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Chinese Society of Dermatology

Chinese Society of Dermatology

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

COMMENTARIES Western Blotting of Human Sera–– Can It Help Diagnose Bed Bug Bites? Goddard, Tardo, and Embers

Aquagenic Acrokeratoderma­–– New Insights Tchernev and Wollina

ORIGINAL CONTRIBUTIONS Topical Tacrolimus and Oral Dapsone Combination Regimen in Lichen Planus Pigmentosus Verma and Pandhi

Onychogryphosis: A Report of Ten Cases Chang and Meaux

REVIEW What Can Be Expected on Irradiated Skin? A Dermatologic Focus on Acute and Chronic Radiotherapeutic Effects, Treatment, and Benign Dermatoses Cuperus, Albregts, and Toonstra

Self-Assessment Examination Lambert

DEPARTMENTS PERILS OF DERMATOPATHOLOGY Cancer From the Cut: How Surgical Flaps Can Move Incidental Tumors to Different Locations John, Singh, Sharma, and Lambert

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

African Association for Dermatology

September/October 2015 • Volume 13 • Issue 5

September/October 2015 • Volume 13 • Issue 5 NEW TO THE CLINIC EDITORIAL Apremilast (Otezla) The 6-Second Specialists: Medicine at Scheinfeld, Abramovits, and Gupta Ellis Island Immigration Station Lowenstein, Rosen, Heaton, Siegel, Brar, and Glick

North American Clinical Dermatologic Society

THE HEYMANN FILE The Association of Bullous Pemphigoid and Neurologic Disorders: A Real Braintease Heymann

HISTORY OF DERMATOLOGY SOCIETY NEWSLETTERS Dermatology in a Bygone Era Lowenstein

Port Wine Nevus Treated With Kromayer Light Bernhardt

case studies Eruptive Syringocystadenoma Papilliferum, Keratoacanthoma, and Verruca Vulgaris in a Keratinocytic Epidermal Nevus on the Leg

CORRESPONDENCE Comment on Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergilllus niger Zaias

Response to “Comment on Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger” Garcia and Arenas

Patient Positioning During Dermatologic Surgery for Optimal Wound Closure Chilukuri, Bridges, Nguyen, and Konda

An Epidemiologic Study on the Relationship Between Hand Dermatitis and Antioxidants Lai and Yew

Pewitt, Burns, and Chan

Linear Nevoid Epidermolytic Hyperkeratosis Localized to the Sole Khanna, Chakravarty, Das, and Bansal

Paradoxical Induction of Psoriasis and Lichen Planus by Tumor Necrosis Factor-α Inhibitors Au and Hernandez

Adult-Onset Blue Rubber Bleb Nevus Syndrome

Ghosh, Dutta, Agarwal, and Chhajer

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TABLE OF CONTENTS September/October 2015 • Volume 13 • Issue 5

EDITORIAL

The 6-Second Specialists: Medicine at Ellis Island Immigration Station ................................................... 341

Eve J. Lowenstein, MD, PhD; Meryl Rosen, MD; Henry Heaton, MD; Daniel Siegel, MD, MPH; Kanwaljit Brar, MD; Sharon Glick, MS, MD

COMMENTARIES

Western Blotting of Human Sera––Can It Help Diagnose Bed Bug Bites? .................................................. 345

Jerome Goddard, PhD; Amanda C. Tardo, MS; Monica E. Embers, PhD

Aquagenic Acrokeratoderma––New Insights .............................................................................................. 347

Georgi Tchernev, MD; Uwe Wollina, MD

ORIGINAL CONTRIBUTIONS

Topical Tacrolimus and Oral Dapsone Combination Regimen in Lichen Planus Pigmentosus .................... 351

Prashant Verma, MD; Deepika Pandhi, MD

Onychogryphosis: A Report of Ten Cases .................................................................................................. 355

Patricia Chang, MD; Tyson Meaux

REVIEW What Can Be Expected on Irradiated Skin? A Dermatologic Focus on Acute and Chronic Radiotherapeutic Effects, Treatment, and Benign Dermatoses .................................................................. 361

B:11”

T:10.75”

S:10.25”

Edwin Cuperus, MD; Miriam Albregts, MD; Johan Toonstra, MD, PhD

SELF ASSESSMENT EXAMINATION ........................................................................................................... 375

W. Clark Lambert, MD, PhD

Departments Perils of Dermatopathology

W. Clark Lambert, MD, PhD, Section Editor

Cancer From the Cut: How Surgical Flaps Can Move Incidental Tumors to Different Locations .................. 377

Ann M. John, BA; Parmvir Singh, BS; Divya Sharma, BA; W. Clark Lambert, MD, PhD

New To The Clinic

Noah Scheinfeld, MD, JD, Section Editor

Apremilast (Otezla) ................................................................................................................................... 381

Noah Scheinfeld, MD, JD; William Abramovits, MD; Aditya K. Gupta, MD, PhD

The Heymann File

Warren R. Heymann, MD, Section Editor

The Association of Bullous Pemphigoid and Neurologic Disorders: A Real Braintease .............................. 386

Warren R. Heymann, MD

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

Dermatology in a Bygone Era .................................................................................................................... 389

Eve J. Lowenstein, MD, PhD

337


TABLE OF CONTENTS September/October 2015 2015 •• Volume Volume 13 13 •• Issue Issue 55 September/October

Port Wine Nevus Treated With Kromayer Light .......................................................................................... 393

Mark Bernhardt, MD

case studies

Vesna Petronic-Rosic, MD, MSc, Section Editor

Eruptive Syringocystadenoma Papilliferum, Keratoacanthoma, and Verruca Vulgaris in a Keratinocytic Epidermal Nevus on the Leg ............................................................................................... 395

Jonathan D. Pewitt, MD; Erin K. Burns, BS; Lawrence S. Chan, MD

Linear Nevoid Epidermolytic Hyperkeratosis Localized to the Sole............................................................. 399

Deepshikha Khanna, MD; Payal Chakravarty, DDVL; Prasenjit Das, MD; Pankaj Bansal, MD

Paradoxical Induction of Psoriasis and Lichen Planus by Tumor Necrosis Factor-α Inhibitors ................... 403

Sonoa Au, MD; Claudia Hernandez, MD

Adult-Onset Blue Rubber Bleb Nevus Syndrome........................................................................................ 406

Sudip Kumar Ghosh, MD, DNB; Dhurjati Prasad Dutta, MD; Megha Agarwal, MBBS; Sourav Chhajer, MBBS

CORRESPONDENCE

Snejina Vassileva, MD, PhD, Section Editor

Comment on Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergilllus niger..... 410

Nardo Zaias, MD

Response to “Comment on Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger”...................................................................................................................................... 410

Carlos Garcia, MD; Roberto Arenas, MD

Patient Positioning During Dermatologic Surgery for Optimal Wound Closure............................................ 411

Suneel Chilukuri, MD; Khari Bridges, MD; Dominic Nguyen, BS; Sailesh Konda, MD

An Epidemiologic Study on the Relationship Between Hand Dermatitis and Antioxidants........................... 412

Yi Chun Lai, MD; Yik Weng Yew, MD

RETRACTION

Notice of Retraction: Duplicate Publication in Sehgal VN, Chatterjee K, Chaudhuri A, Chatterjee G. “Acquired/post-traumatic ectopic nail: onychoheterotopia.” Skinmed. 2014;12:306–307......................... 416

338


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September/October 2015

Volume 13 • Issue 5

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

W. Clark Lambert, MD, PhD

Larry E. Millikan, MD

Jennifer L. Parish, MD

Dallas, TX

Newark, NJ

Meridian, MS

Philadelphia, PA

Aditya K. Gupta, MD, PhD, FRCPC

Vesna Petronic-Rosic, MD, MSc

Marcia Ramos-e-Silva, MD, PhD

London, Ontario, Canada

Chicago, IL

Rio de Janeiro, Brazil

EDITORIAL BOARD Mohamed Amer, MD Cairo, Egypt

Howard A. Epstein, PhD Philadelphia, PA

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Riccarda Serri, MD Milan, Italy

Robert L. Baran, MD Cannes, France

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

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

Charles Steffen, MD Oceanside, CA

George M. Martin, MD Kihei, HI

Alexander J. Stratigos, MD Athens, Greece

Marc S. Micozzi, MD, PhD Rockport, MA

James S. Studdiford III, MD Philadelphia, PA

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

Robert J. Thomsen, MD Los Alamos, NM

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

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

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

Michael H. Gold, MD Nashville, TN Orin M. Goldblum, MD Indianapolis, IN Lowell A. Goldsmith, MD, MPH Chapel Hill, NC Seung-Kyung Hann, MD, PhD Seoul, Korea

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

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

Art Papier, MD Rochester, NY

Daniel Wallach, MD Paris, France

Johannes Ring, MD, DPhil Munich, Germany

Michael A. Waugh, MB, FRCP Leeds, UK

María Daniela Hermida, MD Buenos Aires, Argentina

Roy S. Rogers III, MD Rochester, MN

Wm. Philip Werschler, MD Spokane, WA

Warren R. Heymann, MD Camden, NJ

Donald Rudikoff, MD New York, NY

Joseph A. Witkowski, MD Philadelphia, PA

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Robert I. Rudolph, MD Wyomissing, PA

Ronni Wolf, MD Rechovot, Israel

Camila K. Janniger, MD Englewood, NJ

Vincenzo Ruocco, MD Naples, Italy

Jianzhong Zhang, MD Beijing, China

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Noah Scheinfeld, MD, JD New York, NY

Matthew J. Zirwas, MD Columbus, Ohio

Andrew P. Lazar, MD Washington, DC

Virendra N. Sehgal, MD Delhi, India

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September/October 2015

Volume 13 • Issue 5

Editorial

The 6-Second Specialists: Medicine at Ellis Island Immigration Station Eve J. Lowenstein, MD, PhD;1 Meryl Rosen, MD;1 Henry Heaton, MD;1 Daniel Siegel, MD, MPH;1 Kanwaljit Brar, MD;2 Sharon Glick, MS, MD1 “Give me your tired, your poor, your huddled masses yearning to breathe free.”––Emma Lazarus, “The New Colossus,” 1883 “Give me your tired and poor––Yes! Your sick or feeble-minded––No!”

A

merica in the late 19th century was looking for ablebodied immigrants to work, develop the country, and help it achieve its potential. Ellis Island, called the “Island of Hope, Island of Tears,” served as a doorway into America, being the largest American immigration station in what is to date the largest human migration in history. More than 40% of Americans can trace their family origins through Ellis Island.1 Today, Ellis Island is a national park that is open to the public. Part of the island was a hospital complex, which served to treat those who failed the immigration screening process. It was previously closed to the public until recently. Efforts by the Save Ellis Island Foundation resulted in the rehabilitation of the decaying hospital and in October of 2014 the immigrant hospital opened for private tours. During the tours, visitors have the opportunity to view the artwork of French artist JR, who utilized historic photographs of patients and medical personnel for his wall art. A group of dermatologists and trainees recently had the opportunity to visit the hospital and tour the facilities. With the help of a very informative tour guide, the group learned a great deal about the importance of the immigrant hospital and its practices, which still have relevance today. Background Ellis Island served as a point for legal and medical inspection primarily of immigrants traveling third class or steerage. Those who entered America with greater means were screened on board the ships in the harbor and not detained on Ellis Island, as they were deemed less of a health risk and less of a risk of becoming dependent on the state.2 In the years of its operation between 1892–1954, the Ellis Island immigration station screened more than 12 million immigrants en-

tering the United States, of which more than 95% passed through and were accepted for absorption.2,3 The screening process began with all immigrants answering questions in the ships manifest: • Do you have a sponsor? • Are you a prostitute? • Are you a polygamist? • Are you an anarchist? • Are you a criminal? Of course, there was no way to substantiate the answers given. Still, any hesitation, doubts, or discrepancies found in the responses given would result in the immigrant being brought before a board of inquiry for further questioning.1 The Screening Process Upon arrival to the main facility on Ellis Island, immigrants, including men, women, and children, filed into the great hall in single-file fashion. Under the direct observation of multiple physicians, they were required to make two right-angle turns and climb stairs, which served to highlight any difficulties in musculoskeletal coordination. This also ensured that light would hit both sides of their faces.1 The medical doctors observing the immigrants were commissioned, uniformed officers from the U.S. Public Health Service who were assigned with the task of inspecting thousands of immigrants daily.2 Called the “6-second specialists,” the doctors at Ellis Island screened for 60 infirmities of the body and mind that would prevent an immigrant from functioning in and contributing to the New World.

From SUNY Health Science Center at Brooklyn, Brooklyn, NY;1 and Department of Pediatrics, National Jewish Hospital, Denver, CO2 Address for Correspondence: Eve J. Lowenstein, MD, PhD, South Nassau Dermatology, 258 Merrick Road, Oceanside, NY 11572 • E-mail: evlow13@yahoo.com

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September/October 2015

Editorial

Among these were numerous contagious diseases they wished to keep from entering the country. Immigrants were watched as they entered the facility for physical difficulties: a limp, a swollen eye, a cough, a pregnant belly, or a rash. There were also the indirect clues and cues: a woolen hat worn in the summer to cover a scalp infection, a coat draped over an artificial limb, or an older child carried by a parent masking his inability to walk.4 If any clinical clues were identified, a code was chalked on that person’s garment to mark him or her for possible detention or rejection.

were used as epilation agents, followed by manual epilation of any of the hairs that remained. A linen cap was worn for the duration of the treatment. A “sweat cap test” was used to confirm cure, whereby a rubber cap, designed to exclude air from the scalp and draw any remaining organisms towards the surface, was worn by the patient for 1 week. At the end of the week, microscopic examination of the scalp was performed, and the patient was considered cured only after three rounds of sweat cap testing failed to reveal any organisms.12,13

Irrespective of their final destination, the diseased immigrants were immediately offered medical care in the adjacent hospital facility located on islands two and three of the Ellis Island complex.1 Cost of care was roughly two dollars per day, or roughly 50 dollars in today’s currency.1,5 For those who could not afford the cost, assistance would sometimes be offered through such charity organizations as the Hebrew Immigrant Aid Society.6

The Ellis Island facilities served as a teaching hospital with opportunities for medical students and staff alike to study rare and exotic diseases (Figure 1). The amenities included an autopsy theater, complete with seating for medical students and visiting physicians to observe rarely seen pathology, and an electrically powered mortuary refrigeration unit, capable of holding up to eight cadavers (Figures 2 and 3). Ellis Island even became a site for visiting physicians to see and learn about medical disease.1

Screening for mental competence was performed using a system implemented on Ellis Island by Henry H. Goddard, a prominent American psychologist and researcher during the early 20th century. Goddard, following the example of the French psychologist Alfred Binet, documented the mental capacity of his patients on Ellis Island in legal terms, which we would find offensive today. Moron, imbecile, and idiot were used to distinguish between different classes of intellectual limitation.7 An asylum on island number two housed mentally ill/debilitated patients awaiting evaluation or deportation back to their country of origin. Physicians could certify an immigrant as “mandatorily excludable,” for whom there was no appeal, and deportation would be the consequence. Examples of conditions that were mandatorily excludable include epilepsy, “psychopathic personality,” schizophrenia, and even homosexuality.8

The Hospital Design for Clean Air and No Miasma The architecture of the building represents medical beliefs of the 19th century, long since abandoned. It was designed by proponents of Nurse Florence Nightingale’s theories of keeping air clean and miasma-free.14 Miasma, that “unhealthy fog,” was thought to have a magical ability to transmit illness. Curved corners in the ceilings of the hospital wards were used to prevent miasma from becoming trapped in the rooms, and the 18 wards of the infectious disease hospital were arranged in a staggered fashion off of the main hallway such that it was difficult for air to travel from one ward to enter the next.

The Hospital on Ellis Island The hospital on Ellis Island, open from 1900–1951, was a 750bed facility with a separate pavilion built to house patients with contagious diseases and prevent spread. The infectious disease wards on the south side of the island housed and separated patients with various disorders, including measles, cholera, tuberculosis (two wards), trachoma (two wards), diphtheria, mumps, favus, and scarlet fever. Ironically, patients who were isolated had the best views of Lady Liberty. The treatment of these then-common conditions was quite different in the days of the Ellis Island Contagious Disease Hospital. Favus, for example, required 3 to 6 months of an intensive treatment regimen involving technology that was relatively new at the time. After the patient’s hair was cut short, roentgen rays SKINmed. 2015;13:341–343

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Figure 1. Window mural by artist JR, showing children with towels on their heads during treatment of favus. Medicine at Ellis Island Immigration Station


September/October 2015

Editorial Patients in the tuberculosis ward were separated from patients in the general hospital, and immigrants on the island by more than 400 feet.9,14 Additionally, sterilization measures were in place to prevent the spread of diseases, including a mattress autoclave and an expansive electrically powered washing facility that utilized steam and boiling water. Perhaps, these early beliefs are the origins for the isolation and infection control strategies employed by hospitals today. Reflections

Figure 2. Autopsy suite with mortuary refrigerators (left side), viewed from the gallery.

Interestingly, on Ellis Island, the closer one was to Lady Liberty, the worse his or her chances for actualizing the American dream. Today, one can stand in the now desolate and dilapidated infectious disease ward and imagine lying in a bed, looking out over the water in somber longing at Lady Liberty (Figure 4)––too sick to live but too sick to be admitted. So close and yet so far! References 1 Save Ellis Island Tour Guide. “Hard Hat Tour of Ellis Island’s Contagious Disease Hospital.” Save Ellis Island, Ellis Island, NY. December 17, 2014. 2 Yew E. Medical inspection of immigrants at Ellis Island, 1821–1924. Bull NY Acad Med. 1980;56:488–510. 3 Parascandola J. Doctors at the gate: PHS at Ellis Island. Public Health Rep. 1980;113:83–86. 4 Conway L. Forgotten Ellis Island: The Extraordinary Story of America’s Immigrant Hospital. New York, NY: eHarperCollins; 2007;81–82. 5 Inflation calculator. http://www.usinflationcalculator. com. Accessed December 21, 2014. 6 Wischnitzer M. Visas to Freedom: The History of HIAS. Cleveland, OH: World Publishing Company; 1956. 7 Goddard HH. Mental Tests and the immigrant. J Delinquency. 1977;2:243–277.

Figure 3. Wall mural by artist JR in the medical treatment room, showing surgeons at the ready.

8 Coan PM. Ellis Island Interviews: In Their Own Words. New York, NY: Barnes & Noble Publishing; 1997. 9 Watchorn R. Outlook Magazine, Cited in Harlan Unrau, 1984. Historic Resource Study, vol. 2, New York, NY: National Park Service; 1905;2:239–243, 639–649. 10 Conway L. Forgotten Ellis Island. New York, NY: HarperCollins Publishers; 2007. 11 Watchorn R. Annual Report of the Commissioner General of Immigration. Reports of the Department of Commerce and Labor, 2007. Washington; 1907. 12 Fox H. Treatment of ringworm of the scalp by the roentgen rays. Arch Dermatol Syphilol. 1921;9:13–37. 13 Proceedings of the Pittsburgh Dermatological Society Annual Meeting, April 27, 1922. J.G. Burke, MD, presiding. Arch Dermatol Syphilol 1922;6:252. 14 Ellis Island, Contagious Disease Hospital Kitchen. U.S. Immigration Station. Historic American Buildings Survey NY-6086-S. http://lcweb2.loc.gov/master/pnp/ habshaer/ny/ny2300/ny2376/data/ny2376data.pdf. Accessed February 15, 2015.

Figure 4. View of Lady Liberty from a window in the hospital wing for infectious patients in the isolation wing. SKINmed. 2015;13:341–343

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Medicine at Ellis Island Immigration Station


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刀䔀䜀䤀匀吀䔀刀 一伀圀 戀礀 瘀椀猀椀椀渀最 䄀䴀䐀猀礀洀⸀挀漀洀 


September/October 2015

Volume 13 • Issue 5

COMMENTARY

Western Blotting of Human Sera––Can It Help Diagnose Bed Bug Bites? Jerome Goddard, PhD;1 Amanda C. Tardo, MS;2 Monica E. Embers, PhD2

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eports of bed bug (Cimex lectularius) infestations and bite reactions have dramatically increased over the past decade and should be included in the differential diagnosis in cases of unexplained insect bites.1 Proteins in bed bug saliva are readily recognized by the human immune system, leading to various humoral and cellular responses, including production of cytokines/chemokines.2 Importance of Insect Bite Lesion Identification

Cutaneous reactions to bed bug bites were once considered little more than a nuisance; however, we recently showed that bed bugs may sometimes cause severe cutaneous vasculitis similar to Churg-Strauss syndrome.3 Even though the sialome of bed bugs has been published,4 there are almost no studies attempting to link particular salivary proteins to corresponding cutaneous reactions. In addition, lawsuits may be filed against commercial or rental properties for alleged negligence or failure to follow a “standard of care or best management practice” for bed bug prevention or control.5 In such litigation, plaintiffs often claim that they have been bitten by bed bugs even if no bugs were ever seen or collected. Physicians and other healthcare providers may sometimes get involved in these cases and be asked to testify as to whether bites and eruptions are caused by bed bugs. The problem is, no one can accurately determine whether a particular insect bite lesion is caused by bed bugs, or any other arthropod for that matter. Predaceous insects may bite defensively, leading to immediate pain; however, blood-feeding insects usually produce painless, almost imperceptible bites, which do not become apparent until hours or days later, when the patient’s own sensitivity may or may not lead to itching and other manifestations. In the case of bed bugs, as many as half of people bitten

develop no reaction at all,6 while the others may develop a range of reactions from itchy macules (or maculopapules) to large urticarial wheals, indurations, or bullous lesions.7 There may be bite patterns that are suggestive of particular arthropods. For example, chigger or flea bites are often multiple, occurring on the ankles or legs; spider or tick bites are often singular, occurring on the arms or legs; and black flies often bite in great numbers around the head or at the posterior cervical region at the base of the hair. Bed bugs are anecdotally reported to bite in a line or in groups of three, but only one or a few bites are possible in light infestations. If, for example, a patient has a few bed bug bites on the ankle, how would a healthcare provider know if they are from a bed bug, chigger, or any other arthropod? They all look the same (Figure 1). From a histopathologic perspective, there is nothing pathognomonic about these lesions, and most fall into the generic diagnosis of “probable arthropod assault.” Furthermore, these lesions can be confounded by scratching and resulting excoriation of the skin surface. Considering the widespread variability in bite reactions and biting patterns of arthropods, healthcare providers might/should––at least at this time––avoid proclaiming mysterious pruritic lesions as “bed bug bites.” Developing a Test for Bed Bug Bites New information is needed to help differentiate bed bug bite reactions from other reactions, especially those with an allergic component. In a recent study in our laboratory, we showed that Western blot assays (WBAs) might help identify patients with sensitivity to bed bug bites. In the experiment, Western blotting was conducted twice with the same six human sera, all obtained via university institutional review board study #12-343, including two patients with known bed bug bite reactivity, two frequently bitten with no bite reactivity, and two controls (persons never bitten by bed bugs). For

From the Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, MS;1 and the Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, Covington, LA2 Address for Correspondence: Jerome Goddard, PhD, Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, 100 Twelve Lane, Clay Lyle Entomology Building, Mississippi State, MS 39762 • E-mail: jgoddard@entomology.msstate.edu

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COMMENTARY

antigen, salivary glands of 100-200 C lectularius were dissected and removed to produce a crude extract as previously reported.8 The enzyme-linked immunosorbent assays were performed in 96-Well Costar high-binding EIA plates (Sigma-Aldrich, St. Louis, MO). In the first run, 17 µg of salivary gland extract (SGE) was added to each well and sera diluted 1:100. In the second run, 30 µg of SGE was used and sera diluted 1:50. Blots were developed with goat antihuman IgG (H+L) at 1:1000 dilution.

