Nov / Dec, 2014

November/December 2014 • Volume 12 • Issue 6 EDITORIAL Jewish Dermatologists in Nazi Germany Burgdorf and Parish

COMMENTARY Scleredema Adultorum of Buschke

Carvalho, Costa, de Moura, Quintella, Carneiro, and Ramos-e-Silva

ORIGINAL CONTRIBUTION Radiation-Associated Atypical Vascular Lesions: Vascular Lesions With Endothelial Cell Atypia Presenting in the Radiation Port of Breast Cancer Patients Anzalone, Cohen, Tschen, and MacFarlane

REVIEW Cutaneous Inflammatory Lipid Mediators

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER Physical Modalities in Dermatology: 1870–1975 Lowenstein

case studies Centrally Located Acquired Bilateral Nevus of Ota-Like Macules: A Bizarre Pattern Zhang, Zhu, and Zhou

The Clinical Challenges in the Management of Deep Lymphangioma of the Foot Singal, Gupta, Pande, Mehta, Sahu, and Mahajan

BOOK REVIEW Moderate to Severe Psoriasis Allen

Kutlubay, Tüzün, Wolf, and Engin

Self-Assessment Examination Lambert

CORE CURRICULUM Footwear Dermatitis: Historical Background, Epidemiology, Clinical Connotation—Part II Sehgal, Rasool, Srivastava, Aggarwal, and Verma

DEPARTMENTS NEW THERAPY UPDATE Dalbavancin (Dalvance) for the Treatment of Acute Bacterial Skin Infection Gupta, Foley, Abramovits, and Rosen

Lebanese Dermatological Society

PERILS OF DERMATOPATHOLOGY Don’t Blow Your Top: Protecting the Information Trail in Epidermis—Fragile Skin Biopsies Castor, Szatkowski, Handler, and Lambert

THE HEYMANN FILE Eosinophilic Annular Erythema: Attention Must Be Paid

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

Heymann

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TABLE OF CONTENTS November/December 2014 • Volume 12 • Issue 6

EDITORIAL

Jewish Dermatologists in Nazi Germany ................................................................................................... 333

Walter H.C. Burgdorf, MD; Lawrence Charles Parish, MD, MD (Hon)

COMMENTARY

Scleredema Adultorum of Buschke............................................................................................................ 337

Joana Castro Carvalho, MD; Thaís Neves Costa, MD; Heloisa Helena Gonçalves de Moura, MD; Leonardo Pereira Quintella, MD, PhD; Sueli Carneiro, MD, PhD; Marcia Ramos-e-Silva, MD, PhD

ORIGINAL CONTRIBUTION

Radiation-Associated Atypical Vascular Lesions: Vascular Lesions With Endothelial Cell Atypia Presenting in the Radiation Port of Breast Cancer Patients ............................................................ 344

C. Lane Anzalone, BS; Philip R. Cohen, MD; Jaime A. Tschen, MD; Deborah F. MacFarlane, MD

Review

Cutaneous Inflammatory Lipid Mediators .................................................................................................. 350

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

Self-Assessment Examination ................................................................................................................... 357

W. Clark Lambert, MD, PhD

CORE CURRICULUM

Virendra N. Sehgal, MD, Section Editor

Footwear Dermatitis: Historical Background, Epidemiology, Clinical Connotation—Part II......................... 360

Virendra N. Sehgal, MD; Farhan Rasool, MD; Govind Srivastava, MD; Ashok Aggarwal, MD; Prashant Verma, MD

Departments New Therapy Update

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

Dalbavancin (Dalvance) for the Treatment of Acute Bacterial Skin Infection ............................................ 366

Aditya K. Gupta, MD, PhD, FRCPC; Kelly A. Foley, PhD; William Abramovits, MD; Ted Rosen, MD

Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Don’t Blow Your Top: Protecting the Information Trail in Epidermis—Fragile Skin Biopsies

Marcel Castor, BS; Jesse Szatkowski, BS; M. Zac Handler, MD; W. Clark Lambert, MD, PhD

................... 372

The Heymann File

Warren R. Heymann, MD, Section Editor

Eosinophilic Annular Erythema: Attention Must Be Paid............................................................................ 376

Warren R. Heymann, MD

History of Dermatology Society Newslatter Eve Lowenstein, MD, PhD, Section Editor

Physical Modalities in Dermatology: 1870–1975....................................................................................... 381

Eve Lowenstein, MD, PhD

326

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TABLE OF CONTENTS November/December 2014 2014 •• Volume Volume 12 12 •• Issue Issue 66 November/December

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Centrally Located Acquired Bilateral Nevus of Ota-Like Macules: A Bizarre Pattern................................... 385

Ru-zhi Zhang, MD; Wen-yuan Zhu, MD; Lei Zhou, MD

The Clinical Challenges in the Management of Deep Lymphangioma of the Foot........................................ 390

Rikki Singal, MS; Samita Gupta, MD; Pinky Pande, MD; Vinod Mehta, MD; Pradeep Sahu, MS; N.C. Mahajan, MD

Book Review

Jennifer L. Parish, MD, Section Editor

Moderate to Severe Psoriasis..................................................................................................................... 395

Herbert B. Allen, MD

Editorial

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FOR INTERDIGITAL TINEA PEDIS DUE TO TRICHOPHYTON RUBRUM AND EPIDERMOPHYTON FLOCCOSUM IN ADULT PATIENTS TABLE OF CONTENTS November/December 2014 • Volume 12 • Issue 6

INTRODUCING LUZU L U ZU FA S T: 2 W E EK S, 14 DOS E S Efficacy demonstrated at 4 weeks post-treatment The only topical azole antifungal approved to treat interdigital tinea pedis with once-daily dosing over a 2-week period

Indications and Usage LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum in patients 18 years of age and older.

Important Safety Information • LUZU is indicated for topical use only and is not indicated for ophthalmic, oral or intravaginal use.

• LUZU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Caution should be exercised when LUZU is prescribed for nursing mothers.

Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies. © 2014 Valeant Pharmaceuticals North America LLC.

DM/LUZ/13/0004

329

• The most common adverse reactions in clinical

trials were application site reactions, which occurred in less than 1% of subjects in both LUZU and vehicle arms. Most adverse reactions were mild in severity.

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

Reference: LUZU [prescribing information]. Bridgewater, NJ: Medicis, a division of Valeant Pharmaceuticals; 2013.

S:7�

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION FOR LUZU (luliconazole) This Brief Summary does not include all the information needed to use LUZU safely and effectively. See full Prescribing Information for LUZU. LUZU (luliconazole) Cream, 1% for topical use Initial U.S. Approval: 2013 Rx Only INDICATIONS LUZU (luliconazole) Cream, 1% is an azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older.

DOSAGE AND ADMINISTRATION For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or intravaginal use.

When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for two (2) weeks.

When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for one (1) week.

CONTRAINDICATIONS None ADVERSE REACTIONS

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 three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas.

During clinical trials with LUZU Cream, 1% the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity.

Post-Marketing Experience The following adverse reactions have been identified during post-marketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

DRUG INTERACTIONS The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4.

Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro assessment. The induction potential of luliconazole on CYP enzymes has not been evaluated.

USE IN SPECIFIC POPULATIONS

Pregnancy: Pregnancy Category C.

to pregnant female rats. No treatment related effects on maternal toxicity or malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Increased incidences of skeletal variation (14th rib) were noted at 25 mg/kg/day. No treatment related effects on skeletal variation were noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons).

Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. No treatment related effects on maternal toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day (24 times the MRHD based on BSA comparisons).

In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered from the beginning of organogenesis (gestation day 7) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No treatment effects on postnatal development were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons).

Nursing Mothers It is not known whether luliconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LUZU Cream, 1% is administered to women who are breastfeeding.

Pediatric Use The safety and effectiveness of LUZU Cream, 1% in pediatric patients have not been established. The number of pediatric patients ≼12 years of age were too small to adequately assess safety and efficacy.

Geriatric Use Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent were 65 and over, while 1.4 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted.

Luliconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosomal aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus test).

In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1X MRHD based on BSA comparisons).

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Inform patients that LUZU Cream, 1% is for topical use only.

LUZU Cream, 1% is not intended for intravaginal or ophthalmic use.

Manufactured for: Medicis, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807

There are no adequate and well-controlled studies of LUZU Cream, 1% in pregnant women. LUZU Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The animal multiples of human exposure calculations were based on daily dose body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 1% cream per day (1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day).

Systemic embryofetal development studies were conducted in rats and rabbits.

Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 7-17)

Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215 Product of Japan Issued: 11/2013 140127 DM/LUZ/13/0005(1)

November/December 2014

Volume 12 • Issue 6

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ Vesna Petronic-Rosic, MD, MSc

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

Philadelphia, PA

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD T:10.875” S:10”

Mohamed Amer, MD Cairo, Egypt Robert L. Baran, MD Cannes, France Anthony V. Benedetto, DO Philadelphia, PA

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

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

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN Lowell A. Goldsmith, MD, MPH Chapel Hill, NC

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Virendra N. Sehgal, MD Delhi, India

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

Riccarda Serri, MD Milan, Italy

George M. Martin, MD Kihei, HI

Charles Steffen, MD Oceanside, CA

Marc S. Micozzi, MD, PhD Rockport, MA

Alexander J. Stratigos, MD Athens, Greece

George F. Murphy, MD Boston, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM Julian Trevino, MD Dayton, OH

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

Graham Turner, PhD, CBiol, FSB Port Sunlight, UK

Joseph L. Pace, MD, FRCP Naxxar, Malta

Snejina Vassileva, MD, PhD Sofia, Bulgaria

Art Papier, MD Rochester, NY

Daniel Wallach, MD Paris, France

María Daniela Hermida, MD Buenos Aires, Argentina

Johannes Ring, MD, DPhil Munich, Germany

Michael A. Waugh, MB, FRCP Leeds, UK

Warren R. Heymann, MD Camden, NJ

Roy S. Rogers III, MD Rochester, MN

Wm. Philip Werschler, MD Spokane, WA

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Donald Rudikoff, MD New York, NY

Camila K. Janniger, MD Englewood, NJ

Robert I. Rudolph, MD Wyomissing, PA

Joseph A. Witkowski, MD Philadelphia, 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

Aditya K. Gupta, MD, PhD, FRCPC London, Ontario, Canada Seung-Kyung Hann, MD, PhD Seoul, Korea Roderick J. Hay, BCh, DM, FRCP, FRCPath London, UK

SKINmed. 2014;12:331

331

Ronni Wolf, MD Rechovot, Israel Matthew J. Zirwas, MD Columbus, Ohio

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November/December 2014

Volume 12 • Issue 6

Editorial

Jewish Dermatologists in Nazi Germany Walter H.C. Burgdorf, MD;1 Lawrence Charles Parish, MD, MD (Hon)2

W

ith the development of medical specialties beginning in the 1860s, physicians could devote their time to the study of specific organ systems or surgical approaches. Although Jews had been given full rights in the new Germany by 1871, prejudice and other restrictions often precluded hospital and university appointments. Major specialities, such as internal medicine and surgery were almost closed to Jews, as were obstetrics and gynecology. Dermatology, with its heavy emphasis on sexually transmitted diseases, evolved into a suitable domain for Jewish physicians almost by default. Even those Jews who converted to Christianity were not spared from discrimination. Paul Gerson Unna (1850–1929), a nonpracticing Jew, established his own institute for these reasons to compensate for not achieving a university appointment. Numerous Jewish physicians served in the Kaiser’s army during World War I; this was the first chance for Jews to become officers and many distinguished themselves on the battlefield.

Post–World War I After World War I, there was an increase in anti-Semitism in Germany, fanned by the radical political views of Adolf Hitler (1889–1945) and his National Socialist German Workers’ Party (Nazis) who managed to fan the already-present anti-Semitism and blame the Jews for the many economic and political woes of the country. When the Nazis took over power in January 1933 after doing well in the November 1932 elections and negotiating cleverly, it spelled difficult times for Jewish physicians and especially for the specialty of dermatology. At this time, Jews accounted for 1% of the general population but 16% of all physicians and 25% of all dermatologists.1 The majority of the Jewish physicians were in the large Jewish centers of Berlin, Frankfurt am Main, and Breslau. Other popular specialities for Jews were pediatrics and psychiatry.

The Nazi Regime A series of administrative measures and laws gradually made life intolerable for Jews in Germany. Typical measures included

removing them as civil servants, precluding university employment, and no longer allowing them access to publicly funded insurance patients, drying up a major source of income. The Nuremberg Laws in 1935 defined who was a Jew; many who had converted and were well-assimilated were surprised to learn overnight that they were once again Jews and distinctly secondclass citizens. Leaving Germany became increasingly more attractive. Of the 569 Jewish dermatologists registered in 1933, 276 (49%) successfully immigrated. The United States was the favorite site, receiving 107 new dermatologists; Palestine and the United Kingdom were other favored sites. There were 61 natural deaths, 13 suicides, and 57 documented murders in concentration camps. The fate of 162 (28%) remains unknown, but many in this group also perished.2 In Austria, everything went more rapidly after the Anschluss (fusion of Austria with Germany) in 1938. Vienna had a majority of Jewish dermatologists. Of 125 dermatologists in 1938, 45 are known to have successfully emigrated, while the fate of 32 is unknown.3 Two individuals survived the horrors without leaving their home towns; both had Aryan wives who greatly aided them. In Berlin, Erich Langer (1891–1957) emerged from hiding to become first Chairman of Dermatology at the newly founded Free University,4 while in Vienna, Robert Otto Stein (1880–1951) survived working at the Jewish hospital, and in 1951 was elected President of the Austrian Dermatological Society.5 Immigration to the United States Two countercurrent trends in dermatology made it possible for this influx of just over 100 dermatologists to radically change the nature of the speciality in the United States. First, German dermatology was highly advanced with large university centers and active research programs. Probably the most prominent was Breslau with a long Jewish tradition. Both of the famous chairmen, Albert Neisser (1855–1916) and Josef Jadassohn (1863– 1936), were Jewish, as were many of their disciples. Frankfurt and Berlin also had strong traditions of excellence. At the same time, dermatology was struggling as a relatively new academic

From the Department of Dermatology, Ludwig Maximilian University, Munich, Germany;1 and the Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Walter H. C. Burgdorf, MD, Traubinger Str. 45 A, 82327 Tutzing, Munich, Germany • E-mail: wburgdorf@gmx.de

SKINmed. 2014;12:333–335

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discipline in the United States. There were a few centers of excellence including the Mayo Clinic, University of Michigan, New York Skin and Cancer, and University of Pennsylvania, but most university programs were still based on the preceptorship model, and there was little basic science research. There was room for improvement and several of the Jewish physicians provided a tremendous impetus.

One must distinguish between established physicians who made an immediate impact transferring German dermatologic expertise to the United States and younger ones who received their training in the United States and served more as an individual brain drain. The person who established the best-known program was Stephan Rothman (1894–1963)6 from an old Budapest Jewish family but himself a convert to Roman Catholicism.

He had trained in photobiology in Giessen, Germany, and then returned home. Rothman’s scientific interests were broad, including the epidermal barrier, neurophysiology, and pharmacology. He found a job at the University of Chicago with the help of Samuel W. Becker (1894–1964), whom he had met at meetings and within 5 years had succeeded Becker as Head of Dermatology. He trained a long list of brilliant investigative dermatologists and in 1954 published his epic book Physiology and Biochemistry of the Skin.7 No other German dermatologist succeeded in establishing such a school, but many made individual contributions. Max Jessner (1887–1978), who had just succeeded Jadassohn as chairman in Breslau, moved to New York and became a valued faculty member at Skin and Cancer. Hermann Pinkus (1905–1985), a practicing Lutheran, became chairman at Wayne State University in Detroit and a pioneer in dermatopathology. Of the bright young men who received their training in the United States, Rudolf Baer (1910–1997) at NYU made the biggest impact, succeeding Marion B. Sulzberger (1895–1983), training a huge cadre of national and international leaders and staying active in cutaneous immunological research. Many immigrants chose to go into private practice. Alfred Höllander (1899–1986), one of Unna’s last pupils, practiced in Springfield, Massachusetts; Emil Meirowsky (1876–1960) wound up in Nashville, Tennessee; and Stephan Epstein (1900–1973) in Marshfield Wisconsin. More complete lists are readily available.

Despite the obvious benefits provided by these Jewish colleagues, little attention was paid to the circumstances surrounding their exit from Germany. One of us (WB) had Stephan Epstein for several dermatology lectures at the University of Wisconsin in 1968 and never once thought about how this brilliant man with the funny accent had wound up in Marshfield. In his memoirs in the Journal of the American Academy of Dermatology in 1981, Baer only SKINmed. 2014;12:333–335

gently alluded to the difficulties, writing … “Heightening Nazi persecution in Germany and the deteriorating political situation in Europe… influenced my decision at the age of 23 to leave Europe and emigrate (sic) to the United States.”9 Holländer, writing 2 years later in the American Journal of Dermatopathology, was the first to speak a bit more bluntly in “The tribulations of Jewish dermatologists under the Nazi regime.”10 He discussed the repressive measures and then recounted the fates of many of his friends and colleagues, writing primarily from memory and in a moving fashion. He also pointed out that Karl Herxheimer (1861–1942) and Abraham Buschke (1868–1943) were both murdered in the Theriesenstadt concentration camp near Prague.

The Recording of History Following Holländer’s paper, the dam burst, and there was almost an overabundance of reporting on the disastrous effects of Nazi medicine. The noted geneticist Benno Müller-Hill (1933– ) paved the way in 1984 in Germany with Tödliche Wissenschaft (Murderous Science).11,12 Dermatology was one of the first specialities to confront its Nazi past in detail. Four individuals were primarily responsible. Albrecht Scholz (1940–2013) from Dresden wrote a “Decline of German dermatovenereology under the Nazi regime” with Cathrin Schmidt in 1993 in the International Journal of Dermatology1 and followed this with numerous other valuable contributions.2,13,14 Karl Holubar (1936–2013) from Vienna wrote in the Journal of Investigative Dermatology in 1989 with Klaus Wolff (1935– ) on the role European immigrants had on investigative dermatology in the United States15 and followed with many other contributions. A. Bernard Ackerman (1936– 2008) provided an open forum in “his” journal, the American Journal of Dermatopathology, and then encouraged Wolfgang Weyers (1958–) to write the definitive text on the subject Death of Medicine in Nazi Germany: Dermatology and Dermatopathology Under the Swastika in 1998.16 The next year, Scholz and Sven Eppinger (1970– ) published on the fate of German Jewish dermatologists in the International Journal of Dermatology.2 Two years later, Eppinger’s doctoral thesis Das Schicksal der jüdischen Dermatologen Deutschlands in der Zeit des Nationalsozialismus appeared17; herein, he tried to track down all the Jewish dermatologists registered in Germany in 1933. These pioneer efforts plus the wonders of the Internet today make it possible to learn an enormous amount about the fates of Jewish colleagues in Germany and Austria.

Conclusions The risk is not lack of information but indifference. We all owe it to ourselves and our speciality to work diligently to ensure that such a tragic chain events never repeats itself.

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References 1 Scholz A, Schmidt C. Decline of German dermatovenereology under the Nazi regime. Int J Dermatol. 1993;32:71– 74.

2 Scholz A, Eppinger S. The fate of Germany’s Jewish dermatologists in the period of National Socialism. Int J Dermatol. 1999;38:716–719.

3 Angetter D. Austrian Dermatology 1918–1945. In: Scholz A, Holubar K, Burg G, eds. History of German Language Dermatology. Weinheim, Germany: Wiley-Blackwell; 2009:287–297.

4 Burgdorf WH, Plewig G, Kohl P, Hoenig LJ. Erich Langer: one who came back. JAMA Dermatol. 2014;150:63.

5 Wiedmann A. Zum 70. Geburtstag von R. O. Stein (On the occasion of the 70th birthday of R.O. Stein). Hautarzt. 1950;1:567.

6 Rothman FG, Lorincz AL. Stephen Rothman, pioneer of investigative dermatology. Perspect Biol Med. 1995;39:93–109.

7 Rothman S. Physiology and Biochemistry of the Skin. Chicago, IL: University of Chicago Press; 1954.

8 Burgdorf WH, Bickers DR. Dermatologic relationships between the United States and German-speaking countries: part 2—the exodus of Jewish dermatologists.

JAMA Dermatol. 2013;149:1090–1094.

9 Baer RL. Rudolf L. Baer, M.D. J Am Acad Dermatol.

1981;5:120–124.

