses that appear inconsistent with the clinical presentation or are in any way ambiguous or open to more than one interpretation.

References 1 Singh S, Grummer SE, Hancox JG, Sangueza OP, Feldman SR. The extent of dermatopathology education: A comparison of pathology and dermatology. J Am Acad Dermatol.

2005;53:694–697.

2 Fanburg-Smith JC, Meis-Kindblom JM, Fante R, Kindblom LG. Malignant granular cell tumor of soft tissue: Diagnos-

tic criteria and clinicopathologic correlation. Am J Surg Pathol. 1998;22:779–794.

3 Brauer JA, Shin DB, Troxel AB, et al. Characteristics of dermatologists who read dermatopathology slides. J Cutan Pathol. 2007;34:687–692.

4 Hinshaw M, Hsu P, Lee LY, Startman E. The current state of dermatopathology education: a survey of the Association of Professors of Dermatology. J Cutan Pathol.

2009;36:620–628.

5 Accreditation Council for Graduate Medical Education.

Program requirements for graduate medical education in pathology. July 2007. http://www.acgme.org/acWebsite/ downloads/RRC_progReq/300pathology_07012007.pdf.

Accessed November 3, 2011.

6 Accreditation Council for Graduate Medical Education. Program requirements for graduate medical education in dermatology. July 2007. http://www.acgme.org/acWebsite/ downloads/RRC_progReq/080dermatology_07012007. pdf. Accessed November 3, 2011.

7 Accreditation Council for Graduate Medical Education.

Program requirements for graduate medical education in dermatopathology. July 2007. http://www.acgme.org/ acWebsite/downloads/RRC_progReq/100_dermatopathology_PRs_07012011_1-YR.pdf. Accessed November 3, 2011.

8 Trotter MJ, Bruecks AK. Interpretation of skin biopsies by general pathologists: diagnostic discrepancy rate measured by blinded review. Arch Pathol Lab Med. 2003;127:1489–1492.

9 Shoo BA, Sagebiel RW, Kashani-Sabet M. Discordance in the histopathologic diagnosis of melanoma at a melanoma referral center. J Am Acad Dermatol. 2010;62:751–756.

10 Clark WH, Elder DE, Guerry D, et al. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Human Pathol. 1984;15:1147– 1165.

11 Izumi M, Tang X, Chiu CS, et al. Ten cases of sebaceous carcinoma arising in nevus sebaceous. J Dermatol.

2008;35:704–711.

12 Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Cotran: Pathologic Basis of Disease. 8th ed. Sanders/Elsevier: Philadelphia, PA; 2010:1073, 1074, 1337.

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September/October 2013

Volume 11 • Issue 5

New to the Clinic Noah Scheinfeld, MD, JD, Section Editor

Epiduo (Adapalene 0.1% and Benzoyl Peroxide 2.5%) Approval in Children 9 Years and Older Noah Scheinfeld, MD, JD

A

s a result of complex factors that may pertain to lifestyle, hormonal influences, and diet, acne is occurring at earlier ages in children, specifically before the age of 12, most acne products are indicated for this population by the US Food and Drug Administration (FDA). This is especially important as pharmacy benefit systems will not approve prescription of a medication outside of FDA-approval guidelines (eg, tacrolimus 0.1% for children aged 12). A variety of treatment options exist for the topical treatment of acne, including a preparation of adapalene-benzoyl peroxide (BPO) (Epiduo; Galderma USA, Ft. Worth, TX) for acne used once daily.1 Epidemiologic Factors Research has shown that the onset of acne is frequently seen in patients aged 8 to 12 years, termed pre-adolescent acne.2 A study from Denmark3 showed that the onset of puberty occurred significantly earlier during 2006–2008 (mean age, 11.66 years) than in 1991–1993 (mean age, 11.92 years). These data indicate that acne is not uncommon in children 9 years and older. The presentation of acne in younger pediatric patients typically differs from that observed in patients with a later onset of acne with more comedones and fewer pustules. In a review4 using the National Ambulatory Medical Care Survey database, there was a significant decrease in the mean age of children seeking treatment for acne over this 28-year period (P<.001). There was no significant change in the mean age of black children seeking treatment for acne. Black girls had the lowest mean age, whereas white boys had the highest mean age. The prevalence among participating girls and boys younger than 12 years was 69.9% and 73.6%, respectively. The main risk factors for acne were facial hair growth in boys (odds ratio, 4.9), menarche in girls (OR, 3.1), overweight/obesity (body mass index ≥25 kg/m2 at 18 years) (OR, 2.6), acne history from both parents (OR, 2.6), and from mother alone (OR, 2.1). Nutritional habits, smoking,

or alcohol consumption were not associated with acne.5 The presentation in younger patients tends to be characterized by noninflammatory comedones. The explanation for this difference is determined on the basis of the aforementioned evidence.

Sebum is necessary for Propionibacterium acnes colonization of the skin, along with the immune response that results in the development of inflammatory papules, pustules, and nodules. Patients younger than 12 develop follicular plugs and visible comedones, but they have not yet begun to produce sufficient sebum to support large numbers of P. acnes acteria. This makes retinoids the treatment of choice for patients aged 9 to 11 years, as long as they are accompanied by an agent to sweep up an inflammation generated by P. acnes bacteria, which is ubiquitous in the skin of those who have acne and, as a bacteria, is a growing factor in the propagation of acne as the age of puberty continues to decrease.

Use in Children A 2013 study investigated 142 patients, aged 9 to 11 years, randomized to adapalene-BPO and 143 to vehicle. At study endpoint (week 12), adapalene-BPO was significantly superior to vehicle regarding treatment success (49.3% vs 15.9%, respectively) and percentage of reduction in total lesion count (68.6% vs 19.3%), inflammatory (63.2% vs 14.3%), and noninflammatory lesion counts (70.7% vs 14.6%) (all P<.001). More patients using adapalene-BPO reported that their acne had an impact on their quality of life, with parents noting that their child’s acne significantly improved. Adapalene-BPO was well tolerated, with mean tolerability scores <1 (mild).6,7 Conclusions Based on the aforementioned study of 142 patients and in-house Galderma unpublished studies8 that assessed 285 acne patients aged 9 to 11 years, the FDA approved the use of adapalene-BPO

From the Department of Dermatology, Weill Cornell Medical College, New York, NY Address for Correspondence: Noah Scheinfeld, MD, JD, Assistant Clinical Professor of Dermatology at Weil Cornell Medical College, 150 West 55th Street, New York, NY 10019 • E-mail: NSS32@columbia.edu

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for treatment of acne in patients 9 years and older. AdapaleneBPO is a useful treatment for acne because the retinoid portion of the preparation opens comedones, and the BPO component treats inflammatory papules, pustules, and nodules that become an increasing issue, as the age of the onset of puberty has dipped down into the 9- to 11-year age group. This agent should help treat acne, whose epidemiology has changed in the past several decades.