Figure 1. Known bed bug bites (left) and known chigger bites (right). (Photos courtesy of Kristine T. Edwards and Audrey Sheridan, both at Mississippi State University, Starkville, MS.)

The best sensitivity in our WBAs was obtained when we used 30 µg of SGE antigen (run #2) (Figure 2). All samples were run on the same gel with the same SGE preparation, therefore differences in size were likely legitimate. Both WBA runs revealed the same bands in approximately the same places for patients 3 and 6, whereas immunoreactive bands at ~35 kD and ~75 kD were seen in patient 1. All of these three patients had repeated exposure to bed bug biting, but only patients 1 and 3 routinely develop cutaneous reactions when bitten. Interestingly, patient 6, who is frequently bitten without reaction, showed the same ~37 kD band. Patient 1, who had the most striking cutaneous reactions, exhibited reactivity to two antigens. The 75 kD band in patient 1 seems unique among the others and could perhaps be diagnostic for persons with intense cutaneous reactions. No bands were observed in the two sera from persons never bitten (controls, patients 4 and 5).

Figure 2. Western blot analysis of human sera using bed bug salivary gland proteins. Patients 1 and 3 displayed cutaneous reactions when bitten by bed bugs, patients 2 and 6 have been bitten frequently but never show skin reactions, and patients 4 and 5 have never knowingly been bitten by bed bugs.

References

Conclusions This work provides the first results of western blot profiles of people with varying degrees of cutaneous reactions to bed bug bites and reveals possible unique immunoreactive bands for further analysis. If this work can be cost-effectively confirmed by other laboratories, it could be a valuable tool for clinical diagnosis as well as for cases in the legal profession (lawsuits). Follow-up studies in our laboratory are underway to: (1) identify antigenic targets, and (2) develop a sensitive and specific enzyme-linked immunosorbent assay for detection of bed bug bite responses. Soon, perhaps, new diagnostic tests will help demystify arthropod bite reactions. Acknowledgments Mark Feldlaufer (USDA, Beltsville, MD), Kristine Edwards (Mississippi State University, Starkville, MS), Andrea VarelaStokes (MSU, Starkville, MS), and Mr Frank Meek (Orkin Inc, Atlanta, GA), provided clinical samples for this study. Dr Harold Harlan (Crownsville, MD) provided the live bed bugs. This contribution has been approved for publication as a journal article No. J-12523 of the Mississippi Agriculture and Forestry Experiment Station, Mississippi State University. SKINmed. 2015;13:345–346

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1 Goddard J, de Shazo RD. Bed bugs (Cimex lectularius) and clinical consequences of their bites. JAMA. 2009;301:1358–1366. 2 Goddard J, Hasenkampf N, Edwards KT, de Shazo R, Embers ME. Bed bug saliva causes release of monocytic inflammatory mediators: plausible cause of cutaneous bite reactions. Int Arch Allergy Immunol. 2013;161:127– 130. 3 de Shazo RD, Feldlaufer MF, Mihm MC, Goddard J. Bullous reactions to bed bug bites reflect cutaneous vasculitis. Am J Med. 2012;125:688–694. 4 Francischetti IM, Calvo E, Andersen JF, et al. Insight into the sialome of the bed bug, Cimex lectularius. J Proteome Res. 2010;9:3820–3831. 5 USATODAY. Woman sues Catskills resort for $20M over bedbug attacks: USA Today online. http://www. usatoday.com/travel/hotels/2006-03-08-bedbugscatskills_x.htm March 8, 2006. 6 Goddard J, de Shazo RD. Multiple feeding by the common bed bug, Cimex lectularius, without sensitization. Midsouth Entomol. 2009;2:90–92. 7 Reinhardt K, Kempke RA, Naylor RA, Siva-Jothy MT. Sensitivity to bites by the bedbug, Cimex lectularius. Med Vet Entomol. 2009;23:163–166. 8 Goddard J, Edwards KT. Effects of bed bug saliva on human skin. JAMA Dermatol. 2013;149:372–373.

Western Blotting of Human Sera


September/October 2015

Volume 13 • Issue 5

COMMENTARY

Aquagenic Acrokeratoderma––New Insights Georgi Tchernev, MD;1 Uwe Wollina, MD2

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quagenic keratoderma (AK) is a rare disorder. Of historic interest, patients with a strikingly similar cutaneous condition, hereditary acrokeratoderma, were first reported by researchers in 1973.1 Subsequently, other reports appeared in the literature describing a morphologically similar yet distinct condition known by several names, including aquagenic wrinkling of the palms (AWP), acquired aquagenic palmoplantar keratoderma (PPK), transient reactive papulotranslucent acrokeratoderma, or aquagenic syringeal acrokeratoderma.2–4 PPK comprises a heterogeneous group of hereditary skin disorders characterized by epidermal thickening with predilection of the palms and soles.5 The clinical characteristics of AK are different and include diffuse palmoplantar-located swollen stratum corneum, which distinctively exhibits a whitish spongy appearance upon exposure to water (Figure).5,6 Cystic Fibrosis and AK The majority of reported cases of AK have been associated with cystic fibrosis (CF).6,7 CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes for a protein involved in transepithelial ion transport.6,7 In 2005, investigators8 reported two patients with CF who exhibited homozygosity for the ΔF508 CFTR mutation, suggesting that this particular mutation may also be a predisposing factor for AK. It has been proposed that AK is caused by an increase in the water-binding capacity of keratins mediated by high salt concentrations in the epidermis as seen in CF patients.7 The high sweat salt concentrations as in CF-associated AK contributes to an increased water-holding capacity of the horny layer.6,7,9 An increase in natural moisturizing factor would result in higher water-holding capacity of human epidermis but would require time for synthesis and transport. Aquagenic wrinkling of the palms af-

ter exposure to water occurs with much shorter water exposures in patients with CF compared with AK patients without CF.5,7,8 An alternative proposed pathogenic mechanism in CF patients seems to be the abnormal regulation of cell membrane water channels, such as aquaporin 3, by CFTR.7 Currently, it is difficult to establish a link between healthy salty sweaters and CTFR mutations.10 Ivacaftor, a pharmacologic potentiator of CFTR function, was recently approved for treatment in patients with CF who carry the G551D CFTR mutation. CFTR-directed therapy had an effect on aquagenic wrinkling in a patient with CF, indicating an association of this phenomenon with CFTR dysfunction.11 AQP5 and Ca2+-Permeable Transient Receptor Potential Channel Proteins AK is associated with aberrant and broadened staining of AQP5 in the sweat glands.6,12 After exome sequencing, missense mutations were identified in AQP5, encoding water channel protein aquaporin 5 (AQP5).12 AQP5 in plasma membranes of sweat glands is essential for secretion, providing potential insight into mechanisms underlying mammalian thermoregulation, tactile sensitivity, and the pathophysiology of hyperhidrosis. The protein was localized in plasma membranes of clear cells in the secretory coils, suggesting that it plays a role in producing the primary sweat fluid.13 Remarkable progress has been made in characterization of transient receptor potential channel vanilloids (TRPVs). TRPV4 and AQP5 have both been expressed in eccrine sweat glands and keratinocytes.12–14 TRPV4 activation is necessary for skin barrier recovery. TRVP4 is critical for the prevention of excess dehydration of epidermal keratinocytes after wounding. It is reasonable to speculate that palmoplantar hyperhidrosis and hyperkeratosis in AK are, at least partly, caused by the gain-of-function effect of the AQP5Asn123Tyr/TRPV4 complex.5

From the Policlinic for Dermatology and Venerology, Saint Kliment Ohridski University, University Hospital Lozenetz, Sofia, Bulgaria;1 and the Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany2 Address for Correspondence: Uwe Wollina, MD, Academic Teaching Hospital Dresden-Friedrichstadt, Department of Dermatology and Allergology, Friedrichstrasse 41, 01067 Dresden, Germany • E-mail: wollina-uw@khdf.de

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COMMENTARY Hyperhidrosis and the Autonomic Nervous System The location of wrinkling in patients with AK is limited to the areas positive for iodine-starch test after water exposure, which suggests that AK is etiologically related to hyperhidrosis.6 The water immersion test is used to assess small sympathetic nerve function. It has been demonstrated that fingertip skin wrinkling is related to digit pulp vasoconstriction.19 Histologic examination in some studies has revealed hyperplastic and papillated eccrine glandular epithelium with an enlarged diameter of eccrine coils.16 Immunohistochemically, AQP5 was present exclusively in the dark cells of sweat glands of healthy donors. An aberrant AQP5 staining, extending to the clear cells, was found in a patient with AK.16 The hyperplastic glandular epithelium and aberrant AQP5 staining in the patient’s sweat glands suggest that AK is also related to abnormal sweating.5,16

Figure. Whitish spongy appearance of palmar horny layer after exposure to water restricted to an area of focal hyperhidrosis.

Exposure of salivary gland cells and acini to hypotonicity has been shown to elicit an increase in cell volume and activation of regulatory volume decrease (RVD).6 Hypotonicity also activates Ca2+ entry, which is required for subsequent RVD. Endogenous TRPV4 has been detected in cells and in the apical region of acini along AQP5.15,16 Recent investigations indicate that (1) activation of TRPV4 by hypotonicity depends on AQP5, not on cell swelling per se; and (2) TRPV4 and AQP5 concertedly control regulatory volume decrease.17 These data suggest a potentially important role for TRPV4 in salivary gland function. Water immersion may be the major exogenous factor of higher stratum corneum water binding; furthermore, swelling of the stratum corneum could lead to sweat retention in the whole epidermis.6,18 The stratum corneum water-binding capacity is directly related to the external osmotic pressure.18 TVRT-1 is an osmosensitive receptor. Its sensitivity is further enhanced by temperature and protons.6,18 From clinical experience, higher temperature during water immersion exerts a stronger AK response. Higher salt concentrations in sweat increase thermosensitivity of the receptor. Hyperosmolarity of sweat and increased water temperature lead to increased Ca2+ influx and swelling of cells.6,18 Aberrant expression of AQP5 and disturbed interaction with the TRPV4 receptor are other pathways likely to lead to AK.5,16 Currently, no data are available to support a connection between the three components: AQP5, the disturbed interaction with TRPV4, and the various mutations of the CFTR gene. This suggests that different pathways may cause AK. SKINmed. 2015;13:347–349

Hyperhidrosis shows an aberrant expression of AQP5. The degree to which this abnormal expression and the different localization of AQP5 are paralleled by a disturbed regulation of the interrelation with VRL-2, found additionally on sympathetic and parasympathetic nerve fibers, remains unclear; however, sympathetic overactivity is seen as a key factor in the pathogenesis of hyperhidrosis.6 Drug-Induced AK Rofecoxib is a selective cyclooxygenase 2 (COX-2) inhibitor that has been shown to increase sodium reabsorption in the kidney via the effects on prostaglandin E2 and renal vasculature.20 The COX-2 protein is also expressed by keratinocytes and plays a role in keratinocyte differentiation. Rofecoxib may cause increased sodium reabsorption in the skin, as it does in the kidney. This may stimulate keratin water-binding capacity and cause exaggerated aquagenic wrinkling of the skin, as it occurs in CF.20 Conclusions Currently, the pathogenesis of AK remains unclear. Various research efforts are attempting to pinpoint molecular pathogenic mechanisms. It is probable that AK represents a spectrum of diseases with a heterogeneous pathophysiology. Interestingly, AK has never been observed in one of the various channelopathies related to TRVPs. References

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1 Onwukwe MF, Mihm MC Jr, Toda K. Hereditary papulotranslucent acrokeratoderma. A new variant of familial punctate keratoderma? Arch Dermatol. 1973;108:108– 110.

Aquagenic Acrokeratoderma––New Insights


September/October 2015

COMMENTARY

2 Yan AC, Aasi SZ, Alms WJ, et al. Aquagenic palmoplantar keratoderma. J Am Acad Dermatol. 2001;44:696–699. 3 English JC 3rd, McCollough ML. Transient reactive papulotranslucent acrokeratoderma. J Am Acad Dermatol. 1996;34:686–687. 4 MacCormack MA, Wiss K, Malhotra R. Aquagenic syringeal acrokeratoderma: report of two teenage cases. J Am Acad Dermatol. 2001;45:124–126.

12 Blaydon DC, Lind LK, Plagnol V, et al. Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am J Hum Genet. 2013;93:330–335. 13 Nejsum LN, Kwon TH, Jensen UB, et al. Functional requirement of aquaporin-5 in plasma membranes of sweat glands. Proc Natl Acad Sci USA. 2002;99:511–516.

5 Cao X, Yin J, Wang H, et al. Mutations in AQP5, encoding aquaporin 5, causes palmoplantar keratoderma bothia type. J Invest Dermatol. 2014;134:284–287.

14 Kida N, Sokabe T, Kashio M, et al. Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes. Pflügers Arch. 2012;463:715–725.

6 Tchernev G, Semkova K, Cardoso JC, et al. Aquagenic keratoderma. Two new case reports and a new hypothesis. Indian Dermatol Online J. 2014;5:30–33.

15 Inoue R, Sohara E, Rai T, et al. Immunolocalization and translocation of aquaporin-5 water channel in sweat glands. J Dermatol Sci. 2013;70:26–33.

7 Syed Z, Wanner M, Ibrahimi OA. Aquagenic wrinkling of the palms: a case report and literature review. Dermatol Online J. 2010;16:7.

16 Kabashima K, Shimauchi T, Kobayashi M, et al. Aberrant aquaporin 5 expression in the sweat gland in aquagenic wrinkling of the palms. J Am Acad Dermatol. 2008;59:S28–S32.

8 Katz KA, Yan AC, Turner ML. Aquagenic wrinkling of the palms in patients with cystic fibrosis homozygous for the delta F508 CFTR mutation. Arch Dermatol. 2005;141:621–624. 9 Bouwstra JA, Groenink HW, Kempenaar JA, et al. Water distribution and natural moisturizer factor content in human skin equivalents are regulated by environmental relative humidity. J Invest Dermatol. 2008;128:378–388.

17 Liu X, Bandyopadhyay BC, Nakamoto T, et al. A role for AQP5 in activation of TRPV4 by hypotonicity: concerted involvement of AQP5 and TRPV4 in regulation of cell volume recovery. J Biol Chem. 2006;281:15485–15495. 18 Nishihara E, Hiyama TY, Noda M. Osmosensitivity of transient receptor potential vanilloid 1 is synergistically enhanced by distinct activating stimuli such as temperature and protons. PLoS One. 2011;6:e22246.

10 Brown MB, Haack KK, Pollack BP, et al. Low abundance of sweat duct Cl-channel CFTR in both healthy and cystic fibrosis athletes with exceptionally salty sweat during exercise. Am J Physiol Regul Integr Comp Physiol. 2011;300:R605–R615.

19 Hsieh CH, Huang KF, LiLiang PC, et al. Paradoxical response to water immersion in replanted fingers. Clin Auton Res. 2006;16:223–227.

11 Grasemann H, Ratjen F, Solomon M. Aquagenic wrinkling of the palms in a patient with cystic fibrosis. N Engl J Med. 2013;369:2362–2363.

20 Carder KR, Weston WL. Rofecoxib-induced instant aquagenic wrinkling of the palms. Pediatr Dermatol. 2002;19:353–355.

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September/October 2015

Volume 13 • Issue 5

Original contribution

Topical Tacrolimus and Oral Dapsone Combination Regimen in Lichen Planus Pigmentosus Prashant Verma, MD; Deepika Pandhi, MD Abstract Lichen planus pigmentosus is a well-recognized variant of lichen planus; however, its etiopathogenesis is still unclear. An effective and safe treatment for lichen planus pigmentosus is needed; therefore, the authors examined a series of five patients with lichen planus pigmentosus with successful response to a combination of topical tacrolimus and oral dapsone. (SKINmed. 2015;13:351–354)

L

ichen planus pigmentosus causes significant cosmetic abrasion. It is a macular variant of lichen planus with a largely elusive pathogenesis. There is a possible immunopathological correlation between lichen planus and lichen planus pigmentosus.1 Many treatment modalities are currently available for lichen planus; however, there is a dearth of effective treatment options for lichen planus pigmentosus. The efficacy of dapsone has been well-documented in studies of lichen planus.2–7 Topical tacrolimus has recently shown promising results in lichen planus pigmentosus. Both drugs have different mechanisms of action and hence may produce a synergistic effect; therefore, using a combination of dapsone and tacrolimus in patients with lichen planus pigmentosus was investigated. Case Report Five patients with a clinico-histopathologically compatible diagnosis of lichen planus pigmentosus (Table) were treated with a combination of topical 0.1 % tacrolimus ointment twice daily and oral dapsone 100 mg once daily. None of the patients had accompanying classical lichen planus lesions. All of the patients had an insidious, progressive disease at the time of presentation. Complete blood cell counts, hemoglobin content, and liver function monitored at 2-week intervals were found to be within normal limits. Glucose-6-phosphate dehydrogenase deficiency was ruled out in all five cases before initiating dapsone. Pretreat-

ment photographs were obtained and the combination regimen was given for 4 months. Repeat photographs were taken at 4 months. The progression of the lesions ceased in all cases and a discernible reduction in pigmentation was seen after comparing pretreatment (Figures 1A and 2A) and post-treatment photographs (Figures 1B and 2B). Discussion Lichen planus pigmentosus, a variant of lichen planus, is characterized by brown to steel blue–colored ill-defined irregular macules of varying sizes. Diffuse, followed by reticular, blotchy, linear, and perifollicular patterns, are well-documented, in descending order of frequency.1 The face, upper extremities, abdomen, and upper back are the most frequently afflicted sites.1 In the current report, face and neck involvement was seen in all five patients. Four of the five patients had blotchy pigmentation, while one had a diffuse pattern of pigmentation. Occasionally, oral mucosal lesions were encountered.1,8 Mucosal involvement was not seen. A possible correlation of immunopathogensis has been suggested between lichen planus and lichen planus pigmentosus.1 Its differential diagnosis include erythema dyschromicum perstans, pigmented cosmetic dermatitis, fixed-drug eruption, and idiopathic eruptive macular pigmentation.9 Erythema dyschromicum perstans is characterized by a marginal string of erythema, which was not the case in the illustrated cases. Pigmented cos-

From the University College of Medical Sciences & Associated Guru Teg Bahadur Hospital, University of Delhi, Delhi, India Address for Correspondence: Prashant Verma, MD, Department of Dermatology, Vardhman Mahavir Medical College & Safdarjang Hospital, New Delhi, India • E-mail: drprashant_derma@yahoo.co.in

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ORIGINAL CONTRIBUTION

Table. Lichen Planus Pigmentosus: Clinico-Laboratory Profile of Study Patients

Morphology/Site

Hepatitis B Surface Antigen/ Anti-Hepatitis C Virus Antibody

Patch Test (Cosmetic Series)

Treatment History

6

Blotchy /face and neck

Negative

Negative

Ayurvedic medications of unknown nature with no improvement

40 y/female

9

Blotchy/face and neck

Negative

Negative

Antioxidants for 2 months with no improvement

3

25 y/female

3

Blotchy/face, neck, and arms

Negative

1+ to nickel

None

4

29 y/female

8

Diffuse/face

Negative

Negative

Applied topical herbal preparations with no improvement

5

30 y/male

6

Blotchy/face, neck, chest, and arms

Negative

Negative

None

Series No.

Age/Sex

1

35 y/female

2

Duration, mo

B

A

Figure 1. (A) Pretreatment lichen planus pigmentosus depicting blotchy pigmentation present over the face. (B) Posttreatment reduction in pigmentation at 4 months.

metic dermatitis was ruled out by patch test. Fixed-drug eruptions are characterized by a peculiar sudden onset of round and/ or oval, edematous, dusky red macules/plaques on the skin and/ or mucous membranes, accompanied by burning and/or itching, in the context of a history of offending drug intake. Idiopathic eruptive macular pigmentation is characterized by an eruption SKINmed. 2015;13:351–354

of brownish, nonconfluent, asymptomatic macules involving the trunk, neck, and proximal extremities in children or adolescents; absence of a preceding inflammatory process; no previous drug exposure; basal cell layer hyperpigmentation of the epidermis; and prominent dermal melanophages without visible basal layer damage or lichenoid inflammatory infiltrate.

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A

B

Figure 2. (A) Pretreatment lichen planus pigmentosus illustrating blotchy pigmentation present over the face. (B) Posttreatment reduction in pigmentation at 4 months.

Lichen planus pigmentosus is a chronic recalcitrant disease. More often than not the lesions persist for years together. The current treatment modalities for lichen planus pigmentosus are largely ineffective. Moreover, there is no quality evidence for these treatments and results are based on limited data. Vitamin A and both local and systemic corticosteroids have been shown to hasten the clearance of the lesions.10 Tacrolimus (FK-506) is a strong immunosuppressant that inhibits the proliferative response of lymphocytes to alloantigen stimulation and a variety of T-cell–associated immune reactions. Tacrolimus suppresses the immune responses by inhibiting inflammatory cytokine release.11,12 Recently, topical tacrolimus has been shown to induce the clearance of lesions over a period of 4 months. In the current case series, good results were also achieved at the end of 4 months. Dapsone has a therapeutic effect in several dermatoses and in lichen planus it has been used by several authors.2–7 In one study, 58% patients with lichen planus showed good response at the end of 3 months of therapy.6 The effect of dapsone in lymphocyte-rich dermatoses may be through inhibition of the myeloperoxidase hydrogen peroxide cytotoxic system.13 It may also inhibit the release of inflammatory or chemotactic factors from mast cells.14 The most common adverse effect of dapsone is hemolysis of varying degree. It is dose related and develops in almost every individual treated with 200 mg to 300 mg of dapsone daily.6 SKINmed. 2015;13:351–354

Conclusions In the present series, the patients responded well to a dose of 100 mg daily and no adverse effects were seen; therefore, a combination of tacrolimus 0.1% and dapsone 100 mg daily orally appears to be a viable treatment modality for lichen planus pigmentosus. Randomized, double-blind, controlled trials, however, are warranted to further define the approach of treatment for this cosmetically disabling entity. References

353

1 Kanwar AJ, Dogra S, Handa S, et al. A study of 124 Indian patients with lichen planus pigmentosus. Clin Exp Dermatol. 2003;28:481–485. 2 Falk DK, Latour DL, King LE. Dapsone in the treatment of erosive lichen planus. J Am Acad Dermatol. 1985;12:567. 3 Beck HI, Flemming B. Treatment of erosive lichen planus with dapsone. Acta Derm Venereol (Stockh). 1986;366–367. 4 Kumar B, Kaur I, Sharma VK. Efficacy of dapsone in lichen planus. Indian J Dermatol Venereol Leprol. 1989;55:164–166. 5 Kumar V, Garg BR, Baruah MC, et al. Childhood lichen planus. Dermatol. 1993;20:175–177. 6 Chopra A, Mittal RR, Kaur B. Dapsone versus corticosteroids in lichen planus. Indian J Dermatol Venereol Leprol. 1999;65:66–68.