10 Höllander A. The tribulations of Jewish dermatologists under the Nazi regime. Am J Dermatopathol. 1983;5:19– 26.

11 Müller-Hill B. Tödliche Wissenschaft: die Aussonderung von Juden, Zigeunern und Geisteskranken, 1933–1945. Reinbek bei Hamburg: Rowohlt; 1984.

12 Müller-Hill B. Murderous Science: Elimination by Scientific Selection of Jews, Gypsies, and Others, Germany 1933– 1945. Oxford, England: Oxford University Press; 1988.

13 Scholz A, Burgdorf W. The exodus of German dermatologists and their contributions to their adopted countries. Clin Dermatol. 2005;23:520–526.

14 Scholz S, Scholz A. Die Wissenschaftsentwicklung in der Dermatologie in Deutschland im Verhaltnis zur Emigration judischer Hautarzte wahrend des Nationalsozialismus. [The scientific development in dermatology in Germany in relation to the emigration of Jewish dermatologists during national socialism]. Wien Klin Wochenschr. 1998;110:185–189.

15 Holubar K, Wolff K. The genesis of American investigative dermatology from its roots in Europe. J Invest Dermatol. 1989;92(4 suppl):14S–21S. 16 Weyers W, Weyers W. Death of Medicine in Nazi Germany: Dermatology and Dermatopathology Under the Swastika.

Philadelphia, PA: Lippincott-Raven; 1998.

17 Eppinger S. Das Schicksal der jüdischen Dermatologen Deutschlands in der Zeit des Nationalsozialismus. Frankfurt am Main: Mabuse; 2001.

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November/December 2014

Volume 12 • Issue 6

COMMENTARY

Scleredema Adultorum of Buschke Joana Castro Carvalho, MD; Thaís Neves Costa, MD; Heloisa Helena Gonçalves de Moura, MD; Leonardo Pereira Quintella, MD, PhD; Sueli Carneiro, MD, PhD; Marcia Ramos-e-Silva, MD, PhD

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cleredema of Buschke is a disease of the cutaneous connective tissue, the so-called mucinoses, characterized by increased collagen and glycosaminoglycans deposits. It is a rare cutaneous disease of unknown etiology and uncertain evolution characterized by a symmetrical hardening of the skin.1 It involves mainly the neck, shoulders, trunk, face, and arms, and seldom the buttocks and thighs.1,2 Hands and feet are typically spared.3 There are three types of scleredema adultorum of Buschke. In type I, the disease typically develops in 2 to 3 weeks after an acute infection episode, with sudden onset. Most of these patients have complete remission within a few months to 2 years, and represent 55% of cases.1,3 Type II is not preceded by a feverish disease and is not associated with any underlying illness. It represents 25% of the cases, has an insidious progressive course, and is associated with increased risk for development of paraproteinemias and monoclonal gammopathy, including multiple myeloma.3 Type III, also known as scleredema diabeticorum, commonly affects men older than 40 years with insulin-dependent diabetes mellitus of long duration and poor control with vascular complications associated with diabetes. Twenty percent of patients with this form present a slowly progressive evolution without a tendency to remission.1,3

There are reports of association of dermatosis with internal neoplasias, as insulinoma, gallbladder carcinoma,4 and carcinoid syndrome.5 The precise etiology of scleredema of Buschke is unknown. Researchers have suggested streptococcic hypersensitivity, lymphatic lesion, alteration of the function of the hypophysis, and anomalies of peripheral nerves, but none of these have been confirmed.4 Systemic involvement is rare.6,7 When the picture does not present spontaneous remission, there are several treatments proposed, but none have been proven to be effective.8

The current case illustrates the onset and evolution of scleredema adultorum of Buschke in a patient in whom no comorbidities were found.

Illustrative case A 56-year-old man, who was retired from the Army and presently worked as a security guard, presented to the dermatology department of our hospital with cutaneous hardening in folds that began 3 years ago. It evolved with involvement of the face, trunk, and upper and lower limbs, sparing the acral regions (Figures 1 and 2). At examination, he presented with difficulties in opening his mouth, facial mimicking, and limitation in arm movement (Figure 3). He complained about high dysphagia and denied diabetes, previous infections, or other general symptoms. After a scalpel biopsy in the proximal region of the upper portion of the right limb, histopathologic examination revealed thickened dermis, secretory portions of eccrine glands far from the dermal-hypodermic junction, and thickened collagen fibers with light spaces in between them, without other alterations (Figures 4 and 5). Colloidal iron staining demonstrated mucopolysaccharide deposits in the medium and deep dermis (Figures 6 and 7). Results from hematologic, biochemical, and serologic examinations were normal, except for infection markers of previous hepatitis B. Results for Bence Jones proteinuria were negative and electrophoresis of proteins were normal. The patient denied respiratory symptoms but showed a normal thorax X-ray with a strong purified protein derivative reaction of 10 mm, which led to secondary prophylaxis for tuberculosis with 300 mg/d of isoniazid for 6 months. He presented stomach pH with abnormal reflux in orthostatic position, esophageal manometry with segmented esophageal spasm, and high digestive endoscopy with gastritis and erosions in the antrum. Electroneuromyography revealed neuropathy and axonal and distal motor sensitivity in all four limbs. We began treatment with pentoxifylline and colchicine, and, after 9 months, no satisfactory response was obtained. We suspended colchicine and introduced 7.5-mg methotrexate with a progressive scheme; however, currently, the picture remains unchanged.

From the University Hospital and School of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, Rua Dona Mariana 149/C-32, 22280-020 Rio de Janeiro, Brazil • E-mail: ramos.e.silva@dermato.med.br

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Figure 1. Hardening of the thorax skin and proximal region of the upper limbs.

Figure 4. Panorama of thickened dermis, portions of eccrine secretion glands distant from the dermal-hypodermal junction (hematoxylin and eosin stain, original magnification ×40).

Figure 2. Involvement of the dorsal cervical region.

Figure 5. Thickened collagen strands (hematoxylin and eosin stain, original magnification ×100).

Figure 3. Limitation in opening of the mouth.

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Figure 6. Mucopolysaccharide deposits in the deep dermis (colloidal iron, original magnification ×40).

Figure 7. Portions of eccrine secretion glands distant from the dermal-hypodermal junction, mucopolysaccharide deposits (colloidal iron, ×40).

Discussion Scleredema of Buschke is a rare dermatosis, with about 500 cases described in the literature.6 A symmetrical hardening of the skin of the upper part of the body occurs, with difficulty in folding the affected locations as a result of deposits of mucin and thickening of the dermis.2 Typically, the hands and feet are spared.3 Its etiology is unknown, but it is believed that damage to the lymph system occurs after hypersensitivity to streptococcus, monoclonal gammopathy, or diabetes mellitus in insulin-dependent patients.3,4 In the case of diabetes patients, it occurs mainly in men without glycemic control and those who are overweight.9 There are cases associated with other diseases such as a carcinoid tumor of the rectum, in addition to diabetes mellitus.5 Its evolution is uncertain, with possibility of spontaneous remission between 6 months and 2 years, especially when associated with infection, or, as in the reported case, indefinite persistence of the picture.

SKINmed. 2014;12:337–340

There are no specific laboratorial alterations that help in the diagnosis of scleredema. Biopsy, as in this case, demonstrates an increased dermis thickness as a result of edema and homogenization of collagen fibers, separated by large clear spaces. There is an increase in the amount of mucopolysaccharide in the dermis, which can be identified with special staining.7 System involvement is rare but can manifest as thickening of the tongue, dysarthria, dysphagia, and restriction of eye and articulation movements, involving the cardiac, muscular, and parotid gland; hepatosplenomegaly and pleural spill; and pericardial and peritoneal areas.7 There are also some cases associated with esophageal dysmotility.6 There is no specific treatment, but there are successful reports with electron-beam therapies,7 UV-A phototherapy10 (especially UV-A–1 therapy11,12) extracorporeal photophoresis, and high

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doses of penicillin.7 There are several drugs proposed in the literature, such as systemic corticosteroids, local injection of hyaluronidase, thyroid hormones, methotrexate, cyclosporine, penicilamine, prostaglandin E1, antibiotics, and aminocaproic acid, but none have been proven effective.1,7,8

2 Pitarch G, Torrijos A, Martínez-Aparicio A, Vilata JJ, Fortea JM. Escleredema de Buschke asociado a diabetes mellitus. Estudio de cuatro casos. Actas Dermosifiliogr.

2005;96:46–49.

3 Beers WH, Ince A, Moore TL. Scleredema adultorum of Buschke: a case report and review of the literature. Semin Arthritis Rheum. 2006;35:355–359.

Researchers have used intravenous immunoglobulins in patients with diabetes, reporting an excellent response in trunk mobility and dysphagia after the first cycle and improved cutaneous rigidity at the end of eight cycles of therapy. Intravenous immunoglobulins, whose role was demonstrated in other sclerotic diseases of the skin, are, thus, an alternative in scleredema of patients with diabetes, when treatment is required.9

4 Manchanda Y, Das S, Sharma VK, Srivastava DN. Scleredema associated with carcinoma of the gall bladder. Br J Dermatol. 2005;152:1373–1374.

Another researcher successfully treated a patient with scleredema adultorum of Buschke with carcinoid tumor of the rectum and diabetes mellitus with radiation therapy,5 which may suppress or downregulate the production of fibroblasts or other cells involved in connective tissue or mucin production, possibly through its acute anti-inflammatory effect.13

7 Kurtoglu S, Yüksel S, Gündüz Z, et al. Use of high-dose intravenous corticosteroid treatment in a child with scleredema. J Emerg Med. 2004;26:245–246.

Conclusions Scleredema of Buschke is a rare disease that produces a symmetrical hardening of the skin usually of the upper trunk. In many patients with this disease, the available therapies are not successful. More studies must be performed in order to try to improve outcomes in these patients.

References 1 Ioannidou DI, Krasagakis K, Stefanidou MP, et al. Scleredema adultorum of Buschke presenting as periorbital edema: a diagnostic challenge. J Am Acad Dermatol.

2005;52(2 suppl 1):41–44.

5 Yu JI, Park W, Lee KK, Park W. Scleredema adultorum of Buschke associated with a carcinoid tumor. Int J Dermatol. 2009;48:784–786.

6 Notar-Francesco V, Beatrice B, Cerulli MA, et al. A rare presentation of scleredema adultorum of Buschke with esophageal dysmotility. Am J Gastroenterol. 2002;49(9 suppl 1):S217.

8 Mattheou-Vakali G, Ioannides D, Thomas T, et al.

Cyclosporine in scleredema. J Am Acad Dermatol.

1996;35:990–991.

9 Barde C, Masouyé I, Saurat JH, Le Gal FA. [Scleroedema adultorum Buschke in a diabetic subject: intravenous immunoglobulin therapy]. Ann Dermatol Venereol.

2009;136:360–363.

10 Kroft EB, Berkhof NJ, van de Kerkhof PC, Gerritsen RM, de Jong EM. Ultraviolet A phototherapy for sclerotic skin diseases: a systematic review. J Am Acad Dermatol.

2008;59:1017–1030.

11 Kreuter A, Gambichler T. UV-A1 phototherapy for sclerotic skin diseases. Arch Dermatol. 2008;144:912–915.

12 Kroft EB, de Jong EM. Scleredema diabeticorum case series: successful treatment with UV-A1. Arch Dermatol.

2008;144:947–948.

13 Bowen AR, Smith L, Joes JJ. Scleroderma adultorum of Buschke treated with radiation. Arch Dermtl.

2003;139:780–784.

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Advertorial

Clean Laundry & Gentle on Skin Educate Patients: Who believe they must sacrifice cleaning power for a detergent that is non-irritating Sponsored by Procter & Gamble Researchers have found that nearly 45 percent of people report having “sensitive” or “very sensitive” skin.1 Many dermatologists recommend sensitive-skin patients use a dye- and perfume-free laundry detergent because dyes and fragrances are considered to be one of the most common causes of detergent skin allergies.

Each one of us approaches our laundry with the same goal: to clean it. However, to those with sensitive skin, achieving “clean” has not always been a straightforward task. “A lot of my patients feel they are sacrificing cleaning power when using some dye-free and perfume-free laundry products,” said Dr. Marnie Nussbaum. “As a result, many of my patients compensate by using scented stain removers or even abandon dye-free and perfumefree products in order to get their clothes truly clean.” In fact, surveys of patients with sensitive skin show:

Marnie Nussbaum, MD Dr. Nussbaum specializes in general and cosmetic dermatology.

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

• 80 percent say they are dissatisfied with their current fragrance-free laundry products and believe they must sacrifice cleaning power for a detergent that is non-irritating.

• More than four out of five use a pre-treatment to compensate for a lack of cleaning power.2 More and more dermatologists are now recommending Tide Free & Gentle. New data show it provides a better clean while being mild on sensitive skin in multiple dermatologist supervised studies or tests.

How Does Tide Free & Gentle Clean Better?

In tests, Tide Free & Gentle removes more residue from stains than the leading free detergent. In fact, Tide Pods Free & Gentle outperform the leading free detergent on 10 different stains, including blood, coffee and grass stains, and is mild on sensitive skin.

Tide Free & Gentle’s unique “Lift and Block” technology removes stains and soils to keep clothes clean while being gentle to skin.

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

Original image in B&W. Soil has been colorized to show contrast.

Step 1: Lift

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

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

Step 2: Block

• Anti-Redeposition Technology: Concentrated polymers sweep in to trap the dirt in the wash water, to prevent it from reattaching to the fabric fibers.

Our bodies produce up to 50 grams of body soil per day, including mucus, dead skin, sweat, sebum and bacteria. Clothing may look clean, but in a given laundry load, all that soil combines in the water to create a very dirty environment. This is important because even if a stain appears to have been removed from clothing the first trip through the washing machine, dirt attracts dirt, so any soil residues left on clothing fibers will cause dirt in the wash water to redeposit on clothes over time. See Fig. 2. Dirt redeposition is a primary reason why whites tend to appear dingy after numerous washings – not just dye transfer as is commonly believed.

As larger high efficiency washers continue to become the norm in American households, this issue becomes more pronounced. High efficiency washers use three times less water so soil is more concentrated in the wash water, increasing the likelihood of redeposition of dirt on clothing. However, Tide Free & Gentle’s unique “Lift and Block” technology provides a superior clean from wash to wash. Patients benefit from the gentleness of a dye- and perfume-free detergent without having to sacrifice superior cleaning power.

The Importance of Patient Compliance in a Laundry Regimen

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

Fig. 3 Eighty seven percent of those who use free detergent use scented fabric softeners or dryer sheets.

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

Dermatologists Play an Important Role

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

References

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

2 2010 Habits, Practices and Attitudes conducted by P&G.

November/December 2014

Volume 12 • Issue 6

Original contribution

Radiation-Associated Atypical Vascular Lesions: Vascular Lesions With Endothelial Cell Atypia Presenting in the Radiation Port of Breast Cancer Patients C. Lane Anzalone, BS;1 Philip R. Cohen, MD;2,3,4 Jaime A. Tschen, MD;5,6 Deborah F. MacFarlane, MD4 Abstract Atypical vascular lesions are an uncommon adverse sequela to the radiotherapy of tumors. Many characteristics are shared between atypical vascular lesions caused by radiation port and well-differentiated radiation-induced angiosarcomas. The authors retrospectively reviewed the medical literature using PubMed, searching the terms acquired, atypical, benign, lymphangioma, lymphangioendothelioma, lymphangiomatous, lesion, papules, progressive, and vascular. Patient reports and previous reviews of the subject were critically assessed and the salient features are presented. Atypical vascular lesions associated with the radiation port present as clinically innocuous flesh-colored to erythematous papules or plaques. The condition presents within the radiation field, approximately 3 years after initial treatment. While the exact me chanism remains to be elucidated, growing evidence supports an association between radiation-associated atypical vascular lesions and radiation-induced angiosarcomas. Atypical vascular lesions within a radiation port are suggested to be in a state of morphologic continuum, which may progress into the more aggressive, malignant angiosarcoma. The authors recommend consideration for biopsy of new skin lesions within or adjacent to radiation. While it is clear that atypical vascular lesions caused by radiation are not equivalent to angiosarcoma, growing evidence supports that radiation-associated atypical vascular lesions may progress to angiosarcoma in some patients; therefore, the authors recommend excision of the lesion with margins depending on clinical judgment and the lesion encountered.

(SKINmed. 2014;12:344–348)

O

ver the past few decades, breast-conservation therapies— which include lumpectomy/segmentectomy, axillary staging, and radiation therapy—have largely replaced the radical mastectomy as the preferential treatment of breast cancer.1 This evolution of breast cancer treatment, specifically the implementation of adjuvant radiotherapy, provides a direct association between radiation-associated vascular lesions and cutaneous radiation-induced angiosarcomas in the radiation field.2,3 Many characteristics are shared between radiation port–associated atypical vascular lesions and welldifferentiated radiation-induced angiosarcoma, making diagnosis a challenge. In addition, several reports have described atypical vascular lesions within radiation ports developing into well-differentiated angiosarcomas, suggesting a possible linkage between the radiationassociated malignancies.4,5

Case Reports

Case 1 A 51-year-old Latin American woman presented in February 2008 with an intermittently pruritic, 4×4-mm flesh-colored dermal papule on the right upper lateral chest. She discovered the skin lesion, which was located within her aspect of the radiation port, approximately 4 months earlier. Recently, she noted that the papule had grown larger.

Approximately 4 years earlier, she had been diagnosed with right-sided T2 N1 M0 invasive ductal carcinoma, modified Black’s nuclear grade 3, estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu nega-

From the Medical School1 and the Department of Dermatology,2 University of Texas Medical School at Houston, Houston, TX; the University of Texas Health Science Center, University of Texas, Houston, TX;3 the Department of Dermatology, University of Texas MD Anderson Cancer Center, Houston, TX;4 St. Joseph Dermatopathology, Houston, TX;5 and the Department of Dermatology, Baylor College of Medicine, Houston, TX6 Address for Correspondence: Philip R. Cohen, MD, 10991 Twinleaf Court, San Diego, CA 92131 • E-mail: mitehead@gmail.com

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A

B

Figure 1. Microscopic examination of an atypical vascular proliferation in a 51-year-old Latin American woman.

Low-power view (A) shows superficial epidermis with empty vascular spaces and mild inflammation (hematoxylin and eosin, original magnification ×10). High-power view (B) displays most blood vessels showing few endothelial cells but still confluent with hobnailing endothelial cells along vascular lumina (hematoxylin and eosin, original magnification ×40).

tive by fluorescence in situ hybridization. She initially received 6 cycles of 5-fluorouracil, Adriamycin, and cyclophosphamide.

Subsequently, she received radiation therapy to her right breast and lateral chest. Specifically, she was treated with paired tangential fields to a dose of 50 Gy over 6 weeks, followed by electron beam boost for an additional 10 Gy. Microscopic examination of the lesional punch biopsy showed irregularly shaped thin-walled vessels with focally prominent endothelial cells (Figure 1). The lesion was well-circumscribed and limited to the papillary dermis. Cytologic atypia was only minimal. Correlation of the clinical presentation and pathologic changes were consistent with atypical vascular proliferation, associated with prior radiation therapy to the lesional site.

An additional excision of the biopsy site was requested to ensure that the vascular lesion had been completely removed. The lesion was excised and has not since recurred.

Case 2

with no necrosis. The patient had breast conservation therapy that included a segmental resection and postoperative radiation therapy at another institution. She developed metastatic disease to the left acetabulum in 2002; subsequently, she was treated with radiation therapy at a total dose of 50 Gy/20 fractions using an APPA technique over the course of 4 weeks. Since 2003, the patient has taken 2.5 mg of letrozole daily.

Microscopic examination of the punch biopsy of the lesion revealed cells that focally extended to the deep tissue edge (Figure 3). Correlation of the clinical presentation, including the patient’s prior exposure to radiation therapy at the lesional site, and pathologic changes established a diagnosis of atypical vascular proliferation associated with radiation port. The lesion was excised. The patient died of progressive neoplastic disease 2 years later; however, there was no recurrence of the original vascular lesion.

Discussion

A 59-year-old Asian woman presented in January 2010 with an asymptomatic 2×2-mm flesh-colored papule on her right chest below the axilla that had been present for more than 1 year (Figure 2). The lesion did not itch and was not painful. The lesion was located in the radiation port from initial radiation therapy in 1996.