References 1 Adapalene-benzoyl peroxide (Epiduo) for acne. Med Lett Drugs Ther. 2009;51:31–32.

2

Friedlander SF, Eichenfield LF, Fowler JF Jr, et al. Acne epidemiology and pathophysiology. Semin Cutan Med Surg. 2010;29:2–4.

3 Sørensen K, Aksglaede L, Petersen JH, Juul A Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab.

2010;95:263–270.

4

Goldberg JL, Dabade TS, Davis SA, et al. Changing age of acne vulgaris visits: another sign of earlier puberty?

Pediatr Dermatol. 2011;28:645–648.

5 Karciauskiene J, Valiukeviciene S, Gollnick H, Stang A.The prevalence and risk factors of adolescent acne among schoolchildren in Lithuania: a cross-sectional study. J Eur Acad Dermatol Venereol. 2013 Apr 5. [Epub ahead of print] 6 Eichenfield LF, Draelos Z, Lucky AW, et al. Preadolescent moderate acne vulgaris: a randomized trial of the efficacy and safety of topical adapalene-benzoyl peroxides.

J Drugs Dermatol. 2013;12:611–618.

7 Eichenfeld LE, Hebert AA, Lucy AW, et al. Treatment of acne in children aged 9 to 11 with a fixed dose combination of adapalene-benzoyl peroxide gel. J Am Acad Dermatol. 70 (suppl 1):AB19 (abstract).

8 Epiduo® gel becomes first topical prescription acne treatment available for children as young as 9 years old. http://www.prnewswire.com/news-releases/epiduo-gelbecomes-first-topical-prescription-acne-treatment-available-for-children-as-young-as-9-years-old-191807741. html. Accessed September 17, 2013

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.

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Volume 11 • Issue 5

COSMETIC SCIENCE Howard A. Epstein, PhD, Section Editor

Is It Time to Revise CFR Title 21-Food Drugs & Cosmetics Act for Skin Care Products?

Howard A. Epstein, PhD

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kin care has been of commercial importance since the early days of the founding of the United States. The first American patent issued and signed by George Washington was for a process of making potash and pearl ash for soap manufacturing.

The process became one of global importance as it produced a very high-quality potash-based soap needed in England to wash wool prior to being woven. During the 18th and 19th centuries, skin care products containing dangerous ingredients including lead and mercury were marketed without regulation. The Food and Drug Act (US Food and Drug Administration [FDA]) of 1906 addressed product safety but did not include cosmetic products.

During the early to mid-1930s, as the use of makeup and other cosmetic products become more mainstream, federal legislators remained reluctant to revise the 1906 Food and Drug Act to include cosmetic products. In October of 1933, a newsreel described corneal damage resulting from an eyelash product named Lash Lure that caused blindness to a woman who used the product. In 1933, President Franklin D. Roosevelt initiated his first term in office with a reform agenda that included revising the Food and Drug Act of 1906. A draft of the proposed changes was submitted to the US senate, and it took 5 years for the legislature to be passed.

During this time, the FDA displayed public exhibits highlighting deficiencies of the 1906 Food and Drug Act. Mrs Roosevelt visited the exhibit’s “chamber of horrors,” and it was her shock at seeing pictures of the woman who was blinded as a result of using Lash Lure that led to the 1933 newsreel. The woman blinded

by Lash Lure, Mrs Brown, in all probability reacted to an aniline compound, p-phenylenediamine in the product. During this time, aniline dyes were commonly used in hair-coloring products.

The Lash Lure product contained 25 to 30 times more aniline than used in hair dye products at the time. The use of aniline dyes was already banned in Europe where it was known to be toxic.

Other women using Lash Lure developed infections resulting in permanent diminished vision and at least one person died from

severe infection associated with product use.1,2 This story provides insight into the history of the FDA and its passionate mission to protect the public from dangerous products and false or misleading advertising.

FDA Authority Over Cosmetics The FDA’s consumer Web site advises that “The two most important laws pertaining to cosmetics marketed in the United States are the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Fair Packaging and Labeling Act (FPLA). The FD&C Act prohibits the marketing of adulterated or misbranded cosmetics in interstate commerce. Violations of the Act involving product composition—whether the result from ingredients, contaminants, processing, packaging, or shipping and handling—cause cosmetics to be adulterated and subject to regulatory action.

Under the FD&C Act, a cosmetic is adulterated if it bears or contains any poisonous or deleterious substance that may render it injurious to users under the conditions of use prescribed in the labeling thereof, or under conditions of use as are customary and usual.” Improperly labeled or deceptively packaged products are considered misbranded and subject to regulatory action. Under the FD&C Act, a cosmetic is considered misbranded if: • “its labeling is false or misleading in any particular”; • its label does not include all required information; • the required information is not adequately prominent and conspicuous; • “its container is so made, formed, or filled as to be misleading”; • it is a color additive, other than a hair dye, that does not conform to applicable regulations issued under section 721 of the FD&C Act; and

From EMD Chemicals, Philadelphia, PA Address for Correspondence: EMD Chemicals, Cosmetic Actives, Performance Materials Division-NAFTA Region, Philadelphia, PA • E-mail: howard.epstein@emdmillipore.com

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• “its packaging or labeling is in violation of an applicable regulation issued pursuant to section 3 or 4 of the Poison Prevention Packaging Act of 1970.” (FD&C Act, sec. 602) “In addition, under the authority of the FPLA, FDA requires an ingredient declaration to enable consumers to make informed purchasing decisions. Cosmetics that fail to comply with the FPLA are considered misbranded under the FD&C Act.”3,4 How Does the Law Define a Cosmetic or a Drug?

The FD&C Act defines cosmetics by their intended use as “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to human the human body…for cleansing, beautifying, promoting attractiveness, or altering the appearance FDA Act sec. 201(i). Drugs are defined as, in part, by their intended use, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and articles (other than food) intended to affect the structure or any function of the body of man or other animals3 (FD&C Act, sec. 201(g).1 Who is Responsible for Substantiating the Safety of Cosmetics?

Cosmetic firms are responsible for substantiating the safety of their products and ingredients before marketing. Failure to adequately substantiate the safety of a cosmetic product or its ingredients prior to marketing causes the product to be misbranded unless the following warning statement appears conspicuously on the principal display panel of the product’s label.