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ORIGINAL CONTRIBUTION

7 Basak PY, Basak K. Generalized lichen planus in childhood: is dapsone an effective treatment modality? Turk J Pediatr. 2002;44:346–348.

11 Liu J, Farmer JD Jr, Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBPFK506 complexes. Cell. 1991;66:807–815.

8 Al-Mutairi N, El-Khalawany M. Clinicopathological characteristics of lichen planus pigmentosus and its response to tacrolimus ointment: an open label, nonrandomized, prospective study. J Eur Acad Dermatol Venereol. 2010;24:535–540.

12 Wakamatsu TH, Tanaka M, Satake Y, et al. Eosinophil cationic protein as a marker for assessing the efficacy of tacrolimus ophthalmic solution in the treatment of atopic keratoconjunctivitis. Mol Vis. 2011;17:932–938.

9 Sehgal VN, Verma P, Sharma S, Rasool F. Lichen planus pigmentosus. Skinmed. 2013;11:96–103.

13 Stendahl O, Mobin L, Dahlgren C. The inhibition of polymorphonuclear toxicity by dapsone. J Clin Invest. 1998;62:214–220.

10 Bhutani LK, George M, Bhate SM. Vitamin A in the treatment of lichen planus pigmentosus. Br J Dermatol. 1979;100:473–474.

14 Ruzicka T, Wasserman SI, Soter NA, et al. Inhibition of rat mast cell arachidonic acid cyclo-oxygenase by dapsone. J Allergy Clin Immunol. 1983;72:365–370.

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 391)

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September/October 2015

Volume 13 • Issue 5

Original contribution

Onychogryphosis: A Report of Ten Cases Patricia Chang, MD;1 Tyson Meaux, MD2 Abstract Many diseases can result in nail thickening, such as psoriasis, onychomycosis, pityriasis rubra pilaris, pachyonychia, and ichthyosis. In this report, the authors discuss such a condition, called onychogryphosis. Onychogryphosis is a thickening of the nail plate, with associated gross hyperkeratosis and increased curvature. It can be oyster-like or resemble a ram’s horn. Its irregular surface is marked by longitudinal and transverse striations, the latter of which is more frequent. The diagnosis of onychogryphosis is difficult to identify in the early stages because hypertrophy of the nail plate is the earliest manifestation, with the more classical features appearing later. Onychogryphosis is common on the great toenail of elderly patients and can be associated with self-neglect, homelessness, dementia, old age, trauma, peripheral circulation disorders, diseases of the central nervous system, and foot abnormalities, such as hallux valgus, elephantiasis, long-standing poor personal care, hyperuricemia, and pressure from improper footwear. All fingers and toenails can be affected in hereditary onychogryphosis. In infants and children, the presence of onychogryphosis can be accompanied by congenital malalignment of the great toenail. (SKINmed. 2015;13:355–359)

N

ails can be affected by dermatologic, infectious, and traumatic diseases; drug reactions; and deformities of the toes. Onychogryphosis is a thickening of the nail plate, with gross hyperkeratosis and increased curvature of the nail plate. Ten cases of onychogryphosis, aged between 43 and 92 years, are presented. Onychogryphosis was discovered incidentally during hospitalization on an internal medicine service for reasons that were unrelated to their onychopathy. We discuss the severity of these 10 cases and the limited knowledge that exists about this nail condition.

Discussion Onychogryphosis is a thickening of the nail plate, with gross hyperkeratosis and increased curvature of the nail plate, which can be oyster-like or resemble a ram’s horn.1 This condition can be congenital or acquired, with the congenital type (autosomal dominant) developing as late as the onset of puberty.2 The causes of onychogryphosis include: • Dermatologic diseases, such as ichthyosis, pemphigus, and psoriasis.

Methods and Patients

• Infectious diseases, such as onychomycosis, variola, and syphilis

We examined 10 cases of patients (nine men and one woman) with onychogryphosis, aged between 43 and 92 years, who were hospitalized for stroke (three), heart disease (one), chronic renal failure (two), dizziness (one), diabetes mellitus (one), kidney stones (one), and pneumonia (one). In five cases, all 10 toenails were involved (Figures 1–4), including the big and fifth toenails (Figure 5); in one case, both great toenails were affected (Figure 6); in three cases, only one big toenail was involved (Figures 7–9); and in the last case, onychogryphosis was predominantly on the right fifth and left second toenails (Figure 10).

• Local causes, such as injury of the nail apparatus, repeated minor trauma caused by footwear, and hallux valgus. • Regional causes, such as varicose veins, aneurysms, thrombophlebitis, elephantiasis, and alterations to the peripheral nervous system. • General causes, such as old age, hyperuricemia, homelessness, dementia, and diseases of the central nervous system. • Idiopathic causes, such as acquired and hereditary3 and foot deformities.1

From the Department of Dermatology, Social Security General Hospital IGSS,1 and Medical Student on Elective Dermatology Rotation,2 Guatemala City, Guatemala Address for Correspondence: Patricia Chang, MD, Social Security General Hospital IGSS, 9a Calle 7-55 Zone 9, 01009, Guatemala City, Guatemala • E-mail: pchang2622@gmail.com

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ORIGINAL CONTRIBUTION

Figure 1. Onychogryphosis of all ten toenails in a patient with dizziness.

Figure 2. Onychogryphosis of all toenails in a woman who experienced a stroke.

Figure 3. Onychogryphosis of all ten toenails, with those of the left foot more severe, in an 89-year-old patient with pneumonia. SKINmed. 2015;13:355–359

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ORIGINAL CONTRIBUTION

Figure 4. Onychogryphosis of all ten toenails, predominately on the left big toenail, in a patient with chronic renal failure.

Figure 5. Close-up of the left big toenail mimicking a tower.

Figure 6. Onychogryphosis of the fifth toenail in a diabetic patient. SKINmed. 2015;13:355–359

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ORIGINAL CONTRIBUTION

Figure 7. Onychogryphosis of the great toenail bilaterally in a 92-year-old patient with heart disease.

Onychogryphosis is most often secondary to neglect and failure to cut the nails for extended periods of time.4 It can affect the fingernails and toenails but is most common in the latter and develops most frequently in the great toenails of the elderly3,6 and in those who are unable to care for themselves.5 Although onychogryphosis of the fingernail is uncommon,1 it can be caused by chronic candidiasis5 or associated with orthopedic surgery.6 Congenital onychogryphosis of the fifth toe is fairly common and is described as a leaning tower nail.1 Severe congenital onychogryphosis that affects all 20 nail beds has been recorded in two families who had the dominant allele for a certain gene.7 Onychogryphotic nails can present with an irregular surface, transverse ridges, splits, opaque discoloration, and even an oyster-like appearance.8 The management of onychogryphosis is largely dependent on the cause. When it presents initially, every effort should be made to avoid excessive pressure on the nail bed. Counseling with regard to the appropriate footwear is important. Mild cases can be treated conservatively with regular nail trimming, whereas nail plate avulsion might be required when the deformity is more severe.9 Onychogryphosis is most commonly seen in the elderly. If the blood supply is good, some physicians recommend avulsion of the nail plate and surgical destruction of the matrix with phenol or a carbon dioxide laser.7 Application of 40% urea under occlusion has been associated with effective chemical avulsion. One case of onychogryphosis in a patient with a leg ulcer and edema of the foot has been reported.10 Although onychogryphosis is usually considered to be permanent, treatment of the leg ulcer and edema permitted regrowth of a structurally normal nail. SKINmed. 2015;13:355–359

Figure 8. Onychogryphosis of the great toenail in a 43-year-old woman with kidney stones.

Conclusions In our hospital, one of the most common forms of onychodystrophy in the elderly is onychogryphosis. It is critical to recognize onychogryphosis at all levels, because it is often misdiagnosed as onychomycosis and treated with antifungal medications. Onychogryphosis can be a difficult disease to manage in the elderly, because physicians often deal with other diseases concurrently; nevertheless, onychogryphosis should not remain untreated. Acknowledgments Angela Alvarado Chew translated this manuscript from Spanish to English, and Dr Robert Baran assisted in revising the manuscript.

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ORIGINAL CONTRIBUTION

Figure 9. Onychogryphosis of the great toenail in a 61-year-old patient with chronic renal failure.

Figure 10. Onychogryphosis in a woman with a cerebral vascular accident. Onychogryphosis was predominantly on the right fifth and left second toenails.

References 1 Nath AK, Udayaschankar C. Congenital onychogryphosis: leaning tower nail. Dermatol Online J. 2011;17:9. 2 Higashi N, Matsumura T. The etiology of onychogryphosis of the great toenail and of ingrown nail (in Japan). Skin Res. 1988;30:620–625. 3 Rubin AI, Baran R. Physical signs. In: Baran R, De Berker DAR, Holzberg M, Thomas L, eds. Diseases of the Nail and Their Management. 4th ed. London, England: WileyBlackwell; 2012:59–62. 4 William J, Berger T, Dirk E. Diseases of the skin appendages. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. London, England: Saunders Elsevier; 2005:772. 5 Baran R, Haneke E. Severe nail dystrophy, hyponychia

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and anonychia, and alterations of nail plate. In: The Nail in Differential Diagnosis. London, England: Informa Healthcare; 2007:49. 6 Masood Q, Nisa N, Hassan I, et al. Five fingernail onychogryphosis in a claw hand. Egyptian Dermatol Online J. 2009;5:11. 7 Wikipedia. Onychogryphosis. http://en.wikipedia.org/ wiki/Onychogryphosis. Accessed May 13, 2014. 8 Baran R, Haneke E. Pits, rough nails and other surface alterations. In: The Nail in Differential Diagnosis. London, England: Informa Healthcare; 2007:24. 9 McDermott R, Kidney R. Celtic Tiger: a case of onychogryphosis. Int J Case Reports Images. 2012;3:27–29. 10 Stone OJ. Resolution 1984;34:480.

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Onychogryphosis: A Report of Ten Cases

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September/October 2015

Volume 13 • Issue 5

REVIEW

What Can Be Expected on Irradiated Skin? A Dermatologic Focus on Acute and Chronic Radiotherapeutic Effects, Treatment, and Benign Dermatoses Edwin Cuperus, MD;1 Miriam Albregts, MD;2 Johan Toonstra, MD, PhD1 Abstract Radiotherapy has been a common and well-known treatment for several cancers and benign dermatoses. An overview of the characteristics of acute and chronic cutaneous effects of radiotherapy and its treatment is presented. A current overview of benign dermatoses after radiotherapy, presently only dispersedly published in the literature, is given with the mean age of occurrence, dose of radiotherapy, and their latency time calculated for those described more than 8 times. Benign dermatoses occurring most often after radiotherapy (>20 times described), ie, morphea, bullous pemphigoid, pemphigus vulgaris, and acneiform eruptions are discussed in more detail. Finally, dermatoses with a specific distribution related to the irradiated area are highlighted. This review provides an overview of cutaneous side effects of radiotherapy, especially of the benign dermatoses, as a supplement to the clinical knowledge of dermatologists, oncologists, and wound care specialists. (SKINmed. 2015;12:361–374)

S

ince the discovery of X-rays in 1895 by Wilhelm Roentgen (1845-1923), radiotherapy has become a common and effective treatment for several types of cancer. In the 1930s to the 1960s, radiotherapy was a common treatment for benign skin diseases such as psoriasis, dermatitides, acne, and mostly tinea capitis. In those days, it was usually given by dermatologists and radiotherapists, but radiotherapy is now used by radiation oncologists. Its use for tinea capitis ended with the discovery of griseofulvin in 1959. Different types of exposure are possible, such as external radiation (X-rays) and the use of radionuclides, external via contamination and internal via inhalation, wounds, or ingestion.1 A combined injury, with multiple types of wound etiologies, can be seen with a nuclear explosion.1 In addition, different types of ionizing radiation can be distinguished.1 Alpha particles, very reactive because they consist of two positively charged protons, do not cause any problems when exposed to the skin. Beta particles are high-energy negative electrons and can cause severe burns on contact with the skin. Neutrons and gamma rays can penetrate deep within tissues, but cutaneous contamination does not eas-

ily occur. X-rays are a noncontaminating radiation produced by electrons. The goal of this review is to give an overview of acute and chronic cutaneous effects of local radiotherapy and their treatment, of acute and chronic effects of accidental acute radiation exposure and effects its treatment, and of post-radiation benign dermatoses. Those published more than 20 times are discussed in detail, and latency periods and mean age of first symptoms and signs are given if available. Finally, the relationship of benign dermatoses to the irradiated area is presented. Radiation-related malignant tumors, first recorded in 1902 by Frieben, form a serious side effect of radiotherapy but will not be discussed in the present review. Material and Methods A literature search for the acute and chronic cutaneous effects of radiotherapy was performed using PubMed with the search terms “radiotherapy,” “irradiation,” “post-radiation,” and matching synonyms and were matched with “radiotherapy” as a MESH term.

From the Departments of Dermatology and Venereology1 and Radiotherapy and Oncology,2 University Medical Centre, Utrecht, The Netherlands Address for Correspondence: Edwin Cuperus, MD, Department of Dermatology and Venereology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands • E-mail: edwin_cuperus@yahoo.co.uk

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Publications related to the cutaneous effects of radiotherapy in humans, published during the period 2000–2012 and written in Dutch, English, German, or French, were included. Literature related to radiation-induced benign dermatoses was searched by using the terms “radiation,” “radiotherapy,” “irradiation,” “postradiation,” and related synonyms, in combination with “dermatology,” “skin,” “cutaneous effects,” and their synonyms. Papers written in Dutch, English, German, or French published from 1902 until January 2013 were included. References in these were screened for additional cases. We extracted detailed information about latency periods and used radiation dosages from individual cases. Detailed information about fractionation could not be given, because in most cases the details about fractionation were not available. Cases of patients with genetic syndromes with increased radiosensitivity, such as Gorlin’s syndrome (basal cell nevus syndrome) and xeroderma pigmentosum, were excluded. Local radiotherapy consisted not only of megavoltage X-ray radiation but also included Cobalt-60, neutron beam therapy, and Grenz-ray. Cutaneous Effects of Radiotherapy Radiotherapy affects the epidermis, dermis, and subcutaneous fat and inhibits cell proliferation and new cell production. Local use of radiotherapy causes cutaneous side effects and are generally divided into acute (early, ie, <8 weeks) and chronic (late) effects.2–14 In a few publications, cutaneous side effects have been divided into 4 or 5 categories.1,15,16 The severity of the skin reactions are dependent upon dose, anatomic location, and individual characteristics. Although the goal is to minimize side effects during therapy, 87% of patients will experience moderate to severe skin injuries.17 Acute effects of local radiotherapy Radiation negatively affects the basal cells and the germinative layer in the hair follicle so that proliferation of these stem cells decreases.14,15 The time interval after which the cutaneous effects

of radiotherapy occur is dependent on the turnover time of the skin (4–6 weeks) and is independent of the radiation dose. The severity of radiation response in the epidermis and hair follicles, however, is dose-dependent because the reproductive survival of stem cells is dose-related (Table I).1,15 With 3 Gy, epilation occurs within 2 to 3 weeks after radiation. Late erythema occurs in the same period with a dose of 3 to 6 Gy. Erythema directly following radiation is being accepted as an irritant reaction. An early, transient, erythema occurs within hours, called 24-hour erythema, with dosages higher than 6 Gy. This is an inflammatory reaction in the epidermis and occurs within 8 weeks after initial radiotherapy.8 The number of the remaining viable stem cells, which proliferate rapidly, depends on the radiation dose. With a dose of 10 to 15 Gy, the number of viable stem cells are still high, resulting in dry desquamation (erythema and epidermal hyperplasia but without moist desquamation) between 2 to 4 weeks following radiation. With doses of 15 to 25 Gy, these cells are more disconnected and the result is moist desquamation and blister formation, starting between 2 to 8 weeks after radiation. In the same period, when radiation dosages >25 Gy are used, even large blisters develop. With radiation dosages >50 Gy (some say 80 Gy), few or no viable cells are left in the irradiated field. In those fields, moist desquamation can result in secondary ulceration, followed by infection, dehydration, and epidermal necrosis.15 This will occur within days to months, mostly within 14 to 28 days, but may also present in the first 10 days.9,18,19 Diminished blood flow is seen within 12 weeks after radiation, concomitantly resulting in dermal or subcutaneous necrosis. The most common acute adverse reactions after radiotherapy, such as erythema, pain, edema, and tenderness described in breast cancer patients occur during and up to 8 weeks after initial radiotherapy.7 The histopathology, radiation biology, and treatment of cutaneous effects after radiotherapy have already been well documented by several authors.15,20

Table I. Cutaneous Manifestations of Local Radiation Injury Dose absorbed

Cutaneous Manifestations

Time of Onset

3 Gy

Epilation (hair loss)

2–3 weeks

6 Gy

Early (transient) and late erythema

Hours (early), 2–3 weeks (late)

10 Gy

Dry desquamation

2–4 weeks

>15 Gy

Moist desquamation, small blisters

2–8 weeks

>25 Gy

Moist desquamation, large blisters

2–8 weeks

>50 Gy

Necrosis

Hours to months

Abbreviation: Gy, Gray. Adapted with permission from Leikin and McFee.135 SKINmed. 2015;13:361–374

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Besides dose, anatomic location of radiation is essential. Reactions are more severe when the skin is irradiated in the axilla, submammary area, groin, and perineum.13 Individual factors influencing the severity of the skin reaction are the condition of the patient’s skin, age, medical and surgical history, nutritional status, and race.3,21 Chronic effects of local radiotherapy Chronic cutaneous effects are seen from 40 weeks after radiation.15 It is the result of thinning of the dermis and subcutaneous fat, which is primarily seen after 52 to 78 weeks post-treatment.10,15 Histologically, it is recognizable as epidermal atrophy with changes in the basal layer, dermal sclerosis, atypical fibroblasts, and loss of adnexal structures.22,23 Clinically, it is evident as fibrosis, atrophy, dyspigmentation, alopecia, and teleangiectasia.3,6,8,12,13,15,24 Several authors demonstrated alterations in collagen type I and III in irradiated breasts.11,25 Development of fibrosis is believed to be less severe with fractionation.11 Teleangiectasia are predominantly seen after 52 weeks and may increase even after 10 years. The development of teleangiectasia is dose-related and is also more frequently seen when the process was complicated by moist desquamation.10,15,26 An increase in angiogenesis could be caused by an activation of angiogenetic factors by irradiation or direct radiation damage on blood vessel walls.27 Over the long-term, sometimes after several decades, ulceration may occur.22–24 Postradiation tumors, such as basal cell carcinomas, squamous cell carcinomas, and angiosarcomas, will be discussed elsewhere.28 Patients with increased radiosensitivity Patients with an increased radiosensitivity have well been described.15 Genetic disorders, such as hereditary nevoid basal cell carcinoma (Gorlin’s syndrome), Fanconi anemia, Bloom syndrome, xeroderma pigmentosum, dysplastic naevus syndrome, familial polyposis, Gardner syndrome, and hereditary malignant melanoma, increase radiation sensitivity and predispose these patients to radiation injuries.15 Autoimmune and connective tissue disorders, such as scleroderma, systemic lupus erythematosus, and possibly rheumatoid arthritis, predispose patients to severe radiation effects.15 The cause is unknown. Concomitant use of medications might sensitize these patients. In addition, diabetes mellitus and hyperthyreoidism are associated with increased radiation sensitivity.15 Drugs that are associated with increased radiosensitivity are actinomycin D, doxorubicin, bleomycin, 5-fluorouracil, and methotrexate.15 In conjunction with radiotherapy, mitoxantrone, 5-fluorouracil, cylcophosphamide, paclitaxel, docetaxel, and tamoxifen can result in cutaneous toxicity.15 Radiation-recall SKINmed. 2015;13:361–374

reactions are a radiation-recall–related drug reaction that occurs in a previously irradiated area after drug administration, especially chemotherapeutics (eg, doxorubicin, etoposide, paclitaxel, bleomycin, epirubicin, and gemcitabine), antibiotics (cefotetan), statins (simvastatin), and herbal preparations (hypericin, otherwise known as St. John’s wort).15 These categories of predisposed patients will not be further discussed in this review. Acute radiation syndrome and cutaneous radiation syndrome The term acute radiation syndrome, also called radiation sickness, is preserved for individual cases with total body radiation with high radiation dosages, most of them accidental cases. Such cases are found in history; disasters at nuclear power plants such as Chernobyl (April 1986) and Fukushima (November 2011) and the dropping of atomic bombs on Hiroshima and Nagasaki, which ended World War II in 1945.29–31 Local radiotherapy includes low-dosage radiation and is not the cause of cutaneous radiation syndrome. The level of threshold dose is unknown. Four subtypes of acute radiation syndrome can be divided, according to the organ system affected: hematopoetic, gastrointestinal, cutaneous, and cerebrovascular.1,31 Each of these subtypes can be divided into four phases: prodromal, latent, illness, and recovery or death.1 The cutaneous subtype is also known as cutaneous radiation syndrome and its 4 phases with their symptoms are described in Table II. Researchers studied long-term survivors (99 patients) of Chernobyl during the period 1998–2000.31 In this study, late cutaneous effects, 15 years after the disaster, were reported in 22 patients: epidermal atrophy, teleangiectasia, and hyperpigmentation and hypopigmentation.31 Furthermore, keratotic lesions (14 of 22), cutaneous fibrosis (8 of 22), radiation ulcers (5 of 22), and 2 basal cell carcinomas (1 of 22) were seen.31 Researchers recorded cutaneous cancers caused by radiation exposure at Hiroshima and Nagasaki and found only an increase of basal cell carcinoma rates; however, no increase in squamous cell carcinomas or melanomas was found.29 The increase in basal cell carcinoma after the disaster in Hiroshima and Nagasaki was affirmed by researchers in 2011.30 Prevention and Treatment of Post-Radiation Cutaneous Effects Outstanding reviews on treatment and wound care caused by radiation injury have been published by several authors.1,16,20,32 General recommendations of skin care after radiotherapy are keeping the skin dry and avoiding any rubbing or friction and use of irritants.33 Other principles include minimizing water loss, decreasing pain, and preventing progression to moist desquamation.20 Moisturizing appears to be essential for the prevention of radiothera-

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Table II. Four Phases of Cutaneous Radiation Syndrome Phase

Latency

Persistence

Signs and Symptoms

Prodromal

Minute-hours

Up to 36 hours

Erythema, burning, pruritus, and edema

Manifestation

2–3 weeks

1–2 weeks

Erythema, alopecia, scaling, blisters, and ulcers

Subacute/chronic

4 months to years

Unlimited

Erythema, ulcers, keratoses, fibrosis, atrophy, pigment changes, and teleangiectasias