The use of adjuvant radiation therapy with breast-conserving techniques is a well-known modality for the treatment of primary breast cancer; however, several complications may arise from the usage of radiotherapy. Albeit rare, radiation-associated atypical vascular proliferations and radiation-induced angiosarcomas are two such complications, each of which arises within the field of radiation (Table).4

Fourteen years earlier, in 1996, she had been diagnosed with bilateral intraductal breast carcinoma, Black’s nuclear grade 3,

In 1994, Fineberg and Rosen coined the term “atypical vascular lesion,” now widely accepted as the current nomenclature;

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A

B

Figure 2. Atypical vascular proliferation in a 59-year-old Asian woman. Distant (A) and close-up (B) views of her right upper lateral aspect of the chest reveal a 2×2-mm flesh-colored papule on initial visit 14 years following completion of radiation therapy.

A

B

Figure 3. Microscopic examination of an atypical vascular proliferation in a 59-year-old Asian woman. Low-power view (A) shows vascular proliferation in the upper and mid-dermis with empty-looking spaces (hematoxylin and eosin, original magnification ×10). A foci of chronic inflammation can be seen; the epidermis is normal. High-power view (V) shows hobnailing of endothelial cells with hyperchromatic nuclei (hematoxylin and eosin, original magnification ×40).

however, the condition has also been described in other studies as acquired progressive lymphangioma, benign lymphangioendotheliom, and benign lymphangiomatous papules.3,6 In our patients, the clinically innocuous lesions may appear as fleshcolored papules or erythematous patches or plaques within the radiation field.7 Other neoplasms to be considered in the differential diagnosis of radiation port–associated atypical vascular lesions include acquired progressive lymphangioma hobnail hemangioma, Kaposi’s sarcoma, lymphangioma circumscriptum, retiform hemanSKINmed. 2014;12:344–348

gioendothelioma, and targetoid hemosiderotic hemangioma.7 Fluorescence in situ hybridization for MYC (a proto-oncogene protein) amplification and anti-MYC immunohistochemistry serve as useful clinical diagnostic tools for the assessment of atypical vascular proliferations.8 Atypical vascular lesions within a radiation port have an average latency of 3 to 4 years; in comparison, radiation-induced angiosarcomas typically present 6 years after radiotherapy.6,9 While the exact mechanism leading to radiation-associated atypical vascular lesions (as well as radiation-induced angio-

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Table. Vascular Lesions Within the Radiation Field Radiation-Associated Lesion

Clinical Appearance

Onset Following Completion of Radiotherapy

Reference

Atypical vascular lesion of the radiation port

Flesh-colored to erythematous papules or plaques

3 years

4

Radiation-induced angiosarcoma

Violaceous nodules or plaques

6 years

4

sarcomas) remains to be elucidated, well-founded pathogenic explanations have been postulated on the subject. The skin area corresponding to the radiation port is representative of an immunocompromised district.10 Ionizing radiation profoundly alters local lymph circulation (with interruption of some routes and formation of new anastomosing vessels) and consequently hinders the trafficking of immune cells. In addition, radiation-induced dermal fibrosis affects the local peripheral sensory nerve fibers, causing the release of neuromediators in the irradiated region.10,11 The result is a locally disrupted neuroimmune interaction with subsequent decline of the antineoplastic immune surveillance, presenting the opportunity for a new-onset malignancy.

Histologic examination yields further similarities between radiation port–induced atypical vascular proliferations and radiation-induced angiosarcomas. Anastomosing vessels and hyperchromatic endothelial cells are common to both conditions; dissection of dermal collagen may be present as well.6,12 Radiation-induced angiosarcomas display an infiltrative growth pattern, frequently extend into the subcutis, and exhibit a more prominent nucleoli, cytologic atypia, mitotic activity, and multilayering of endothelial cells; whereas radiation-associated atypical vascular proliferations are characterized by relatively circumscribed dilated vascular spaces within the dermis, associated chronic inflammation, and absence of nuclear pleomorphism, mitotic activity, and hemorrhage.6,12 Researchers proposed two different histologic patterns for radiation port–associated atypical vascular lesions based on heterogeneity among the histologic presentations: a lymphatic type and a vascular type.5 The lymphatic type is defined as “thin-walled, variably anastomosing lymphatic vessels lined by attenuated or slightly protuberant (hobnail) endothelial cells; the vascular type was described as “round to linear, capillary-sized vessels, giving an appearance intermediate between a capillary and a cavernous hemangioma.” The lymphatic type correlates with the classic histologic presentation of atypical vascular lesions; yet, the lymphatic type of atypical vascular lesions were found to be the more common of the two patterns.5 SKINmed. 2014;12:344–348

Although radiation port–associated atypical vascular lesions were originally thought to be a benign lesion, researchers reported a tendency for these vascular tumors to develop additional lesions within the radiation field and possibly progress to angiosarcoma.4 A clinicopathologic study of 11 patients with post-radiotherapy vascular proliferations further supported the possibility that atypical vascular lesions within a radiation port may represent a precursor to angiosarcoma.1 Investigators also described a range of changes of the lymphatic type of radiation port–induced atypical vascular lesion, from superficial, circumscribed proliferations to more complex deep lesions; these data support the notion of morphologic continuum of the lesion.5 Atypical vascular lesion–like areas in the peripheral and lateral margins of angiosarcoma excisions—coined the “tip of the iceberg” phenomenon—give additional credence to this theory.1 Subsequent efforts should be carried out to further confirm this relationship.

Conclusions Atypical vascular proliferations are rare adverse sequelae to radiotherapy of tumors. Careful long-term observation of the radiation field is important, as the atypical vascular proliferation associated with the radiation port can present, on average, three years after therapy. We recommend consideration for biopsy of new skin lesions within or adjacent to radiation ports. While it is clear that radiation-associated atypical vascular lesions are not equivalent to radiation-induced angiosarcoma, growing evidence supports that some of the atypical vascular lesions associated with radiation may progress to radiation-induced angiosarcoma; therefore, we recommend excision of the lesion with clear margins depending on clinical judgment and the lesion encountered.

References

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1 Mattoch IW, Robbins JB, Kempson RL, Kohler S. Postradiotherapy vascular proliferations in mammary skin: a clinicopathologic study of 11 cases. J Am Acad Dermatol.

2007;57:126–133.

2 Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Am J Surg Pathol. 2004;28:781–788.

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ORIGINAL CONTRIBUTION

3 Fineberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol.

1994;102:757–763.

4 Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol.

2005;29:983–996.

5 Patton KT, Deyrup AT, Weiss SW. Atypical vascular lesions after surgery and radiation of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma. Am J Surg Pathol. 2008;32:943–950.

6 Uchin JM, Billings SD. Radiotherapy-associated atypical vascular lesions of the breast. J Cutan Pathol.

2009;36:87–88.

7 Diaz-Cascajo C, Borghi S, Weyers W, et al. Benign lymphangiomatous papules of the skin following radiotherapy: a report of five new cases and review of the literature.

Histopathology. 1999;35:319–327.

8 Fernandez AP, Sun Y, Tubbs RR, Goldblum JR, Billings SD. FISH for MYC amplification and anti-MYC immunohistochemistry: useful diagnostic tools in the assessment of secondary angiosarcoma and atypical vascular proliferations. J Cutan Pathol. 2012;39:234–242.

9 Esler-Brauer L, Jaggernauth W, Zeitouni NC. Angiosarcoma developing after conservative treatment for breast carcinoma: case report with review of the current literature. Dermatol Surg. 2007;33:749–755.

10 Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. J Eur Acad Dermatol Venereol. 2009;23:1364–1373.

11 Ruocco V, Ruocco E, Brunetti G, Sangiuliano S, Wolf R. Opportunistic localization of skin lesions on vulnerable areas. Clin Dermatol. 2011;29:483–488.

12 Mandrell J, Mehta S, McClure S. Atypical vascular lesion of the breast. J Am Acad Dermatol. 2010;63:337–340.

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Ichthyosis: Courtesy of Museo delle Cere Anatomiche L. Cattaneo, University of Bologna, Italy. Photo by Cristian Mancini.

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November/December 2014

Volume 12 • Issue 6

REVIEW

Cutaneous Inflammatory Lipid Mediators Zekayi Kutlubay, MD;1 Yalçın Tüzün, MD;1 Ronni Wolf, MD;2 Burhan Engin, MD1 Abstract Inflammation is the physiological response of the organism to different stimuli such as infection, trauma, or immunological mechanisms. Lipid mediators play a major role in skin inflammation and are known as “local mediators” acting in the intercellular microenvironments, where they reach considerable levels. A complex family of lipid mediators regulates a wide variety of physiological responses and pathological processes. Lipid mediators are produced by all human tissues, differing widely in the amounts of the various enzymes they contain and, therefore, in the relative proportions and amounts of products. The authors emphasize the effects and roles of lipid mediators in skin inflammation, focusing particularly on evidence provided by recently published studies. In the future, pharmacologic manipulation of lipid mediators and their receptors may provide a novel approach for controlling inflammation. (SKINmed. 2014;12:350–356)

D

uring the past few decades, intensive research in the fields of chronic and acute skin inflammatory disorders has resulted in a better understanding of the pathophysiology and diagnosis of dermatologic diseases. Modern therapeutic approaches are still not satisfactory enough; however, the treatment of inflammatory skin diseases such as psoriasis and atopic dermatitis is a complex and unresolved process.

The inflammatory reaction is characterized by the stimulation of humoral and cellular mediator systems. When a great variety of inflammatory mediators are released, alterations in microvascular tone and permeability are observed. The products of the classical cascade systems and various other mediators are capable of activating the lipid mediator syntheses, which are essentially involved in the regulation of the complex inflammatory reaction.1 Many factors such as environmental, microbiological, immunological, and toxic agents as well as UV light can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid mediators are released and play a crucial role in cutaneous inflammation. Arachidonic acid (AA), the main substance of the proinflammatory lipid mediators, is released from membrane phospholipids in the course of inflammatory activation and is metabolized to prostaglandins (PGs) and leukotrienes (LTs).2 Eicosanoids derived from the metabolism of AA are a family of lipid mediators. Lipid mediators such as prostanoids and LTs

have a wide range of biological actions including potent effects on inflammation and immunity.2 In general, during inflammation, eicosanoids act as proinflammatory molecules (PGH2), chemoattractants (LTB4), platelet-aggregating factors (TXA2), contractors of smooth muscle (CysLTs), and modifiers of vascular permeability (LTs). PGs might act as both proinflammatory and anti-inflammatory mediators. LTs also appear to play an active part in controlling the resolution of inflammation.

Therefore, targeting LTs might be worth investigating as an approach for the treatment of inflammatory diseases.3 The excessive production of lipid mediators can be controlled on different levels of biochemical pathways. These pathways include inhibition of phospholipase A, blockade of cyclooxygenase (COX) and lipoxygenase (LO) pathways, and the development of receptor antagonists against platelet-activating factor and LTs.2 The eicosanoid system such as linoleic acid (LA), γ-linoleic acid, α-linoleic acid (ALA), or AA depends on dietary intake. Because LA and ALA cannot be synthesized de novo, they are essential to the human diet.4 The term eicosanoid (pronounced “eye-cosa-noid,” from the Greek “eikosi,” the number 20) denotes one of a family of enzymatically generated metabolites of 20-carbon polyunsaturated fatty acids. Major diseases related to the skin and cardiovascular, gastrointestinal, and many other organ systems need proinflammatory eicosanoid production.5 Eicosanoids such as PGs, LTs, and lipoxins (LXs) are signalling molecules.

They are produced primarily through an oxidative pathway from

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

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AA (Figure) but also from pathways originating from eicosapentaenoic and dihomo-γ-linolenic acids.6,7 The fact that levels of one or more of the lipid mediators are abnormally elevated or sustained in relation to disease activity points to the participation of lipid mediators in inflammatory diseases. Examples include increased plasma concentrations and urine levels of excretion of metabolites of PGD2 from mast cells in systemic mastocytosis and severe systemic allergic reactions and increased urinary excretion of LTE4 by atopic children with severe pulmonary cystic fibrosis.8 AA Biosynthesis A key step in the production of precursors for the biosynthesis of inflammatory lipid mediators is the activation of the phospholipase A2 (PLA2) family. The production of three important classes of inflammatory lipids (PGs, LTs, and PAF) is suppressed by inhibition of this enzyme. It offers an attractive therapeutic approach to the design of novel agents for the treatment of inflammation and tissue injury. The PLA2 family is a series of enzymes serving in phospholipid catabolism. Their protein sequence databases contain more than 150 PLA2 amino acid sequences. PLA2 plays an important role in both the rapid and the prolonged cellular responses occurring during inflammatory processes.2 The availability of free AA is necessary for the biosynthesis of eicosanoids. AA present in the epidermis must therefore come from either dietary sources or transported to the epidermis from other endogenous sources such as the liver. In the cell, AA is stored in the membrane fraction, primarily esterified to phospholipids at the second carbon (sn-2) of the phospholipid glycerol backbone. PLA2 releases the phospholipids in the cell membrane. When skin is exposed to irritation and injury, keratinocytes respond to stimuli by a rapid but transient activation of AA metabolism. AA is produced from membrane phospholipids by the influence of diverse pathophysiological stimuli, such as growth factors, hormones, or cytokines. The PLA2s are a diverse class of enzymes with regard to function, localization, regulation, mechanism, sequence, and structure. Thus, they essentially carry out the same reaction, namely the hydrolysis of the sn-2 fatty acyl bond of phospholipids.9 Both the secretory PLA2 (sPLA2) and the cytoplasmic PLA2 (cPLA2) are present in human skin.

Both involved and uninvolved psoriatic skin have been shown to contain higher levels of sPLA2 than normal skin. The fact that IL-1b induces expression and secretion of sPLA2 in a variety of cells has been shown.10 In several studies, PLA2 has been suggested to play an important role in inflammatory skin diseases. Intradermal injection of SKINmed. 2014;12:350–356

purified sPLA2 induces cellular infiltration, vascular permeability, interstitial edema, and hyperemia. In the human epidermis, PLA2 has been suggested to be subject to positive feedback regulation, as its activity was stimulated by PGE2 and PGF2α. Direct phosphorylating activities may also regulate PLA2 activity.

PLA2 activity may be indirectly regulated by phosphorylationdephosphorylation of a soluble 35 kDa PLA2 inhibitory protein termed lipocortin.10,11 It has been suggested that upon phosphorylation, lipocortin loses its inhibitory properties, resulting in expression of PLA2 activity, and hyperphosphorylation of lipocortin has been suggested as the reason for increased PLA2 activity in uninvolved psoriatic epidermis.12 PLA2 activity is also inhibited by glucocorticosteroids via transcriptional control of lipocortin synthesis, and topical use of glucocorticosteroids to the skin results in reduction of PLA2 activity. Most mammalian cells and tissues, including human epidermis, have phospholipase C (PLC) activity. Epidermal PLC has been demonstrated as a Ca2+-dependent enzyme with maximal activity at pH 7.0.

PLC activity in psoriatic plaque has been shown to be increased 188% compared with normal epidermis and may thus contribute to the elevated AA levels observed in this tissue.10 P-450 epoxygenase, COX, and LOs are three main pathways that enzymatically metabolize AA. The P-450 epoxygenase pathway results in production of both hydroxyeicosatetraenoic acids (HETEs) and epoxides. The COX pathway produces PGG2 and PGH2, which are subsequently converted into PGs and thromboxanes (TXs) (Figure).6 COX-Mediated PG Production Cell stimulation causes the synthesis of PGs, and their pharmacologic actions are shown on target cells in close proximity. As products of COX catalysis, PGs have critical physiological and pathophysiological roles in inflammation and nociception. Both swelling along with increased blood flow and vascular permeability are classic signs of acute inflammation, excluding pain. PGs are primarily involved in inflammation-related vasodilation and synergize with other proinflammatory mediators (eg, histamine and bradykinin) to increase vascular permeability and promote edema. The most potent vasodilators among the PGs are PGE2 and PGI2, and they are determined at high concentrations at sites of skin inflammation; however, they cause vasoconstriction in human nasal mucosal vessels.5 As a result of COX pathway, the first step in AA metabolism is the formation of PGH2 by the COX or PGH synthase. Two COXs localized in the endoplasmic reticulum and nuclear envelope convert AA to TX and PGs. These two mammalian COX isoforms, COX-1 and COX-2, metabolize AA by an identical

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Membrane Bound Phospholipids Phospholipase A2 Arachidonic Acids (AA) Cyclooxygenases (COX1-, Cox2)

Prostaglandin G2

Lypoxygenases

5-HETEs

12-HPETEs

Leukotrien A4

12-HETEs

PGH synthase Prostaglandin H2

Isomerases/Synthases

• Prostaglandins (PGD2, PGE2, PGF2a)

• Prostacyclin (PGI2)

Cysteinyl leukotrienes • LTC4 • LTD4 • LTE4

Leukotrien B4

Lipoxins LXA4 LXB4

Cytocrome p450

15-HPETEs (15-hydroxyeicosapenta enoic acids

HETEsEpoxides

15-HETEs

Lipoxins LXA4 LXB4

• Trompoxanes (TXA2, TXB2)

Anti-inflammatory mediators • Sensitisation (PGE2) • Hyperalgesia (PGE2) • Mucosa protection (PGE2) • Inflammatory response (PGE2) • Na+/water excretion (PGF2a) • Contractility ↑ in uterus (PGF2a)

• Smooth muscle relaxation • Fibrinolysis • Platelet aggregation • Mucosa protection • H+ secretion • Cortical and glomerular blood flow ↑

• Platelet aggregation • Contraction • GFR regulation

Figure. Eicosanoid biosynthesis from arachidonic acid

mechanism. PGH2 is further metabolized to physiologically important PGs: TXA2, PGI2, PGE2, PGF2α, and PGD2. An extremely potent vasodilatation agent is TXA2. TXA2 also causes increased platelet aggregation, while PGI2 causes vasodilatation SKINmed. 2014;12:350–356

and has antiaggregation effects on platelets. Nonsteroidal antiinflammatory drugs such as aspirin and indomethacin inhibit COX. This inhibition largely accounts for the anti-inflammatory and analgesic effects of these agents.13

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Platelet COX-1 is the main responsible enzyme for TXA2 production. COX-1 is associated with cellular homeostasis and COX-2 is associated with synthesis of proinflammatory PGs. Much attention has therefore been paid to develop specific inhibitors of COX-2. COX-2 has been associated with keratinocyte differentiation in normal human epidermis. COX-1 immunostaining is detected throughout the epidermis in normal human skin, whereas COX-2 immunostaining is increased in differentiated keratinocytes. COX-2 has also been implicated in the development of skin cancer.10,14 Monocytes and macrophages induce COX-2 at sites of inflammation, and it is thought that the key mediators of chronic inflammatory processes are COX-2–derived eicosanoids. Many studies suggest that eicosanoid products of COX-2 catalysis support inflammation and diseases such as cancer. COX-2 generates more PGE2 than other PGs. The multiple associations between PGE2 synthase and COX-2 suggest that these two enzymes are physiologically coupled and that COX-2 may be linked preferentially over COX-1 to the terminal PGEs. These data raise the intriguing possibility that PGEs might be an accessible target for future anti-inflammatory drug development.15 A major AA COX product in human epidermis is PGE2. PGE2 formation has also been demonstrated to be important for keratinocyte differentiation. PGD synthase has been demonstrated in the dermal macrophages and mast cells.10 LO-Mediated LT and Lipoxin Production The products of LO and CO are present in both normal and inflamed skin, in both constituent cells (keratinocytes [not 5-LO], macrophages, mast cells, fibroblasts, and vascular endothelium) and blood-borne cells (polymorphonuclear leukocytes [PMNs], monocytes, eosinophils, and platelets). Lymphocytes do not appear to generate either CO or LO products. AA-derived metabolites in the LX family are endogenous lipid mediators that actively promote the resolution of inflammation.16,17 The initial product of AA is the (mono)-hydroperoxyeicosatetraenoic acid (HPETE) that is made by four distinct mammalian LOs. An oxygen molecule is introduced into the respective position of the AA backbone by 5-, 8-, 12-, and 15-LOs giving rise to unstable HPETEs. An HPETE undergoes reduction to its corresponding HETE and under certain circumstances further oxidation to diHETEs. The biologically active LTs are among the diHETEs of the 5-LO pathway. 15-LO is involved in LX production and is found in PMNs and other myeloid cells, whereas 12-LO is present in both leukocytes and platelets. Because of its involvement in pro-inflammatory LT synthesis and its potential as a therapeutic target, the 5-LO pathway is important (Figure).5,18 SKINmed. 2014;12:350–356