In general, except for color additives and those ingredients which are prohibited or restricted from use in cosmetics by regulation, a manufacturer may use any ingredient in the formulation of a cosmetic provided that the ingredient and the finished cosmetic are safe, the product is properly labeled, and the use of the ingredient does not otherwise cause the cosmetic to be adulterated or misbranded under the laws that FDA enforces.3,4 Why Is It Necessary to Revise the FD&C Act? The FDA does not recognize what has become a common category of cosmetic skin care products referred to as “cosmeceuticals.” The term has been used for more than 20 years and is not accepted as a product category by the FDA. Skin care experts have considered cosmeceutical products as products that do not harm the public and might be beneficial. Recently, the FDA has become more aggressive, sending warning letters addressing drug claims for products marketed as cosmetics.5,6 In addition to monitoring imported prodSKINmed. 2013;11:297–299

ucts and products manufactured in the United States, the agency is monitoring social media and has cited a company for promoting unapproved new drugs on its Facebook page.7 Skin Care in the Genomic and Epigenomic Era In the age of proteomics, genomics, and epigenetics we must continuously update our perspective and consider redefinition of structure and function and perhaps safety. For example, with respect to epigenetics, it is conceivable that a revised concept of structure and function of skin can be proposed in the context of cellular communication. Skin cells in different parts of the body adapt their function to their specific location. The system of cell signaling is not completely well understood, recent findings indicate that specific gene expression profiles are involved in skin patterning, termed positional identity.

Studies of skin development show that site-specific differentiation of epithelia critically depends on epithelial-mesenchymal interactions.

The findings imply that skin is dynamic and that the epithelial and fibroblast cells, for example, are continuously transitioning as the cells mature over time. This was the rationale used8 when investigators proposed a model of epithelial cell plasticity. Epithelial-mesenchymal transitions (EMT) involve the formation of mobile cells from parent nonmobile cells. Discrete age or stage-dependent conversion of the primitive epithelial cells by EMT is seen in early embryogenesis.

Later in organogenesis, and once again later through expression of local developmental cytokines as they become secondary epithelial cells. In adult life, the cytokine bath generated by persistent tissue injury drives the formation of an abundance of fibroblasts by the same mechanism. The investigators propose 3 different types of EMT: type 1 involves primitive epithelial cells transitioning to motile cells during embryonic development; type 2 EMT involves secondary epithelial cells transitioning to resident tissue fibroblasts; and type 3 EMT in response to persistent inflammation involving epithelial carcinoma cells in primary nodules transitioning to metastatic tumor cells. In this context, the structure and function of skin is dynamic and influenced by many factors beyond topically applied cosmeceutical products.

Various EMT studies show that skin exhibits site-specific morphologies and function in response to treatment. A study of approximately 21,000 genes in 50 primary human fibroblasts cultured from 10 anatomic sites revealed that while fibroblast are morphologically similar, their gene expression patterns are different relative to their anatomical site. In the context of homeostasis, how can we determine exactly what the structure-function relationship is other than in broad undefined terms?

Conclusions Cosmeceuticals are the “gray” area of skin care in the cosmetics industry. While the application of gene expression studies, epigenetics, are early in our understanding, data are being generated

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providing new information and interpretations currently guiding the development of improved skin care products. While gene expression is currently being used to generate safety data, full interpretation of data for skin care remains to be more fully understood.

There is a need to educate our legislatures and the public on this rapidly advancing science and its contribution to the development of safe, effective skin care products that should be treated as cosmetics or, perhaps more appropriately, cosmeceuticals. The FDA and industry need to apply current information into agreed-upon terms to communicate product benefits to the public.

The question is when will the time be right to revise the FD&C Act and what should the revisions include?

References 1 Kay G. Healthy Public Relations: The FDA’s 1930s Legislative Campaign. Bull Hist Med. 2011;75:446–487.

2 Meyers B. Cosmetic Safety: From Personal Choice to Public Health. learningcenter.nsta.org/products/symposia_seminars/boston08/FDA/webseminarII.aspx.Accessed December 17, 2012.

3 Federal Food, Drug, and Cosmetic Act. www.fda.gov/ regulatoryinformation/legislation/federalfooddrugandcosmeticfdcact. Accessed December 17, 2012 4 Fair Packaging and Labeling Act. www.fda.gov/regulatoryinformation/legislation/ucm148722.htn. Accessed December 17, 2012.

5 US Food and Drug Administration. Cosmetics Warning Letters Address Drug Claims Made for Products Marketed as Cosmetics. www.fda.gov/cosmetics/guidanceregulatoryinformation/complianceenforcement/warningletters/ucm081086.htm. Accessed December 18, 2012.

6 US Food and Drug Administration. Import Alert 66-38. www.accessdata.fda.gov/cms_ia/importalert_188.html.

Accessed December 17, 2012 7 Egan K. Warning Letters Matter: Nov 2011 Summary. http://www.healthcarelawmatters.com/warning-lettersmatter/selected-fda-warning-letters. Accessed December 18, 2012.

8 Rinn RL, Wang JK, Liu H, et al. A systems biology approach to anatomic diversity of skin. J Invest Dermatol.

2007;128:776–782.

9 Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429– 1437.

Historical Diagnosis and treatment: epithelioma

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September/October 2013

Volume 11 • Issue 5

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

Multiple Cystic Disease: K17 Dysfunction?

Hugo Néstor Cabrera, MD;1 María Daniela Hermida, MD;2 Elba Griffa, MD;3 Claudia Civitillo, MD;1 José Porta, MD1 Our patient is a 29-year-old woman without any previous disease who presented with different kinds of lesions on her face, neck, and chest. She first noticed the lesions 10 years ago and, since that time, they have become more numerous. She has no affected relatives. On physical examination, she had multiple cystic lesions on her neck, chest, and vulva, which were between 0.3 cm and 1 cm and skin-colored or yellowish (Figure 1). She presented with small, white papules on her face measuring approximately 0.2 cm, localized on her forehead and cheeks. Some of these papules had a blueish appearance (Figure 2). She also presented clinically typical eruptive syringomas on her upper and lower eyelids and neck and multiple facial milia. Finally, a sacrococcygeal pilonidal cyst was diagnosed and surgically removed.

Her nails and teeth were clinically normal. Biopsies of each kind of lesion were performed, with the following results: (1) neck cystic lesion: steatocystoma; (2) small, white facial papule: eccrine hidrocystoma; (3) blueish facial papule: apocrine hidrocystoma; and (4) small neck papule: syringoma (Figure 3). With these findings, our diagnosis was steatocystoma multiplex with multiple eccrine and apocrine hidrocystomas, eruptive syringomas, and sacrococcygeal pilonidal cyst. (SKINmed. 2013;11:301–303)

K

17 is a type I keratin with a complex pattern of expression. During development, the single-layered epithelial cells that express K17 give rise to placodes, the precursors of ectoderm-derived appendages (hair, glands, nails, and teeth). After birth, its constitutive expression is restricted to hair follicles, nail matrix, and the myoepithelium surrounding secretory glandular cells.1

tor in the activation, migration, and division of epithelium with important stromal interactions.