Late

Decades

Unlimited

Ulcers, atrophy, teleangiectasias, angiomas, fibrosis, keratoses, BCCs, and SCCs

Abbreviations: BCC, basal cell carcinoma; SCC, squamous cell carcinoma. Adapted with permission from Steinert et al.31

py-induced dermatitis. Suggestions include hyaluronic acid, Dpanthenol, hydrophobic and hydrophilic ointments, chamomile, almond ointment, barrier creams, lanolin, steroid creams, and aloe vera with variable results.16,20,32–36 Significant improvement in radiotherapy-induced dermatitis was reported while using oil-inwater emulsions containing linoleic acid37 or 3% urea lotion.38 No protective effect of vitamin E has been demonstrated.39 Further treatment of acute radiation dermatitis is aimed at reduction of pain, erythema, dry desquamation, or moist desquamation.20,40,41 Erythema is treated by obeying the basic principles of skin protection and using emollients (preferred creams or ointments). Dry desquamation is treated with petrolatum-based emollients, castor oil, balsam of Peru, trypsin, or triethanolamine. Corticosteroids, often recommended for mild reactions, may, however, actually slow the healing process of radiation-induced skin and their use is therefore controversial.42 Moist desquamation during radiotherapy can be diminished by using hydrogel and hydrocolloid dressings. In case of exudative wounds, burn pads, alginate, and foam dressings are advised. In addition, infections should be treated based on bacterial cultures. Moist desquamation after radiotherapy and infected wounds can both be treated with topical antibiotics, ionic silver pads, cadexomer iodine, and maltodextrin powder. Treatment of chronic wounds are based on the presence of ulcers and their concomitant treatment.20,40,41 Teleangietasia and fibrosis can be treated with a vascular laser and pentoxifylline (even with vitamin E), interferon gamma, or superoxide dismutase, respectively.20,40,41 Post-Radiation Benign Dermatoses Several benign dermatoses following radiotherapy have been described in the last decennia and, more than 8 times published, are summarized in Table III. Sporadic cases reported fewer than 8 times in the literature are not described in detail in this review and include cases of Darier’s disease,43,44 Grover’s disease,45,46 erythema nodosum,47,48 herpes zoster,49 Sweet’s syndrome,50,51 SKINmed. 2015;13:361–374

graft versus host disease,52–56 lichen slerosus,57,58 lupus erythematodes,59 nonspecific eosinophilic eruption,60,61 subcutaneous calcifications,62 eczematoid dermatitis,63 xanthogranuloma,64 trichilemmal tumor,65 mastocytosis,66–68 polyarthritis nodosa,69 alopecia,70–72 and erythema exudativum multiforme.73,74 The most common benign dermatoses (more than 20 times published), ie, morphea, bullous pemphigoid, acneiform eruptions, radiogenic acne, and pemphigus vulgaris will be discussed in more detail. Benign atypical vascular lesions after radiotherapy, closely related to angiosarcoma, will be discussed elsewhere. Morphea The first report of radiation-induced morphea (RIM) dates from 1987, in which the authors suggest a relationship between local scleroderma and radiotherapy for breast carcinoma.75 The incidence is about 2 per 1000 irradiated patients, in contrast to morphea of any origin in 2.7 per 100,000 patients per year. Recently, a series of 54 patients with RIM since 1989 have been published.76 To date, a total of 57 cases of RIM have been described in the literature. In 48 cases (84.2%), RIM was related to breast carcinoma (Figure 1) and had its onset within the first year after treatment in 23 of the 57 (40.4%) cases. The remaining cases occurred after radiotherapy for endocervical carcinoma,77–80 an adenocarcinoma in the axilla of unknown origin,79 a tumor in the head and neck region,77 a subcutaneous lymphoma in an HIV-positive patient,81 and a gastric stump carcinoma.82 The median age of occurrence is 58 years. The onset of RIM varied but could be as late as 32 years after radiotherapy. Although most authors assume that radiotherapy alone can be a causative factor for RIM, it has also been described after surgery without radiotherapy.79 Recently, researchers postulated that there may be a synergistic pathogenic effect of surgery and radiotherapy that triggers the manifestation of morphea.83 RIM must be separated from other close variants such as postradiation lichen sclerosus atrophicus and post-radiation pseudo-

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Table III. Overview of Frequent Occurring Benign Dermatoses Following Radiotherapy Year of first Publication

Patients, No.

Sex, m/f/NA

Age, y (median)

Latency period (median)

Dose RT, Gy

References

Morphea

1987

57

2/50/5

34–87 (58)

1 month– 32 years (1 year)

40–70

17,69,75,77– 83,136–157

Bullous pemphigoid

1963

38

3/30/4

39–94 (66)

1 week–16 years (4 months)

20–66

86–97,158– 177

12–70

99–101,106– 117,119,120, 122,123, 178–182

Dermatosis

Acne

1947

34

19/14/1

26–75 (50)

2 weeks– 6 months (2 months)

Pemphigus vulgaris

1987

20

6/9/5

39–71 (54)

1 week– 1 year (4 weeks)

28–100

126,128– 134,183–192

Eosinophilic, polymorphic, and pruritic eruption

1999

18

0/18/0

50.4 (mean)

NA

26–67

60,193–195

Porokeratosis

1980

13

6/6/1

29–78 (53)

24 min to 7 years (4.5 years)

44–50

196–206

Lichen planus (Figure 4)

1998

10

3/3/1

44-68 (58)

0–5 months (2.5 months)

45–66.8

207–216

Vitiligo

1968

9

0/4/5

37–52 (42.5)

2–8 months (6.5 months)

40–55

217–223

Graft versus host disease

1980

8

2/2/4

20–82 (50.5)

5–50 weeks (6.2 months)

7.5–51

52–56

Pseudosclerodermatous panniculitis

1993

8

0/8/0

44–73 (60)

1–8 months (2.5 months)

46–50

52–56,84,85

Abbreviations: f, female; Gy, Gray; m, male; NA, not available.

sclerodermatous panniculitis, which are distinguished mainly on histological grounds.84,85 Clinical lesions of post-radiation pseudosclerodermatous panniculitis consist of indurated plaques that mimic the diagnosis of subcutaneous metastatic disease. Bullous Pemphigoid

Figure 1. Localized post-irradiation morphea on the right breast after radiotherapy. SKINmed. 2015;13:361–374

Although radiation-induced bullous pemphigoid (RIBP) was first described in 1963 after radiotherapy for cervical carcinoma,86 29 of the 38 cases published occurred after radiotherapy for breast cancer, of which the first case was published in 1982.87 The remainder of cases occurred after radiotherapy for cervix carcinoma,86,88 non-Hodgkin lymphoma,89 bronchus carcinoma,90 esophagus carcinoma,91 vulvar carcinoma,92,93 parotid gland carcinoma,94 and metastatic nodes of squamous cell carcinoma.95 Radiation-induced bullous pemphigoid is illustrated in Figure 2.

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RIBP is considered a single entity and not as coincidence. The median age of occurrence is 66 years and the mean age is 68 years (range, 39–94 years), both lower than that of patients who did not receive radiotherapy. The mean dose at which it occurs is 50 Gy, but it can be seen after a minimum dose of 20 Gy.91,95,96 RIBP can occur during radiation (17%), days or weeks afterward (59%) (within the first 6 months after radiotherapy), or even after 3 to 16 years. RIBP can be considered an early as well as a late adverse effect of radiotherapy. Recently, RIBP was reported after a rechallenge with radiotherapy.97 In the majority of cases, RIBP was restricted to an irradiated area but it can also spread to other regions (Table II). In one case, the patient was familiar with a bullous pemphigoid and the irradiated area was selectively spared but caused the development of pre-existing bullous pemphigus lesions.96 The etiology for sparing the irradiated field could not be given. One of the theories to explain spreading may be that circulating antibodies transport to surrounding areas and induce BP lesions in nonradiated skin.96 A 2007 review described 27 cases of RIBP with particular attention on pathogenesis.98 Therapy for RIBP does not differ from that of ordinary BP and includes topical and systemic corticosteroids. Success rates of therapy in RIBP, however, could not be found in the literature. Radiogenic acne and acneiform eruptions Good overviews of radiogenic acne and the comedo skin reaction were presented in 2000 and 2002, respectively.99,100 Radiogenic acne is also known as radiation-induced Favre-Racouchot-like disease.101 Ironically, in the 1970s, radiotherapy was a treatment for mild to severe acne.102–105 Some researchers have stated that radiogenic acne occurs within months to years after being irradiated.99 In the 34 cases we found in the literature, however, the median latency period was only 2 months (range, 2 weeks to 6 months [Table III]). Radiogenic acne can be self-limiting within months after radiotherapy. Local comedolytic treatment with adapelene, topical retinoids, excision of cysts, and laser dermabrasion have been successful.99 Acneiform eruptions after radiotherapy, first described in 1947,106 only occur with the simultaneous use of medications, being mostly steroids,100,107,108 estrogen therapy (tamoxifen),109–111 anticonvulsants (carbamazepin),99 phenytoin and phenobarbital,112,113 LHRH analogs (goserelin),114 EGFR inhibitors (erlotinib),115,116 and cetuximab.117 The clinical picture includes erythematous papules and papulopustules as well as comedones (Figure 3). In contrast, true radiogenic acne occurs without the simultaneous use of medication and is characterized by only closed and open comedones, millia, and cysts in an irSKINmed. 2015;13:361–374

Figure 2. Localized bullous pemphigoid on the right breast after radiotherapy. (Courtesy of B.G. Baumert, MD, radiation oncologist, Maastricht, the Netherlands.)

radiated sebaceous-rich area or in its surrounding area (Figure 3) but seldom with the papules and papulopustels of the medication-related acneiform eruptions.107,108,110,113,118–123 This also differs from the usual acne seen in nonradiated skin, which includes papules and papulopustules. Pemphigus vulgaris and pemphigus foliaceous We found 25 cases of radiation-induced pemphigus (RIP), of which 21 were cases of pemphigus vulgaris and 4 of pemphigus foliaceous. The cases of pemphigus foliaceous, however, are not mentioned separately in Table III.124–127 Paraneoplastic pemphigus was not included. In our series, RIP vulgaris and pemphigus foliaceous occurred at a median age of 54 years (range, 39–71) and 70 years (range, 37–92), respectively (Table III). The median latency period was 4 weeks (range, 1 week to 1 year) and 4.5 months (range, 1 month to 1 year), respectively (Table III). Six cases (30%) of RIP vulgaris were related to radiotherapy for breast carcinoma. Other indications for radiotherapy were spinocellular carcinoma in the larynx, lip, or lung126,128,129; actinic keratosis130; lymphoma131; bronchuscarcinoma132; bladder carcinoma133; and epidermoid cancer of the piriform sinus.134 Initial diagnoses of RIP foliaceous were breast cancer (50%), thymoma, and laryngeal spinocellular carcinoma. Remarkably, all cases of pemphigus foliaceous spread outside the irradiated area. In pemphigus vulgaris and pemphigus foliaceous, the median initial radiation dose was 65 Gy (range, 28–100 Gy) and 55 Gy (range, 33–60 Gy), respectively. Histologically, RIP does not differ from endogenous pemphigus, and, in one case of RIP, focal keratinocytic necrosis was reported, which is not typical for RIP but is frequently seen in paraneoplastic pemphigus.134

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Figure 3. Radiation-induced comedos 6 months after radiotherapy for basal cell carcinoma.

Figure 4. Lichen planus in the radiation field on the right breast after radiotherapy.

In some cases of pemphigus vulgaris and in all cases of pemphigus foliaceous, patients were already known to have circulating antibodies and cutaneous pemphigus prior to radiotherapy; therefore, caution is advised when using radiotherapy in pemphigus patients. RIP responds well to systemic corticosteroids and immunosuppressants within a few months.

irradiated area are listed. The dermatoses that start inside the irradiated area and spread outward consist of two types of porokeratosis (disseminated superficial actinic porokeratoses and multiple minute digitate hyperkeratosis), bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceous, lichen planus, and morphea.

Dermatoses and Their Spacial Relationship to the Radiation Area

Conclusions

Dermatoses following radiotherapy are related to the site of irradiation. Most occur only within the irradiated area, whereas some start inside and spread outside the irradiated area. A sporadic case of bullous pemphigoid selectively sparing the irradiated area has been described.96 In Table IV, the number of cases that spread outside the irradiated area and the ones sparing the

An overview of cutaneous effects of radiotherapy and their treatment is presented. It comprises the acute and chronic effects of local and whole body radiation, as well as secondary post-radiation dermatoses. Acute effects depend on different types of radiation exposure and ionizing radiation. Most acute effects are the result of low-dose, fractioned, local radiotherapy. They depend on the radiation dose and include epilation,

Table IV. Distribution of Dermatoses Beyond the Radiated Area (Number of Cases) Total After Radiotherapy

In and Out Radiated Area (%)

Spared Radiated Area (%)

Reference

Morphea

57

15 (26)

69,78–80,82,136, 144,151,154,155

Bullous pemphigoid

38

12 (32)

1 (3)

86,88,90–93,98, 160,161,166,169, 173

Pemphigus vulgaris

21

3 (14)

128,131,186

Minimal multiple digitate hyperkeratosis

7

1 (14)

203

Lichen planus

10

2 (20)

208,210

Pemphigus foliaceous

4

4 (100)

124–127

Disseminated superficial actinic porokeratosis

3

2 (67)

199,205

Dermatosis

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erythema, dry and moist desquamation, bullae, vesicles, and necrosis. Acute effects after very high-dose radiation, affecting most parts or the whole body, are mostly related to effects of the environment disasters of the nuclear power plants in Chernobyl and Fukushima and the effects of the atomic bombs in Hiroshima and Nagasaki. This causes an acute radiation syndrome with the cutaneous radiation syndrome as cutaneous subtype. Cutaneous radiation syndrome includes 4 phases characterized by erythema, pruritus, alopecia, blisters, scaling, and poikiloderma. Most common chronic cutaneous effects of radiotherapy are teleangiectasia, atrophy, and pigment alterations. A special category of late effects of radiotherapy is secondary benign dermatoses, mostly inflammatory and bullous, that appear in the irradiated area. Morphea, bullous pemphigoid, pemphigus vulgaris, acne, and acneiform eruptions are the most common but still are rare; nonetheless, we assume that these dermatoses are more common in practice and underreported in the literature. Benign dermatoses, such as acne, pemphigus vulgaris, lichen planus, vitiligo, and graft versus host disease, present within the first weeks to months, all within the first year after radiotherapy has ended. Although all post-radiation dermatoses have a median latency period shorter than 1 year, durations of many years have also been reported. The majority of published cases of dermatoses occurred after radiotherapy for breast cancer. Dermatologists, surgeons, radiotherapists, radio-oncologists, and wound care specialists should be aware of these diseases that can appear during radiotherapy, even in the weeks, months, and even years after initial therapy. References 1 Ward KA, Jaimes JP, Coots NV. Cutaneous manifestations of acute radiation exposure: a review. Int J Dermatol. 2012;51:1282–1291. 2 Bernstein EF, Sullivan FJ, Mitchell JB, et al. Biology of chronic radiation effect on tissues and wound healing. Clin Plast Surg. 1993;20:435–453. 3 Blackmar A. Radiation-induced skin alterations. Medsurg Nurs. 1997;6:172–175. 4 Carrotte-Lefebvre I, Delaporte E, Mirabel X, et al. [Radiation-induced skin reactions (except malignant tumors)]. Bull Cancer. 2003;90:319–325. 5 Clavere P, Bonnafoux-Clavere A, Bonnetblanc JM. [Radiation induced skin reactions]. Ann Dermatol Venereol. 2008;spec no 1:1–4.

8 Hopewell JW. Experimental studies of early and late responses in normal tissues: an overview 197. In: Steel,GG, Adams,GE, Peckham,MJ, eds. The Biological Basis of Radiotherapy. New York, NY: Elsevier; 1983:157–166. 9 Hopewell JW. Mechanisms of the action of radiation on skin and underlying tissues. Br J Radiol Suppl. 1986;19:39–47. 10 Hopewell JW. The skin: its structure and response to ionizing radiation. Int J Radiat Biol. 1990;57:751–773. 11 Keskikuru R, Jukkola A, Nuutinen J, et al. Radiation-induced changes in skin type I and III collagen synthesis during and after conventionally fractionated radiotherapy. Radiother Oncol. 2004;70:243–248. 12 Lopez E, Guerrero R, Nunez MI, et al. Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes. Breast Cancer Res. 2005;7:R690–R698. 13 Sitton E. Early and late radiation-induced skin alterations. Part I: mechanisms of skin changes. Oncol Nurs Forum. 1992;19:801–807. 14 Wang J, Boerma M, Fu Q, et al. Radiation responses in skin and connective tissues: effect on wound healing and surgical outcome. Hernia. 2006;10:502–506. 15 Balter S, Hopewell JW, Miller DL, et al. Fluoroscopically guided interventional procedures: a review of radiation effects on patients’ skin and hair. Radiology. 2010;254:326–341. 16 Gottlober P, Krahn G, Peter RU. Cutaneous radiation syndrome: clinical features, diagnosis and therapy. Hautarzt. 2000;51:567–574. 17 Fisher J, Scott C, Stevens R, et al. Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13. Int J Radiat Oncol Biol Phys. 2000;48:1307–1310. 18 Barabanova A, Osanov DP. The dependence of skin lesions on the depth-dose distribution from beta-irradiation of people in the Chernobyl nuclear power plant accident. Int J Radiat Biol. 1990;57:775–782. 19 Peter RU, Braun-Falco O, Birioukov A, et al. Chronic cutaneous damage after accidental exposure to ionizing radiation: the Chernobyl experience. J Am Acad Dermatol. 1994;30:719–723. 20 Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol. 2006;54:28–46. 21 Ryan JL, Bole C, Hickok JT, et al. Post-treatment skin reactions reported by cancer patients differ by race, not by treatment or expectations. Br J Cancer. 2007;97:14–21.

6 Devalia HL, Mansfield L. Radiotherapy and wound healing. Int Wound J. 2008;5:40–44.

22 Rao J, Dekoven JG, Beatty JD, et al. Cutaneous angiosarcoma as a delayed complication of radiation therapy for carcinoma of the breast. J Am Acad Dermatol. 2003;49:532–538.

7 Holli K, Pitkanen M, Jarvenpaa R, et al. Early skin and lung reactions in breast cancer patients after radiotherapy: prospective study. Radiother Oncol. 2002;64:163– 169.

23 Spittle M, Kelly C. Radiotherapy and reactions to ionizing radiation. In: Burns T, ed. Rook’s Textbook of Dermatology. 7th ed. Oxford, England: Blackwell Science Ltd; 2004:6–7.

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24 FitzGerald TJ, Jodoin MB, Tillman G, et al. Radiation therapy toxicity to the skin. Dermatol Clin. 2008;26:161–172, ix. 25 Riekki R, Parikka M, Jukkola A, et al. Increased expression of collagen types I and III in human skin as a consequence of radiotherapy. Arch Dermatol Res. 2002;294:178–184. 26 Bentzen SM, Overgaard M. Relationship between early and late normal-tissue injury after postmastectomy radiotherapy. Radiother Oncol. 1991;20:159–165. 27 Riekki R, Jukkola A, Oikarinen A, et al. Radiation therapy induces tenascin expression and angiogenesis in human skin. Acta Derm Venereol. 2001;81:329–333. 28 Cuperus E, Leguit R, Albregts M, et al. Post radiation skin tumors: basal cell carcinomas, squamous cell carcinomas and angiosarcomas. A review of this late effect of radiotherapy. Eur J Dermatol. 2013;23:749–757. 29 Kishikawa M, Koyama K, Iseki M, et al. Histologic characteristics of skin cancer in Hiroshima and Nagasaki: background incidence and radiation effects. Int J Cancer. 2005;117:363–369. 30 Sobue T. Scientific approach to radiation-induced cancer risk. Fukushima J Med Sci. 2011;57:90–92. 31 Steinert M, Weiss M, Gottlober P, et al. Delayed effects of accidental cutaneous radiation exposure: fifteen years of follow-up after the Chernobyl accident. J Am Acad Dermatol. 2003;49:417–423. 32 McQuestion M. Evidence-based skin care management in radiation therapy: clinical update. Semin Oncol Nurs. 2011;27:e1–e17. 33 Maddocks-Jennings W, Wilkinson JM, Shillington D. Novel approaches to radiotherapy-induced skin reactions: a literature review. Complement Ther Clin Pract. 2005;11:224–231. 34 Kirova YM, Fromantin I, De RY, et al. Can we decrease the skin reaction in breast cancer patients using hyaluronic acid during radiation therapy? Results of phase III randomised trial. Radiother Oncol. 2011;100:205–209. 35 Olsen DL, Raub W, Jr, Bradley C, et al. The effect of aloe vera gel/mild soap versus mild soap alone in preventing skin reactions in patients undergoing radiation therapy. Oncol Nurs Forum. 2001;28:543–547.

41 Smith APS, Fife CE. Advanced therapeutics: the biochemistry and biophysical basis of wound products. In: Sheffield PJ, ed. Wound Care Practice. Flagstaff, AZ: Best Publishing Company; 2004:685–728. 42 Potera ME, Lookingbill DP, Stryker JA. Prophylaxis of radiation dermatitis with a topical cortisone cream. Radiology. 1982;143:775–777. 43 Chopra S, Sharma V, Nischal KC, et al. Darier’s disease following radiotherapy for carcinoma of cervix. Indian J Dermatol Venereol Leprol. 2004;70:300–303. 44 Mac Manus M, Cavalleri G, Ball D, et al. Exacerbation, then clearance, of mutation-proven Darier’s disease of the skin after radiotherapy for bronchial carcinoma: a case of radiation-induced epidermal differentiation? Radiat Res. 2010;156:724–730. 45 Held JL, Bank D, Grossman ME. Grover’s disease provoked by ionizing radiation. J Am Acad Dermatol. 1988;19:137–138. 46 Pasolini G, Lonati A, Manganoni AM, et al. Grover’s-like disease associated with radiotherapy. Euro J Dermatol. 1992;2:91–93. 47 Fearfield LA, Bunker CB. Radiotherapy and erythema nodosum. Br J Dermatol. 2000;142:189. 48 Takagawa S, Nakamura S, Yokozeki H, et al. Radiation-induced erythema nodosum. Br J Dermatol. 1999;140:372–373. 49 Dunst J, Steil B, Furch S, et al. Herpes zoster in breast cancer patients after radiotherapy. Strahlenther Onkol. 2000;176:513–516. 50 Van der Meij EH, Epstein JB, Hay J, et al. Sweet’s syndrome in a patient with oral cancer associated with radiotherapy. Eur J Cancer B Oral Oncol. 1996;32B:133– 136. 51 Vergara G, Vargas-Machuca I, Pastor MA, et al. Localization of Sweet’s syndrome in radiation-induced locus minoris resistentae. J Am Acad Dermatol. 2003;49:907– 909. 52 LeBoit PE. Subacute radiation dermatitis: a histologic imitator of acute cutaneous graft-versus-host disease. J Am Acad Dermatol. 1989;20:236–241.

36 Williams MS, Burk M, Loprinzi CL, et al. Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys. 1996;36:345–349.

53 Okamoto S, Takahashi S, Inoue T, et al. Cutaneous chronic graft-versus-host disease localized to the field of total lymphoid irradiation. Bone Marrow Transplant. 1996;17:111–113.