CPLA2 is approved to be the most important enzyme for providing substrate for LT biosynthesis, among the family of PLA2 enzymes.19 The free fatty acid is then oxygenated at C-5 by 5-LO in concert with the AA-binding protein 5-LO-activating protein (FLAP) to generate the epoxide intermediate LTA4. An increase in intracellular calcium level is necessary for the activation of both cPLA2 and 5-LO enzymes and is further enhanced by activation of certain protein kinases. LTA4 is then converted to LTB4 by the effect of LTA4 hydrolase or conjugated with reduced glutathione by LTC4 synthase to form LTC4. LTB4 is best known as a leukocyte chemoattractant and activator, and LTC4 is the parent compound of the cysteinyl LTs (cysLTs), which also include LTD4 and LTE4 and which account for the myotropic activity previously identified as slow-reacting substance (of anaphylaxis), important in the pathogenesis of asthma. CysLTs exert a range of proinflammatory effects and have proved to be important mediators in cutaneous inflammatory conditions and in other diseases. Each of the particular LTs has varying actions, but, in general, the cysLTs (LTC4, LTD4 and LTE4) are involved with bronchoconstriction, smooth muscle contraction, increased permeability of microvessels, mucosal edema, and mucus secretion. LTB4 is a chemoattractant and can induce leukocyte chemotaxis, degranulation, cytokine secretion, adherence, and IgE synthesis. With short-term exposure to LTB4 there is often an increase in the population of neutrophils, but with longer exposures, additional granulocytes, such as eosinophils, are recruited. LTB4 has also been noted to increase keratinocyte proliferation.17,20,21,22 5-(S)-HPETE derives LTA4 being the biologically most important LT intermediate. Epoxide opening by glutathione Stransferase (LTC4 synthase) leads to LTC4. LTC4 to LTD4 and then to LTE4 are converted by transpeptidases. Although LTs have been implicated in inflammatory skin diseases such as psoriasis and atopic dermatitis, the capacity of the human skin itself to biosynthesize the LTs has been questioned. The fact that freshly isolated human epidermal cells and cultured mouse keratinocytes can synthesize low quantities of LTB4 has been reported.10,20 5-LO is a rarely distributed enzyme, being found primarily in cells of myeloid origin (PMNs, mast cells, basophils, and macrophages). Notably, 5-LO is not required for LT production. The 5-LO activity in human keratinocytes is very limited. PMNs in human whole blood predominantly synthesize LTs (especially LTB4), whereas eosinophils favor LTC4 production.5,23 It is known that LTs cannot be formed from AA in the epidermis. The fact that both human cultured keratinocytes and human epidermis transform neutrophil-derived LTA4 into LTB4

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in vitro has been reported. LTA4 hydrolase is the key enzyme in transcellular LTB4 formation in the epidermis. The LTA4 hydrolase has been localized in the human epidermis.24 In inflammatory skin diseases such as psoriasis, neutrophils migrate into the epidermis and get into close contact with the keratinocytes. Release of LTA4 into the extracellular space has previously been demonstrated by activated neutrophils, and very recently it was demonstrated that more than 50% of the LTA4 formed in neutrophils is released from the cell. The human epidermis can contribute significantly to LTB4 formation in inflammatory skin diseases by means of transcellular LT synthesis.10,22 The 8-LO is one of the most recently discovered LOs in the skin. Only brief reports have been published on the enzymatic production of 8-HETE in human tissues and cell types such as human leukocytes, tracheal cells, and psoriatic skin. Enzyme activity was localized in the cytosolic fraction of the cells in the suprabasal compartment of the epidermis, and both phosphatidylcholine and lecithin stimulate enzyme activity. ATP, calcium, and nicotinamide adenine dinucleotide phosphate-oxidase are not needed. 12-HETE is one of the main lipid mediators formed by the epidermis and large quantities of 12-HETE have been discovered in human psoriatic lesions.18,25,26 The epidermal 12-LO has gained considerable interest. 12-LO activity results in the formation of 12-HPETE, which is reduced to 12-HETE. The 12-LO has been partially characterized in human epidermis and keratinocytes.27 The cytoplasmic 12-LO is named as the leukocyte-type LO whereas the microsomal 12-LO is termed the platelet type. Only the platelet-type 12-LO is detectable in normal human epidermis, involved psoriatic epidermis, and cultured human keratinocytes. 12-HETE in psoriatic scale is not the expected LO-derived 12(S)-HETE but instead predominantly consists of 12(R)-HETE. This stereochemical difference may indicate that 12-HETE is synthesized by different enzymes. A variety of tissues including human skin and keratinocytes possess 15-LO activity. 15-LO is the main enzyme initiating LX biosynthesis and converting LTA4 into LXs. An intercellular biosynthetic circuit involving infiltrating PMNs produces LXs at sites of injury or inflammation.18,28 Upper epidermal layers mainly produce 12-HETE, whereas 15-HETE is predominantly formed by the basal keratinocytes.17,29 For cellular homeostasis and for limiting the proinflammatory effects of LT it is essential that the generated LTs in the skin are catabolized to less biologically active compounds. The metabolism of LTB4 differs among tissues. In human epidermis, LTB4 is metabolized by a v-oxidation pathway into 20-hydroxy-LTB4 and 20-carboxy-LTB4.10 SKINmed. 2014;12:350–356

Platelet-Activating Factor Platelet-activating factor (PAF) is another important lipid mediator maintaining further inflammatory activity. It stimulates neutrophils and partially effects vascular tone and permeability.

Moreover, PAF is a chemotactic agent contributing to leucocytemediated injury in inflammatory processes. PAF is an extraordinarily potent lipid mediator of shock and allergic and inflammatory reactions. Both cutaneous cells and cells infiltrating the skin from the blood produce PAF. PAF is a PLA2-dependent phospholipid that exerts its biological effects by activating the PAF receptor, consequently stimulating protein kinase C and increasing intracellular Ca++. Most biological fluids contain PAF and it is synthesized in most cell types. Microvascular permeability is markedly increased by PAF, allowing fluids to leak out of the circulation. In the area of hemodynamic effects, PAF is negatively inotropic and lowers arterial blood pressure. It is a potent platelet aggregator and leucocyte activator, and it strongly promotes AA metabolism. In addition, it plays a crucial role in the pathogenesis of rheumatoid arthritis, asthma, endotoxin shock, and acute renal transplant rejection.2 PAF has been identified in allergic cutaneous reactions and in psoriatic lesions. Cell membrane receptors mediate the biological activity of PAF. Studies have shown that PAF antagonists play a role in animal models of cutaneous inflammation. In atopic patients, PAF antagonists showed minimal therapeutic improvement in studies of antigen-induced cutaneous responses. In one study,30 the effect of a potent PAF antagonist (Ro 24-0238) was investigated in 10 patients with chronic plaque psoriasis. This study demonstrated that a 10% solution of the PAF antagonist Ro 24-0238 was not effective at the clinical or cell biological level after a 4-week treatment period. The fact that PAF is not a significant factor in the pathogenesis of psoriasis is the most appropriate explanation for these negative observations.

Supplementation of Omega-3 Fatty Acids as Anti-inflammatory Macronutrients Excessive eicosanoid production is believed to contribute to the skin inflammation underlying some dermatologic diseases. Disease risk is reduced by dietary supplementation with omega-3 fatty acids, prominently Îą-linolenic acid from plant sources and the long-chain eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish, and it is inversely related to biomarkers of inflammation. Encouraging results have been obtained by dietary supplementation with long-chain omega-3 fatty acids such as EPA. EPA is released to compete with AA for enzymatic metabolism thus inducing the production of less inflammatory and chemotactic derivatives in case of inflammation.2,31

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A generally improved blood lipid profile and eicosanoid-independent factors such as altered membrane fluidity incompletely explain the salutary effects of omega-3 fatty acid consumption.

The anti-inflammatory nature of omega-3 fatty acids appears to reflect their role as alternate substrates for human eicosanoid formation from linoleic acid, the fundamental omega-6 fatty acid transformed into AA. Although both omega-3 and omega-6 fatty acids share the same enzymes for PG and LT biosynthesis, the products generated from each are molecularly and physiologically distinct. When the COX substrate is EPA, TXA3 and PGE3 are produced instead of AA-derived TXA2 and PGE2. TXA3 is less proaggregatory and vasoconstrictive than TXA2, and PGE3 is less proinflammatory than PGE2.32 Compared with the AA-derived TXA2, the EPA-derived COX product of the 3-series TXA3 has considerably reduced proaggregatory and vasoconstrictive properties, while PGI3 possesses similar antiaggregatory and vasodilative effects to those of PGI2.

In addition, the generation of proinflammatory PAF is reduced

by EPA via interference with the PAF precursor pool.2,31 At equimolar concentrations, EPA is a better substrate for 5-LO than AA, forming LTA5 instead of LTA4. Subsequently, LTA5 is converted into LTB5 and not AA-derived LTB4, the most potent chemotactic agent known at this time. Furthermore, LTA5-derived cysLTs (ie, LTD5 and LTC5) are less proinflammatory and vasoconstrictive than AA-derived cysLTs. The ratio of dietary omega-3 to omega-6 fatty acid esterified to membrane phospholipids and subsequently available for eicosanoid biosynthesis following phospholipase A2-mediated mobilization has a critical impact on global proinflammatory eicosanoid tone.5

activated neutrophils was reduced by 37% and the generation of LTB4, 6-trans-LTB4 diastereoisomers, and 5-HETE was decreased by 48%. This study emphasizes that diets enriched with fish oil–derived fatty acids may have anti-inflammatory effects by inhibiting the 5-LO pathway in neutrophils and monocytes and by inhibiting the LTB4-mediated functions of neutrophils.

Conclusions Lipid mediators are “local mediators” that act in the intercellular microenvironments, where they reach considerable levels. They are released from various tissues and cells and usually develop their effects at the site of production as a result of their short half-life and rapid enzymatic inactivation. Numerous mediators stimulate the lipid mediator cascade, generating proinflammatory eicosanoids, which increase their own synthesis via positive feedback loops.

Cascade systems may become self-perpetuating and finally cause tissue damage. Research efforts performed more recently have showed important beneficial anti-inflammatory and immunemodulating properties of lipid mediator antagonism.

References

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Relative proportion of omega-3 vs omega-6 fatty-acid precursors in tissue membrane phospholipid stores is the main determinant of the proinflammatory nature of tissue eicosanoid responses. In turn, the determinant of the contents of omega-3 vs omega-6 fatty acids esterified to membrane phospholipids is their relative supply in the diet. The excessive amounts of omega-6 fatty acids and the very high omega-6/omega-3 ratio in today’s Western diets support a diet-induced proinflammatory state, which may contribute to increases in the incidences of skin, cardiovascular, autoimmune, and neoplastic diseases.31 Researchers33 performed an experiment with seven healthy patients who supplemented their normal diet for 6 weeks with 3.2 g EPA and 2.2 g DHA per day to study the effects of dietary fish oil fatty acids on the 5-LO pathway in human monocytes and neutrophils. The release of labeled AA and its metabolites from SKINmed. 2014;12:350–356

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Somnambulism (Sleepwalking, Noctambulism) Medications known to be associated with it: Alcohol Ambien Depakote Inderal

Mellaril Noctec Paxil Resoril

Thorazine Topamax Trilafon Zyprexa

Adapted from Litt, JZ: Curious, Odd, Rare, and Abnormal Reactions to Medications. Fort Lee, NJ, Barricade Books, 2009:83–86.

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Volume 12 • Issue 6

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD Instructions: For each numbered question, choose the single most appropriate numbered response unless instructed otherwise.

1. Arachidonic acid (AA), the main source of the proinflammatory lipid mediators, is metabolized to (Choose two.): a. Bradykinin. b. Histamine. c. Leukotrienes (LTs). d. Lipocortin. e. Platelet-activating factor (PAF). f. Prostaglandins (PGs).

4. Platelet activating factor (PAF) appears not to be a significant factor in the pathogenesis of: a. Acute renal transplant rejection. b. Asthma. c. Endotoxic shock. d. Psoriasis. e. Rhematoid arthritis.

5. Each of the following statements regarding lipid inflammatory mediators is correct, except: a. They are released from various tissues and cells. b. They usually develop their effects at the site of production. c. T hey have a long half-life. d. They increase their own synthesis via positive feedback loops. e. Their cascade systems may become selfperpetuating. f. They may cause tissue damage.

ANSWERS TO CME EXAMINATION: 4. d.

5. c.

Today’s Western diet contains excessive amounts of: Alpha linoleic acid.

Docosahexaenoic acid (DHA).

Eicosapentaenoic acid (EPA).

Omega-3 fatty acids.

Omega-6 fatty acids.

3. e.

3. a. b. c. d. e.

1. c,f. 2. b.

2. Of the following, which is the most potent chemoattractant? a. LTA4. b. LTB4. c. LTC4. d. LTD4. e. LTE4. f. Platelet-activating factor (PAF).

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA

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

SKINmed. 2014;12:357

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www.Collagenpin.com

877-746-4407

November/December 2014

Volume 12 • Issue 6

Core curriculum Virendra N. Sehgal, MD, Section Editor

Footwear Dermatitis: Historical Background, Epidemiology, Clinical Connotation—Part II Virendra N. Sehgal, MD;1 Farhan Rasool, MD;1 Govind Srivastava, MD;1 Ashok Aggarwal, MD;1 Prashant Verma, MD2

Footwear dermatitis is a disabling condition that is identified by blistering and/or weeping feet that may become secondarily infected and painful. Fissuring is a common feature, resulting in an inability to walk, and it may prevent the wearing of footwear, especially when shoes are the cause of the dermatosis. In the absence of adequate care and therapy, footwear dermatitis may turn into a chronic distressing disease that largely effects the daily quality of life of patients.1 (SKINmed. 2014;12:360–364)

C

ontact dermatitis is an inflammatory skin reaction as a result of direct contact with certain agents.2 In the first century AD, Pliny (61–112 AD) reported that workers cutting pine trees experienced severe itching.3 Greek physician Hippocrates (460–370 BC) reported that environmental influences might be a likely cause of disease and had portrayed lesions on the buttocks of horsemen. Bernardino Ramazzini (1633–1714), considered to be the founder of modern occupational medicine,4 reported the issue of occupational dermatitis among laundry women and soap workers.5 In 1831, Charles Turner Thackrah (1795–1833) described sugar in grocers, lime in bricklayers, flour in bakers, and sulfuric acid in hatters as causes of eczema.6 In 1847, French physician Pierre Louis Alphee Cazenave (1802–1877) first classified eczema into acute and chronic subtypes.5

ings of shoes were identified as causes of dermatitis by Duhring as early as 1877.11 Systemic poisoning caused by absorption of aniline and nitrobenzene dyes in shoe leather was reported by Muehlberger in 1925.12 In 1929, Bloch was the first to report a case of dermatitis of the feet caused by sensitivity to shoe leather in English literature.13 In 1931, Lewis reported 2 men, both with dermatitis of the feet, who reacted to patch test with pieces of leather from their shoes.14 In 1932, Lazenberg described cases of dermatitis of the feet caused by dyes.15 In 1938, Bonnevie described 29 men sensitive to 0.5 % bichromate solution.16 In 1949, Pirila and Kilpio reported 45 cases of dermatitis caused by bichromates.17 In addition, in 1957, Morris described 3 cases of dermatitis of the feet in patients who reacted to a patch test with 0.2% basic chromic sulphate (trivalent).18

Irritant dermatitis became the most studied form of contact dermatitis by the end of the 19th century. In 1869, Hebra tested the irritant potential of croton oil.7 In 1891, Kaposi confirmed that croton oil with potassium soap could produce dermatitis even in healthy individuals.8 Allergic sensitization of the skin was first established by Bloch and Steiner-Woerlich using Primula extract on humans.9 The frequency of allergic contact dermatitis and these common sensitizers, however, were not fully investigated in clinical studies until the early 20th century.10 Socks and the lin-

Patch Testing Patch testing has a long history with contact dermatitis because it was one of the only tools available for identifying causative substances associated with skin eruptions.2 Ferdinand Von Hebra (1816–1880) marked the beginning of etiological research of contact dermatitis by demonstrating that croton oil caused eczematous dermatitis on normal human skin.5 In 1847, Stadeler described a method to reproduce the lesions caused

Part I appeared in 2012;10:291-297.

From the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati, Delhi, India, Skin Institute, and School of Dermatology, Greater Kailash, New Delhi, India;1 and the Department of Dermatology and STD, University College of Medical Sciences, University of Delhi and Associated GTB Hospital, Delhi, India2 Address for Correspondence: Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond), Dermato Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6, Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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core curriculum

by Anacardium occidentale on human skin (Stadeler’s blotting paper strip technique).19,27 This was the first time that any test was actually designed and described in full detail. Josef Jadassohn (1863–1936) has often been regarded as the modern-day father of patch testing, having discovered “funktionelle Hauptprüfung” (patch testing) while a young professor in Bern, Switzerland.2,20 He suspected the significance of specific intolerance at a time when the term allergy had not yet been created.21 His first presentation of the technique was at the 5th Congress of the German Academy of Dermatology in 1895.5 He reported on the diagnostic tests on idiosyncratic eczema, especially from mercury, at the Congress, which was later published in 1896.22 As pointed out by Foussereau, Jadassohn most probably applied and expanded the observations and interpretations previously made by Neisser in 1884.3,23 In 1897, Fabre studied the effects of various anatomical parts of the processionary caterpillar on his own skin.24 Later, Rostenberg and Solomon also emphasized the importance of this methodology.25 Similarly, various attempts were made during the 20th century to isolate various allergens and irritants encountered in the environment.

Bruno Bloch is known as one of the pioneers in the field of patch testing, continuing and expanding on Jadassohn’s clinical and experimental work.26 He produced the grading system for patch test reaction26 and also introduced the concept of standard series of allergens.27 Marion Sulzberger introduced the technique of patch testing to new world.28 In 1938, Poul Bonnevie proposed a list of common allergens, which is considered the prototype of the standard series of patch testing,29 later published by Marcussen in 1962.30 A Scandinavian Committee for Standardization of Routine Patch Testing was formed in 1962, which finally expanded to form the International Contact Dermatitis Research Group.21,31 The function of the group was to standardize the patch testing procedure at an international level.

For footwear dermatitis, Fisher recommended the use of a screening tray for patch testing patients.32 He later included 0.25% potassium dichromate (hexavalent) and 5% nickel sulphate in screening tray series.32,33 Epidemiology

Prevalence The prevalence of contact dermatitis in the general population has been reported to vary from 2% to 11% and accounts for 4% to 7% of all dermatological consultations.34 In India, contact dermatitis is a major health problem, with an incidence of 4% to 7%.35 With the growth of industrialization, skin disease ranks as the second most common cause of occupational illness SKINmed. 2014;12:360–364

after trauma and accounts for 13% to 34% of all occupational diseases.36,37 Studies in different parts of the world have reported variable frequency rates of footwear dermatitis, with prevalence rates among patients with contact dermatitis estimated to be between 1.5% and 25%.38,39 In children, feet are one of the most common sites for contact dermatitis, and footwear is the second leading cause of contact dermatitis.40 Some researchers identified the condition in 1.9% of 2243 inpatients,41 while others reported a prevalence rate of footwear dermatitis of 3% among patients with contact dermatitis.42 Investigators also reported a rate of 6.3% among 2607 patients with contact dermatitis.43 In a study from London, Cronin documented 196 cases of footwear dermatitis over a span of 13 years.44 In a study from Nigeria, 136 of 545 (25%) patients attending a contact dermatitis clinic had dermatitis of the feet caused by footwear.45 In an Indian study, researchers46 diagnosed 47 cases of shoe dermatitis over a span of 18 months and observed incidence rates of approximately 1 case every 2 weeks. Other investigators39 reported an 11.7% overall prevalence rate of footwear dermatitis among patients with contact dermatitis. Another Indian study47 reported an incidence rate of 24.22% of footwear dermatitis (n=155) among 640 patients undergoing patch test during a period of 1 year.47

Age Groups The majority of patients with shoe dermatitis fall into the age group of 15 to 45 years, which may be explained by the fact that it is the most active stage of life, necessitating more travel and more frequent use of footwear, leading to increased risk.38,43 Patients of all ages, ranging from 3 to 80 years, have been reported to be affected by footwear dermatitis.44,48

Sex Distribution Results of the sex prevalence of footwear dermatitis have largely been contradictory. A female preponderance of 4.7:1 to 8.8:1 has been noted, including in Greece,49–51 perhaps emphasizing a wide variety of footwear used by women and the uncommon use of socks, exposing them to direct contact with a multitude of potent sensitizers in footwear. In addition, the increased awareness of cosmetic disfigurement in women leads to more frequent reporting of cases. A few studies, however, have shown almost equal and comparable sex incidences, including a study from Australia in which of 55 patients with footwear dermatitis, 47% were women and 53% were men.48 A male preponderance has also been reported from India and foreign countries.39,42,52 The reasons for this may be that men usually wear more occlusive footwear and are involved in more strenuous activity, leading to increased sweating within the footwear, which increases the risk of contact sensitization to footwear chemicals.