The finding that links these two patterns of expression (embryologic and adult) is that K17 is strongly inducible in epidermis following acute injury. During the epidermal repair process, expression of K17 spreads distally from the edge of the wound and is maintained in karatinocytes that are migrating to the site. Follicular K17 expressing keratinocytes greatly contribute to the process.1 In addition, it has recently been studied that in the absence of epidermis, eccrine sweat glands can start wound repair possibly through myoepithelium K17-expressing cells.2

K17 mutations give rise to pachyonychia congenita type 2 (PC2) and steatocystoma multiplex (SM), both autosomal-dominant disorders. Currently, 14 missense mutations have been identified that occur within the helix initiation motif.4 This sequence may be directly involved in keratin filaments assembly through endto-end interactions; however, any phenotype can arise from the same mutation and, at the same time, these two diseases show highly heterogeneous clinical features. In SM, multiple steatocystomas develop around puberty. Milia and vellus hair cysts can also be present. Patients with PC-2 show hypertrophic nail dystrophy, focal keratoderma, follicular keratosis, teeth and hair abnormalities, and multiple cystic lesions of different kinds. These “follicular hybrid cysts” are highly heterogeneous and include steatocystomas, epidermal cysts, milia, vellus hair cysts, hidradenitis suppurativa–like cysts, and vulvar and scrotal cystomatosis.5

In pathological situations such as hyperproliferation or abnormal differentiation, K17 expression is also increased. Psoriasis, inflammatory states, viral infections, and basal cell carcinoma are some examples.3 K17 up-regulation seems to be a key fac-

We can only speculate about the functional alterations of K17 derived from its mutations. In SM and PC-2, K17 structural function may be impeded giving room to hair shaft abnormalities and nail dystrophy, hyperkeratosis can contribute to infun-

From the Dermatology Department, Hospital Nacional Profesor Alejandro Posadas,1 The Department of Dermatology at CEMIC,2 and the Dermatology Department, Hospital Petrona de San Fernando,3 Buenos Aires, Argentina Address for Correspondence: Maria Daniela Hermida, MD, Avda Presidente Peron 10298, Club de Campo Los Pingüinos UF 216, Ituzaingo 1714, Buenos Aires, Argentina • E-mail: mdhermida@gmail.com

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Figure 1. Multiple steatocystomas localized on the patient’s neck.

Figure 2. Apocrine hidrocystoma (arrow).

A

B

C

D

Figure 3. Histologic slides: (A) steatocystoma (hematoxylin-eosin stain, original magnification ×200); (B) eccrine hydrocystoma (hematoxylin-eosin stain, original magnification ×200); (C) apocrine hydrocystoma (hematoxylin-eosin stain, original magnification ×200); (D) syringoma (hematoxylin-eosin stain, original magnification ×200).

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dibular occlusion and formation of retention cysts, and developmental alterations in appendage formation could be related to cystic, adenomatous, or hyperproliferative lesions.

2 Miller S, Burke EM, Rader MD, Coulombe PA, Lavker RM. Re-epithelization of porcine skin wounds by the sweat apparatus. J Invest Dermatol. 1998;110:13–19.

3 Bianchi N, Depianto D, McGowan K, Gu C, Coulombe

Conclusions

PA. Exploiting the keratin 17 gene promoter to visualize

Our patient presented with multiple steatocystomas and other lesions, most of them cysts derived both from eccrine and apocrine sweat glands, exhibiting a unique spectrum of clinical features. The presence of hydrocystomas exceeds a diagnosis of SM, and PC-2 would lack nail, teeth, or hair shaft alterations. We believe that a mutation in K17 could explain this phenotype, which has not been previously reported in the literature.

live cells in epithelial appendages of mice. Mol Cell Biol.

2005;25:7249–7259.

4 Se-Woong OH, Moon Young KIM, Jeong Sun LEE, SooChan KIM. Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity. J Dermatol.

2006;33:161–164.

5 Covello SP, Smith FJ, Sillevis Simitt JH, et al. Kera-

References 1 McGowan K, Coulombe PA. Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development. J Cell Biol. 1998;143:469–486.

tin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol.

1998;139:475–480.

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September/October 2013

Volume 11 • Issue 5

CASE STUDY

Multiple Giant Vulvar Syringoma: An Extraordinary Report Giti Sadeghian, MD;1 Hengameh Ziaei2 A 26 year-old woman presented with asymptomatic multiple skin-colored eruptions affecting the vulva. She claimed that the lesions had started at the age of 15. The eruptions have been increasing in size and extent since her presentation. There was a family history of similar eruptions around the eyes of one of her sisters. Examination of the skin surface was marked by the presence of multiple, 2- to 3-cm firm, skin-colored, nodules on the labia majora (Figure 1). They were bilateral and symmetrical. One of the lesions was excised, and histopathologic serial sections were prepared and stained with hematoxylin and eosin. Sections showed clusters of small comma-shaped ducts lined by 2 cell–thick epithelium surrounded by a fibrotic stroma. Solid strands of basophilic epithelial cells independent of ducts were documented in the dermis (Figure 2). Accordingly, a diagnosis of syrangoma was made. (SKINmed. 2013;11:305–306)

S

yringoma, an appendageal tumor originating from the intraepidermal eccrine sweat gland ducts, is more common in women than in men. Its usual time of onset is adolescence.1 The face, neck, chest, and occasionally the genital regions are the most common sites of involvement. Vulvar syringoma is its rare clinical variant, which is symmetrically distributed on the labia majora. The lesions are usually asymptomatic. Occasionally, they may cause severe pruritus of the genitals.2 They are often incidentally detected during routine gynecologic examination. The tumor(s) are usually 1 to 3 mm in diameter.1 Syringoma was first described in 1872 by Kaposi and Biesiadeki as lymphangioma3,4 tuberosum multiplex. Since then, monoclonal antikeratin antibody tests, electron microscopy, and histochemistry have confirmed the intraepidermal eccrine sweat gland nature of this disease.5 Syringoma is a benign adnexal tumor derived from intraepidermal eccrine duct that may present as single or multiple papules, commonly on the eyelids, and predominantly in women at puberty or later in life in 6% of the population.4 In more than half of patients, the reported age of onset has been during the second and third decades of life.6 Vulvar syringoma manifests as small, multiple, bilateral, and skincolored to yellowish or brownish pruritic papules over the labia majora. Typical syringoma on the eyelids may coexist in one third of cases.7 A Friedmom and Butler classification of syringoma consists of 4 principal clinical variants: a localized form, a familiar form, a form associated with Down syndrome, and a generalized form that encompasses multiple and eruptive syringoma.8 In the

Figure 1. Symmetrical skin-colored nodules on the labia majora.

pathology, the upper portion of the dermis and mid-dermis reveal a plethora of small colloid material containing cystic ducts and solid epithelial strands contained within the surrounding fibrous stroma of these two layers. Two rows of flat epithelial cells with a clear cytoplasm line the walls of these ducts, sometimes making a comma-shaped “tadpole” tail.1 In the differential diagnosis of vulvar syringoma Fox-Fordyce disease, epidermal cysts, senile angiomas, lichen simplex chronicus, condyloma acuminate, and steatocystoma multiplex should be considered9,10 (Table).