37 Jensen JM, Gau T, Schultze J, et al. Treatment of acute radiodermatitis with an oil-in-water emulsion following radiation therapy for breast cancer: a controlled, randomized trial. Strahlenther Onkol. 2011;187:378–384.

54 Socie G, Gluckman E, Cosset JM, et al. Unusual localization of cutaneous chronic graft-versus-host disease in the radiation fields in four cases. Bone Marrow Transplant. 1989;4:133–135.

38 Momm F, Weissenberger C, Bartelt S, et al. Moist skin care can diminish acute radiation-induced skin toxicity. Strahlenther Onkol. 2003;179:708–712.

55 van de Donk NW, van Dijk MR, Lokhorst HM. Localized graft-versus-host disease of the skin provoked by radiotherapy. Leuk Res. 2010;34:e266–e267.

39 Dirier A, Akmansu M, Bora H, et al. The effect of vitamin E on acute skin reaction caused by radiotherapy. Clin Exp Dermatol. 2007;32:571–573.

56 Zwaan FE, Jansen J, Noordijk EM. Graft-versus-host disease limited to area of irradiated skin. Lancet. 1980;1:1081–1082.

40 Hom DB, Adams G, Koreis M, et al. Choosing the optimal wound dressing for irradiated soft tissue wounds. Otolaryngol Head Neck Surg. 1999;121:591–598.

57 Tournillac I, Dandurand M, Guillot B. Bullous lichen sclerosus after radiotherapy. Ann Dermatol Venereol. 1998;125:121–123.

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58 Yates VM, King CM, Dave VK. Lichen sclerosus et atrophicus following radiation therapy. Arch Dermatol. 1985;121:1044–1047.

76 Alhathlool A, Hein R, Andres C, et al. Post-Irradiation morphea: case report and review of the literature. J Dermatol Case Rep. 2012;6:73–77.

59 Balabanova MB, Botev IN, Michailova JI. Subacute cutaneous lupus erythematosus induced by radiation therapy. Br J Dermatol. 1997;137:648–649.

77 Abu-Shakra M, Guillemin F, Lee P. Cancer in systemic sclerosis. Arthritis Rheum. 1993;36:460–464.

60 Rueda RA, Valencia IC, Covelli C, et al. Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy. Arch Dermatol. 1999;135:804–810. 61 Sherber NS, Wigley FM, Paget SA. Diffuse fasciitis with eosinophilia developing after local irradiation for breast cancer. Clin Rheumatol. 2009;28:729–732. 62 Steinert M, Gottlober P, Gall H, et al. [Subcutaneous calcifications after radiotherapy]. Hautarzt. 2001;52:518– 521. 63 Roa WH, Gardiner DB, Krause BE, et al. Generalized autosensitization to a localized eczematoid dermatitis induced by ionizing radiation. J Am Acad Dermatol. 1994;30:489–490. 64 Cohen PR, Prieto VG. Radiation port xanthogranuloma: solitary xanthogranuloma occurring within the irradiated skin of a breast cancer patient-report and review of cutaneous neoplasms developing at the site of radiotherapy. J Cutan Pathol. 2010;37:891–894. 65 Yoshizawa K, Kakinuma H. Verrucous trichilemmal tumour arising on chronic grenz ray dermatitis. Eur J Dermatol. 1997;7:589–592. 66 Comte C, Bessis D, Dereure O, et al. Urticaria pigmentosa localized on radiation field. Eur J Dermatol. 2003;13:408–409. 67 MacDonald A, Feiwel M. Cutaneous mastocytosis: an unusual radiation dermatitis. Proc R Soc Med. 1971;64:29– 30. 68 Soilleux EJ, Brown VL, Bowling J. Cutaneous mastocytosis localized to a radiotherapy field. Clin Exp Dermatol. 2009;34:111–112. 69 Reddy SM, Pui JC, Gold LI, et al. Postirradiation morphea and subcutaneous polyarteritis nodosa: case report and literature review. Semin Arthritis Rheum. 2005;34:728– 734. 70 Al-Mohanna H, Al-Khenaizan S. Permanent alopecia following cranial irradiation in a child. J Cutan Med Surg. 2010;14:141–143. 71 Lawenda BD, Gagne HM, Gierga DP, et al. Permanent alopecia after cranial irradiation: dose-response relationship. Int J Radiat Oncol Biol Phys. 2004;60:879– 887. 72 Severs GA, Griffin T, Werner-Wasik M. Cicatricial alopecia secondary to radiation therapy: case report and review of the literature. Cutis. 2008;81:147–153. 73 Chalmers D. A fatal case of erythema multiforme following deep x-ray therapy. Br J Dermatol. 1959;71:256–260.

78 Akay BN, Sanli H, Heper AO. Postirradiation linear morphoea. Clin Exp Dermatol. 2010;35:e106–e108. 79 Colver GB, Rodger A, Mortimer PS, et al. Post-irradiation morphoea. Br J Dermatol. 1989;120:831–835. 80 Ullen H, Bjorkholm E. Localized scleroderma in a woman irradiated at two sites for endometrial and breast carcinoma: a case history and a review of the literature. Int J Gynecol Cancer. 2003;13:77–82. 81 Smith KJ, Yeager J, Skelton HG. Localized scleroderma in breast cancer patients treated with supervoltage external beam radiation: radiation port scleroderma. J Am Acad Dermatol. 1997;37:806–808. 82 Kreft B, Wohlrab J, Radant K, et al. Unrecognized radiation-induced localized scleroderma: a cause of postoperative wound-healing disorder. Clin Exp Dermatol. 2009;34:e383–e384. 83 Mosterd K, Winnepenninckx V, Vermeulen A, et al. Morphea following surgery and radiotherapy: an evolving problem. J Eur Acad Dermatol Venereol. 2009;23:1099– 1101. 84 Carrasco L, Moreno C, Pastor MA, et al. Postirradiation pseudosclerodermatous panniculitis. Am J Dermatopathol. 2001;23:283–287. 85 Winkelmann RK, Grado GL, Quimby SR, et al. Pseudosclerodermatous panniculitis after irradiation: an unusual complication of megavoltage treatment of breast carcinoma. Mayo Clin Proc. 1993;68:122–127. 86 Ive FA. Metastatic carcinoma of cervix with acanthosis nigricans, bullous pemphigoid and hypertrophic pulmonary osteoarthropathy 297. Proc R Soc Med. 1963;56:910. 87 Ernst TM, Marsch WC. Develop of localized pemphigoid following radiation treatment (author’s transl). Dermatologica. 1982;164:73–81. 88 Frederich M. Hospice health care: management of a case of bullous pemphigoid utilizing the hospice interdisciplinary team. Hosp J. 1989;5:79–83. 89 Bourdon-Lanoy E, Roujeau JC, Joly P, et al. Bullous pemphigoid in young patients: a retrospective study of 74 cases. Ann Dermatol Venereol. 2005;132:115–122. 90 Emery EW, Hare PJ, Abadir R. Pemphigoid, bronchial neoplasm and radiotherapy. Proc R Soc Med. 1967;60:1271– 1272. 91 Furukawa F, Ozaki M, Imamura S, et al. Bullous pemphigoid associated with radiotherapy for esophageal carcinoma. Dermatologica. 1981;162:451–454.

74 DAVIS J, PACK GT. Erythema multiforme following deep x-ray therapy. AMA Arch Derm Syphilol. 1952;66:41–48.

92 Parikh SK, Ravi A, Kuo DY, et al. Bullous pemphigoid masquerading as acute radiation dermatitis: case report. Eur J Gynaecol Oncol. 2001;22:322–324.

75 Ransom DT, Cameron FG. Scleroderma, a possible contra-indication to lumpectomy and radiotherapy in breast carcinoma. Australas Radiol. 1987;31:317–318.

93 Srifi N, Benomar S, Zaghba N, et al. Generalized bullous pemphigoid induced by radiotherapy. Ann Dermatol Venereol. 2011;138:311–314.

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115 Acharya J, Lyon C, Bottomley DM. Folliculitis-perifolliculitis related to erlotinib therapy spares previously irradiated skin. J Am Acad Dermatol. 2009;60:154– 157. 116 Yalcin S, Dizdar O, Yalcin B, et al. Sparing of previously irradiated skin from erlotinib-induced acneiform rash. J Am Acad Dermatol. 2008;58:178–179. 117 Mydin AR, Armstrong JG. Acneiform rash secondary to cetuximab plus head and neck radiotherapy. Radiother Oncol. 2007;85:171. 118 Albright EC, Allday RW. Thyroid carcinoma after radiation therapy for adolescent acne vulgaris. JAMA. 1967;199:280–281. 119 Engels EP, Leavell U, Maruyama Y. Radiogenic acne and comedones. Radiol Clin Biol. 1974;43:48–55. 120 Finn OA. Localised acneiform eruption following X-ray irradiation. Br J Clin Pract. 1981;35:57–58. 121 Jansen T, Peter RU, Plewig G. Komedonen nach ioniserenden Strahlen. Akt Dermatol. 1996;22:210–212. 122 Swift S. Localized acne following deep x-ray therapy. AMA Arch Derm. 1956;74:97–98. 123 Trunnell TN, Baer RL, Michaelides P. Acneform changes in areas of cobalt irradiation. Arch Dermatol. 1972;106:73– 75. 124 Ambay A, Stratman E. Ionizing radiation-induced pemphigus foliaceus. J Am Acad Dermatol. 2006;54:251– 252. 125 Cianchini G, Lembo L, Colonna L, et al. Pemphigus foliaceus induced by radiotherapy and responsive to dapsone. J Dermatolog Treat. 2006;17:244–246. 126 Low GJ, Keeling JH. Ionizing radiation-induced pemphigus. Case presentations and literature review. Arch Dermatol. 1990;126:1319–1323. 127 Tagami H, Imamura S, Noguchi S, et al. Coexistence of peculiar pemphigus, myasthenia gravis and malignant thymoma. Dermatologica. 1976;152:181–190.

107 Myskowski PL, Safai B. Localized comedo formation after cobalt irradiation. Int J Dermatol. 1981;20:550–551.

128 Mseddi M, Bouassida S, Khemakhem M, et al. [Radiotherapy-induced pemphigus: a case report]. Cancer Radiother. 2005;9:96–98.

108 Stein KM, Leyden JJ, Goldschmidt H. Localized acneiform eruption following cobalt irradiation. Br J Dermatol. 1972;87:274–279.

129 Robbins AC, Lazarova Z, Janson MM, et al. Pemphigus vulgaris presenting in a radiation portal. J Am Acad Dermatol. 2007;56:S82–S85.

109 Adriaans B, du VA. Acne in an irradiated area. Arch Dermatol. 1989;125:1005.

130 Hunziker T, Zala L, Krebs A. [Roentgen ray-induced pemphigus vulgaris]. Hautarzt. 1988;39:308–310.

110 Hepburn NC. Dermatological problems in British troops during the Gulf War. Br J Dermatol. 1992;126:200–201.

131 Delaporte E, Piette F, Bergoend H. [Pemphigus vulgaris induced by radiotherapy]. Ann Dermatol Venereol. 1991;118:447–451.

111 Yoshii N, Kanekura T, Churei H, et al. Syringoma-like eccrine sweat duct proliferation induced by radiation. J Dermatol. 2006;33:36–39. 112 Friedman SJ, Su WP. Favre-Racouchot syndrome associated with radiation therapy. Cutis. 1983;31:306–310. 113 Walter JF. Cobalt radiation-induced comedones. Arch Dermatol. 1980;116:1073–1074. 114 Karrer S, Schafer CB, Allgauer M, et al. [Acne comedonica following radiation therapy]. Dtsch Med Wochenschr. 1998;123:527–530.

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132 Girolomoni G, Mazzone E, Zambruno G. Pemphigus vulgaris following cobalt therapy for bronchial carcinoma. Dermatologica. 1989;178:37–38. 133 Krain LS, Bierman SM. Pemphigus vulgaris and internal malignancy. Cancer. 1974;33:1091–1099. 134 Badri T, Hammami H, Lachkham A, et al. Radiotherapy-induced pemphigus vulgaris with autoantibodies targeting a 110 kDa epidermal antigen. Int J Dermatol. 2011;50:1475–1479.

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135 Leikin JB, McFee RB. A primer for nuclear terrorism preparedness. In: Leikin JB, McFee RB, Kerscher R, eds. Handbook of Nuclear, Biological and Chemical Agent Exposure. Boca Raton, FL; CRC Press; 2007:526–555.

152 Schaffer JV, Carroll C, Dvoretsky I, et al. Postirradiation morphea of the breast presentation of two cases and review of the literature. Dermatology. 2000;200:67–71.

136 Ardern-Jones MR, Black MM. Widespread morphoea following radiotherapy for carcinoma of the breast. Clin Exp Dermatol. 2003;28:160–162.

153 Seale M, Koh W, Henderson M, et al. Imaging surveillance of the breast in a patient diagnosed with scleroderma after breast-conserving surgery and radiotherapy. Breast J. 2008;14:379–381.

137 Bleasel NR, Stapleton KM, Commens C, et al. Radiationinduced localized scleroderma in breast cancer patients. Australas J Dermatol. 1999;40:99–102.

154 Trattner A, Figer A, David M, et al. Circumscribed scleroderma induced by postlumpectomy radiation therapy. Cancer. 1991;68:2131–2133.

138 Cheah NL, Wong DW, Chetiyawardana AD. Radiation-induced morphea of the breast: a case report. J Med Case Reports. 2008;2:136.

155 Walsh N, Rheaume D, Barnes P, et al. Postirradiation morphea: an underrecognized complication of treatment for breast cancer. Hum Pathol. 2008;39:1680– 1688.

139 Cooper SG, Denham JW. Progressive systemic sclerosis (diffuse scleroderma) and radiotherapy. Br J Radiol. 1990;63:804–805. 140 Dancey AL, Waters RA. Morphea of the breast. Two case reports and discussion of the literature. J Plast Reconstr Aesthet Surg. 2006;59:1114–1117. 141 Davis DA, Cohen PR, McNeese MD, et al. Localized scleroderma in breast cancer patients treated with supervoltage external beam radiation: radiation port scleroderma. J Am Acad Dermatol. 1996;35:923–927. 142 De G, V, Santi R, Grazzini M, et al. Synchronous angiosarcoma, melanoma and morphea of the breast skin 14 years after radiotherapy for mammary carcinoma. Acta Derm Venereol. 2010;90:283–286.

156 Wernicke AG, Goltser Y, Trichter S, et al. Morphea as a consequence of accelerated partial breast irradiation. Clin Breast Cancer. 2011;11:67–70. 157 Woo DK, Reilly GD, Elenitsas R. Breast erythema and induration in a 77-year-old woman. Arch Dermatol. 2006;142:101–106. 158 Bernhardt M. Bullous pemphigoid after irradiation therapy. J Am Acad Dermatol. 1989;20:141–142. 159 Cabrera-Rodriguez JJ, Munoz-Garcia JL, Quiros RJ, et al. Radio-induced bullous pemphigoid. Clin Transl Oncol. 2010;12:66–68.

143 Dubner S, Bovi J, White J, et al. Postirradiation morphea in a breast cancer patient. Breast J. 2006;12:173–176.

160 Calikoglu E, Anadolu R, Erdem C, et al. Localized bullous pemphigoid as an unusual complication of radiation therapy. J Eur Acad Dermatol Venereol. 2002;16:646– 647.

144 Forbes AM, Woodrow JC, Verbov JL, et al. Carcinoma of breast and scleroderma: four further cases and a literature review. Br J Rheumatol. 1989;28:65–69.

161 Callens A, Vaillant L, Machet MC, et al. Localized atypical pemphigoid on lymphoedema following radiotherapy. Acta Derm Venereol. 1993;73:461–464.

145 Gollob MH, Dekoven JG, Bell MJ, et al. Postradiation morphea. J Rheumatol. 1998;25:2267–2269.

162 Clayton AS, Angeloni V. Bullous pemphigoid in a previously irradiated site. Cutis. 1998;61:73–76.

146 Herrmann T, Gunther C, Csere P. Localized morphea-a rare but significant secondary complication following breast cancer radiotherapy. Case report and review of the literature on radiation reaction among patients with scleroderma/morphea. Strahlenther Onkol. 2009;185:603–607.

163 Cliff S, Harland CC. Bullous pemphigoid following radiotherapy. Clin Exp Dermatol. 1995;20:360–361.

147 Kushi J, Csuka ME. Generalized morphea after breast cancer radiation therapy. Case Rep Rheumatol. 2011;2011:951948. 148 Laetsch B, Hofer T, Lombriser N,, et al. Irradiation-induced morphea: x-rays as triggers of autoimmunity. Dermatology. 2011;223:9–12 149 Mayr NA, Riggs CE, Jr, Saag KG, et al. Mixed connective tissue disease and radiation toxicity. A case report. Cancer. 1997;79:612–618. 150 Morganroth PA, Dehoratius D, Curry H, et al. Postirradiation morphea: a case report with a review of the literature and summary of the clinicopathologic differential diagnosis. Am J Dermatopathol. 2013 Oct 4. [Epub ahead of print] 151 Robertson JM, Clarke DH, Pevzner MM, et al. Breast conservation therapy. Severe breast fibrosis after radiation therapy in patients with collagen vascular disease. Cancer. 1991;68:502–508.

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164 Cliff S, Harland CC, Fallowfield ME, et al. Localised bullous pemphigoid following radiotherapy. Acta Derm Venereol. 1996;76:330–331. 165 Delaporte E, Podglajen-Wecxsteen O, Nicolas JF, et al. [Localized pemphigoid after radiotherapy]. Ann Dermatol Venereol. 1993;120:774–776. 166 Folliero G, Zurlo A, Amanti C, et al. Bullous pemphigoid induced by radiation therapy. Clin Oncol (R Coll Radiol). 1995;7:266–267. 167 Honl BA, Elston DM. Autoimmune bullous eruption localized to a breast reconstruction site: response to niacinamide. Cutis. 1998;62:85–86. 168 Isohashi F, Konishi K, Umegaki N, et al. A case of bullous pemphigoid exacerbated by irradiation after breast conservative radiotherapy. Jpn J Clin Oncol. 2011;41:811–813. 169 Jappe U, Bonnekoh B, Gollnick H. Guess what! Initially localized bullous pemphigoid at the irradiation site of breast carcinoma. Eur J Dermatol. 1999;9:139–141. 170 Knoell KA, Patterson JW, Gampper TJ, et al. Localized bullous pemphigoid following radiotherapy for breast carcinoma. Arch Dermatol. 1998;134:514–515.

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171 Laimer M, Nischler E, Anderhuber K, et al. [Unilateral localized bullous pemphigoid following radiotherapy]. Hautarzt. 2009;60:494–497.

191 Saint-Jean M, Quereux G, Peuvrel P, et al. [Post-radiotherapy erosive lesion]. Ann Dermatol Venereol. 2008;135:780–782.

172 Leconte-Boulard C, Dompmartin A, Verneuil L, et al. [Localized bullous pemphigoid following radiotherapy]. Ann Dermatol Venereol. 2000;127:70–72.

192 Vigna-Taglianti R, Russi EG, Denaro N, et al. Radiationinduced pemphigus vulgaris of the breast. Cancer Radiother. 2011;15:334–337.

173 Melani L, Giomi B, Antiga E, et al. Radiation therapy as a trigger factor for initially localized bullous pemphigoid. Breast J. 2005;11:485–486.

193 Garcia-Silva J, Velasco-Benito JA, Pena-Penabad C, et al. Basal cell carcinoma in a girl after cobalt irradiation to the cranium for acute lymphoblastic leukemia: case report and literature review. Pediatr Dermatol. 1996;13:54–57.

174 Ohata C, Shirabe H, Takagi K, et al. Localized bullous pemphigoid after radiation therapy: two cases. Acta Derm Venereol. 1997;77:157. 175 Olsha O, Lijoretzky G, Grenader T. Bullous pemphigoid following adjuvant radiotherapy for breast cancer. Breast J. 2011;17:204–205. 176 Sheerin N, Bourke JF, Holder J, et al. Bullous pemphigoid following radiotherapy. Clin Exp Dermatol. 1995;20:80– 82. 177 van Geest AJ, Steijlen PM. Parapemphigus na radiotherapie. Nederlands Tijdschrift voor Dermatologie en Venereologie. 2005;15:90–91. 178 Aversa AJ, Nagy R. Localized comedones following radiation therapy. Cutis. 1983;31:296–303. 179 Breit S, Flaig MJ, Wolff H, et al. Favre-Racouchot-like disease after radiation therapy. J Am Acad Dermatol. 2003;49:117–119. 180 Larsen FS, Heydenreich G, Christiansen JV. Comedo formation following cobalt irradiation. Dermatologica. 1979;158:287–292. 181 Nasca MR, Micali G, Ferrau F. Steroid acne sparing an area of previous irradiation. Acta Derm Venereol. 1995;75:495.

194 Masuno Y, Matsumura Y, Katoh M, et al. Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) mimicking bullous pemphigoid in a patient with anaplastic large cell lymphoma. Eur J Dermatol. 2011;21:421–422. 195 Werchniak AE, Perry AE, Dinulos JG. Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy (EPPER) in a patient with breast cancer. J Am Acad Dermatol. 2006;54:728–729. 196 Batchelor JM, Fife K, Burrows NP. Localized porokeratosis secondary to ionizing radiotherapy for prostate carcinoma. Arch Dermatol. 2010;146:1318–1320. 197 Burns DA. Post-irradiation digitate keratoses. Clin Exp Dermatol. 1986;11:646–649. 198 Cockerell CJ. Induction of disseminated superficial actinic porokeratosis by phototherapy for psoriasis. J Am Acad Dermatol. 1991;24:301–302. 199 Fields LL, White CR, Jr., Maziarz RT. Rapid development of disseminated superficial porokeratosis after transplant induction therapy. Bone Marrow Transplant. 1995;15:993–995.

182 Ronchese F. Cicatrical comedos and milia. Arch Derm Syphilol. 1950;61:498–500.

200 Halper S, Medinica M. Porokeratosis in a patient treated with total body electron beam radiation. J Am Acad Dermatol. 1990;23:754–755.

183 Aguado L, Marquina M, Pretel M, et al. Lesions of pemphigus vulgaris on irradiated skin. Clin Exp Dermatol. 2009;34:e148–e150.

201 James AJ, Clarke LE, Elenitsas R, et al. Segmental porokeratosis after radiation therapy for follicular lymphoma. J Am Acad Dermatol. 2008;58:S49–S50.

184 Bar-Sela G, Baum S, Trau H, et al. Pemphigus vulgaris of the larynx and upper gastro-intestinal tract induced by radiotherapy. Acta Oncol. 2008;47:324–326.

202 Lee A, Griffiths WAD. Localised superficial porokeratosis caused by radiotherapy. Retinoids. 2001;17:79–80.

185 Breitkopf C, Suter L. [Unusual radiation reaction after soft roentgen radiotherapy in a patient with pemphigus vulgaris]. Hautarzt. 1995;46:502–504. 186 Crovato F, Desirello G, Nazzari G, et al. Linear pemphigus vulgaris after X-ray irradiation. Dermatologica. 1989;179:135–136. 187 David M, Feuerman EJ. Induction of pemphigus by X-ray irradiation. Clin Exp Dermatol. 1987;12:197–199. 188 Krauze E, Wygledowska-Kania M, Kaminska-Budzinska G, et al. [Radiotherapy induced pemphigus vulgaris]. Ann Dermatol Venereol. 2003;130:549–550.