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core curriculum Clinical Connotation Footwear dermatitis, generally a chronic and recalcitrant problem,41,48,50 is a well-appreciated clinical entity. It may be severe enough to warrant an early consultation or may be mild enough so that many months may elapse before the aid of the physician is sought.50

Figure 1. Footwear dermatitis showing erythema, edema, erosion, crusting, and scaling on the dorsa of the feet extending to the toes.

In an Australian study,48 the duration of the disease was found to vary from 1 year to more than 20 years. About 20% of patients had the condition for more than 5 years, with a mean duration of 4 years and 8 months. In various Indian studies, however, its duration was found to range between 1 month and 25 years.39,46,47,53,54 The disease is usually sporadic, with exacerbation seen in the summer and monsoon seasons.39,49 Other exacerbating factors include hyperhydrosis, food, and metal allergy. A personal/family history of atopy has been found in 6% to 43% of cases.39,48,49 Pruritus at the site of involvement is the most common symptom. Other symptoms include burning sensation and pain,49 difficulty in walking, and carrying out daily activities.41 The pattern of footwear dermatitis usually corresponds to the location of the offending chemicals.55 The chemicals may migrate to the adjoining parts of the shoe or even stockings, disguising the clinical presentation.41 Indian sandal strap dermatitis has the characteristic pattern involving the first toe web, adjoining toes, and the dorsa of the feet.39,46,53 The rate of affliction of the dorsa of the feet is 90% to 100%, the most common site of presentation39,49,56 (Figure 1 and Figures 2a and 2b). This is because of its large surface area, thin stratum corneum, and prolonged and close contact with the shoe. The involvement of the plantar aspect of the sole may either be confined to the anterior aspect, the weight-bearing area, or the entire sole, sparing the insteps.44 The involvement of the entire sole may be seen, following allergy caused by sports shoes, where the entire sole is mounded into the instep.57 Dermatitis confined to the heel pad is yet another pattern.41 Interdigital webspaces, except the first webspaces, are usually spared and their involvement points more toward a fungal etiology of the disease.57 The predominant sole involvement and clinical picture may simulate psoriasis.57 Secondary vesicular dermatitis or “id�-like eruptions may be seen as a result of autosensitization.41 Sites other than the feet may be involved, including the legs, fingers, hands, forearms, thighs, and trunk.41

2a

2b Figure 2a and 2b. Footwear dermatitis showing erythema, edema, vesiculation, and crusting on the dorsa of the feet.

SKINmed. 2014;12:360–364

The morphology of the lesions depends on the stage of the disease.

In the acute stage, patients may present with diffuse erythema, vesiculation, edema, or scaly papular dermatitis.40 Eczematization, lichenification, and fissuring develop as the lesions become

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core curriculum 8 Kaposi M. Pathologie et traitement des maladies de la peau Paris: Masson. 1891:1.

9 Bloch B, Steiner-Wourlisch A. Die willkurliche Erzeugung der Primeluberemfindlichkeit beim Menschen and ihre Bedeutung fur das Idiosyndrasieproblem. Arch Dermatol Syphilol. 1926; 152: 283–303 10 Hjorth N. History of contact dermatitis and its influence on today’s occupational dermatology. Hautarzt.

1980:31:621–626.

11 Duhring LA. A Practical Treatise on Diseases of the Skin.

Philadelphia, PA: J. B. Lippincott & Co; 1877:32.

12 Muehlberger CW. Shoe 1925;84:1987–1991.

dye

poisoning.

JAMA.

13 Bloch B. The role of idiosyncrasy and allergy in dermatology. Arch Dermatol Syphilol. 1929;19:175–197.

14 Lewis GM. Dermatitis venenata due to shoe leather: two cases. Arch Dermatol Syphilol. 1931;24:597.

Figure 3. Footwear dermatitis showing depigmentation over the dorsa of the feet corresponding to the rubber strap of a chappal.

15 Lanzenberg P. Artificial eruption of feet provoked by dyed shoe leather. Bull Soc Franç Dermat Syph.

1932;39:1464.

chronic.58 Depigmented lesions may develop in cases of sensitization by adhesives such as hydroquinone (Figure 3), epoxy, neoprene, or para-tertiary butylphenol formaldehyde resins.55 Petechial/purpuric lesions may develop in cases of sensitization by black rubber boots.57 The lesions are usually secondarily infected and complications such as cellulitis, lymphangitis, lymphadenitis, thrombophlebitis, and nephritis may develop.41,57

16 Bonnevie P. Etiologico-pathogenetical experiences of professional skin diseases with a view to their prophylaxis. Acta Derm Venereol. 1938;20:645.

17 Pirila V, Kilpio VO. On dermatoses caused by bichromates. Acta Derm venereol. 1949;29:550–563.

18 Morris GE. Cross-sensitization of feet and hands due to chrome-tanned leather shoes and gloves. N Engl J Med. 1957;19:257–567.

Conclusions

19 Stadeler J. Uber die eigenthumlichen Bestandtheile der Anacardium Fruchte. Ann Chemie Pharmacie.

1847;63:117–165.

The differential diagnosis of footwear dermatitis includes juvenile plantar dermatosis, atopic dermatitis, tinea pedis, endogenous eczema, lichen simplex chronicus, psoriasis, and lichen planus.49

21 Larese Filon F, Bagnato E. Occupational allergy in health personnel. Med Lav. 2003;94:265–270.

References 1 Sehgal VN, Rasool F, Srivastava G, Aggarwal A, Verma P. Footwear dermatitis: pathogenesis—part I. Skinmed.

2012;10:291–297.

2 Lachapelle JM. Historical aspects. In: Frosch PJ, Menne T, Lepoittevin JP, eds. Contact Dermatitis. 4th ed. Berlin, Birkhäuser; 2006:1–7.

3 Foussereau J. History of epicutaneous testing: the blotting paper and other methods. Contact Dermatitis.

1984;11:219–223.

4 Triosi FM. Bernardino Ramazzini, 1633–1714, founder of occupational medicine. Ind Med Surg. 1953:22:403– 409.

5 Wright RC, Goldman L. Contact dermatitis: a historical perspective. Int J Dermatol. 1979;18:665–668.

6 Anning ST. A short history of dermatology in the Leeds region. British J Dermatol. 1969:81:375–380.

7 Hebra F. Traite des maladies de la peau, Paris: Masson.

1869;1:493–496 and 541–542.

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20 Adams RM. Profiles of greats in contact dermatitis. Am J Contact Dermat. 1993;4:58–59.

22 Jadassohn J. zur kenntnis der Arzneiexantheme. Arch Dermatol Forch. 1896;34:103.

23 Neisser A. Ueber Jodoform-Exantheme. Dtsch Med Iodoformidiosynkrasie. Exp Pathol Ther. 1911;9:509–538.

24 Fabre JH. Souvenirs entomologiques. Delagrave. Paris, France. 1897;6:378–401.

25 Rostenberg A Jr, Solomon LM. Jean Henri Fabre and the patch test. Arch Dermatol. 1968;98:188–190.

26 Bloch B. Experimentelle Studien uber das Wesen der Jodoformidiosynkrasie. Exp Pathol Ther. 1911;9:509– 538.

27 Bloch B, Karrer P. Chemische und biologische Untersuchungen über die Primelidiosynkrasie. Beibl Vierteljahrsschr Naturforsch Gesell, Zürich. 1927;72:1–25.

28 Sulzberger MB. Dermatologic Allergy. Charles C. Thomas: Baltimore, MD; 1940.

29 Bonnevie P. Aetiologie und pathogenese der Ekzamkranktheiten. Klinische studien uber die Ursachen der ekzeme unter besoderer Berucksichtigung des Diagnostischen Wertes der ekzemproben. Busch. Copenhagen and Barth: Leipzig; 1939.

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30 Marcussen PV. Variations in the incidence of contact hypersensitivities. Trans St Johns Hosp Dermatol Soc. 1962;8:40–48.

31 Dakin R. Remarks on a cutaneous affection produced by certain poisonous vegetables. Am J Med Sci. 1829;4:98– 100.

32 Fisher AA. Some practical aspects of the diagnosis and management of shoe dermatitis. AMA Arch Dermatol.

1959;79:267–274.

33 Fisher AA. Contact dermatitis. 2nd ed. Philadelphia, PA: Lea and Febiger; 1973.

34 Diepgen TL, Coenraads PJ. Inflammatory skin diseases II: contact dermatitis: In: Williams HC, Strachan DP, eds.

The Challenge of Dermatoepidemiology. Boca Raton, FL: CRC Press; 1997:145–161.

35 Sudhashree VP, Parasuramalu BG, Rajanna MS. A clinicoepidemiological study of allergens in patients with dermatitis. Indian J Dermatol Venereol Leprol. 2006;72:235– 237.

36 Marc A, Frank P. Occupational contact dermatitis. Immunol Allergy Clin N Am. 2003;23:269–290.

37 Keil JE, Shmunes E. The epidemiology of work related skin disease in South Carolina. Arch Dermatol.

1983;118:650–654.

38 Shackelford KE, Belsito DV. The etiology of allergic-appearing foot dermatitis: a 5-year retrospective study. J Am Acad Dermatol. 2002;47:715–721.

39 Saha M, Srinivas CR, Shenoy SD, et al. Footwear dermatitis. Contact Dermatitis. 1993;28:260–264.

40 Romaguera C, Vilaplana J. Contact dermatitis in children: 6 years experience (1992–1997). Contact Dermatitis. 1998;39:277–280.

41 Shatin H, Reisch M. Dermatitis of the feet due to shoes.

AMA Arch Derm Syphilil. 1954;69:651–666.

42 Calnan CD, Sarkany I. Studies in contact dermatitis IX shoe dermatitis. Trans St John Hosp Dermatol Soc. 1959;43:8–26.

45 Olumide Y. Contact dermatitis in Nigeria. (IV). Dermatitis of the feet. Contact Dermatitis. 1987;17:142–145.

46 Bajaj AK, Gupta SC, Chatterjee AK, Singh KG. Shoe dermatitis in India. Contact Dermatitis. 1988:19:372–375.

47 Chowdhuri S, Ghosh S. Epidemio-allergological study in 155 cases of footwear dermatitis. Indian J Dermatol Venereol Leprol. 2007;73:319–322.

48 Freeman S. Shoe 1997;36:247–251.

dermatitis.

Contact Dermatitis.

49 Rani Z, Hussain I, Haroon TS. Common allergens in shoe dermatitis: our experience in Lahore, Pakistan. Int J Dermatol. 2003;42:605–607.

50 Blank IH, Miller OG. A study of rubber adhesives in shoes as the cause of dermatitis of the feet. J Am Med Assoc. 1952;149:1371–1374.

51 Varelzides A, Katsambas A, Georgala S, Capetanakis J. Shoe dermatitis in Greece. Dermatologica.

1974;149:236–239.

52 Lynde CW, Warshawski L, Mitchell JC. Patch test results with a shoewear screening tray in 119 patients, 1977– 80. Contact Dermatitis. 1982;8:423–425.

53 Priya KS, Kamath G, Martis J, et al. Foot eczema: the role of patch test in determining the causative agent using standard series. Indian J Dermatol. 2008;53:68– 69.

54 Handa S, Sharma SC, Sharma VK, Kaur S. Foot wear dermatitis: clinical patterns and contact allergens. Indian J Dermatol Venereol Leprol. 1991;57:174–177.

55 Rietschel RL, Fowler JF Jr. Textile and shoe dermatitis.

In: Rietschel RL, Fowler JF Jr, eds. Fisher’s Contact Dermatitis. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:305–319.

56 Lazzarini R, Duarte I, Marzagao C. Contact dermatitis of the feet. A study of 53 cases. Dermatitis. 2004;15:125– 130.

43 Angelini G, Vena GA, Meneghini CL. Shoe contact dermatitis. Contact Dermatitis. 1980;6:279–283.

57 Roberts JL, Hanifin JM. Athletic shoe dermatitis. Contact allergy to ethyl butyl thiourea. JAMA. 1979;241:275– 276.

44 Cronin E. Shoe dermatitis. Br J Dermatol. 1966;78:617– 625.

58 de Vries HR. Allergic dermatitis due to shoes. Dermatologica. 1964;128:68–75.

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November/December 2014

Volume 12 • Issue 6

NEW THERAPY UPDATE William Abramovits, MD; Aditya K. Gupta, MD, PhD, Section Editors

Dalbavancin (Dalvance) for the Treatment of Acute Bacterial Skin Infection Aditya K. Gupta, MD, PhD, FRCPC;1,2 Kelly A. Foley, PhD;2 William Abramovits, MD;3,4,5 Ted Rosen, MD6

A

cute bacterial skin and skin structure infections (ABSSSIs) refer to what was previously known as complicated skin and skin structure (or tissue) infections and often lead to hospitalization and intravenous antibiotic treatment.1 ABSSSIs can be diverse in nature and include wound infections, cutaneous abscesses, burn infections, or cellulitis/erysipelas. For clinical trials, the characteristic definition of ABSSSIs is an infection of at least 75 cm2 that can be accompanied by any of the above as well as redness, edema, or induration.1 The most prevalent Gram-positive bacteria species responsible for ABSSSIs is Staphylococci aureus, including methicillin-resistant S aureus (MRSA), as well as strains of β-hemolytic streptococci and coagulase-negative staphylococci.2,3 MRSA infections can be particularly difficult to eradicate. Globally, significant MRSA infections carry an increased risk of mortality compared with similar infections because of methicillin-sensitive S aureus.4 While vancomycin is considered the gold standard of treatment for MRSA, daptomycin, linezolid, and ceftaroline have also been shown to be effective.2,5 As concern over antibiotic resistance grows, new agents are being developed to expand treatment options for microbial infections.

Dalbavancin hydrochloride, a semisynthetic lipoglycopeptide, inhibits bacterial cell wall synthesis6 and has demonstrated activity against more than 6000 strains of Gram-positive bacteria in vitro.7 It exhibits greater activity than many antimicrobials for Staphylococci and Streptococci species, including MRSA strains, and this activity spectrum and potency has been sustained over a number of years.8–10 Dalbavancin was the first antimicrobial

agent expedited through the Qualified Infectious Disease Product Program and received Food and Drug Administration (FDA) approval for the treatment of ABSSSIs in May 2014. Under the Generating Antibiotic Incentives Now title of the US FDA Safety and Innovation Act, dalbavancin was granted qualified infectious disease product designation, because it is an antibacterial or antifungal human drug intended to treat a serious or life-threatening infection. Several additional new antibiotics have recently also had expedited review and approval under this provision (tedizolid in June 2014 and oritivancin in August 2014).

Clinical Studies The efficacy of 2 weekly doses of dalbavancin was demonstrated in a proof-of-concept randomized, controlled, open-label, multicenter phase II trial.11 One dose (1100 mg intravenous [IV]) and 2 weekly doses (day 1, 1000 mg IV; day 8, 500 mg IV) of dalbavancin were compared with various other antimicrobial treatments (piperacillin and tazobactam combination, ceftriaxone, cefazolin, vancomycin alone or in combination, and clindamycin, linezolid, cephalexin alone) in patients with ABSSSIs. Clinical success (cure or improvement) was measured at the end of treatment (10 days following last dalbavancin dose or day of last dose of comparator) and at 14-day follow-up. At both end-oftreatment and follow-up, success with two doses of dalbavancin was similar to comparators and numerically greater than one dose of dalbavancin. Microbiologic success at follow-up showed that two doses of dalbavancin were effective in eradicating (or presumed to eradicate) Gram-positive pathogens (Table I).11 A second phase II randomized, open-label trial compared the two-

From the University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc, London, Ontario, Canada;2 the Department of Medicine, Baylor University Medical Center, Dallas, TX;3 the Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School, Dallas, TX;4 the Dermatology Treatment and Research Center, Dallas, TX;5 and Baylor College of Medicine, Houston, TX6 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Phase II Efficacy Outcomes of One Dose vs Two Doses of Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections11 One Dose of Dalbavancin

Two Doses of Dalbavancin

Comparators

16 (81)

17 (94)

21 (81)

13 (62)

17 (94)

21 (76)

Staphylococcus aureus

10 (50)

10 (90)

10 (60)

Miscellaneous species

3 (67)

5 (80)

7 (71)

End Point Clinical success, No. (%) End of treatment Follow-up Microbiological success (follow-up), No. (%) a

Microbiologic population: patients with a positive baseline test for Gram-positive pathogen.

Adapted with permission from Seltzer et al.11 a

dose regimen of dalbavancin with a 14-day treatment of vancomycin in patients with catheter-related bloodstream infections.12 Dalbavancin was significantly more effective than vancomycin at day 15 and 16 and 3 weeks post-treatment (end of treatment: 91.3% vs 64.3% and follow-up: 87% vs 50%; P<.05).12 Phase III noninferiority trials compared dalbavancin with linezolid13 and with a combination of vancomycin/linezolid.14 In 2005, researchers conducted a randomized, double-blind, multicenter trial that spanned 7 countries and enrolled 854 patients with ABSSSIs.13 Infections to be studied required one of the following: deeper soft tissue affected, surgical intervention, or known/suspected cause of MRSA, coupled with at least 2 local signs or symptoms of infection and at least 1 sign of systemic infection (such as fever). Dalbavancin 1000 mg IV was administered on day 1 and 500 mg IV on day 8, while linezolid was administered at a dose of 600 mg IV every 12 hours for 14 days, with the possibility of switching to oral linezolid after at least 24 hours of IV therapy. Patients in the dalbavancin group received placebo IV/oral placebo every 12 hours for 14 days.13 Clinical success, as defined by signs and symptoms of infection diminishing so that no further therapy was needed, was assessed at the end of treatment (day 14) and 2 weeks later (day 28) as a test for cure (TOC).13 Microbiologic success, or absence of pathogen, was measured at these endpoints in the eligible population, ie, the patients who tested positive at baseline for the presence of a Gram-positive pathogen. Dalbavancin proved to produce a high efficacy rate that was also comparable to linezolid (Table II), including rates of MRSA eradication (91% vs 89%), and was noninferior to linezolid treatment at the primary outcome (day 28). In addition, only 0.6% of patients who achieved clinical success in each of the dalbavancin and linezolid groups experienced relapse 1 month after the TOC visit.13 SKINmed. 2014;12:366â&#x20AC;&#x201C;369

Recently published data from two phase III trials indicate that dalbavancin is also noninferior to a combination of vancomycin and linezolid in patients with ABSSSIs.14 Two double-blind, multicenter trials were pooled together for analysis. Dalbavancin (n=659) was administered weekly, on day 1 and day 8, 1000 mg IV and 500 mg IV, while vancomycin (1000 mg IV) was administered every 12 hours for at least 3 days before a possible switch to oral linezolid (600 mg) every 12 hours until 14 days of treatment was completed (n=653). The primary endpoint was early clinical response, as indicated by no increase in erythema associated with the infection and no fever for 12 hours. Measured after 48 to 72 hours of therapy, both dalbavancin (79.7%) and vancomycin/ linezolid (79.8%) treatments were successful in producing early clinical responses.14 At the end of treatment (day 14), treatment success was indicated by a decrease in lesion size, low temperature, and none to mild local symptoms. Again, patients in both the dalbavancin (90.7%) and vancomycin/linezolid (92.1%) arms produced similar treatment success.14 Both dalbavancin and vancomycin/linezolid treatments resulted in treatment success in patients with MRSA (89.2% vs 96%) and methicillin-sensitive S aureus (MSSA) (91.5% vs 92.9%) infections.14 Safety Single and multiple doses of dalbavancin have been administered to healthy volunteers. No major changes in intestinal microflora were seen with a single dose of dalbavancin.15 A 2004 report showed that 67% of healthy volunteers experienced at least one adverse event (AE); however, none met the criteria for dose-limiting toxicity.16 The most frequently reported AEs in both dalbavancin- and placebo-treated healthy volunteers were pyrexia, headache, and nausea.16 Infrequent dosing of this agent is possible, as demonstrated in these healthy volunteers, as a result of a very long half-life (150â&#x20AC;&#x201C;250 hours) and maintenance of serum bactericidal activity against MRSA for 1 week.16

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Table II. Efficacy Outcomes for Phase III Noninferiority Trial of Dalbavancin vs Linezolid End Point

Dalbavancin

Linezolid

434

226

End of treatment (day 14), %

92.3

94.2

Test of cure (day 28), %

88.9

91.2

Microbiological success, No.a

277

152

End of treatment (day 14), %

87.5

90.2

Test of cure (day 28), %

89.5

87.5

Clinical success (eligible population), No.