From the Skin Disease and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran;1 and the Medical School of Isfahan University of Medical Sciences, Isfahan, Iran2 Address for Correspondence: Giti Sadeghian, MD, Skin Disease and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran • E-mail: sadeghian@sdlrc.mui.ac.ir

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A

Figure 2. Clusters of small comma-shaped ducts lined by 2 cell–thick epithelium surrounded by a fibrotic stroma.

Solid strands of basophilic epithelial cells independent of ducts were present in the dermis. Hematoxylin and eosin stain, original magnification ×200 (A) and hematoxylin and eosin stain, original magnification ×400 (B).

3 Kaposi M. Hebra diseases of the skin. Lymphangioma Tuberosum Multiplex. London, England: The New Sydenham Society; 1874;386:3

Table. Differential Diagnosis of Vulvar Syrangoma Fox-Fordyce disease

4 Biesiadeki A. Anatomischen Tuberosum multiplex: untersuchungen aus der Pathologisch Lymphangioma Institute in Krakau. Vienna: Wilhelm Braumuller; 1972:2

Epidermal cysts Senile angioma Lichen simplex chronicus

5 Hashimoto K, Gross, BG, Lever WF. Syringoma: histochemical and electronmicroscopy studies. J Invest Dermatol. 1966;46:150–166.

Condyloma acuminatum Steatocystoma multiplex

Previously reported methods for the treatment of syringoma include surgical methods such as electrodesiccation, cryotherapy, CO2 laser ablation, and excision or chemical therapy such as topical or systemic retinoids.11,12 A report suggests the use of topical atropin to alleviate the pruritus in symptomatic eruptive syringoma.13 There is also a report of vulvar syringoma successfully treated with tranilast.14

6 Lee JH, Chang JY, Lee KH. Syringoma: a clinicopathologic and immunohistologic study and results of treatment.

Yonsei Med J. 2007;48:35–40.

7 Patrizi A, Neri I, Marzaduri S, et al. Syringoma: a review of twenty-nine cases. Acta Derm Venereol. 1998;78:460–462.

8 Friedman SJ, Butler DF. Syringoma presenting as milia.

J Am Acad Dermatol. 1987;16:310–314.

9 Trager JD, Silvers J, Reed JA, et al. Neck and vulvar papules in an 8-year-old girl. Arch Dermatol. 1999;135:203, 206.

10 Isaacson D, Turner ML. Localized vulvar syringomas. J Am Acad Dermatol. 1979;1:352–356.

Conclusions Previously, one case of solitary giant vulvar syringoma has been reported,15 but here we described a case of multiple giant syringoma of the vulve, which has not to our knowledge been previously reported. The patient was treated with surgical excision, and, after 2 years of follow-up, there was no recurring of lesions and the patient was satisfied with her condition.

References

11 Soler-Carrillo J, Estrach T, Mascaro JM. Eruptive syringoma: 27 new cases and review of the literature. J Eur Acad Dermatol Venereol. 2001;15:242–246.

12 Frazier CC, Camacho AP, Cockerell CJ. The treatment of eruptive syringomas in an African American patient with a combination of trichloroacetic acid and CO2 laser destruction. Dermatol Surg. 2001;27:489–492.

13 Sanchez TS, Dauden E, Casas AP, et al. Eruptive pruritic syringomas: treatment with topical atropine. J Am Acad Dermatol. 2001;44:148–149.

1 Miranda JJ, Shahabi S, Salih S, et al. Vulvar syringoma, report of a case and review of the literature. Yale J Biol Med. 2002;75:207–210.

14 Iwao F, Onozuka T, Kawashima T. Vulval syringoma successfully treated with tranilast. Br J Dermatol.

2005;153:1228–1230.

2 Kavala M, Can B, Zindanci I, et al. Vulvar pruritus caused by syringoma of the vulva. Int J Dermatol. 2008;47:831–832.

15 Blasdale C, Macleland J. Solitary giant vulval syringoma.

Br J Dermatol. 1999;14:350–392.

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September/October 2013

Volume 11 • Issue 5

CASE STUDY

Epidermolysis Bullosa Pruriginosa Affecting 3 Successive Generations Piyush Kumar, MD;1 Ashim Kumar Mondal, MD;2 Niharika Ranjan Lal, MD;2 Ramesh Chandra Gharami, MD2 A 24-year-old man presented with multiple mildly itchy flesh-colored papules and plaques on both legs for the past decade. The lesions were preceded by transient vesicles that contained clear fluid. The papules and plaques used to develop on sites where vesicles had healed. Many family members in three generations had similar lesions (Figure 1). On examination, multiple discrete flesh-colored papules and plaques were found on both lower extremities, extending from the feet up to the knees (Figures 2 and 3). A few of the plaques were excoriated. No vesicles or bullae were noted, and the skin in between the lesions appeared normal. The nail of left great toe was discolored and dystrophic. The rest of the mucocutaneous examination was unremarkable. Bullous lichen planus, Neckam’s disease, lichenoid amyloidosis, and epidermolysis bullosa pruriginosa (EBP) were considered as differential diagnoses. Histopathology from the plaque showed a subepidermal cleft with no inflammatory cells. The epidermis was acanthotic at places, and the dermis appeared normal (Figure 4a and 4b). Based on clinical presentation and histopathology, a diagnosis of EBP was made. (SKINmed. 2013;11:308–309)

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linically, history of vesicles preceding development of plaques and absence of prominent itching were suggestive of EBP.1 Bullous lichen planus presents with itchy papules and plaques followed by development of bulla over them.2 Histopathology can easily differentiate between the two. EBP, a rare variant of dystrophic epidermolysis bullosa (DEB), is caused by a mutation in the type VII collagen gene and is characterized by pruritic lichenified plaques or prurigo-like lesions, milia, nail dystrophy, and albopapuloid lesions.3 The lesions present either at birth or between 6 months to 10 years of age and occur mostly on the shins, other parts of the legs, forearms, elbows, dorsal aspect of the hands, shoulders, and lower aspect of the back, with sparing of the face and flexures.4 Patients often give a history of vesicles preceding lesions, but vesicles and blisters are rare on clinical examination. Microscopic studies of EBP show typical findings of DEB; however, subepidermal cleft may not be observed in all fields. Ultrastructural studies showed a reduction of anchoring fibrils in lesional, perilesional, and nonlesional skin. Treatment is largely unsatisfactory and is mainly symptomatic, ie, control of itching. Other than antihistamines, potent topical steroids under occlusion and intralesional triamcinolone can be used to control pruritus. Cryotherapy has been found to be useful in some patients.3,4 Our case had many family members affected in 3 generations. The pattern of involvement is consistent with the autosomal-dominant nature of the condition.