203 Mizuno K, Okamoto H, Imamura S. Postirradiation multiple minute digitate hyperkeratoses. Clin Exp Dermatol. 1995;20:425–427. 204 Pujol RM, Perez-Losada E, Matias-Guiu X, et al. Postirradiation multiple minute digitate porokeratosis. J Cutan Med Surg. 2001;5:126–130. 205 Romani J, Pujol RM, Casanova JM, et al. Disseminated superficial porokeratosis developing after electron-beam total skin irradiation for mycosis fungoides. Clin Exp Dermatol. 1996;21:310–312. 206 Vestey JP, Hunter JA, Mallet RB, et al. Post irradiation conical keratosis. J R Soc Med. 1989;82:166–167.

189 Lunder M. Una rara combinazione del pemfigo con cancro della mamella. Minerva Dermatol. 1973;108;576– 577.

207 Brodkin RH, Bleiberg J. Grenz rays and lichen planus. Report of a case of isomorphic phenomenon following grenz ray therapy. Arch Dermatol. 1965;91:149–150.

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208 Eichbaum M, Harms W, Bolz S, et al. Generalized lichen ruber planus--induced by radiotherapy of the breast? Onkologie. 2006;29:521–523.

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209 Kim JH, Krivda SJ. Lichen planus confined to a radiation therapy site. J Am Acad Dermatol. 2002;46:604–605. 210 Morar N, Francis ND. Generalized lichen planus induced by radiotherapy: shared molecular mechanisms? Clin Exp Dermatol. 2009;34:e434–e435. 211 Perez E, Barnadas MA, Garcia-Patos V, et al. Kaposi’s sarcoma in a patient with erythroblastopenia and thymoma: reactivation after topical corticosteroids. Dermatology. 1998;197:264–267. 212 Pretel M, Espana A. Lichen planus induced by radiotherapy. Clin Exp Dermatol. 2007;32:582–583. 213 Sciallis GF, Loprinzi CL, Davis MD. Progressive linear lichen planus and metastatic carcinoma. Br J Dermatol. 2005;152:399–401. 214 Shurman D, Reich HL, James WD. Lichen planus confined to a radiation field: the “isoradiotopic” response. J Am Acad Dermatol. 2004;50:482–483. 215 Vergilis-Kalner IJ, Sharma V, Sethi A. Lichen planus arising in radiation therapy treatment sites. Cutis. 2008;82:353–355. 216 Wang Y, Chen H, Wang B, et al. Oral and esophageal lichen planus following radiotherapy of nasopharyngeal carcinoma. Acta Derm.Venereol. 2011;91:94–95.

217 Koo SW, Suh CO, Hann SK. Vitiligo following radiotherapy for carcinoma of the breast. Br J Dermatol. 1996;135:852–853. 218 Levine EL, Ribeiro GG. Vitiligo and radiotherapy: the Koebner phenomenon demonstrated in patients with vitiligo undergoing radiotherapy for carcinoma of the breast. Clin Oncol (R Coll Radiol). 1994;6:133–134. 219 Munshi A, Jain S, Budrukkar A, et al. Radiotherapy-induced depigmentation in a patient with breast cancer. Indian J Cancer. 2007;44:157–158. 220 Pajonk F, Weissenberger C, Witucki G, et al. Vitiligo at the sites of irradiation in a patient with Hodgkin’s disease. Strahlenther Onkol. 2002;178:159–162. 221 Polat M, Yalcin B, Alli N. Vitiligo at the site of radiotherapy for nasopharyngeal carcinoma. Am J Clin Dermatol. 2007;8:247–249. 222 Roth WG. [Vitiligo following x-irradiation of multiple melanoma metastases]. Hautarzt. 1968;19:178–180. 223 Weitzen R, Pfeffer R, Mandel M. Benign lesions in cancer patients: Case 3. Vitiligo after radiotherapy for breast cancer in a woman with depigmentation disorder. J Clin Oncol. 2005;23:644.

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Volume 13 • Issue 5

SELF ASSESSMENT EXAMINATION W. Clark Lambert, MD, PhD For each numbered question, choose the single best lettered response.

3. Between 1930 and 1959 the entity most commonly treated with radiation was: a. Acne. b. Eczema. c. Psoriasis. d. Tinea capitis. e. Tinea cruris.

5. Acute radiation syndrome has been observed in each of the following populations, except: a. Patients treated with local radiotherapy. b. Survivors of the atomic bomb attack on Hiroshima, 1945. c. Survivors of the atomic bomb attack on Nagasaki, 1945. d. Survivors of the nuclear power plant disaster in Chernobyl, April, 1986. e. Survivors of the nuclear power plant disaster in Fukushima, November, 2011. ANSWERS TO EXAMINATION: 5. a

2. Severe burns on contact with skin are particularly a concern with: a. Alpha particles. b. Beta particles. c. Gamma rays. d. Neutrons. e. X rays.

4. Drugs which have been associated with increased radiosensitivity include: a. Actinomycin D. b. Bleomycin. c. Doxorubicin. d. 5-Fluorouracil. e. Methotrexate. f. All of the above.

1. e 2. b 3. d 4. f

1. Disorders reported to occur following radiation therapy include: a. Acneiform eruptions. b. Bullous pemphigoid. c. Morphea. d. Pemphigus vulgaris. e. All of the above.

VINTAGE LABEL

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

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


September/October 2015

Volume 13 • Issue 5

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

Cancer From the Cut: How Surgical Flaps Can Move Incidental Tumors to Different Locations Ann M. John, BA;1 Parmvir Singh, BS;1 Divya Sharma, BA;1 W. Clark Lambert, MD, PhD2 “If you take shortcuts, you get cut short.”––Gary Busey, American actor

A

number of surgical flaps involve transposing areas of skin over a defect.1 In the process of moving skin cells, incidental tumors in the area of excision may also be dispersed. A patient may subsequently present with two or more distinct neoplasms that are actually from the original incidental tumor. We provide a hypothetical analysis for the spread of cancer after the formation of a surgical flap, using the Z-plasty as our example.

gular skin flaps are subsequently formed.8 The angle between the central and lateral limbs should range from 30 to 75 degrees. The 60-degree angle is generally used, as it results in a scar realignment of 90 degrees and avoids difficulty in transposing flaps. Lateral limbs are usually between 6 mm and 10 mm in length. Multiple Z-plasties can be performed for larger scars to avoid this complication8,9; however, multiple Z-plasties result in more manipulation of the skin.

Background

After the scar is excised and limb incisions are made, the central incision is transposed so that the new location is perpendicular to the original scar. This is achieved by lifting and transposing the two triangular flaps. In the process, there is a gain of length and dispersion of the scar (Figure 1). There are several variations of the Z-plasty, including double opposing Z-plasties, use of unequal triangular flaps, four-flap Z-plasty, compound Z-plasty, and planimetric Z-plasty. These variations allow for greater versatility of the Z-plasty and the type of scars or wounds it can correct.2,3,10

The first documentation of Z-plasty dates to the early 1800s, but it has evolved over time to a useful and quick procedure to lengthen skin and change the direction of scars.2 There are three major uses of the Z-plasty: (1) to lengthen a scar or release the webbing and contracture of a scar, (2) to disperse a scar to make it less noticeable, and (3) to realign a scar by changing the direction to align it with existing skin tension lines. Z-plasty is especially useful for areas with little tissue to spare, because it does not require the excision of more tissue and, in fact, results in a gain of skin length.4 Within dermatology, Zplasty is used for many cosmetic procedures, such as correcting an ectropion, repairing a bifid earlobe, reconstructing regions after tumor removal, correcting lip misalignment, and minimizing scars.1,5,6 The technique involves three incisions in a Z-formation, with the central incision aligning with the scar or area of excision.7 The two remaining incisions are the lateral limbs and should be relatively equal in length to prevent skin puckering. Two trian-

Unforeseen Problems The Z-plasty procedure is not without complications, which include infection, bleeding, and dissatisfying aesthetic outcome7; however, can Z-plasty be associated with spreading of cancer cells? The development of skin cancers within scars from burns, vaccinations, and other injuries has been well reported.11 Of the reported cases of malignancy within scars, 71% were squamous cell carcinomas, 12% were basal cell carcinomas, and 6% were cutaneous melanomas.12 In addition, specific burn scar carcinomas, including Kangri, Kang, and Kairo cancers, have been

From Rutgers-New Jersey Medical School,1 and the Departments of Dermatology and of Dermatology and Laboratory Medicine, Rutgers-New Jersey Medical School,2 Newark, NJ Address for Correspondence: W. Clark Lambert, MD, PhD, Room H576 Medical Science Building, Rutgers University – New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103 • E-mail: lamberwc@njms.rutgers.edu

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PERILS OF DERMATOPATHOLOGY with chronic osteomyelitis, scars from epidermolysis bullosa, and scars from excision of pre-existing cancers.11,12 With the malignant potential of scars, surgeons generally attempt to ensure that tissue is clear of any such malignancy prior to manipulating it. The rotation of tissue may transport cells from one area to another, thus mobilizing cancer cells in the area of the scar to other areas around the scar (Figure 2). This is the case with any surgical flap that involves transposing skin from one area to another. In addition, by creating new incisions to negate one scar, there is a risk of development of malignancy in the new scars.

Figure 1. The technique of classic Z-plasty. In panel 1, a central incision is made at the area of the scar, with two equilateral incisions made at various angles. In this case, the lateral limbs are cut at 60-degree angles to the central incision. Two triangular flaps are formed. In panel 2, these flaps are lifted and transposed. The end result is shown in panel 3, with the central incision perpendicular to the original incision and a consequent gain in length of the original scar. As seen, three new incisions and thus scars are formed. The locations of original points after performing Z-plasty are designated with letters A–F.

Conclusions While the development of a malignancy from such procedures is remote, the surgeon should have to take this into account. The clinician should be aware that a seemingly different malignancy in a patient with a scar from a surgical flap may actually be the result of an existing tumor at the original site of excision. References 1 Barreiros H, Goulao J. Z-Plasty: useful uses in dermatologic surgery. An Bras Dermatol. 2014;89:187–188. 2 Hove CR, Williams EF 3rd, Rodgers BJ. Z-plasty: a concise review. Facial Plast Surg. 2001;17:289–294. 3 Aasi SZ. Z-plasty made simple. Dermatol Res Pract. 2010;2010:982623. 4 Lee KK, Mehrany K, Swanson NA. Surgical revision. Dermatol Clin. 2005;23:141–150. 5 Wentzell JM, Lund JJ. Z-plasty innovations in vertical lip reconstructions. Dermatol Surg. 2011;37:1646–1662. 6 Sokol JA, Schwarcz RM. A better way to repair torn earlobes using a modified z-plasty. Dermatol Surg. 2011;37:1506–1508. 7 Salam GA, Amin JP. The basic Z-plasty. Am Fam Physician. 2003;67:2329–2332. 8 Shockley WW. Scar revision techniques: z-plasty, w-plasty, and geometric broken line closure. Facial Plast Surg Clin North Am. 2011;19:455–463.

Figure 2. These three diagrams demonstrate the incisions of the classic Z-plasty. In each example in the top row, there is an incidental tumor in the central area of excision (circle). The bottom row demonstrates where the tumor cells can be transported (semicircles) after transposing tissue.

9 Suzuki S, Um SC, Kim BM, et al. Versatility of modified planimetric Z-plasties in the treatment of scar with contracture. Br J Plast Surg. 1998;51:363–369. 10 Garg S, Dahiya N, Gupta S. Surgical scar revision: an overview. J Cutan Aesthet Surg. 2014;7:3–13.

reported.11 The etiology of these cancers is most likely attributable to proliferation after chronic inflammation of tissue with continuous exposure to toxins and compromised vascularization. All together, these factors result in an environment with low immunologic surveillance in the area of the scar.11,13 Specifically, cancers can arise in Marjolin’s ulcers, nonhealing wounds, scars from discoid lupus erythematosus, sinus tracts in patients SKINmed. 2015;13:377–378

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11 Wallingford SC, Olsen CM, Plasmeijer E, Green AC. Skin cancer arising in scars: a systematic review. Dermatol Surg. 2011;37:1239–1244. 12 Kowal-Vern A, Criswell BK. Burn scar neoplasms: a literature review and statistical analysis. Burns. 2005;31:403– 413. 13 O’Byrne KJ, Dalgleish AG. Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer. 2001;85:473–483.

How Surgical Flaps Can Move Incidental Tumors


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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.

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September/October 2015

Volume 13 • Issue 5

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

Apremilast (Otezla) Noah Scheinfeld, MD, JD;1 William Abramovits, MD;2 Aditya K. Gupta, MD, PhD3

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premilast, is an oral agent that decreases and modulates inflammation by inhibiting phosphodiesterase type IV (PDE4), one of the major phosphodiesterases expressed in leukocytes. PDE4 inhibitors cause accumulation of intracellular cyclic adenosine monophosphate (cAMP).1 This effect is anti-inflammatory. The reason that inhibiting cAMP production ameliorates psoriasis is unknown.

Dosing The dosing schedule for PS and PsA without renal impairment is initiated incrementally, with a maintenance dosage of 30 mg twice daily (BID) (Table I). In patients with severe renal impairment, the recommended dosage is 10 mg on day 1, 20 mg on day 2, and 30 mg once daily thereafter.2 Pivotal Trial for PsA Phase III Data

Clinical Implications The US Food and Drug Administration approved Calgene’s apremilast (Otezla; Calgene Corporation, Summit, NJ) in patients older than 18 years with active psoriatic arthritis (PsA) on March 21, 2014, and for psoriasis (PS) on September 23, 2014, for the treatment of patients with moderate to severe plaque PS who could be candidates for phototherapy or systemic therapy.2 Apremilast’s package insert does not require or suggest laboratory testing before use, distinguishing apremilast from other systemic drugs for PS and PsA. Mechanism of Action PDE4 is an inflammatory feeder of PsA and PS. It induces significant cutaneous reductions in CD11c, CD3, and CD56, indicating suppression of myeloid dendritic cells, T cells, and natural killer (NK) cells or NK T-cell infiltration, suggesting a downregulation of interleukin (IL) 23/Th17 and Th22 response pathways.3 Apremilast blocks the synthesis of several proinflammatory cytokines and chemokines, such as tumor necrosis factor α (TNF-α), IL-23, CXCL9, and CXCL10 in multiple cell types including human rheumatoid synovial cells.1 As opposed to TNF-α, apremilast modulates levels of mRNA expression.3 Apremilast also interferes with the production of leukotriene B4, inducible nitric oxide synthase, and matrix metalloproteinase, reducing complex inflammatory processes.4 The specific implications of this activity on the pathophysiology of PS are unknown.

Safety and efficacy were confirmed in a 24-week, pivotal, placebo-controlled study.5 Patients continued taking existing methotrexate, leflunomide, and/or sulfasalazine. Participants were randomized (1:1:1) to placebo, apremilast 20 mg BID, or apremilast 30 mg BID. The primary outcome measure was an American College of Rheumatology Joint Severity Score (ACR) of 20 at week 16. Patients taking placebo were then placed on apremilast. Significantly more patients in the apremilast 20-mg BID group (31%) and apremilast 30-mg BID group (40%) achieved ACR20 than those in the placebo group (19%). The 30-mg group had higher and more consistent response rates. Safety and utility was demonstrated in phase II and III PS studies. Phase II Trials The first study enrolled 30 participants in a 24-week open-label trial.3 Mean percent improvements from baseline were 59% for Psoriasis Area and Severity Index (PASI) and 53% for body surface area. At week 12, a total of 67% of patients had a ≥1-point improvement in static Physician’s Global Assessment (PGA) score, meeting treatment effect criterion. Most adverse events were mild and resolved with treatment cessation. The second study was a 16-week, placebo-controlled trial of 352 patients with moderate to severe plaque PS.6 Participants were

From the Department of Dermatology Weill Cornell Medical College, New York, NY;1 the Department of Medicine (Dermatology) Baylor University Medical Center, Dallas, TX;2 and the Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario3 Address for Correspondence: Noah Scheinfeld, MD, JD, Weill Cornell Medical College, 150 West 55th Street, New York, NY 10019 • E-mail: scheinfeld@earthlink.net

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Table I. Dosing Schedule for Apremilast Day 1

Day 2

Day 3

Day 4

Day 6 and Thereafter

Day 5

AM

AM

PM

AM

PM

AM

PM

AM

PM

AM

PM

10 mg

10 mg

10 mg

10 mg

20 mg

20 mg

20 mg

20 mg

30 mg

30 mg

30 mg

Table II. Summary of PSOR Trial Data for PASI and sPGA2 PASI-75 for Apremilast

PASI-75 for Placebo

sPGA Score for Apremilast

sPGA Score for Placebo

PSOR-1, No. (%)

186 (33.1)

15 (5.3)

122 (27.7)

11 (3.9)

PSOR-2, No. (%)

79 (28.8)

8 (5.8)

56 (20.4)

6 (4.4)

Abbreviations: PASI, Psoriasis Area and Severity Index; sPGA, Static Physician Global Assessment. TNF-α inhibitors can cause headache and fatigue. Apremilast’s side effects include insomnia and depression to a far greater extent than any biologic.

randomized to placebo or apremilast 10 mg, 20 mg, or 30 mg BID. Outcome measures were improvements in Dermatology Life Quality Index (DLQI), pruritus visual analog scale, and 36Item Short-Form Health Survey (SF-36) to assess health-related quality of life. Investigators analyzed changes from baseline and patients reported improvements in minimum clinically important differences (MCIDs). DLQI improved with apremilast 20 mg BID (–5.9) and 30 mg BID (–4.4) compared with placebo (–1.9), with more patients reporting improvements in MCIDs (20 mg BID, 49.4%; 30 mg BID, 44.3%) vs placebo (25.0%). Pruritus scores improved with apremilast 20 mg BID (–35.5%) and 30 mg BID (–43.7%) vs placebo (–6.1%). SF-36 mental component summary scores and Bodily Pain, Mental Health, and Role-Emotional domains improved with all apremilast doses; social functioning improved with apremilast 20 or 30 mg BID; and physical functioning improved with apremilast 20 mg BID. The third trial was a 12-week, multicenter, double-blind, placebo-controlled study of 259 patients with PS randomized 1:1:1 to placebo or apremilast 20 mg once daily (QD) or BID.7 Apremilast 20 mg BID achieved a PASI-75 score in 24.4% of patients vs placebo (10.3%). The average reduction in PASI score from baseline was 17.4% for placebo, 30.3% for apremilast 20 mg QD, and 52.1% for apremilast 20 mg BID. A phase IIb, multicenter, randomized, placebo-controlled, doseranging study included 89 psoriatic patients aged 18 years and older with moderate to severe PS randomly assigned in a 1:1:1:1 ratio to receive oral placebo or apremilast 10 mg, 20 mg, or 30 mg BID. At week 16, PASI-75 was achieved in 6% of patients assigned placebo, 11% of patients assigned 10 mg BID, 29% SKINmed. 2015;13:381–384

of patients assigned 20 mg BID, and 41% of patients assigned 30 mg BID. The effect of apremilast 10 mg vs placebo was not significant. Phase III Trials Two studies (PSOR-1 and PSOR-2) were conducted in 1257 patients 18 years and older with moderate to severe plaque PS.9 PSOR-1 enrolled 844 patients and PSOR-2 enrolled 413 patients. In both studies, patients were randomized 2:1 to apremilast 30 mg BID or placebo for 16 weeks. Both trials assessed the proportion of patients who achieved PASI-75 at week 16 and who achieved a subjective PGA score of clear (0) or almost clear (1) at week 16 (Table II). Severe worsening of PS (rebound) occurred in 0.3% of patients (4 of 1184) following discontinuation of apremilast; however, retrospective analysis of pooled data from these studies showed that 14% of patients experienced a rebound after discontinuation. Treatment-Emergent Adverse Events As an oral medication, apremilast is associated with treatmentemergent adverse events (TEAEs) including diarrhea (~8.5%), nausea (~8%), vomiting (~2%), and abdominal pain (~1.3%). As an immunosuppresive agent, the rate of upper respiratory tract infection (~2.1) and nasopharngytis (~1.3%) are unsurprising and not clinically significant. Other TEAEs (0.5%–2%) include fatigue, tension headache, decreased appetite, worsening of depression, and insomnia; the basis of which is not understood. Other treatments for PS, such as anti–IL-17, anti-IL12/23, and TNF-α inhibitors, can cause headache and fatigue, although less commonly than insomnia and depression with apremilast.