Microbiologic population: patients with a positive baseline test for Gram-positive pathogen.

a

The majority (>90%) of patients reported AEs in phase II trials,11,12 with a little more than half reporting AEs in a phase III trial.14 Most AEs were mild to moderate. Common AEs related to dalbavancin treatment were nausea and pruritus,14 diarrhea,12,14 fever, constipation, and oral candidosis.12 While the number of patients reporting AEs related to either dalbavancin (12.3%) or vancomycin/linezolid (13.7%) was similar, reports of diarrhea and pruritus were significantly less with dalbavancin treatment compared with vancomycin/linezolid.13 The duration of AEs was also shown to be 1 day shorter with dalbavancin compared with linezolid.13 In phase III trials, serious AEs reported with dalbavancin were cellulitis and anaphylactoid reaction in one patient each,14 while 7.5% patients reported serious AEs that, with the exception of one abnormal laboratory report (mild leukopenia), were determined to be unrelated or unlikely related to dalbavancin.13 Overall, abnormalities in hematologic and laboratory tests were few and either not reported as AEs11,12 or were quickly resolved.13 No patients discontinued dalbavancin in the phase II studies because of AEs,11,12 with only modest discontinuation rates of 3.9%13 and 2.1%14 in phase III studies. To put discontinuation rates into perspective, discontinuation in comparator groups ranged from 3.2% to 8.8% in the phase II and III trials, respectively.11–14 Dalbavancin does not adversely affect patients with mild or moderate renal impairment, end-stage renal disease (with hemodialysis), or mild hepatic impairment.17,18 An increase in exposure to dalbavancin in patients with severe renal impairment (creatinine clearance <30 mL/min and not receiving regular hemodialysis) prompted a dose adjustment to 750 mg IV on first administration and 375 mg IV 1 week later.17,18 While age does not affect the efficacy of dalbavancin, excretion by the kidneys and decreased renal function with age may increase elderly patients’ susceptibility to AEs.18 SKINmed. 2014;12:366–369

Of additional importance, dalbavancin is not a substrate for the cytochrome p450 system; hence, it is neither an inducer nor an inhibitor. Consequently, no significant drug-drug interactions have been identified between dalbavancin and other medications.18 Conclusions Dalbavancin has been approved by the FDA in adults for the treatment of ABSSSIs caused by strains of Gram-positive bacteria. Two doses should be intravenously administered: 1000 mg IV over 30 minutes and 500 mg IV over 30 minutes1 week later.

The long half-life of dalbavancin sets it apart from conventional antimicrobials,6 enabling a two-dose regimen, 1 week apart, as opposed to twice-daily infusions. Dose adjustment should be made for patients with severe renal impairment. In phase III noninferiority trials, dalbavancin was shown to be clinically equivalent to linezolid and to a combination of vancomycin and linezolid. Treatment success rates hovered around 90% and dalbavancin was also effective in treating MRSA and MSSA infections, an area where new antibiotics will be welcomed.13,14 While indicated for treatment of ABSSSIs, there are other difficult-to-treat MRSA-caused infections where dalbavancin may also prove beneficial.19 The expansion of available antimicrobial treatments shows promise in the ongoing battle to combat a global increase in antibiotic-resistant micro-organisms.4 The infrequent dosing schedule also facilitates outpatient intravenous therapy in a manner not readily possible with comparably effective agents, which require more frequent dosing. Thus, aggregate savings in hospitalization expenses (thousands of dollars per patient for a course of vancomycin) and avoidance of longindwelling intravenous lines (and their attendant infection risks) may balance the relatively high commercial cost of the drug (approximately $4500 per course).

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References 1 Moran GJ, Abrahamian FM, Lovecchio F, Talan DA. Acute bacterial skin infections: developments since the 2005 Infectious Diseases Society of America (IDSA) guidelines. J Emerg Med. 2013;44:e397–e412.

2 Dryden MS. Complicated skin and soft tissue infection. J Antimicrob Chemother. 2010;65 suppl 3:iii35–iii44.

3 Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998-2004). Diagn Microbiol Infect Dis. 2007;57:7–13.

4 World Health Organization. Antimicrobial resistance: global report on surveillance 2014. http://www.who.int/ drugresistance/documents/surveillancereport/en/. Accessed August 12, 2014.

5 Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011;52:285–292.

6 Pope SD, Roecker AM. Dalbavancin: a novel lipoglycopeptide antibacterial. Pharmacotherapy. 2006;26:908– 918.

7 Streit JM, Fritsche TR, Sader HS, Jones RN. Worldwide assessment of dalbavancin activity and spectrum against over 6,000 clinical isolates. Diagn Microbiol Infect Dis. 2004;48:137–143.

8 Biedenbach DJ, Jones RN. Multicenter evaluation of the in vitro activity of dalbavancin tested against staphylococci and streptococci in 5 European countries: results from the DECIDE Surveillance Program (2007). Diagn Microbiol Infect Dis. 2009;64:177–184.

9 Jones RN, Stilwell MG, Sader HS, Fritsche TR, Goldstein BP. Spectrum and potency of dalbavancin tested against 3322 Gram-positive cocci isolated in the United States Surveillance Program (2004). Diagn Microbiol Infect Dis. 2006;54:149–153.

10 Jones RN, Sader HS, Flamm RK. Update of dalbavancin spectrum and potency in the USA: report from the SENTRY Antimicrobial Surveillance Program (2011). Diagn Microbiol Infect Dis. 2013;75:304–307.

11 Seltzer E, Dorr MB, Goldstein BP, et al. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections.

Clin Infect Dis Off Publ Infect Dis Soc Am. 2003;37:1298– 1303.

12 Raad I, Darouiche R, Vazquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens.

Clin Infect Dis Off Publ Infect Dis Soc Am. 2005;40:374– 380.

13 Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2005;41:1407–1415.

14 Boucher HW, Wilcox M, Talbot GH, et al. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014;370:2169–2179.

15 Nord CE, Rasmanis G, Wahlund E. Effect of dalbavancin on the normal intestinal microflora. J Antimicrob Chemother. 2006;58:627–631.

16 Leighton A, Gottlieb AB, Dorr MB, et al. Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in healthy volunteers. Antimicrob Agents Chemother. 2004;48:940–945.

17 Marbury T, Dowell JA, Seltzer E, Buckwalter M. Pharmacokinetics of dalbavancin in patients with renal or hepatic impairment. J Clin Pharmacol. 2009;49:465–476.

18 Durata Therapeutics Inc. Dalbavancin (Dalvance) Product Label. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2014/021883s000lbl.pdf. Accessed August 12, 2014.

19 Citron DM, Tyrrell KL, Goldstein EJ. Comparative in vitro activities of dalbavancin and seven comparator agents against 41 Staphylococcus species cultured from osteomyelitis infections and 18 VISA and hVISA strains. Diagn Microbiol Infect Dis. 2014;79:438–440.

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Michael H. Gold, Md • Lawrence Charles Parish, Md • Wm. Phillip Werschler, Md Joel Cohen, Md • dr. Erin Gilbert, Md, Phd • dr. Miles Graivier, Md • Michael Kane, Md Mukta Sachdev, Md • dr. Julie Woodward, Md, Phd TRIALS INCLUDED:

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Editors: Michael H. Gold, MD Lawrence Charles Parish, MD Wm. Philip Werschler, MD Joel Cohen, MD Dr. Erin Gilbert, MD, PhD Dr. Miles Graivier, MD Michael Kane, MD Mukta Sachdev, MD Dr. Julie Woodward, MD, PhD Danny Vleggaar, MD

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IntroductIon and HIstory of BotulInum toxIns BotulInum toxIns – suBtypes BotulInum toxIns In use In aestHetIc medIcIne Botox Cosmetic Dysport Xeomin PurTox Neuronox ChinaTox Other Toxins InjectIon tecHnIques for cosmetIc IndIcatIons Glabella Crow’s Feet and Lower Eyelid Forehead Brow Lift Bunny Lines Nose Nasolabial Folds Gummy Smile Upper and Lower Lip Lines Marionette Lines Cobblestone Chin Neck and Platysmal Bands BotulInum toxIn for HyperHIdrosIs BotulInum toxIn–otHer IndIcatIons used for aestHetIc medIcIne BotulInum toxIn–comBInatIon tHerapy wItH otHer modalItIes With Fillers With Lasers and Light Sources With Chemical Peels With Surgical Procedures adverse events of BotulInum toxIn topIcal BotulInum toxIns future devIces and tHeIr role In muscle relaxtIon Index

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COMING SOON: TAAG FILLERS EdITORS: Michael H. Gold, Md • Lawrence Charles Parish, Md • Wm. Phillip Werschler, Md

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November/December 2014

Volume 12 • Issue 6

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

Don’t Blow Your Top: Protecting the Information Trail in Epidermis—Fragile Skin Biopsies Marcel Castor, BS; Jesse Szatkowski, BS; M. Zac Handler, MD; W. Clark Lambert, MD, PhD “Not all those who wander are lost.”—J.R.R. Tolkien “Everything should be made as simple as possible, but not one bit simpler.”—Albert Einstein

D

iseases that cause separation of the epidermal cellular adhesions lead to potential difficulties when collecting, processing, and analyzing a biopsy as a result of the epidermal layers wandering from the deeper cutaneous structures.

The separation of the epidermis from the underlying dermis creates a situation in which the epidermal portion of a biopsy may be lost or inadvertently missed. In these diseases, if the epidermis is not correctly fixed and prepared on the slide, it may become challenging to make a definitive diagnosis histologically.

Pathogenesis Nonpathologic desquamation is the shedding of superficial keratinocytes, which occurs as a result of progressive degradation of desmosomes in the middle and upper layers of the stratum corneum.1 Desquamation maintains a proper balance of skin thickness. The pathophysiologic mechanisms that can lead to loss of cellular adhesion include three main categories: acantholysis, epidermal cell death, and dermoepidermal separation. Acantholysis is the loss of cellular adhesion molecules between cells in the epidermis, which occurs in diseases such as pemphigus vulgaris in which autoantibodies target desmosomes involved in cell-tocell adhesion.2 Separation of the dermoepidermal junction occurs in bullous pemphigoid, a disease where autoantibodies are directed against the hemidesmosomes at the epidermal basement membrane, leading to complement binding and separation of the dermoepidermal junction.2,3 In toxic epidermal necrolysis, there is apoptosis of keratinocytes in the epidermis caused by CD8+ T-cell release of granzyme B/perforin and Fas-Fas ligand pathways.4,5

Our task as dermatologists and dermatopathologists is to be sure that “not all who wander are lost,” and, indeed, to ensure that no one who wanders gets lost. Adherence to each of the following steps is necessary to achieve this goal.

Recommendations For dermatologists and dermatopathologists, the goal is to have for analysis and then to analyze a complete intact specimen on a slide even if portions of it wander on, or before it gets to, the slide. In order to guarantee that a complete specimen is correctly prepared, it is necessary to follow the information trail with a series of proper steps, adhering to the principle that “everything should be made as simple as possible, but not one bit simpler,” as follows.

First, if the differential diagnosis includes one of the diseases listed in the Table or otherwise associated with epidermal fragility, one should take extra precautions to ensure proper handling of the biopsy specimen. After performing the punch biopsy, be sure that the entire specimen is in the specimen container and that none of it is left in the punch. This requires ascertaining that the dermis and epidermis are both present in the container, as they may have become separated during the biopsy process.

Second, once the punch biopsy is taken, it needs to be immediately fully submerged within the fixative because of a tendency of specimens that are dropped into the container to float on top of the solution or even to adhere to the bottle top, leading to autolysis of the specimen and loss of the sample’s architecture.

Also, swirl the container to ensure that the specimen is fully immersed.

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

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Table. Examples of Mechanisms Leading to Loss of Cutaneous Cellular Adhesion and Associated Diseases Acantholysis

Staphylococcal scalded skin syndrome, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous impetigo

Epidermal necrolysis

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme

Dermoepidermal separation

Bullous pemphigoid, epidermolysis bullosa, linear IgA bullous dermatosis

Third, reexamine the specimen bottle 20 minutes later to again be sure that both the epidermis and the dermis are submerged in the fixative. Again, swirl the container.

Fourth, a prominent label, such as a red sticker, should be placed on the specimen container to alert all personnel further in the processing chain that it requires special handling. As with all specimens, it is essential to include adequate clinical information regarding the patient’s history and specimen description such as lesion size, site, appearance, and possible risk for epidermal separation. Even if the specimen is whole when placed in the specimen container, the epidermis may become separated during transport. Thus, for any specimen at risk for epidermal separation, your concern should be noted on the requisition form in prominent lettering and/or starred.

Fifth, if possible, direct communication with the histotechnologist and pathologist is an excellent way to ensure that there is a clear understanding of how the specimen should be handled.

properly in the tissue block. This may require separate blocks for each.

Seventh, the technician sectioning the block must be sure that both epidermis and dermis are properly represented on the slide(s) provided to the dermatopathologist.

Eighth, the dermatopathologist must be sure that he or she has read both the epidermis and the dermis present on the slide(s), even if they are widely separated. An example is shown in Figures 1 and 2. Figure 1 shows dermis with almost no epidermis present, making the correct diagnosis challenging. Figure 2 shows epidermis only, located on the slide some distance away from the tissue shown in Figure 1. Figure 2 shows the epidermis to be broadly necrotic, establishing the diagnosis (along with the clinical presentation) of toxic epidermal necrolysis, a potentially life-threatening condition.

Sixth, the technician handling the embedding of the specimen must be sure that both epidermis and dermis are embedded

It is largely because of cases such as this one that dermatopathologists are taught to hold a slide up to the light, so as to identify every fragment of tissue on it, before examining it under a microscope. If all eight steps listed above are not carefully followed,

Figure 1. Dermis biopsy specimen of a case of toxic epidermal necrolysis. (Hematoxylin and eosin stain, original magnification ×240.)

Figure 2. Same case as Figure 1. Epidermis, located on a separate area of the slide. (Hematoxylin and eosin stain, original magnification ×240.)

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the dermatopathologist may still not see the critical diagnostic tissue and the diagnosis may be missed.

2 Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid.

Autoimmun Rev. 2014;13:477–481.

Conclusions

3 Stanley JR, Hawley-Nelson P, Yuspa SH, et al. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell. 1981;24:897–903.

Punch biopsies are often the only diagnostic tool available early on in desquamative disease processes. In order to confirm an accurate diagnosis, a complete specimen is required that includes the dermis and epidermis. Through proper communication at various stages of tissue processing, the preservation of a complete sample is possible and necessary.

References 1 Jackson SM, Williams ML, Feingold KR, Elias PM. Pathobiology of the stratum corneum. West J Med. 1993;158:279–285.

4 Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol.

2013;69:173–184.

5 Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013;69:187–202.

6 Lester SC. Manual of Surgical Pathology. 2nd ed. Edinburgh, Scotland: Elsevier Churchill Livingstone; 2006.

“Carcinoma basalioma terebrans.” Moulage No. 250, made by Lotte Volger in 1918 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Volume 12 • Issue 6

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

Eosinophilic Annular Erythema: Attention Must Be Paid Warren R. Heymann, MD

H

aving never heard of eosinophilic annular erythema (EAE) prior to the spring of 2014, I have now seen two such cases presented at clinical conferences in Philadelphia (Duhring Conference, Perelman School of Medicine at the University of Pennsylvania, April 17th, 2014; Figure 1) and Odense, Denmark (Danish Dermatologic Society, May 3rd, 2014) within weeks of each other. Whether serendipitous or not, and despite the fact that EAE appears to be a rare, benign condition of minimal consequence, just like Willy Loman’s life in Arthur Miller’s Death of a Salesman, attention must be paid.

In 1981, Peterson and Jarratt first described annular erythema of infancy (AEI) in a 6-month-old boy with annular, urticarial lesions that progressed from papules to arciform lesions, without any vesiculation or scaling, over 36 to 48 hours before resolving without a trace. Histologic examination revealed a perivascular mononuclear infiltrate with eosinophils. Findings from direct immunofluorescence (DIF) were negative, as was the workup for infectious or autoimmune diseases. The condition resolved spontaneously within 8 months.1 More recently, there was a case of AEI in a 5-day-old girl that lasted several weeks. Just as in the original case of AEI, flame figures were not appreciated histologically and a systemic workup was unremarkable. Lesions responded to either systemic or topical steroids. In their review of the literature of AEI, it was noted that there have been reports of AEI that have persisted.2 For the majority of cases, the pathogenesis is unknown; however, it is presumed to be a hypersensitivity reaction to an unknown antigen, although a case in a 4.5-month-old boy was attributed to lower intestinal colonization with Candida. His AEI resolved rapidly following the administration of oral amphotericin B.3

Controversy Since the initial description of AEI, similar cases have been described in children and adults. Controversy has ensued as to whether these are distinct entities (possibly caused by exposure to different antigens) or whether they are variants of Wells syndrome (eosinophilic cellulitis).

There was a case of a 4-year-old boy diagnosed with a condition called annular erythema in childhood (AEC).4 The first case reported in an adult was that of a 62-year-old woman with a history of thyroiditis; her dermatitis displayed only modest improvement with systemic or topical corticosteroids, but it cleared within 2 months of chloroquine administration. This is the first case in the literature classified as EAE.5 Subsequently, there have been other cases of EAE that have also responded to antimalarial therapy.6,7 A 52-year-old woman with EAE (with a thorough, negative evaluation for autoimmune and infectious diseases) responded to indomethacin after only 5 days of treatment; however, this was discontinued because of syncope attributed to the medication.8 Just as in children, several reports have observed that EAE may resolve spontaneously.9 This spontaneous resolution has occurred even in the presence of Blastocystis hominis in a stool specimen.10 Another group has questioned whether EAE is a distinct entity or a subset of Wells syndrome. Although their patient had some unique histologic findings (ie, vacuolar alteration at the dermoepidermal junction and interstitial mucin) in addition to the tissue eosinophila, the classical flame figures of Wells syndrome were absent.8 There is another report of 4 men (aged 35–85 years) with EAE of 4 to 12 months’ duration: none of the initial

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

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the heymann file though they are not seen in the majority of cases of EAE, their presence in some persistent cases permits a reasonable conclusion that EAE is part of the Wells syndrome spectrum. For clinicians who insist on a precise subclassification, AEI, AEC, and EAE have their characteristic features. Unfortunately, a precise clinical diagnosis does not translate into an understanding of the pathophysiologic mechanisms that cause these conditions. More research is necessary to allow us to refine our evaluation and management of these patients. What attention should be paid to these annular erythemas?

Figure. A 13-year-old boy with pink-to-red papules and annular plaques consistent with eosinophilic annular erythema. The biopsy demonstrated marked eosinophilia with incipient flame figure formation. (Courtesy of Patrick McMahon, MD.)

biopsies demonstrated flame figures; subsequent biopsies of 2 patients demonstrated flame figures and granulomatous inflammation characteristic of Wells syndrome. One patient died of a clear cell renal carcinoma.11 A multicenter study of 10 patients (aged 31–54 years; 7 women and 3 men) with EAE demonstrated that flame figures were only observed in well-developed, long-standing lesions. Associated diseases included chronic gastritis, diabetes, chronic hepatitis C, and chronic kidney disease. Their patients had a chronic course and were resistant to treatment with systemic steroids alone or in combination with hydroxychloroquine and cyclosporine. The authors concluded that EAE is a peculiar clinical variant of Wells syndrome.12

When assessing a patient with an annular erythematous eruption (without vesiculation or scaling) consider the following: (1) a thorough review of systems; (2) obtaining a detailed medication history—if possible, discontinue any potential culprits; (3) checking routine laboratory studies based on the history (ie, complete blood cell count, comprehensive metabolic profile, sedimentation rate, thyroid function studies, antinuclear antibody, hepatitis profile); and (4) biopsying for routine microscopy and DIF. The differential diagnosis of EAE includes Wells syndrome (if you believe that EAE is a disease sui generis), the deep form of erythema annulare centrifugum (no eosinophilia), tumid lupus erythematosus (lymphocytic inflammation, ample mucin, no eosinophilia, positive DIF in approximately half of these patients), Jessner lymphocytic infiltration (no tissue eosinophilia), urticaria (without prominent tissue eosinophilia),8 urticarial bullous pemphigoid (eosinophils and a positive DIF of linear IgG and C3), erythema migrans (may show some eosinophils early near the tick bite, plasma cells more peripherally), granuloma annulare, interstitial granulomatous dermatitis (some eosinophils in drug-induced or autoimmune cases), and sarcoidosis (naked granulomas).