Figure 1. Pedigree chart showing affected members in a family.

Conclusions Epidermolysis bullosa (EB) is a heterogeneous group of hereditary blistering disorders. The clinical presentation is varied, and awareness of different presentations is a prerequisite to diagnose various EBs. The combination of lichenified papules and plaques preceded by blisters and histopathology show subepidermal cleft with no inflammation is unique for EBP.

From the Department of Dermatology, Katihar Medical College, Katihar,1 and the Department of Dermatology, Medical College & Hospital, Kolkata, India2 Address for Correspondence: Piyush Kumar, Deptepartment of Dermatology, Katihar Medical College, Karim bagh, Katihar, Inida. Pin 854105 • E-mail: docpiyush@gmail.com

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Figure 4A. Hyperkeratosis and subepidermal cleft with no inflammatory cells. Lymphatics and blood vessels appear to be increased in number.

Figure 2. Multiple discrete lichenoid plaques on both feet. Note dystrophy of the left great toe nail.

Figure 3. Close-up view of lesions over the leg.

References 1 Fine JD. Inherited epidermolysis bullosa. http://www. ojrd.com/content/5/1/12. Accessed November 18, 2011.

2 Joshi A, Khaitan KB, Verma KK, Singh MK. Generalized and bullous lichen planus treated successfully with oral mini-pulse therapy. Indian J Dermatol Venereol Leprol.

1999;65:303–304.

3 Das JK, Sengupta S, Gangopadhyay AK. Epidermolysis bullosa pruriginosa—report of three cases. Indian J Dermatol Venereol Leprol. 2005;71:109–111.

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Figure 4B. Hyperkeratosis, acanthosis, and apparently normal dermis. Note the absence of the subepidermal cleft in this view.

4 Yesudia D, Krishnan S, Jayaraaman M, Janaki VR, . Epidermolysis bullosa pruriginosa. Indian J Dermatol Venereol Leprol. 2000;66:249–250.

Epidermolysis Bullosa Pruriginosa

September/October 2013

Volume 11 • Issue 5

CASE STUDY

An Unusual Presentation and Distribution of Generalized Eruptive Syringomas Conroy Chow, MD;1 Nima M. Gharavi, MD, PhD;2 Chandra N. Smart, MD;2 Sharona Yashar, MD;2,3 Lorraine C. Young, MD2

A 19-year-old Caucasian man presented with numerous erythematous to flesh-colored papules that appeared in crops on his neck, axillae, buttocks, and lower back. The lesions started on his anterior neck at age 12. At 18 years, new crops of papules appeared on his axillae, back, and buttocks over several months. He reported pruritus in the lesions following exercise and perspiration. He denied any family history of similar lesions. His primary care physician treated him with topical triamcinolone 0.1% cream, which made the lesions smaller, less erythematous, and less pruritic; however, the papules never fully resolved. After discontinuation of the steroids, these erythematous pruritic papules gradually recurred in the same areas of his body. The patient denied any other medical complaints. (SKINmed. 2013;11:311–312)

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n examination, numerous skin-colored to erythematous, firm, 1- to 5-mm papules in clusters on the anterior portion of the neck, axillae, buttocks, and lower part of the back were seen (Figure 1). No lesions were observed on the face, chest, abdomen, scrotum, or penis. Rapid plasma reagin serology results were negative. Biopsies from the axilla and buttock (Figure 2) were consistent with syringomas, and a diagnosis of generalized eruptive syringomas was made.

Discussion

Syringomas are benign eccrine sweat gland tumors that commonly present as asymptomatic skin-colored to yellow, firm papules on the lower eyelids, cheeks, axillae, umbilicus, and abdomen.1 There are 4 main types of syringomas based on clinical features and potential associations with other medical conditions.2 Eruptive syringomas are a rare form in which numerous papules appear in successive crops, most often on the anterior portion of the trunk, neck, abdomen, and axillae over a span of years.2,3 These lesions typically initially appear in the peri-pubertal period, and additional lesions can develop later in life.2,3 Syringomas are generally asymptomatic, but rare cases have been associated with pruritus following perspiration.2,3

Clinical diagnosis of eruptive syringomas can be difficult, because they present similarly to other skin diseases, including mastocytosis, Langerhans cell histiocytosis, folliculitis, lichen planus, and secondary syphilis. Definitive diagnosis can be obtained by histopathologic examination, which demonstrates numerous small ducts in a background of sclerotic collagen in the superficial dermis.2,3 The ducts are usually lined by two layers of cuboidal to flattened epithelial cells and may contain positive periodic acidSchiff, eosinophilic, amorphous debris in the lumen.4,5 The outer layer of ductal epithelium may bulge outward to form a commalike tail so that the duct has the shape of a tadpole.4,5 Conclusions We report an unusual case of generalized eruptive syringomas presenting with erythematous pruritic papules on atypical body locations. While the patient developed fairly classic lesions on his anterior neck and axillae, diffuse involvement of the back and buttocks is extremely rare.1,5 Additional unusual features are the erythema and pruritus associated with the syringomas, as they are typically skin-colored and asymptomatic.2 Finally, while regression of the lesions is rare, a response to topical steroids, as noted by our patient, has not been previously reported in the literature.

From the University of Michigan Medical School, Ann Arbor, Michigan;1 the Department of Medicine, Division of Dermatology, David Geffen School of Medicine, UCLA, Los Angeles, CA;2 and the Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA3 Address for Correspondence: Lorraine C. Young, MD, UCLA Med-Derm, Box 956957, 200 Med Plaza #450, Los Angeles, CA 90095-6957 • E-mail: lcyoung@mednet.ucla.edu

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Figure 1. Clinical presentation of numerous skin-colored to erythematous papules noted in the axillae (left) and buttocks (right). Similar-appearing additional lesions were also noted on the anterior portion of the neck and back.

Figure 2. Histopathologic biopsy was taken from the buttocks and showed numerous small eccrine ducts lined by 2 layers of cuboidal to flattened epithelial cells in a sclerotic superficial dermis.

References 1 Paquette DL, Massa MC. An unusual presentation of syringomas on the buttocks. J Am Acad Dermatol.

1998;39:1032–1033.

2 Patrizi A, Neri I, Marzaduri S, Varotti E, Passarini B. Syringoma: a review of twenty-nine cases. Acta Derm Venerol. 1998;78:460–462.