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Apremilast does not trigger or facilitate opportunistic infections. Apremilast can induce weight loss, which physicians must continuously assess. It occurs over 24 weeks, with a 5% to 10% weight decrease in 10% of patients (vs 3.3% in patients taking placebo). Worsening depression, suicidal thoughts, and other mood changes may occur. Risks and benefits of therapy must be carefully evaluated by a health professional before apremilast is prescribed to patients with a history of depression and/or suicidal ideation. Apremilast is pregnancy category C. Apremilast interacts with CYP4AP3 inducers (eg, rifampin), leading to a loss of efficacy. This is a disadvantage for patients on polypharmacy, as compared with biologics or phototherapy, which have no effect on the cytochrome system. Apremilast 52-Week and 104-Week Data for PsA and PS In the Psoriatic Arthritis Long-Term Assessment of Clinical Efficacy 1 (PALACE 1) trial,11 84% (144 of 171) of patients who completed 52 weeks of 30-mg twice-daily therapy continued to receive apremilast at 104 weeks. Improvements in efficacy measures observed at 52 weeks were sustained through 104 weeks of treatment. At week 104, among patients receiving apremilast 30 mg BID, the ACR-20 response rate was 65.3%. ACR-50 and ACR-70 were 34% and 19.6%, respectively.11 Similar findings were observed in PALACE 4, where nearly 84% (168 of 201) of patients naive to disease-modifying antirheumatic drugs who completed 1 year of apremilast 30 mg BID monotherapy continued to receive it at 2 years. At week 104, among patients taking apremilast 30 mg BID monotherapy, an ACR-20, ACR-50, and ACR-70 was reached by 61.4%, 40.7%, and 19.2% of patients, respectively. Improvements in PS were maintained in PALACE 1 and 4.11 At week 104 in the PALACE 1 and 4 trials, respectively, rates of diarrhea were 1.8% and 2.0%, nausea 0.6% and 2.0%, headache 4.7% and 1.0%, and urinary tract infection 4.7% and 4.5%. Serious adverse events occurred in 4.7% and 5.0% of patients, respectively.11 Nail and Scalp PS Apremilast significantly improved nail and scalp PS and healthrelated quality-of-life measures in the phase III Study to Evaluate Safety and Effectiveness of Oral Apremilast (CC-10004) in Patients With Moderate to Severe Plaque Psoriasis (ESTEEM).12 Investigators assessed the effects of apremilast in 558 patients with nail PS and in 563 patients with at least moderate scalp PS. After 16 weeks of treatment, patients taking apremilast 30 mg BID had significantly greater improvements in Nail Psoriasis Severity SKINmed. 2015;13:381–384

Index scores than those taking placebo, showing an improvement of 22.5% vs a worsening of 6.5%, respectively (P<.0001). Improvement continued through 32 weeks of treatment for patients taking apremilast 30 mg BID (43.6%). Scalp PS also improved with apremilast 30 mg BID; after 16 weeks, significantly more patients taking apremilast 30 mg achieved a scalp PGA score of clear or almost clear, compared with those taking placebo (46.5% vs.17.5%, respectively; P<.0001). This effect was maintained for patients taking apremilast through week 32. In a separate analysis, the treatment with apremilast of 844 patients in ESTEEM 1 also significantly improved health-related quality of life, as assessed by a variety of standardized measurements, including the DLQI, Patient Health Questionnaire (PHQ-8), the European Quality of Life 5 Dimensions Questionnaire (EQ-5D), and the SF-36 mental component summary. Significant improvements in these measurement tools were seen after 16 weeks on apremilast and maintained through 32 weeks. Patients initially treated with placebo for 16 weeks who were then treated with apremilast for a subsequent 16 weeks also showed improvements in these measures. In these analyses of ESTEEM 1, the overall safety and tolerability profile of apremilast in patients with moderate to severe PS was consistent with previously reported findings. Conclusions For patients with PS and/or PsA who have contraindications to TNF-α inhibitors or prefer an oral agent, apremilast should be considered. While methotrexate may limit antibody induction by biologics, apremilast has not shown a similar effect. Apremilast is less clinically effective for PS than ustekinumab. The fact that apremilast is an oral agent appeals to some PS patients. Participants still experience immunosuppressive effects and may require annual tuberculosis testing. Some patients seem willing to substitute five ustekinumab injections the first year of therapy and four a year thereafter for improved efficacy. There are ustekinumab failures, where apremilast could be an alternative. Another alternative is secukinumab, an IL-17 blocker, which reached the market in February 2015 and is more effective than apremilast in treating skin PS. These IL-17 blockers are likely also effective at ameliorating PsA. Apremilast may also have an advantage in women of childbearing potential who prefer oral agents and in whom acitretin and methotrexate) are contraindicated.10 It appears that apremilast is less effective than TNF-α inhibitors in the treatment of both axial and peripheral arthritis. From the point of view of peripheral arthritis, an ACR-20 rate of 41% at 12 weeks does not match the 59% for etanercept or 58% for adalimumab, although new data suggest that more patients will

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achieve ACR-20 with continued exposure to apremilast.10 It is interesting that while all other approved drugs for PsA effectively treat ankylosing spondylitis, 24 weeks of apremilast failed to do so.13 ACR rates of 50 or 70 are needed for the patient to feel there has been real improvement in PsA, and apremilast does not achieve ACR rates of 50 or 70.10 Head-to-head studies comparing apremilast with other agents are lacking. The use of apremilast in combination with biologics is intriguing, and patients who do not fully benefit from them at the skin or joint level may realize better results. The full implications of apremilast’s effect on mood, weight, and induction of rebound have yet to be defined with continuous use. At a cost of $22,000, but with generous coupon assistance, it has a place in the armamentarium for treating PS that requires further delineation. Disclosures Dr Scheinfeld has been a clinical investigator for Celegene. Dr Abramovits has received support from Abbvie, Allergan, Anacor Pharm, Aqua, Celgene, Eli Lilly, Galderma, Genentech, Innocutis, Jansson, Leo, Novartis, Pfizer, Pharma Derm, Quinnova, Regeneron, Stiefel (GSK), Taro, Tolmar, and Valeant. Dr Gupta has received support from Abbvie, Amgen, Astellas, Lilly, Merck, Novartis, LEO, and Pfizer. References 1 Schett G, Sloan VS, Stevens RM, Schafer P. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010;2:271. 2 Otezla [package insert]. Summit, NJ: Celgene; September 2014. 3 Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol. 2013;12:888–897. 4 Schafer P. Apremilast mechanism of action and applica-

tion to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83:1583–1590. 5 Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebocontrolled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73:1020–1026. 6 Strand V, Fiorentino D, Hu C, et al. Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: results from a phase IIb randomized, controlled study. Health Qual Life Outcomes. 2013;11:82. 7 Papp KA, Kaufmann R, Thaçi D, et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study. J Eur Acad Dermatol Venereol. 2013;27:e376–e383. 8 Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012;380:738– 746. 9 Otezla (apremilast). ClinicalTrials.gov Web site. Accessed November 20, 2014. 10 Wittmann M, Helliwell PS. Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatol Ther (Heidelb). 2013;3:1–15. 11 Oral OTEZLA® (Apremilast) Showed Sustained Clinical Response over Two Years in Patients with Active Psoriatic Arthritis. http://ir.celgene.com/releasedetail. cfm?releaseid=883541. Accessed December 21, 2014. 12 Oral Apremilast Significantly Improved Nail and Scalp Psoriasis and Health-Related Quality-of-Life Measures in Phase III ESTEEM 1 Study. http://ir.celgene.com/releasedetail.cfm?releaseid=800402. Accessed December 21, 2014. 13 Celgene Reports Results from the Phase III POSTURE Study Evaluating Oral OTEZLA® in Ankylosing Spondylitis. http://ir.celgene.com/releasedetail. cfm?releaseid=858785. Accessed December 21, 2014.

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Volume 13 • Issue 5

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

The Association of Bullous Pemphigoid and Neurologic Disorders: A Real Braintease Warren R. Heymann, MD

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s America ages, disorders that accompany the elderly will become more prevalent. In the United States, life expectancy has reached 78.8 years (76.4 years for men and 81.2 years for women) for a child born in 2012. One would expect that diseases seen in advanced years, such as bullous pemphigoid (BP) and neurologic disorders, including dementia and Parkinson disease, would occasionally occur in the same patient, but could there be an association between these disorders? Recent studies suggest the affirmative. The brainteasers are in deciphering the pathomechanism of this association and considering its clinical implications.

fold increase in the odds of BP in patients with dementia and Parkinson disease and a twofold increase in patients with stroke and epilepsy. Multiple sclerosis was also associated with BP, but the odds estimates were imprecise.2 Most recently, a third group reported 87 patients with BP who were matched with 261 controls. The odds of a previous diagnosis of any neurologic disorder or history of dementia were significantly increased among patients compared with controls (with an odds ratio of 6.85). Both Parkinson disease and any other type of neurologic disorder were significantly more likely to develop in patients with BP, with hazard ratios of 8.56 and 2.02, respectively.3

Epidemiologic Studies

Pathogenesis

BP is the most common autoimmune blistering disease and is characterized by large tense bullae arising from normal skin or urticarial plaques. Recently, there have been an increasing number of reports of neurologic diseases associated with BP, including cerebrovascular disease, dementia, multiple sclerosis, seizures, Parkinson disease, and amyotrophic lateral sclerosis.

BP is mediated by antibodies against the hemidesmosomal component of the basement membrane zone, notably a 230-kDa protein (BP antigen 1, BPAG1) and a 180-kDa transmembrane protein (BP antigen 2, BPAG2, collagen XVII). The pathogenic role of anti-BPAG2 antibodies is widely accepted, with serum levels paralleling disease activity. The role of anti-BPAG1 antibodies in the pathogenesis is controversial but may be associated with BP in patients with mucosal disease or those who do not have anti-BPAG2 antibodies.4 Several isoforms of BPAG1 have been described: epithelial BPAG1 (BPAG1-e) in the skin, BPAG1-b in striated muscle, and BPAG1-a (which is very similar to BPAG1-e) in the nervous system.5 Less is known about BPAG2 in the central nervous system, although collagen XVII has been identified in the human brain by immunohistochemical techniques. It is believed to play a role in disorders of neuronal migration and synaptic plasticity.6 Pathogenically, one can speculate that neuroectoderm has common antigens in the skin, including isoforms of BPAG1 and possibly BPAG2.

In a study of 90 consecutive patients with BP compared with 141 controls, at least one neurologic diagnosis was present in 42 patients (46%) compared with 16 controls (11%). Four major neurologic diseases were observed (cerebrovascular disease [CVD], dementia, Parkinson disease, and epilepsy), with statistical significance for CVD and Parkinson disease. BP followed neurologic disease in 72% of patients with a median interval of 5.5 years.1 Another group studied 868 patients with BP compared with 3453 controls. There was a significant increase in the odds of developing BP in patients diagnosed with neurologic disorders more than 12 months previously. They found a three-

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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Perhaps neurologic inflammation or injury allows alteration of the blood-brain barrier to initiate cutaneous autoimmunity. Neuroautoimmunity, associated with aging or neurologic disease, may be involved with the development of BP via an autoimmune response against dystonin, a neuronal cytoplasmic protein that shares homology with BPAG1. This suggests that BP could be a marker for a neuroimmune response that causes neurodegeneration.4 Clinical Relevance

Conclusions My father had Alzheimer disease. Fortunately, his condition was not complicated by BP. It is difficult to watch the relentless deterioration of the mind and body of a previously robust, dynamic individual you love. Perhaps these new insights regarding autoimmunity, skin, and the nervous system will lead to advances that impede the ravages of the elderly. References

What are the practical implications of the association of neurologic disease (predominantly dementia and Parkinson disease) with BP? It appears that neurologic disease usually precedes BP. In evaluating the skin of patients with chronic neurologic disorders, we should keep BP in our differential diagnosis. While classical cases of BP present little diagnostic challenge, the diagnosis may be delayed in morphologically unusual cases (eg, urticarial BP, dyshidrosiform BP, or cases presenting as pruritus). The threshold for performing a biopsy for routine microscopy and direct immunofluorescence and/or obtaining enzyme-linked immunosorbent assay studies for BPAG1 and BPAG2 should be low. Alternatively, BP can possibly affect neurologic function; indeed, that is the implication in the study where a significant risk of Parkinson disease was noted following the diagnosis of BP.3 These potential associations could have profound influences on how we approach these patients. Further research is warranted to determine which therapy (if any) has the potential to decrease the risk of Parkinson disease following BP. Would there be any difference in outcome between systemic steroids, tetracycline/ niacinamide, mycophenolate mofetil, or rituximab?

1 Taghipour K, Chi CC, Vincent A, et al. The association of bullous pemphigoid with cerebrovascular disease and dementia. Arch Dermatol. 2010;146:1251–1254. 2 Langan SM, Groves RW, West J. The relationship between neurological disease and bullous pemphigoid: a population-based case-control study. J Invest Dermatol. 2011;131:631–636. 3 Brick KE, Weaver CH, Savica R, et al. A populationbased study of the association between bullous pemphigoid and neurologic disorders. J Am Acad Dermatol. 2014;71:1191–1197. 4 Vassileva S, Drenovska K, Manuelyan K. Autoimmune blistering diseases as systemic diseases. Clin Dermatol. 2014;32:364–375. 5 Casas-de-la-Asunción E, Ruano-Ruiz J, Rodriguez-Martin AM, Vélez Garcia-Nieto A, Moreno-Giménez JC. Association between bullous pemphigoid and neurologic diseases: a case-control study. Actas Dermosifiliogr. 2014;105:860–865. 6 Seppänen A, Autio-Harmainen H, Alafuzoff I, et al. Collagen XVII is expressed in human CNS neurons. Matrix Biol. 2006;25:185–188.

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

Dermatology in a Bygone Era Eve J. Lowenstein, MD, PhD

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he 2015 meeting of the History of Dermatology Society on March 19th in San Francisco, California, was entitled Dermatology in a Bygone Era. The following are some highlights from the seminar. Introductory Presentation Mauricio Goihman-Yahr discussed physicians as the toolmaker and tool user, decision maker, and patient advocate. He emphasized that this has been our role and should continue as such. Diagnoses––No Longer Made Robert Norman presented on chlorosis, the “green sickness,” a green tint of skin related to hypochromic anemia. Chlorosis was first reported in the 16th century by a prominent German physician, Lang (1485–1566), who felt it was “peculiar to virgins” and proposed the cure for young women to copulate and conceive. In more modern history, chlorosis has been linked with neurosis, hysteria, and psychosomatic disease, with the appellation morbus virgineus ascribed until the late 19th century. Curiously, the skin’s green tint has never been proven as a real clinical finding. Ankuri Desai discussed the discarded diagnosis of dropsy, although hydrops is the original Greek term. During the past 2 centuries, there has been an evolution of our understanding into a variety of etiologies, including heart failure and myxedema. Epidemic dropsy still exists from ingestion of mustard oil contaminated by the Mexican poppy. Le Mal du Roi: A History of Scrofula, presented by Daniel Parish, has been called “The King’s Evil,” as the English and French kings were thought to be divinely gifted with the ability to heal. This also served as proof of the king’s legitimacy and piety. The cure ceremony became part of the royals’ power. There were even

minted “Angel Coins,” ordered by Henry VII to provide and/or maintain a cure for scrofula. In Noah Scheinfeld’s discussion of leprosy, known as Tsara’at, he pointed out that Tsara’at was mentioned in the Book of Leviticus as a spiritual disease related to impurity secondary to moral transgression. Multiple examples of Tsara’at exist in the bible, ie, Miriam was plagued with Tsara’at after a wrongdoing. The skin involvement bears some similarity to vitiligo, eczema, or leprosy, but these modern diseases seem to bear only superficial similarity to Tsara’at and, therefore, it is not necessarily leprosy as we know it. Robert Thomsen, dressed as the medieval physician, presented on Paracelsus the Great, the Monarch Medicorum. He was the first to advocate for the treatment of the whole body using the four pillars of medicine: • Philosophy of nature: man is a microcosm of the world and best understood through the study of nature. • Astronomy: knowledge of stars in man. • Alchemy: chemicals used to cure or poisons, depending on dose. • Pillar: a virtue, and the power of love. Lichen ruber moniliformis, an entity no longer diagnosed, was associated with dome-like and reticulated lesions. Larry Millikan noted that they were likely related to a hodgepodge of modern conditions we now term as lichen niditus, lichen striatus, psoriasis, bromoderma, syphilis, tuberous sclerosis, and even trichoepitheliomas. Mark Bernhardt discussed meralgia paresthetica. Vladimir Karlovich Roth, a Russian neuropathologist, first coined the

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

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term meralgia paresthetica or Bernhardt syndrome in 1878, after studying two cases of peripheral neuropathy. It corresponds with a condition we today call lateral femoral cutaneous nerve syndrome, which is associated with a variety of symptoms and alopecia. Sigmund Freud described meralgia in himself and his son, being the first to report on familial meralgia. Synonyms include Bernhardt syndrome. This diagnosis is related to a variety of causes, included the wearing of tight pants, and still exists today. Natalie Curcio described embolia cutis medicamentosa (Nicolau syndrome), a livedoid dermatitis secondary to intravascular injection that leads to compression or intravascular blockage. John Hall presented on Sutton’s ulcer (periadenitis mucosa necrotica recurrens), which is currently called minor aphthosis. The condition was first described by Richard Lightburn Sutton, Sr (after whom Sutton nevus was also named), who authored two dermatology textbooks and was a leader in dermatology and its education in the early part of the 20th century. The next presentations by Paul Benedetto and Mark Valentine addressed plica neuropathica and plica polonica, respectively, which were first described in the 16th century and are now referred to as dreadlocks. The condition is associated with an acquired group of disorders of the hair shaft wherein the hairs become sticky, matted together, and malodorous secondary to neglect. The earliest evidence of dreadlocks was found in the Australian Aborigines more than 40,000 years ago. In ancient India 2500 BCE, plica was thought to be a sign of holiness in Hindu priests. The term “neuropathic plica,” coined in 1884 by Le Page, was thought to be precipitated by hysteria. Other synonyms include trica Incubarus (devil’s hair) and Weichselzopf. Based on ideas expounded by Kaposi and Hebra in 1847, it is now generally accepted that dreadlocks result from neglect of the use of a comb or brush for a variety of reasons. Mohamed Amer presented on the topic of prurigo. Ferdinand von Hebra and Ernest H. Besnier were two significant contributors to our understanding of this condition. Variants include prurigo simplex (also known as prurigo of Hebra), prurigo nodularis, and prurigo pigmentosa. Christopher Löser discussed St. Anthony’s fire, also known as ergotism, a poisoning from ingestion of the alkaloid produced by fungi that infects rye or cereal, leading to convulsions or gangrene secondary to limb amputations. Eponyms famously misused, zoster and erysipelas, have been incorrectly ascribed to this condition in recent textbooks of dermatology. Modern-day outbreaks have appeared in recent years in Ethiopia. SKINmed. 2015;13:389–391

Etiologies––Concepts Discarded Daniel Wallach spoke about the history of nosology of the Dartres in a presentation entitled: The Dartrous Trio: Alibert, Hardy, and Bazin. The word Dartres, no longer used today, attempts to classify diseases based on etiology, which at the time was unknown. Dartres were classified into seven classes that existed outside of the morphologic descriptions of skin disease. Alibert expanded the definition of disease to include 12 classes (1829), but they were not understood by his cohorts and not generally used. Alfred Hardy wrote about Dartres, feeling the nature of the disease was more important than morphology. Dartres Werwe was a much-criticized idea and the concept was ultimately discarded after the discovery of bacteria. Derek Ho spoke on the evolution of the concept of erythema multiforme. In 1860, Hebra was the first to describe erythema exudativum multiforme. The earliest morphologic description was made in 1817 of the characteristic primary lesion known as the Herpes iris of Bateman. In 1922, a more serious variant of erythema multiforme––Stevens-Johnson Syndrome––was described, and in 1950, Bernard Thomas coined the terms erythema multiforme minor and major. In 1956, Alan Lyell initially described toxic epidermal necrolysis. Finally, in 1993, the current classification of the spectrum of disease was developed. Yusuf Anwar discussed the history of herpes zoster and the etymology of “chicken pox,” the term of which was derived from the appearance of chicken pecks or seeds eaten by chickens. During the middle ages, the word “pox” meant curse, while herpes zoster come from Greek meaning “creeping belt.” Giovanni Filippo of Palermo provided the first description of chickenpox. Gerd Plewig presented: Heredity, Infectious, or Rotten Fish? Danielssen, Hansen, Hutchinson, and Neisser’s Plagiarism. In a 1856 study, it was noted that in a fishing area in Bergen, Norway, with poor housing conditions and close living quarters, 25 of 1000 people were affected. Daniel Cornelius Danielssen theorized that leprosy was hereditable. Gerhard Hansen insisted it was infectious, and they soon worked together in search of the cause of leprosy. Hansen’s work with Virchow demonstrated histologic brown bodies thought to be bacteria in skin samples of patients with leprosy. Hansen published this finding in a Norwegian journal in 1874, which initially received no attention. Hansen infected a patient without the patient’s consent as part of his studies, for which he was disciplined, losing hospital privileges. Albert Neisser, who joined Hansen in his studies, published proof of the bacilli in leprous tissue samples he had obtained from Hansen without giving credit. This eventually came

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to light, with Neisser being censured and Hansen receiving his due credit. Interestingly, Jonathan Hutchinson maintained his beliefs that leprosy came from eating rotten fish. This did not stop him from publishing his theory in 1906; years after Mycobacterium leprae had been identified. Eve Lowenstein presented on Red Madness: The Dramatic Public Health Tale of Pellagra. Pellagra was first noted in Spain and Italy, where it got its names Mal de la Rosa and Pell (skin) agra (sour). The consumption of corn was suspected in its pathogenesis from early times. Pellagra was first noticed in America in the early 20th century, reaching epidemic proportions in the South. The prevailing theory was that pellagra was an infectious contagion. Joseph Goldberger conducted studies in volunteer prison inmates and organized “filth parties,” where he and other volunteers tried to contract the disease by ingesting contaminates. Eventually, Goldberger discovered brewer’s yeast as a cure for pellagra, but Conrad Elvehjem later identified niacin as the missing vitamin. By the time the pandemic ended, pellagra had

claimed more than 3 million lives in the South and was responsible for 100,000 deaths. Branka Marinovic presented the final topic: Syphilis: Etiologic Concepts Discarded. Syphilis transmission was blamed from its onset on “the other guy”: called French disease, Italian disease, Neapolitan disease, morbus gallicus/European disease, morbus Portuguese, morbus Naples, Polish disease, Russian disease, Christian disease, Turkish disease, and even Chinese disease. Osler is quoted as saying: “To know syphilis is to know all of medicine.” Famous people known to have syphilis include Charles Baudelaire, Al Capone, Paul Gauguin, Heinrich Heine, James Joyce, Edouard Manet, Guy de Maupassant, Henri de Toulouse-Lautrec, and Vincent van Gogh. Conclusions The glimpses of history provided by these presentations and sessions offer insight and perspective into how our current understanding of skin diseases has evolved.

Historical Diagnosis and treatment

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HISTORY OF DERMATOLOGY SOCIETY NEWSLETTER

Port Wine Nevus Treated With Kromayer Light Mark Bernhardt, MD

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rnst Ludwig Franz Kromayer was a born rebel in a culture that rewarded complacency. He was a brilliant innovator whose outspokenness ruined any hope for academic success. He was a rich entrepreneur whose politics lay firmly with the proletariat. Finally, he was an idealistic pacifist in a time of increasing bellicosity. Kromayer was born September 26, 1862, in the provincial Prussian town of Stralsund. A remarkably quiet child, his mother for a time feared he was mute. Once he began his formal schooling, however, he quickly demonstrated not only his intellectual brilliance, but also his quick temper. While studying medicine in Wurzburg in 1883 he was jailed for 6 weeks for his involvement in a saber duel. After a brief stint as a general practitioner, Kromayer decided to pursue a career in academia. He worked for a year at the Pathologic Institute in Bonn and then concentrated on dermatologic studies in Breslau and Vienna. His career arc seemed assured in 1899, when the Prussian government authorized him to establish the first dermatology clinic in Halle. Unfortunately, his tenure was marked by constant fights with the authorities over funding and support staff. In 1904, fed up with what he perceived as an ignorant lazy bureaucracy, Kromayer published a scathing retaliation against his enemies, resigned his position as the first Professor of Dermatology at the University of Halle, and decamped to Berlin. Kromayer in Berlin

It was here that Kromayer hit his stride. His water-cooled ultraviolet lamp made him famous and his surgical skills––a pioneer in cosmetic surgery,1 introducing dermabrasion to dermatology––made him rich. An astute businessman who was as comfort-

able in the stock exchange as in the clinic, Kromayer soon had a luxurious villa in the ritziest neighborhood of Berlin. Although he clearly enjoyed the trappings of his wealth from fine wines to a chauffeur-driven car, politically, Kromayer was an ardent advocate for the leftist Social Democrats. True to his political ideals, Kromayer not only had a hospital in the wealthy part of town, but also one in the proletarian slum. He even granted shares in his practice to all of his loyal employees. Financial success and professional fame did not mellow Kromayer. Every potential employee had to accompany Kromayer on a pilgrimage to the cemetery where lay the martyrs of the populist 1848 uprising against the monarchy. He was notorious for abruptly ending any political discussion that was not to his liking and retiring to a solitary game of billiards. Woe betides any patient whose ramblings bored the doctor! Kromayer would just ignore the patient and start talking with his pet German shepherd, Kulikazius, who was always at his feet. Already afflicted with a terminal illness when Adolf Hitler rose to power in 1933, Kromayer realized he was in a fight he could not hope to win. His radical leftist politics, his publicized pacifism, his support for proletarian causes, let alone his Jewish ancestry, marked him as a ready target for the Nazis. Seeing a future without hope, on May 6, 1933, Kromayer took his own life. Reference 1 Clark WL. Port wine nevus treated with Kromayer light. J Cutan Dis Incl Syph.1915;33:470–473.