Conclusions Once the diagnosis of EAE is established, patients may be reassured that the majority of cases are self-limited and may resolve spontaneously. If therapy is desired, the condition may be improved by therapeutic intervention (steroids, nonsteroidal antiinflammatory drugs, or antimalarials). While the pathogenesis remains an enigma, fortunately, it does not appear to be a severe disease. It will, however, command attention from patients and physicians alike.

References

Classification Problems Nosologic classification schemes are fraught with controversy, especially if the etiology is unknown. Arbitrarily, “flame figures” are considered a diagnostic criterion for Wells syndrome.11 AlSKINmed. 2014;12:376–378

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1 Peterson AO Jr, Jarratt M. Annular erythema of infancy.

Arch Dermatol. 1981;117:145–148.

2 Pfingstler LF, Miller KP, Pride H. Recurring diffuse annular erythematous plaques in a newborn. JAMA Dermatol.

2014;150:565–566.

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3 Stachowitz S, Abeck D, Schmidt T, Ring J. Persistent annular erythema of infancy associated with intestinal Candida colonization. Clin Exp Dermatol. 2000;25;404– 405.

4 Kunz M, Hamm K, Bröcker EB, Hamm H. Annular erythema in childhood—a new eosinophilic dermatosis [German]. Hautarzt. 1998;49:131–134.

5 Kahofer P, Grabmaier E, Aberer E. Treatment of eosinophilic annular erythema with chloroquine [French]. Acta Derm Venereol. 2000;80:70–71.

6 Deruere O, Guilhou JJ. Eosinophilic-like erythema: a clinical subset of Wells’ eosinophilic cellulitis responding to antimalarial drugs? Ann Dermatol Venereol. 2002;129(5 pt 1):720–723.

7 Mebazaa A, Kenani N, Ghariani N, et al. Eosinophilic annular erythema responsive to chloroquin. Eur J Dermatol.

2009;19:84–85.

8 Howes R, Girgis L, Kossard S. Eosinophilic annular erythema: a subset of Wells’ syndrome or a distinct entity?

Australas J Dermatol. 2008;49:159–163.

9 Sempau L, Larralde M, Luna PC, Casas J, Staiger H. Eosinophilic annular erythema. Dermatol Online J. 2012;18:8.

10 Prajapati V, Cheung-Lee M, Schloss E, Thomas G. Spontaneously resolving eosinophilic annular erythema. J Am Acad Dermatol. 2012;67:e75–e77.

11 Rongioletti F, Fausti V, Kempf W, Rebora A, Parodi F. Eosinophilic annular erythema: an expression of the clinical and pathological polymorphism of Wells syndrome.

J Am Acad Dermatol. 2011;65:e135–e137.

12 El-Khalawany M, Al-Mutairi N, Sultan M, Shaaban D. Eosinophilic annular erythema is a peculiar subtype in the spectrum of Wells syndrome: a multicentre longterm follow-up study. J Eur Acad Dermatol Venereol.

2013;27;973–979.

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

(Continued on page 383) SKINmed. 2014;12:376–378

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Volume 12 • Issue 6

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

Physical Modalities in Dermatology: 1870–1975 Eve Lowenstein, MD, PhD

T

he 2014 meeting of the History of Dermatology Society on March 20th in Denver Colorado was entitled: Physical Modalities in Dermatology: 1870–1975. The following are some highlights from the seminar.

Introductory Presentation The meeting opened with Mauricio Goihman-Yahr discussing the backdrop of change in medicine, where changes involving bureaucracy and modernization have at times undermined the ethical practice of medicine.

Instrumentation Noah Scheinfeld discussed the comedo extractor, first devised

by Henry Piffard in 1873. The discussed evolution and various versions of the comedo extractor was rich with the history of famous dermatologists, a veritable who’s who of the past century, including Alibert, Thibierge, Saalfeld, Unna, Blau, Schamberg, Walton, Orentriech, and Shalita. While the utility of acne surgery has been debated, it is a frequently utilized technique today, playing a defined role in acne management.1

Eleanor Feldman described the earliest applications of dermabrasion in the Egyptian Ebers Papyrus 1500 BCE by Paulus Aegineta in 7th-century Greece and by Arab physicians in the 9th century who performed a procedure known as Batikha. In 1905, Ernest Kromayer, a German dermatologist, was first credited with its modern application using dental burrs and rasps.

Preston Iverson was a plastic surgeon who first published its use for tattoo removal in 1947. Abner Kurtin (one of the first physicians in the Dachau concentration camp after its liberation) used dermabrasion to remove tattoos from prisoners, and his publications popularized ambulatory dermabrasion. Despite controversy surrounding this approach, it persists to this day.

Derek Ho presented the technique of hair transplantation. A Japanese ophthalmologist, Shoji Okuda is infrequently recognized for

his pioneering work at punch grafting of eyebrow hairs in 1939.

Hajime Tamura successfully performed single hair grafts, and Keiichi Fujita’s work supported the concept of “recipient influence” on hair growth. The field further evolved with the Hamilton classification in 1950 and Ludwig classification in 1977. Norman Orentriech famously identified the concept of hair “donor dominance.” Recent years have seen much evolution in the techniques of follicular unit extraction and scalp closure on donor sites.2 Robert Thomsen described cautery (from the Greek word, to brand) and curettage (from the French word, to scoop). Henry Piffard is credited with inventing the first curette. It was utilized and publicized by many famous dermatologists of the time first for facial lupus, including Duhring, Hebra, Kaposi, Auspitz, Neumann, and Wigglesworth. At the turn of the 20th century, Norman Walker and W.S. Gottheil applied this to basal cell skin cancer for the first time, an approach still highly used today with excellent cure rates. The medical use of thermocautery extends back to ancient times, modernized by Paquelin where control of heat was improved greatly in the 19th century. Solar, Galvanic, Bovie, and Birtcher hyfrecator were seen leading up to the 1960s acceptance of curettage and desiccation as a standard approach to many skin cancers.3,4 Natalie Curcio discussed the History & Evolution of Mohs Micrographic Surgery. Fredric Mohs first discovered the technique, originally using “chemosurgery” with zinc paste, a painful process for the patient. The technique evolved to a fresh tissue technique used today, with Appropriate Use Criteria (AUC) developed to guide physicians in deciding which cancers are most appropriately managed via the Mohs technique.

W. Clark Lambert’s presentation focused on the history and proper use of the potassium hydroxide preparation (KOH) test. The Clinical Laboratory Improvement Amendments (CLIA) enacted in 1988 extended its auspices in 2004 and made the performance of KOH preparations illegal in the office without special licensure

Address for Correspondence: Eve Lowenstein, MD, PhD, Department of Dermatology, SUNY Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 43, Brooklyn, NY 11203 • E-mail: evlow13@yahoo.com

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in the United States. This was discussed as an example of how implemented laws to improve safety have ultimately limited access to a diagnostic test and thereby harmed patients.

In my presentation on the history of glove use in skin surgery, the mid-19th century saw a revolution in our understanding of infection. Alexander Gordon of Aberdeen, Scotland, was the first to make a connection between physician carrier of infectious puerperal fever. Thomas Watson in London (1842) and Oliver Wendell Holmes (1843) in the United States also relayed that contagion and puerperal fever were related to personal cleanliness of the doctor. Ignaz Semmelweiss (1847) was the first to champion washing before examining the patient. His aseptic technique to avoid puerperal fever was initially ridiculed, but ultimately resulted in a reduction in maternal death rate from 18% to 1%. Joseph Lister (1867) first introduced carbolic acid washes before surgery5–7; however, it was with the knowledge of Koch’s postulates (1882) that the field of bacteriology was born and the way paved for the ensuing revolution in aseptic surgical technique. The late 1890s saw a crisis of aseptic surgery, with growing insecurity among surgeons related to surgical practices, resulting in a revolution in the field and the advent of sterile technique as a direct result. First introduced in the United States

by William Halstead, glove use in surgery was met with great resistance initially but quickly became a standard of care. More than 100 years later, the use of sterile gloves is coming more into question as it is found to be costly and of no added benefit in certain surgical circumstances, including limited skin surgery.8 Injections Mohamed Amer discussed autohemotherapy, first described in 1913 by Paul Ravaut. This technique, instituted primarily in Europe and South America, was used for a variety of inflammatory conditions, although evidence supporting its use is limited.

Radiation and Light Robert Norman discussed the history of radiotherapy. Soon after its discovery, x-rays were applied medically, with Leopold Freund described as the founder of rontgenotherapy, or medical radiology, publishing the first textbook on its use in 1901. Emil Grubbe was the first American physician to use x-ray therapy for cancer.

Gerd Plewig discussed Finsen light. Developed by Niels Ryberg Finsen, a lamp based on electric carbon arcs was used for skin therapy, especially lupus vulgaris/cutaneous tuberculosis, and ultimately earned him the Nobel Prize in Medicine in 1903.9 In her discussion of the history of psoralen–UV-A, Ankuri Desai reflected on how Ancient Egypt and India were both aware SKINmed. 2014;12:381–383

of photosensitizing compounds for use in therapy of diseases such as vitiligo more than 2000 years ago. In 1947, with the isolation of psoralen, the way was paved for modern phototherapy. El-Mofty, an Egyptian dermatologist, began to use 5-methoxypsoralen (5-MOP), but access to this drug was difficult and delayed its introduction to worldwide dermatologic care until the 1970s, when Klaus Wolf and Thomas Fitzpatrick published on its use.

Yusuf Anwar spoke about radium and the fascinating history of its medical use and misuse. After its discovery, this misunderstood element became the latest craze, being used in all sorts of agents: soaps, toothpastes, and suppositories, as well as in bread and chocolate bars. He describes the Radium Girls, who were employed to paint radium on watch dials, and licked the paint brushes during their work, resulting in medical complications such as radium jaw fractures and anemia.

Temperature Changes Larry Millikan described the history of thermal spring therapies in the development of balneotherapy, thalassotherapy, and climatotherapy. These springs throughout the world have a variety of putative therapeutic elements, including radon, lithium, manganese, magnesium, sulfur, and trace elements. In 1895, Kaposi published on the use of springs for many disorders with varying additives, including tar.

Christoph Loeser discussed the use of cooling therapy, with early treatments such as tuberculosis with cold in 1885. Cryotherapy first reported in 1905 and liquid nitrogen use was first described in a landmark paper in 1950 by Allington for a variety of disorders.

Mark Valentine similarly described the history of cold therapy, noting early cancer cooling therapy. William Pusey recognized that carbon dioxide (CO2) snow was colder than salt/ice (1850s) and ethyl chloride (1900), easier to control than CO2 gas (1905), and much more readily available than liquid air (1899). In 1911, Cranston Low published on the use of CO2 snow, describing use in guidelines and applications.

Conclusions Instruments, injectables, and electromagnetic energy have been devised or manipulated to treat humanity’s ailments. The therapeutic interventions described are some of the many that have revolutionized medicine and made history. Individual small steps moving forward the machine of medicine.

History never looks like history when you are living through it.10

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References 1 Scheinfeld N. Does acne surgery have a role? A look at the advantages and disadvantages of comedo extraction. Skin & Aging. 2007;15:52–54.

2 Jandali S, Low D. Past, present, future of hair restoration. Ann Plast Surg. 2010;65:437–442.

3 Sebben JE. Cutaneous Electrosurgery. Chicago, IL: Yearbook Medical Publishers; 1989.

4 Otto J, Blumberg T. Techniques of Office Electrosurgery: A Review of the Literature with Bibliography. Cincinnati, OH: The Liebel-Flarsheim Company; 1949.

5 Stewardson A, Allegranzi B, Sax H, Kilpatrick C, Pittet D. Back to the future: rising to the Semmelweis challenge in hand hygiene. Future Microbiol. 2011;6:855–876.

6 Newsom SW. Pioneers in infection control. Ingaz Philipp Semmelweis. J Hosp Infect. 1993;23:175–187.

7 Best M, Neuhauser D. Ingaz Semmelweis and the birth of infection control. Qual Saf Health Care. 2004;13:233– 234.

8 Schlich T Negotiating technologies in surgery: the controversy about surgical gloves in the 1890s. Bull Hist Med. 2013;87:170–197.

9 Grzybowski A, Pietrzak K. From patient to discoverer— Niels Ryberg Finsen (1860–1904)—the founder of phototherapy in dermatology. Clin Dermatol. 2012;30:451–455.

10 John W. Gardner. http://www.quotationspage.com/ search.php3?homesearch=History+never+looks+like+hi story+when+you+are+living+through+it&startsearch=S earch. Accessed November 18, 2014.

Historical Diagnosis and treatment: epithelioma

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History of Dermatology society 42nd annual meeting, san francisco, ca The History of Dermatology Society will convene on Thursday, March 19, 2015, at the Taj Campton Place, 340 Stockton Street, San Francisco, CA 94108. H of D Day begins at 10 am with a tour of the Asian Art Museum of San Francisco, 200 Larkin Street.

Lunch follows at noon at the Taj Campton Place, during which Dr. Erika Reid will present the “History of Dermatology at Woman’s Medical College of Pennsylvania.” The afternoon seminar is entitled “Dermatology in a Bye-Gone Era” and will begin promptly at 1:30 pm.

The Annual Dinner and Zakon Lecture will be held at the Taj Campton Place, beginning with a cocktail reception at 7:00 pm.

Dr. Kenneth Arndt will present the annual Samuel J. Zakon Lecture, entitled “One Thing Leads to another.” The annual Marion B. Sulzberger Toast, Herman Beerman Toast, John T. Crissey Toast, and Poet Laureate presentation will complete the evening festivities. The 2015 Samuel J. Zakon Prize will also be announced.

A block of rooms has been reserved at the Taj Campton Place. Please contact: Taj Reservations Department at 415-781-5555 and request the History of Dermatology Society Group Rate.

RegistRation FoRm: HistoRY oF DeRmatoLogY soCietY 42nd annual meeting, san Francisco, Ca march 19, 2015 Registrant’s name: Address: City: Country: Guest’s name: Tel:

State:

Fax:

MEDIA PARTNER

Zip:

E-mail:

thursday, march 19, 2015

Price

tour and lecture: 10:00 am Asian Art Museum of San Francisco, 200 Larkin Street

$10 for 65+ $2 for reciprocal museum members $12 group rate

luncheon: 12:00–1:00 pm Dr. Erika Reid, “History of Dermatology at the Woman’s Medical College of Pennsylvania” Taj Campton Place, 340 Stockton Street

$40 members $55 non-members

afternoon seminar: 1:30–5:00 pm “Dermatology in a Bye-Gone Era” Taj Campton Place, 340 Stockton Street

$50 non-members Free for members

annual Banquet – cocktail reception: 7:00 pm Taj Campton Place, 340 Stockton Street Dinner and samuel J. Zakon lecture: 8:00 pm Dr. Kenneth Arndt, “One Thing Leads to Another”

$95 members $125 non-members

membership Dues – includes a free subscription to SKINmed

$185

tickets

amount

Total Please make a copy of this page and return it with the total amount due in US$: Check: mail to Dr. Anthony V. Benedetto, Secretary/Treasurer, History of Dermatology Society, 2221 Garrett Road, Drexel Hill, PA 19026 Credit card (Visa or Mastercard): # Expiration: 3 or 4 digit Security Code: Tel: 1 610-623-5885 Fax: 1 610-623-7276 E-mail: avb@benedettoderm.com Web: www.dermato.med.br/hds

November/December 2014

Volume 12 • Issue 6

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

Centrally Located Acquired Bilateral Nevus of Ota-Like Macules: A Bizarre Pattern Ru-zhi Zhang, MD;1 Wen-yuan Zhu, MD;2 Lei Zhou, MD3 A 22-year-old woman was referred to our hospital for pigmented lesions located on her face. These had gradually increased during the past 4 years. Computed tomography (CT) of her head revealed no significant parenchymal abnormalities of temporal, maxillary and sphenoid bones or of either parietal bone. Further screening, including neurologic, ophthalmologic, orthopedic, and visceral investigations, did not reveal any abnormalities. There was no family history of abnormal cutaneous pigmentation. (SKINmed.

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hysical examination revealed a triangular smoky gray patch on the middle of her face, although the color was irregular. The skin over the dorsal surface of her nose was light brown, but in contrast, the skin on the medial angle of her eyes was sable to blue-brown with jagged pigmented borders (Figure 1). No mucosal pigmentation or other pigmentary lesions on her skin was observed. A biopsy from a pigmented lesion on her face was stained with hematoxylin-eosin HE and Fontana, and immunohistochemical studies using the streptavidin-peroxidase method were employed. Markers examined included NKI/ beteb, HMB45, vimentin, S-100 protein, and Ki67. Histologic and immunohistochemical findings showed increased melanin in the keratinocytes, without elongation of the rete ridges and excessive numbers of melanocytes. A few scattered, bipolar or irregular melanocytes and some melanin deposits were noted in the reticular dermis (Figure 2A and 2B). According to the clinical and histopathologic findings, we made the diagnosis of acquired bilateral nevus of Ota-like macules (ABNOM). Our patient refused to undergo any therapy. She was lost to follow-up.

Discussion ABNOM, first described by Hori et al. in 1984, also known as Hori’s nevus, is classified as an acquired dermal melanocytosis (ADM).1 It usually appears in the third or fourth decade of life and shows a marked preponderance in Asian women. ABNOM

is known to be distributed mainly on peripheral areas of the face.

It is mainly located on the lateral side of the forehead, the lateral part of the upper eyelids, the malar area, the root of the nose, and the alae of the nose. It is one of the more common types of ADM, and yet very little is known about this clinical entity.

Nevus fusco-caeruleus zygomaticus and acquired circumscribed dermal facial melanocytoses are alternate designations routinely encountered in the literature for this entity.2,3 Clinically, ABNOM is characterized by multiple speckled blue-brown and/or slate-gray macules occurring bilaterally on the malar regions or less commonly on the forehead, upper eyelids, cheeks, and nose.4 Histologically, there are irregularly shaped, bipolar melanocytes dispersed in the papillary and mid dermis, particularly in the subpapillary dermis, without disturbance of the normal skin architecture. Fontana-Masson silver staining reveals abundant brown pigment within the cytoplasm of the spindle cells, which also show immunoreactivity for S-100 protein, Melan-A and HMB-45.5 In the skin, anti-S100 is not specific for melanocytes, as it also labels Langerhans cells, Schwann cells, and sweat glands. HMB-45 and NKI/beteb react with different epitopes of the same antigen found in early stage melanosomes and premelanosomes. This antigen is found exclusively in melanocytes, making these two antibodies specific to the melanocyte cell lineage.

HMB-45 failed to label normal melanocytes, while NKI/beteb has been found to detect normal adult melanocytes. Vimentin

From the Department of Dermatology, Third Affiliated Hospital of Suzhou University, 185 Juqian Road, Changzhou, 213003, China;1 the Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China;2 and the Department of Pathology, The First Affiliated Hospital of Bengbu Medical College, Anhui 233004, China3 Address for Correspondence: Wen-yuan Zhu, Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China • E-mail: zhuwenyuan@yahoo.com

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A

Figure 1. A triangular smoky gray patch with heterogeneous color in the middle of the face of a young woman.

was deemed too nonspecific, as it also labeled dermal fibroblasts and other mesenchymal elements, making the identification of normal melanocytes extremely difficult.

Although the clinicopathologic features of ABNOM have been described, the origin of the dermal melanocytes and the pathogenesis of ABNOM are still poorly understood.6 It has been postulated that dermal melanocytes appear when melanocytes, migrating from the neural crest during embryologic development, fail to reach their proper location in the basal layer of the epidermis. Alternatively, dermal melanocytes may migrate from the basal layer of the epidermis (dropping off) or from follicular bulbs. Dormant dermal melanocytes may be present but unnoticed from birth, and the melanin synthesizing pathway may be activated later by inflammation, local trauma, sex hormones or some unknown ageing stimuli.7 Our case is of great interest due to the distribution of the lesions, which were crowded at the central area of the patientâ&#x20AC;&#x2122;s face rather than in the peripheral area, and presented as a bizarre triangle. In the literature, there are reports of a 27-year-old Korean woman with ABNOM that mimicked dark circles under her eyes8 and a 46-year-old woman presenting with multiple hyperpigmented macules over the medial side of both her upper and lower eyelids, glabellar area, root of the nose, and both alae of the nose, present for for 3 years. Up to now, the triangle-like pattern of ABNOM was not previously reported. This variety in ABNOM may be misdiagnosed as a centrofacial type of melasma. In melasma, SKINmed. 2014;12:385â&#x20AC;&#x201C;387

B Figure 2. Histologic features of the pigmented lesion.