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3 Soler-Carrillo J, Estrach T, Mascaro JM. Eruptive syringoma: 27 new cases and review of the literature. J Eur Acad Dermatol Venereol. 2001;15:242–246.

4 Lee AY, Kawashima M, Nakagawa H, Ishibashi Y. Generalized eruptive syringoma. J Am Acad Dermatol. 1991;25:570–571.

5 Powell CL, Smith EP, Graham BS. Eruptive syringomas: an usual presentation on the buttocks. Cutis.

2005;76:267–269.

Generalized Eruptive Syringomas

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Volume 11 • Issue 5

CASE STUDY

An Unusual Presentation of Perforating Metastatic Calcinosis Cutis Matthew Livingood, MD; Sabrina A. Newman, MD

A 37-year-old white man diagnosed with multiple myeloma was admitted for respiratory distress. He was found to have hypercalcemia (13.1 mg/dL), hyperphosphatemia (7.2 mg/dL), hyponatremia (121 mEq/L), and acute renal failure (serum urea nitrogen, 116 mg/dL; creatinine, 4.9 mg/dL). On hospital day 7, skin lesions over his elbows, wrists, and fingers were noticed and the dermatology department was consulted.

Physical examination revealed 0.5- to 3.0-cm erythematous denuded patches with yellow crusts at the periphery that were localized to the bilateral interdigital web spaces, medial elbows, and volar wrists (Figure 1 and Figure 2). No oral mucosal or conjunctival findings were present.

Results from skin biopsies of the lesions revealed focal epidermal necrosis with zones of amorphous basophilic material that focally appeared to perforate the epidermis (Figure 3). Results from Congo red and Verhoeff-van Gieson stains were negative, and results from Von Kossa stain were positive, confirming the perforating material as calcium. Ten days after initial dermatology examination, the patient’s respiratory distress worsened and he subsequently died. Autopsy revealed diffuse pulmonary calcinosis and renal tubular calcification. As a result of the autopsy findings, the patient was diagnosed with perforating metastatic calcinosis cutis. (SKINmed. 2013;11:314–315)

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etastatic calcinosis cutis is the precipitation of calcium salts into tissues as the result of an underlying defect in calcium and/or phosphate metabolism.1 Common sites of calcium deposition include visceral organs such as the lung, kidneys, blood vessels, and gastrointestinal mucosa. Additionally, cutaneous and subcutaneous tissues may be involved. Metastatic calcinosis cutis is generally associated with hypercalcemia and/or hyperphosphatemia. Specifically, the size and number of calcifications tend to correlate with the degree of hyperphosphatemia, and calcifications disappear with normalization of calcium and phosphate levels.1 A variety of systemic disorders may lead to metastatic calcification, but it is most commonly associated with chronic renal failure and prolonged secondary hyperparathyroidism and rarely with multiple myeloma.1

Metastatic calcinosis cutis is one of five types of calcinosis cutis that also include dystrophic, iatrogenic, idiopathic, and calciphylaxis.2 Calciphylaxis has traditionally been classified as a subtype of metastatic calcinosis cutis, but recent literature suggests a unique pathomechanism that separates it into its own subtype. Metastatic calcinosis cutis typically presents as itchy and painful indurated papules, nodules, or plaques of varying sizes with gritty or rockhard consistency.3,4 The patient had no history of local factors such as repeated trauma, needle sticks, or medical studies with saturated electrode paste, ruling out dystrophic and iatrogenic components

to these skin lesions. In terms of transepidermal elimination of calcium in these lesions, it can occur with any of the five types of calcinosis cutis.5,6 Of interest, it has been recently hypothesized that calcium deposition in calcinosis cutis may occur in areas of local tissue damage where injured tissue serves as a local minoris resistentiae.7 This case has several unique features. In addition to the unusual clinical presentation of metastatic calcinosis cutis, its occurrence in the setting of multiple myeloma makes this case of clinical interest. Metastatic calcinosis cutis is uncommon in multiple myeloma; only two case reports exist.3,8 One report described widespread arterial calcification of subcutaneous tissue.8 The second case reported that the combination of multiple myeloma and renal failure, coupled with the increase of temperature produced by an electric blanket, caused precipitation of calcium salts into the skin.3 More common cutaneous presentations in multiple myeloma result from infiltration of the skin by either malignant cells or products they produce.9 In the present case, it is believed that hypercalcemia as a result of the patient’s underlying multiple myeloma, coupled with the sudden increase in phosphorus caused by acute renal failure, may have provided the ideal environment for the precipitation of calcium salts within the skin and extensively within other organs.

From The George Washington University School of Medicine & Health Sciences, Washington, DC Address for Correspondence: Sabrina A. Newman, MD, Medical Faculty Associates, George Washington University, 2150 Pennsylvania Avenue, 2nd Floor, Washington, DC 20037 • E-mail: snewman@mfa.gwu.edu

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Figure 1. Left volar wrist: 0.5- to 3.0-cm erythematous denuded patches with overlying yellow crust.

Figure 2. Interdigital web spaces and fingers: 0.5- to 1.0-cm erythematous erosions with overlying hemorrhagic crusts.

Figure 3. Dermatopathology: focal epidermal necrosis with zones of amorphous basophilic material that focally appeared to perforate the epidermis (hematoxylin-eosin, original magnification ×20). Results from Brown and Bren stain were positive for focal surface bacteria.

References 1 Walsh JS, Fairly JA. Calcifying disorders of the skin. J Am Acad Dermatol. 1995;33:693–-706.

2 Reiter N, El-Shabrawi L, Leinweber B, Berghold A, Aberer E. Calcinosis cutis: part I. Diagnostic pathway. J Am Acad Dermatol. 2011;65:1–12.

3 Alvarez C, Saval H, Enriquez M, Martinez C. Metastatic calcinosis cutis in multiple myeloma. Br J Dermatol. 2000;142:820.

4 Raimer SS, Archer ME, Jorizzo JM. Metastatic calcinosis cutis. Cutis. 1983;32:463–465.

5 Patterson JW. The perforating disorders. J Am Acad Dermatol. 1984;10:561–581.

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6 Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol.

2007;56:569–579.

7 Pugashetti R, Shinkai K, Ruben BS, et al. Calcium may preferentially deposit in areas of elastic tissue damage.

J Am Acad Dermatol. 2011;64:296–301.

8 Raper RF, Ibels LS. Osteosclerotic myeloma complicated by diffuse arteritis, vascular calcification and extensive cutaneous necrosis. Nephron. 1985;39:389.

9 Bayer-Garner IB, Smoller BR. The spectrum of cutaneous disease in multiple myeloma. J Am Acad Dermatol.

2003;48:497–507.