Epidermal hyperpigmentation without elongation of the rete ridges. A few scattered, bipolar or irregular melanocytes and some melanin deposits were noted in the reticular dermis. A: Hematoxylin and eosin staining; B: immunostaining with NKI/beteb. (Original magnification Ă&#x2014;200.)

melanin deposition is increased in the basal layer of the epidermis and within melanophages of the papillary dermis. The dermal melanocytes seen in ABNOM can not be found in melasma.

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Q-switched laser devices have been widely accepted as the treatment of choice for nevus of Ota on the principle of selective photothermolysis and ABNOM is histopathologically similar to the nevus of Ota.10 QS lasers, such as the QS ruby laser, QS neodymium: yttrium-aluminum-garnet laser, and QS alexandrite laser, have all been used for the treatment of ABNOM.

4 Wang BQ, Shen ZY, Fei Y, et al. A population-based study of acquired bilateral nevus-of-Ota-like macules in Shanghai, China. J Invest Dermatol. 2011;131:358362.

Acknowledgments

6 Park JM, Tsao H, Tsao S. Acquired bilateral nevus of Ota-like macules (Hori nevus): Etiologic and therapeutic considerations. J Am Acad Dermatol. 2009;61:8893.

We thank Professor V. J. Hearing, Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD, for English-language review of this contribution. Supported by the National Natural Science Foundation of China (No 81171516 ).

References

5 Lee JY, Kim EH, Kim KH, et al. Acquired bilateral naevus of Ota-like macules: an immunohistological analysis of dermal melanogenic paracrine cytokine networks. Br J Dermatol. 2011;164:580-585.

7 Long TF, Liu L, He L, et al. Androgen, estrogen and progesterone receptors in acquired bilateral nevus of Otalike macules. Pigment Cell Melanoma Res. 2010;23:144146.

1 Hori Y, Kawashima M, Oohara K, et al. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol.

1984;10:961-964.

8 Cho S, Lee S, Chung WS, et al. Acquired bilateral nevus of Ota-like macules mimicking dark circles under the eyes. J Cosm Laser Ther. 2010;12:143–144.

2 Sun CC, Lü YC, Lee EF, et al. Naevus fusco-caeruleus zygomaticus. Br J Dermatol. 1987;117:545-553.

9 Kim SK, Kang HY. Centrally located acquired bilateral nevus of Ota-like macules (Hori’s nevus): is this a novel type? Eur J Dermatol. 2008;18:596.

3 Murakami F, Soma Y, Mizoguchi M. Acquired symmetrical dermal melanocytosis (naevus of Hori) developing after aggravated atopic dermatitis. Br J Dermatol.

2005;152:903-908.

10 Lee WJ, Han SS, Chang SE, et al. Q-Switched Nd:YAG laser therapy of acquired bilateral nevus of Ota-like macules. Ann Dermatol. 2009;21:255-260.

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November/December 2014

Volume 12 • Issue 6

CASE STUDY

The Clinical Challenges in the Management of Deep Lymphangioma of the Foot Rikki Singal, MS;1 Samita Gupta, MD;2 Pinky Pande, MD;3 Vinod Mehta, MD;2 Pradeep Sahu, MS;1 N.C. Mahajan, MD3

A 12-year-old girl presented with swelling on the lateral aspect of the left foot since early childhood, progressively increasing in size and now causing pain on walking. Pain was relieved with medication only. There was also history of a single episode of blood-tinged discharge from the swelling 3 years prior. There was no history of trauma, diabetes, or hypertension. (SKINmed. 2014;12:390–392)

O

n local examination, a solitary, bluish swelling was present near the base of the left fifth toe on lateral aspect of the foot (Figure 1). The temperature was normal and mild tenderness was present over the swelling. It was 8×6×2 cm in size, soft in nature, and nonpulsatile and had a smooth surface. No neuromuscular deficit was evident. Draining lymph nodes were not enlarged or tender.

On X-ray of the foot, nonspecific opacity was seen on the lateral aspect, but findings from ultrasonography (USG) revealed an irregular cystic mass with septation in the distal aspect of the left foot adjoining the fifth metatarsophalangeal joint region (Figure 2A). Results from color Doppler study did not show any feeding vessels or vascularity within the lesion; hence, the diagnosis of lymphangioma of the left foot was made (Figure 2B).

On exploration, swelling was found adherent to the surrounding structures (Figure 3). It was dissected from the muscles, tendons, and bone with adequate clearance of the margins. Primary closure of the incision was achieved (Figure 4). Grossly, the cyst was pale white and soft in nature. Microscopic examination revealed dilated lymphatic channels lined by flattened endothelial cells along with fibrocollagenous stroma, and diagnosis of lymphangioma with clear margins was confirmed (Figure 5A and 5B).

Figure 1. Soft tissue swelling in the left foot.

No recurrence or difficulty in movement was seen after 16 months of follow-up. Motor and sensory functions of the foot were maintained, including the appearance.

Discussion Deep lymphangiomas are rare lymphatic malformations in the body, particularly in the feet. The most difficult problem for a clinician is to assess the need of surgical management of the

From the Department of Surgery, Maharishi Markandeshwer Institute of Medical Sciences and Research, Mullana (Distt-Ambala), Haryana, India;1 the Department of Radiodiagnosis and Imaging, Maharishi Markandeshwer Institute of Medical Sciences and Research, Mullana (Distt-Ambala), Haryana, India;2 and the Department of Pathology, Maharishi Markandeshwer Institute of Medical Sciences and Research, Mullana (Distt-Ambala), Haryana, India3 Address for Correspondence: Rikki Singal, MS, c/o Dr. Kundan Lal Hospital, Ahmedgarh, Distt-Sangrur, Pin Code-148021, Punjab, India • E-mail: singalsurgery@yahoo.com

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Figure 3. Intraoperative image showing a deep cystic tumor adherent to the tendon and muscles.

A

B Figure 2. X-ray and ultrasonography of the foot showing a soft tissue cystic tumor (A). Color Doppler study revealing no flow in the mass diagnosed as lymphangioma (B).

Figure 4. Gross appearance of the resected specimen and skin closed primarily.

benign tumors of soft tissue of the feet. We report a rare case of deep lymphangioma of the foot in a 12-year-old girl initially diagnosed by USG and confirmed by histopathological examination. Surgical excision was achieved, which resulted in satisfactory functional and cosmetic outcome. The patient is still doing well without any recurrence after 16 months of follow-up.

Lymphangiomas originate from sequestered embryionic lymphatic sacs, which are either congenital lesions or later develop into the acquired forms, and usually have a preponderance for superficial locations over the body surfaces. Superficial lymphangiomas generally appear as small grouped translucent vesicles containing fluid/blood or a yellowish bubble that forms plaques in the skin or mucous membranes.1 Deep lymphangiomas are composed of large dilated lymphatic, and lie down within the deeper facial layers, as seen in our case. Acquired progressive lymphangioma is a rare disorder that presents in childhood or in early adolescence and occurs after radiation, malformation, or surgery.2 SKINmed. 2014;12:390â&#x20AC;&#x201C;392

Acquired progressive lymphangioma is an uncommon abnormality that is seen in childhood or early adolescence in the form of deep lymphatic proliferation that gradually increases in size. These malformations are present at birth in 60% of cases, becoming apparent by the time the child reaches 2 years of age in 90% of cases.1 Spontaneous regression is rarely seen.

Lymphangiomas are commonly seen over the face/neck, axilla, and chest but are rarely seen in the feet and in deeper planes, as in our case. In 1996, a case of a lymphangioma on the anterior aspect of the ankle was described.3 Lymphangiography for diagnosis and complete surgical excision for treatment were employed.

As with other vascular malformations, these lesions may be superficial or deep and localized or diffuse. They steadily increase in size, although some enlarge more rapidly depending on the size and site. Lesions may cause localized pain or recurrent infections and may later affect patient quality of life.1 Lymphan-

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Case Study

B

A

Figure 5. Photomicrograph showing dilated lymphatic channels underneath the covering skin of stratified squamous epithelium (hematoxylin and eosin stain, original magnification ×40) (A). Photomicrograph showing numerous dilated lymphatic channels lined by flattened endothelial cells along with fibrocollagenous stroma (hematoxylin and eosin stain, original magnification ×100) (B).

gioma circumscriptum is a superficial lymphatic hamartomatous malformation of the lymphatic channels of the skin. It has two components: (1) dermal vesicular and (2) deeper subcutaneous cisternal elements.4 According to our search of the world literature, very few cases of deep lymphangioma over the foot have been reported.5

in our case of deep lymphangioma, total excision was carried out, and after 16 months of follow-up, there was no recurrence/ complications. Patients in whom open surgery is not recommended for any reason, alternative nonsurgical options include diathermy, radiation therapy, or intralesional injection of sclerosing agents with good functional and cosmetic results.

USG can visualize these lesions with specific morphological features due to the peculiar cystic nature. USG findings may include multiple septations of varying thickness and fluid-fluid levels that represent layering of the hemorrhagic components of the lesion.6 It can also help in differentiating between the lymphangioma and hemangioma, as there is no significant Doppler flow in a lymphangioma. Deep lymphangiomas are rarely seen over the foot, as diagnosed in the current case, and managed surgically without any recurrence.

Acknowledgment Professor Bir Singh and Dr Amit Mittal participated in the management of this patient.

References

The main complications of lymphangiomas are intralesional bleeding and infection. Bacterial cellulitis, however, is more dangerous and requires prolonged intravenous antibiotics. The most widely accepted treatment for these lesions is surgical excision, which decreases the rate of recurrence; however, because of the infiltrating nature of the lesion, complete excision is reported in only 18% to 50% of cases.6

1 Juca NB, Crisostomo MG, de Oliveira LM, Cavalcante HA, de Sousa AR. Acral microcystic lymphangioma: differential diagnosis in verrucous lesions of the extremities. An Bras Dermatol. 2011;86:343–346.

2 Linda YH, Carrie KG, Rob NP, Sylvia H. Acquired progressive lymphangioma. J Am Acad Dermatol. 2003;49:250– 251.

3 Wu K. Lymphangioma of the ankle region. J Foot Ankle Surg. 1996;35:263–265.

4 Sachdeva S. Lymphangioma circumscriptum treated with radiofrequency ablation. Indian J Dermatol.

2011;56:77–78.

Conclusions

5 Verelst W, Huygh J, Van Marck E, et al. Persistent swelling at the ankle joint: presentation, diagnosis and discussion. Skeletal Radiol. 2008;37:1157–1158.

The prognosis of lymphangiomas depends on the position, extent of the lesion, and presence of associated abnormalities. As

6 Ly JQ, Gilbert BC, Davis SW, Beall DP, Richardson RR. Lymphangioma of the foot. AJR Am J Roentgenol.

2005;184:205–206.

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November/December 2014

Volume 12 • Issue 6

Book Review Jennifer L. Parish, MD, Section Editor

Moderate to Severe Psoriasis

By Koo JYM, Levin EC, Leon A, Wu JJ, Gottlieb AB. Fourth Edition.

Boca Raton, FL: CRC Press; 2014. Pages 214. $139.95

T

his is a superb review of moderate to severe psoriasis, which continues to be one of the most challenging dermatologic diseases to treat. An excellent overview of the disease is followed by an extensive discussion of the numerous different modes of treatment ranging from topical therapy to phototherapy, systemic to combination therapy, and the increasing number of biologic therapies. The sequencing of these therapies is presented in some length, always with a solid rationale for the particular treatment chosen.

Biologic therapy makes up nearly two thirds of the book, and each of the currently available treatments is discussed in detail.

Expectations for results and side effects are dutifully reported. The recently introduced concept of biologic fatigue is included, along with ways to mitigate its presence.

An example of this in-depth coverage is that of adalimumab, which is the most widely used of the biologics in psoriasis. It is also the first fully human monoclonal antibody targeted at tumor necrosis factor α. The phase III trials involving the integument in more than 1200 patients are well presented, as are the trials in psoriatic arthritis involving 138 patients, which was later expanded to 285 in an open-label effort. In another trial, this agent was compared with methotrexate, and the efficacy in the improvement of the Psoriasis Area and Severity Index (PASI) in all of the trials was highly significant (P=.001). This included those trials compared with placebo and the head-to-head trial with methotrexate. After week 24, dose escalation (to weekly administration), in patients with less than PASI 50 response was attempted but was successful in only a minority of patients.

There is also presentation of the safety factors, which put the black box warnings in perspective. Of note is the knowledge that the side effects and adverse advents are similar for the biologics in general, including those for infections, tuberculosis, injection site reactions, malignancies (avoid the use of biologics in patients with malignancy or a history of malignancy and discontinuing such an agent should the patient develop a malignancy), and neurologic

events (avoid the use of biologics in patients with demyelinating disease, be it overt or diagnosed in first-degree relatives). Additional points include contraindications and precautions in patients with hepatitis B and congestive heart failure. Needless to say, the agent should not be administered to pregnant women or those who are breast-feeding.

The chapters on phototherapy, corticosteroid therapy, the use of vitamin D analogues, and cyclosporine all contribute to the thoroughness of this latest addition. Psoriatic arthritis and pediatric psoriasis are each nicely presented. New therapeutic agents on the horizon are discussed, and diseases that are among the most severe, such as psoriatic erythroderma and psoriatic arthritis, receive special mention. In all, this is an excellent reference book for physicians who treat the most severe variants of psoriasis. This latest revision would be useful in the library of any clinician taking care of psoriatic patients, as well as in department collections. The editors and their contributors have done a commendable job.

Reviewed by Herbert B. Allen, MD, Professor and Chair of Dermatology, Drexel University College of Medicine, 219 North Broad Street, 4th Floor, Philadelphia, PA 19107 • E-mail: Herbert.Allen@DrexelMed.edu

SKINmed. 2014;12:395

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© 2014 Pulse Marketing & Communications, LLC

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IMPORTANT INFORMATION ABOUT ®

Mirvaso

(Brimonidine) Topical Gel, 0.33%* *Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base BRIEF SUMMARY This summary contains important information about MIRVASO (Mer-VAY-Soe) Gel. It is not meant to take the place of the full Prescribing Information.

Read this information carefully before you prescribe MIRVASO Gel. For full Prescribing Information and Patient Information please see package insert.

WHAT IS MIRVASO GEL? MIRVASO (brimonidine) Topical Gel, 0.33% is a prescription medicine that is used on the skin (topical) to treat facial redness due to rosacea that does not go away (persistent).

WHO IS MIRVASO GEL FOR? MIRVASO Gel is for use in adults ages 18 years and older.

WHAT WARNINGS AND PRECAUTIONS SHOULD I BE AWARE OF? MIRVASO Gel should be used with caution in patients that: • • • • • • • • •

have depression have heart or blood vessel problems have dizziness or blood pressure problems have problems with blood circulation or have had a stroke have dry mouth or Sjögren’s Syndrome have skin tightening or Scleroderma have Raynaud’s phenomenon have irritated skin or open sores are pregnant or plan to become pregnant. It is not known if MIRVASO Gel will harm an unborn baby.

• are breastfeeding. It is not known if MIRVASO Gel passes into breast milk.

You and your female patient should decide if she will use MIRVASO Gel or breastfeed. She should not do both.

Ask your patient about all the medicines they take, including prescription and over-the-counter medicines, skin products, vitamins and herbal supplements. Using MIRVASO Gel with certain other medicines may affect each other and can cause serious side effects.

Keep MIRVASO Gel out of the reach of children.

If anyone, especially a child, accidentally swallows MIRVASO Gel, they may have serious side effects and need to be treated in a hospital. Get medical help right away if you, your patient, a child, or anyone else swallows MIRVASO Gel and has any of these symptoms:

MIRVASO Gel can lower blood pressure in people with certain heart or blood vessel problems. See “What warnings and precautions should I be aware of?”

These are not all of the possible side effects of MIRVASO Gel. Remind your patients to call you for medical advice about side effects.

You are also encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

HOW SHOULD MIRVASO GEL BE APPLIED? • Remind your patients to use MIRVASO Gel exactly as you instruct them.

They should not use more MIRVASO Gel than prescribed.

• Patients should not apply MIRVASO Gel to irritated skin or open wounds.

• Important: MIRVASO Gel is for use on the face only. Patients should not use MIRVASO Gel in their eyes, mouth, or vagina. They should also avoid contact with the lips and eyes.

• Instruct your patients to see the detailed Instructions for Use that come with MIRVASO Gel for information about how to apply MIRVASO Gel correctly.

GENERAL INFORMATION ABOUT THE SAFE AND EFFECTIVE USE OF MIRVASO GEL Remind your patients not to use MIRVASO Gel for a condition for which it was not prescribed and to not give MIRVASO Gel to other people, even if they have the same symptoms. It may harm them.

WHAT ARE THE INGREDIENTS IN MIRVASO GEL? Active Ingredient: brimonidine tartrate Inactive Ingredients: carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, purified water, sodium hydroxide, titanium dioxide.

WHERE SHOULD I GO FOR MORE INFORMATION ABOUT MIRVASO GEL? • Go to www.mirvaso.com or call 1-866-735-4137 GALDERMA LABORATORIES, L.P. Fort Worth, Texas 76177 USA Revised: August, 2013 HCP

• Lack of energy, trouble breathing or stops breathing, a slow heart beat, confusion, sweating, restlessness, muscle spasms or twitching.

WHAT ARE THE POSSIBLE SIDE EFFECTS OF MIRVASO GEL? The most common side effects of using MIRVASO Gel include: • redness, flushing, burning sensation of the skin, skin irritation Skin redness and flushing may happen about 3 to 4 hours after applying MIRVASO Gel. Ask your patients to tell you if they get skin redness and flushing that is uncomfortable.

Mirvaso and Galderma are registered trademarks. ©2013 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway Fort Worth, TX 76177 MIR-164B Printed in USA 08/13 Mirvaso Brief Summary HCP R3.indd 1

References: 1. Fowler J Jr, Jackson JM, Moore A, et al; Brimonidine Phase III Study Group. Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, vehicle-controlled pivotal studies.

J Drugs Dermatol. 2013;12(6):650-656. 2. Mirvaso [package insert]. Galderma Laboratories, L.P. Fort Worth, TX; 2013.

9/4/13 11:51 AM

Help your patients with facial erythema of rosacea experience...

Not an actual patient. Individual results may vary. Results are simulated to show a 2-grade improvement of erythema. At hour 12 on day 29, 22% of subjects using Mirvaso Gel experienced a 2-grade improvement of erythema compared with 9% of subjects using the vehicle gel.*

RAPID AND SUSTAINED ERYTHEMA REDUCTION BROUGHT TO YOU BY ® M I R V A S O ( b r i m o n i d i n e ) T O P I C A L G E L , 0 . 3 3 %† • The first and only FDA-approved topical treatment specifically developed and indicated for the facial erythema of rosacea1 • Fast results that last up to 12 hours1 • The most commonly reported adverse events in controlled clinical studies included erythema (4%), flushing (2%), skin-burning sensation (2%), and contact dermatitis (1%)2 Important Safety Information Indication: Mirvaso® (brimonidine) topical gel, 0.33% is an alpha-2 adrenergic agonist indicated for the topical treatment of persistent (nontransient) facial erythema of rosacea in adults 18 years of age or older. Adverse Events: In clinical trials, the most common adverse reactions (≥1%) included erythema, flushing, skin-burning sensation, and contact dermatitis. Warnings/Precautions: Mirvaso Gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Alpha-2 adrenergic agents can lower blood pressure.

Mirvaso Gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease. Serious adverse reactions following accidental ingestion of Mirvaso Gel by children have been reported. Keep Mirvaso Gel out of the reach of children. Not for oral, ophthalmic, or intravaginal use.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see brief summary of full Prescribing Information on the following page.

See for yourself. Visit www.mirvaso.com/hcp. *Phase 3 clinical studies of 553 subjects 18 and older. Subjects were randomized 1:1 to either Mirvaso Gel or vehicle for 29 days. Subjects and clinicians were asked to grade the improvement they saw at 30 minutes and hours 3, 6, 9, and 12 following application. † Each gram of gel contains 5 mg of brimonidine tartrate equivalent to 3.3 mg of brimonidine free base.