Perforating Metastatic Calcinosis Cutis

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Volume 11 • Issue 5

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Acneiform Eruption and Pruritus in a Patient With Quetiapine Therapy Naveen Kumar Kansal, MD; Meghna Sharma, MD To the Editor: Quetiapine is a second-generation antipsychotic used in the management of schizophrenia and manic/depressive episodes, as well as in the maintenance phase of bipolar 1 disorder. Quetiapine is usually well tolerated, with a small risk of extrapyramidal reactions, although concerns remain about metabolic effects such as hyperlipidemia, hyperglycemia, and weight gain.1 Cutaneous adverse events with quetiapine are rare and may require specific attention and referral to a dermatologist for evaluation. We report a patient who developed an acneiform eruption with pruritus during therapy with quetiapine.

A 22-year-old man was referred from a psychiatry outpatient department with complaints of itchy, erythematous dermatitis for 1 month. The patient was known to have bipolar disorder. His medication history was notable for quetiapine 100 mg twice a day about 6 weeks ago for the management of depression; he was not taking any other prescription or overthe-counter medication. On cutaneous examination, an erythematous, monomorphic, diffuse, papular eruption without any comedones was noted on the upper portion of the back, shoulders, and arms (Figure) and forehead. Because the patient was stable, he was prescribed clindamycin phosphate 1% gel to be applied locally twice a day with levocetirizine 5-mg tablets once at night, and quetiapine was continued. At his follow-up visit 2 weeks later, however, the patient had no improvement.

At this time, in consultation with the patient’s psychiatrist, a decision was made to change his psychotropic medicine. The patient was started on an extended-release (ER) preparation of divalproex sodium (divalproex sodium ER 500-mg tablet once at night). Quetiapine was gradually tailed off in 2 weeks, and the dosage of divalproex sodium was increased to 500 mg 3 times a day. The patient responded well, and his eruption resolved by the fifth week. He remained stable on divalproex sodium after regular follow-up visits.

Figure. Acneiform eruption on the upper aspect of the back, shoulder, and arm. No comedones are seen.

Conclusions In addition to pruritus and acneiform eruption, quetiapine is also reported to cause maculopapular dermatitis, fixed-drug eruption, drug-induced pigmentation, exfoliative dermati-

From the Department of Dermatology and Venereology, Gian Sagar Medical College and Hospital, Ramnagar, Patiala-140601, India Address for Correspondence: Naveen Kumar Kansal, MD, Department of Dermatology & Venereology, Gian Sagar Medical College & Hospital, Ramnagar, Patiala-140601, India • E-mail: kansalnaveen@gmail.com

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tis, psoriasiform eruption, hyperhydrosis, skin discoloration, contact dermatitis, and seborrheic dermatitis-like eruption.1–3 In our index case, as per the Naranjo adverse drug reaction probability scale,4 the association between acneiform eruption and quetiapine is probable with a score of 5. Among other antipsychotics, aripiprazole5 and haloperidol3 are also reported to cause acneiform eruption. In our patient, acneiform eruption associated with pruritus is likely to have an impact on a patient’s medication compliance. In such cases, physician-patient rapport is important and an early dermatologic evaluation may eliminate risk of noncompliance and relapse of psychiatric illness.

References 1 Seroquel. Prescribing information. AstraZeneca Pharamaceuticals, Wilmington, DE; 2012. http://www1.astrazeneca-us.com/pi/Seroquel.pdf. Accessed October 20, 2012.

2 Rashid J, Wang R, Ramer SL. Atypical antipsychotics and seborrheic dermatitis: three case reports. Pharmacopsychiatry. 2007;40:103–106.

3 Warnock JK, Morris DW. Adverse cutaneous reactions to antipsychotics. Am J Clin Dermatol. 2002;3:629–636.

4 Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.

5 Mishra B, Praharaj SK, Prakash R, Sinha VK. Aripiprazole-induced acneiform eruption. Gen Hosp Psychiatry.

2008;30:479–481.

Acquired Reactive Perforating Collagenosis Namrata Chhabra, MD; Sonal Sharma, MD To the Editor: A 50-year-old man with poorly controlled type 2 diabetes mellitus presented with a 3-month history of pruritic eruptions on the whole body, sparing the face, palm, and soles. Examination revealed multiple umbilicated brown papules, mostly with adherent keratotic plugs (Figure 1).

Koebner phenomenon was evident (Figure 2). Histologic analysis from the lesion showed cup-shaped depression of epidermis filled with necrotic plug, inflammatory cells, and collagen fibres (Figure 3). On Masson’s trichrome staining, perforating bundles of collagen were seen in the lower part of the plug (Figure 4). Laboratory findings were normal except for fasting blood glucose (300 mg/dL; normal: 70–110 mg/dL); hence, a diagnosis of acquired reactive perforating collagenosis with diabetes mellitus was made. The patient was started on narrowband UV-B, oral antihistaminics, and a potent topical steroid and referred to the medicine department for control of diabetes.

Acquired reactive perforating collagenosis has been recognized as an uncommon distinct dermatosis in which altered collagen is eliminated through the epidermis, particularly among patients with diabetes mellitus or renal failure. There are several treatment modalities proposed, including topical steroids and UV-B, topical retinoic acid, and isotretinoin or allopurinol.

Figure 1. Umbilicated brown papules with adherent keratotic plugs over the legs.

From the Department of Dermatology and STD and Pathology, University College of Medical Sciences and GTB Hospital, University of Delhi New Delhi-110095, India Address for Correspondence: Namrata Chhabra, MD, Senior Resident, Department of Dermatology and STD, University College of Medical Sciences and GTB Hospital, 86-B, Pocket F, GTB Enclave, Dilshad Garden, Delhi-110095, India • E-mail: chhabra.namrata@gmail.com

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Figure 2. Dark brown papules with central keratotic plugs over the back showing the Koebner phenomenon.

Figure 4. Masson’s trichrome staining of the section showing perforating bundles of collagen in the lower part of the keratin plug.

Figure 3. Histopathology of the cutaneous lesion showing cup-shaped depression of epidermis filled with necrotic plug, inflammatory cells, and collagen fibres (haematoxylin and eosin, original magnification × 400).

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Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2013;11:317–319

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Acquired Reactive Perforating Collagenosis

MEDIA PARTNER

T H E

T I M E

N O W

F D A

H A S

C O M E

A P P R O V E D

*

BROUGHT TO YOU BY

T O L E A R N M O R E , V I S I T W W W. M I RVA S O . C O M / H C P 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. *Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base.

Mirvaso and Galderma are registered trademarks. Š2013 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 MIR-173 Printed in USA 08/13

T H E

T I M E

N O W

F D A

H A S

C O M E

A P P R O V E D

*

BROUGHT TO YOU BY

T O L E A R N M O R E , V I S I T W W W. M I RVA S O . C O M / H C P 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. *Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base.

Mirvaso and Galderma are registered trademarks. Š2013 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 MIR-173 Printed in USA 08/13