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

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

Eruptive Syringocystadenoma Papilliferum, Keratoacanthoma, and Verruca Vulgaris in a Keratinocytic Epidermal Nevus on the Leg Jonathan D. Pewitt, MD;1 Erin K. Burns, BS;2 Lawrence S. Chan, MD1

An otherwise healthy 43-year-old man presented with seven papules that had all erupted within the previous 6 months from an epidermal nevus on his left lower extremity. He reported that one of the new growths was painful and bled with minor trauma. Physical examination revealed a linear blaschkoid cobblestoned dark brown plaque that extended from the disto-lateral left thigh 30 cm to the mid-calf. Within the plaque inferior to the lateral popliteal fossa were six verrucous papules and a 4-mm round, pink, crusted, exophytic papule (Figure 1). A punch biopsy was taken from the plaque and saucerization shave biopsies of all the discrete papules. (SKINmed. 2015;13:395–397)

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he histology of the linear dark brown plaque showed acanthosis and papillomatous epidermal hyperplasia with hyperpigmentation of the basal keratinocytes. No abnormal hair follicles, apocrine glands, or sebaceous differentiation were seen within the epidermis or dermis consistent with a keratinocytic epidermal nevus (Figure 2). The histology of the pink papule showed an epidermal invagination and cystic dilation in the dermis with papillary projections protruding into the luminal space (Figure 3a). The papillary projections were lined with a double layer of cells: a cuboidal basal layer and a luminal layer of columnar cells demonstrating decapitation secretion. An inflammatory infiltrate of primarily plasma cells, a few lymphocytes, and neutrophils were present in the superficial dermis (Figure 3b). Of the remaining six papules, four had typical features of verruca vulgaris (Figure 4) and two had features of keratoacanthoma (Figure 5). The margins of the saucerization biopsies on the two keratoacanthomas were clear. The patient had no reoccurrence of any lesions after 3 months but was then lost to follow-up.

Figure 1. A portion of the epidermal nevus that demonstrates a previous biopsy site with hemorrhagic crust, one of the verrucous papules, and the round pink exophytic papule.

From the Department of Dermatology, University of Illinois at Chicago College of Medicine, Chicago, IL;1 and the University of Missouri-Kansas City School of Medicine, Kansas City, KS2 Address for Correspondence: Jonathan D. Pewitt, MD, Harbin Clinic, Department of Dermatology, 550 Redmond Road, Rome, GA 30165 • jonathan.pewitt@gmail.com

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Discussion Syringocystadenoma papilliferum (SCAP) is a rare, benign adnexal tumor of disputed origin, notably apocrine or apoeccrine differentiation. The primary lesions of SCAP have been described as papules, nodules, or exophytic tumors with highly variable coloration.1–4 Most patients present with a solitary lesion; however, multiple lesions in linear arrays have been described both within nevus sebaceus and without any associated nevus.1,4 Treatment of SCAP is primarily by surgical excision, although other methods of destruction have also been used for this benign adnexal neoplasm.5

SCAP shows a predilection for the head and neck region in approximately 75% of cases, but may also appear on other parts of the body.1 Uncommon sites of occurrence include the trunk (21%), upper extremities (0.6%), lower extremities (5%), breast, scrotum, and vulva.1–4,10 Most cases of SCAP on the lower extremities are localized to the thigh. Only four cases reported in the English literature note SCAP presenting on the lower leg and foot.1–3 Thus, our case represents the fifth case of lower leg SCAP. SCAP is usually reported in association with a nevus sebaceous, although it may also present de novo.1 In a study of nearly 600 cases of nevus sebaceus, SCAP and trichoblastoma were found to be the most frequent associated neoplasms.6 There is infrequent association with condyloma acuminata and keratoacanthoma.6–10 In one case series, viral warts were commonly found within nevus sebaceous perhaps favoring the epidermal hyperplasia present.6 Conclusions

Figure 2. Keratinocytic epidermal nevus demonstrating acanthosis and papillomatous epidermal hyperplasia with hyperpigmentation of the basal keratinocytes (hematoxylin and eosin stain, original magnification ×100).

a

Multiple benign and rarely malignant tumors have been reported in epidermal nevi, most commonly in the nevus sebaceus.5,6,9 Malignant tumors reported in epidermal nevi have included basal cell carcinoma, syringocystadenocarcinoma, and squamous cell carcinomas.5,6,9,11,12 This case represents a rare example of keratoacanthoma, verruca vulgaris, and SCAP concurrently arising within a keratinocytic epidermal nevus on the leg. Rare malignancies and varied appearance make clinical diagnosis difficult and any new discrete growth within an epidermal nevus should be viewed with suspicion.

b

Figure 3. Histological findings of syringocystadenoma papilliferum. (a) Epidermal invagination and cystic dilation in the dermis with papillary projections protruding into the luminal space (hematoxylin and eosin stain, original magnification ×40). (b) Papillary projections with a cuboidal basal layer and a luminal layer of columnar cells demonstrating decapitation secretion. Inflammatory infiltrate with plasma cells in the dermis (hematoxylin and eosin stain, original magnification ×400). SKINmed. 2015;13:395–397

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Figure 5. Keratoacanthoma. Exoendophytic proliferation of well-differentiated keratinocytes with increased hyperkeratosis and parakeratosis. There is mild keratinocytic cytologic atypia and scattered dyskeratosis without evidence of infiltrative growth. Within the dermis is a superficial perivascular and interstitial inflammatory cell infiltrate of lymphocytes and eosinophils (hematoxylin and eosin stain, original magnification ×20).

Figure 4. Verruca vulgaris. Papillomatous epidermal hyperplasia with hypergranulosis, columns of parakeratosis, and koilocytes. Within the superficial dermis are sparse perivascular lymphocytes (hematoxylin and eosin stain, original magnification ×100).

References 1 Mammino JJ, Vidmar DA. Syringocystadenoma papilliferum. Int J Dermatol. 1991;30:763–766. 2 Yoshii N, Kanekura T, Setoyama M, et al. Syringocystadenoma papilliferum: report of the first case on the lower leg. J Dermatol. 2004;31:939–942. 3 Townsend TC, Bowen AR, Nobuhara KK. Syringocystadenoma papilliferum: an unusual cutaneous lesion in a pediatric patient. J Pediatr. 2004;145:131–133.

7 Skelton HG 3rd, Smith KJ, Young D, et al. Condyloma acuminatum associated with syringocystadenoma papilliferum. Am J Dermatopathol. 1994;16:628–630. 8 Sardesai VR, Agarwal VM, Manwatkar PP, et al. Giant condyloma acuminata with syringocystadenoma papilliferum. Indian J Dermatol Venereol Leprol. 2009;75:330. 9 Rosen T. Keratoacanthomas arising within a linear epidermal nevus. J Dermatol Surg Oncol. 1982;8:878– 880.

4 Yap FB, Lee BR, Baba RB. Syringocystadenoma papilliferum in an unusual location beyond the head and neck region: a case report and review of literature. Dermatol Online J. 2010;16:4.

10 Coyne JD, Fitzgibbon JF. Mixed syringocystadenoma papilliferum and papillary eccrine adenoma occurring in a scrotal condyloma. J Cutan Pathol. 2000;27:199– 201.

5 Hoekzema R, Leenarts MF, Nijhuis EW. Syringocystadenocarcinoma papilliferum in a linear nevus verrucosus. J Cutan Pathol. 2011;38:246–250.

11 Affleck AG, Leach IH, Varma S. Two squamous cell carcinomas arising in a linear epidermal naevus in a 28-yearold female. Clin Exp Dermatol. 2005;30:382–384.

6 Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42:263–268.

12 Masood Q, Narayan D. Squamous cell carcinoma in a linear epidermal nevus. J Plast Reconstr Aesthet Surg. 2009;62:693–694.

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September/October 2015

Volume 13 • Issue 5

CASE STUDY

Linear Nevoid Epidermolytic Hyperkeratosis Localized to the Sole Deepshikha Khanna, MD;1 Payal Chakravarty, DDVL;1 Prasenjit Das, MD;2 Pankaj Bansal, MD2

The term epidermolytic hyperkeratosis, used synonymously for bullous ichthyosiform erythroderma, is in fact a histopathologic reaction pattern. Clinically, it may present as a generalized, localized, or palmoplantar variant. Generalized epidermolytic hyperkeratosis is a genetic disorder, while localized epidermolytic hyperkeratosis occurs sporadically as a result of mosaicism. The authors report a case of linear nevoid epidermolytic hyperkeratosis localized to the sole. (SKINmed. 2015;13:399–401)

A

6-year-old girl, daughter of a nonconsanguineous marriage, presented with complaints of skin thickening over the left sole causing discomfort while walking. The thickening was noticed in early infancy in the middle of the foot but progressively worsened and increased in extent to involve the toes and heel. There was no history of similar lesions elsewhere in the patient or other family members. The child was of average build with normal general physical and systemic examination. Cutaneous examination revealed a linear band of brown-colored grossly thickened skin extending from the undersurface of the proximal part of second and third toes to the center of the heel. The surface was rough with numerous shallow and deep fissures (Figure 1). The right sole and both palms were not involved. Mucosae, hair, and nails were all normal. Provisional diagnosis of verrucous epidermal nevus was considered and a skin biopsy was sent for histopathology, with hematoxylin and eosin stain that revealed marked compact hyperkeratosis with mounds of parakeratosis, acanthosis, papillomatosis, and thickened granular layer (Figure 2a). On higher magnification, swollen keratinocytes with indistinct boundaries and perinuclear vacuolization were seen in the stratum granulosum and spinosum. The keratinocytes surrounding these swollen keratinocytes showed prominent keratohyaline granules. Epidermolytic hyperkeratosis was focal, alternating with normal areas (Figure 2b). The above three features differentiated this lesion from a nonepidermolytic verrucous epidermal nevus. A

Figure 1. Right sole with a linear band of brown, grossly thickened skin covering the entire length of the sole with numerous shallow and deep fissures.

diagnosis of linear nevoid epidermolytic hyperkeratosis (EHK) was made and the patient was treated with keratolytic emollients including 10% urea with partial improvement. EHK is essentially a histopathologic reaction pattern as proposed by Ackermann in 1970.1 It is characterized by (1) perinuclear vacuolization of keratinocytes in the granular and spinous layers, (2) increased number of irregularly shaped keratohyaline granules in the granular and upper spinous layers, (3) keratino-

From the Departments of Dermatology1 and Pathology,2 Chacha Nehru Bal Chikitsalaya (Children Hospital), Geeta Colony, Delhi 110032, India Address for Correspondence: Deepshikha Khanna, MD, C 101 Narwana Apartments 89 IP Extension, Delhi 110092, India • E-mail: medico.doc@gmail.com

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Figure 2. (A) Skin biopsy with epidermal acanthosis, papillomatosis, and compact hyperkeratosis (arrow) (hematoxylin and eosin stain, original magnification ×40). (B) High-power photomicrograph showing foci with an increased number of keratohyaline granules (black arrow), perinuclear vacuolization in stratum granulosum (green arrow), and irregular cellular boundaries peripheral to vacuolization (yellow arrow) (hematoxylin and eosin stain, original magnification × 200). These features (consistent with epidermolytic hyperkeratosis) differentiate this lesion from a nonepidermolytic verrucous epidermal nevus.

cytes exhibiting ill-defined margins, and (4) moderate to marked hyperkeratosis.1 It manifests in a generalized form (generalized EHK), often referred to as congenital bullous ichthyosiform erythroderma, a localized form (localized EHK), which resembles verrucous epidermal nevus clinically, and a diffuse palmoplantar form (palmoplantar EHK) seen in keratosis palmaris et plantaris (Vorner’s palmoplantar keratoderma).2 Mutation in keratin 1 and 10 have been implicated in generalized and localized EHK and in keratin 9 and 1 in palmoplantar EHK.3 More recently, EHK has been reclassified as generalized clinical EHK and mosaic clinical EHK (similar to localized EHK).1 It is also seen in many other conditions such as ichthyosis hystrix, isolated epidermolytic acanthoma, hard nevus of Unna, sebaceous cyst, seborrheic keratosis, lichen amyloidosus, granuloma annulare, squamous cell carcinoma, basal cell carcinoma, nevus comedonicus, oral and genital mucosal leukoplakia, nevoid follicular epidermolytic hyperkeratosis, and solar keratosis.4,5 It may even occur as an incidental histologic finding in normal skin or normal oral mucosa. Generalized EHK or bullous ichthyosiform erythroderma is an inherited, autosomal dominant disease with complete penetrance. It presents as erythroderma, widespread bullae, and desquamation resulting in denuded skin at birth and in the neonatal period. After the first few months of life, erythema and blistering become less prominent and severe, as verrucous hyperSKINmed. 2015;13:399–401

keratosis predominates, especially over flexor surfaces. The palms and soles are also hyperkeratotic, but hair, nails, and mucosae are usually not involved. On the other hand, localized EHK, also known as mosaic clinical EHK, appears to be a sporadic disease and presents as a hyperkeratotic lesion along the lines of Blaschko. The clinical appearance is more warty and indistinguishable from verrucous epidermal nevus; hence, it also being classified as epidermolytic verrucous epidermal nevus.4 Localized EHK is a rare entity with only a few case reports, and presentation localized to only one sole without involvement of glabrous skin has not been previously reported.6,7 Absence of parakeratosis and focal involvement within the granular and spinous layer as seen in our patient has been reported to be suggestive of mosaic clinical EHK.4 The genetic mechanism points to mosaicism, and a patient with localized EHK can give rise to a child with generalized EHK possibly by a postzygotic mutation involving the germ line.4,8 In the literature, there was a case of a 15-year-old female patient with skin thickening along the lines of Blaschko limited to one palm and sole since birth. On histopathology, EHK with mutation in K16, a type 1 keratin, was detected. The authors labeled the condition as unilateral palmoplantar verrucous nevus and not as focal epidermolytic palmoplantar keratoderma.9 The distinction between localized EHK to only the palm/sole and focal epidermolytic palmoplantar kerato-

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derma is challenging but vital. This has future prognostic significance as EHK occurring in palmoplantar keratoderma of Vorner and palmoplantar keratoderma nummularis has never been reported to be transmitted to offspring as generalized EHK.2

References

Treatment options for localized EHK include surgical excision, carbon dioxide laser vaporization, cryotherapy, and topical therapies with corticosteroids, retinoic acid, tar, anthralin, 5-fluorouracil, and podophyllin, but recurrences are frequent.7 In patients with extensive lesions, however, topical therapy may be impractical and systemic retinoid therapy may have to be considered. In addition, recognition of EHK is important as initial high-dose retinoid therapy may lead to blistering in these patients. Conclusions Histopathologic examination of all lesions resembling a verrucous epidermal nevus should be undertaken to detect the presence of EHK. As bullous ichthyosiform erythroderma (or generalized EHK) is a debilitating disease with significant morbidity, appropriate genetic counseling and prenatal diagnoses should be offered to all pregnant patients with localized EHK to prevent transmission of a generalized form of EHK. Our case demonstrates unilateral linear nevoid presentation of EHK in a rather unusual location on one sole that, to the best of our knowledge, has not been reported earlier.

1 Ackermann AB. Histopahologic concept of epidermolytic hyperkeratosis. Arch Dermatol. 1970;102:253–259. 2 Reddy BS, Thadeus J, Kumar SK, Jaishanker T, Garg BR. Generalized epidermolytic hyperkeratosis in a child born to a parent with systematized epidermolytic verrucous epidermal nevus. Int J Dermatol. 1997;36:198–200. 3 Chamcheu JC, Siddiqui IA, Syed DN, et al. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys. 2011;508:123–137. 4 Ross R, DiGiovanna JJ, Capaldi L, et al. Histopathologic characterization of epidermolytic hyperkeratosis: a systematic review of histology from the National Registry for Ichthyosis and Related Skin Disorders. J Am Acad Dermatol. 2008;59:86–90. 5 Su WP. Histopathological varieties of epidermal nevus. A study of 160 cases. Am J Dermatopathol. 1982;4:161–170. 6 Swann MH, Pujals JS, Pillow J, et al. Localized epidermolytic hyperkeratosis of the female external genitalia. J Cutan Pathol. 2003;30:379–381. 7 Sarifakioglu E, Yenidunya S. Linear epidermolytic verrucous epidermal nevus of the male genitalia. Pediatr Dermatol. 2007;24:447–448. 8 Paller AS, Syder AJ, Chan YM, et al. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med. 1994;331:1408–1415. 9 Terrinoni A, Puddu P, Didona B, et al. A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. J Invest Dermatol. 2000:114:1136– 1140.

“Ulcus basocellulare terebrans”. Moulage No. 679, made by Lotte Volger in 1935 in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2015;13:399–401

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56 PM AM 01 19

IMPORTANT INFORMATION ABOUT September/October 2015

SOOLANTRA®

Volume 13 • Issue 5

(ivermectin) Cream, 1% CASE STUDY

Paradoxical Induction of Psoriasis and Lichen Planus by Tumor Necrosis Factor-α Inhibitors SOOLANTRA Cream is supplied in a child-resistant capped tube.

BRIEF SUMMARY This summary contains important information about SOOLANTRA (soo lan’ trah) Cream. Read this information carefully before you prescribe SOOLANTRA Cream. For full Prescribing Information and Patient Information please see the package insert.

• To open, gently press down on the child resistant cap and twist counterclockwise. To avoid spilling, do not squeeze the tube while opening or closing. • To close, gently press down on the child resistant cap and twist

Sonoa Au, MD; Claudiaclockwise. Hernandez, MD

WHAT IS SOOLANTRA CREAM? SOOLANTRA Cream is a topical prescription medicine indicated for the treatment of the inflammatory lesions of rosacea.

WHAT ARE THE INGREDIENTS IN SOOLANTRA CREAM? Active ingredient: ivermectin. Inactive ingredients: carbomer copolymer Case 1. A 33-year-old white woman presented to our clinic with a new-onset psoriasiform pustular eruption involving her palms type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetateand WHO IS SOOLANTRA CREAM FOR? soles 4 months after the initiation of adalimumab for Crohn’s disease. Her medical historyisopropyl was significant formethylparaben, childhood atopic disodium, glycerin, palmitate, oleyl dermatialcohol, SOOLANTRA Cream is indicated for people with inflammatory lesions phenoxyethanol, cetostearyl ether, propylene glycol, tis and hidradenitis suppurativa, but she had no personal or family history of psoriasis.polyoxyl Topical 20 corticosteroids including hydrocortisone of rosacea. It is not known if SOOLANTRA Cream is safe and effective purifiedimprovement. water, sodium hydroxide, sorbitan monostearate, 2.5%, triamcinolone 0.1%, fluocinonide 0.05%, and clobetasol 0.05%propylparaben, were used without The pustular eruption spread for children. Advise your patients to not use SOOLANTRA Cream for a and stearyl alcohol. to her scalp, trunk, and proximal extremities, and her toenails developed onycholysis and dystrophy. Her adalimumab was withdrawn condition for which it was not prescribed and remind them to not give for 1 month due suspicion of a ifparadoxical pustular psoriasis reaction. After 2 weeks off adalimumab, the pustular dermatosis had SOOLANTRA Cream to to other people, even they have the same symptoms WHEREtoSHOULD I GO FOR MORE INFORMATION ABOUT diminished and her gastroenterologist changed her medication methotrexate. Her eruption continued to clear over the as itsignificantly may harm them. SOOLANTRA CREAM? course of the next 6 months. (SKINmed. 2015;13:403–405) • This Brief Summary summarizes the most important information WHAT SHOULD I ASK MY PATIENTS BEFORE PRESCRIBING about SOOLANTRA Cream. For full Prescribing Information and SOOLANTRA CREAM? Patient Information please see the package insert. Before you prescribe SOOLANTRA Cream, ask your patients if they: • Go to www.soolantra.com or call 1-866-735-4137 • have anyase other conditions.Asian woman with a longstand- ing etanercept and her frequent traveling, she opted to restart 2. medical A 62-year-old

C

• are pregnant or planning become pregnant. It iswith not known if ing history of to psoriasis presented oral pain SOOLANTRA Cream harmfruits an unborn erbated by can citrus and baby. toothpaste. She had

exacbeen taking etanerceptorfor past 7 years excellent control of • are breastfeeding planthe to breastfeed. It is with not known if Cream passes into breastwas milksignificant and if it can for harmhyperlipida baby. herSOOLANTRA disease. Her medical history emia and osteoarthritis. A culture of the oral mucosa taken by WHAT ARE THE MOST COMMON SIDE EFFECTS OF her primary care physician grew Candida albicans; yet, despite SOOLANTRA CREAM? treatment with nystatin suspension, sheusing experienced minimal The most commonly reported side effects when SOOLANTRA Cream relief for her orodynia. During this period she presented to the include skin burning sensation and skin irritation. Remind your patients to tell you if they have any side effect that bothers them or that does not go of dermatology department for follow-up. Physical examination away.buccal These are not all showed of the possible side effects of SOOLANTRA Cream. the mucosa a reticulated white plaque consistent For more information, see the full Prescribing Information. with Wickham’s striae and erythematous superficial erosions. Three mucosa biopsies had by drugs the otoYou arebuccal encouraged to report negative sidebeen effectsperformed of prescription to laryngology department in theorweeks prior to her appointment. the FDA at www.fda.gov/medwatch call 1-800-FDA-1088. You may also contact GALDERMA LABORATORIES, L.P. AT 1-866-735-4137. All showed inflammation in a lichenoid pattern that were consistent with lichen planus (LP) or other lichenoid mucositis. Given HOW SHOULD PATIENTS USE SOOLANTRA CREAM? these findings, an LP-like eruption (LPLE) caused by etanercept • SOOLANTRA Cream is for use on the face only and should not be used in was suspected and discontinuation was recommended. She was the eyes, mouth, or vagina. then treated tacrolimus 0.1% ointment and fluocinonide 0.05% • SOOLANTRA Cream should be applied to the affected areas of the face gelonce for aher oral lesions. Three weeks later, she reported a 50% imday. provement in her symptoms. Unfortunately, her psoriasis flared significantly after stopping APPLYING SOOLANTRA CREAM: the etanercept, and she was started • A ustekinumab pea-sized amount of SOOLANTRA Cream should applied tocourse each of on due to dissatisfaction with abeprevious area of the facehowever, (forehead,due chin,to nose, cheek) thatwith is affected. adalimumab; hereach familiarity administerAvoid contact with the lips and eyes.

etanercept after a short course of ustekinumab. Her oral lesions Trademarks are the property of their respective owners. worsened after restarting etanercept, but she chose to continue this course of treatmentL.P., with useTexas of 76177 topical GALDERMA LABORATORIES, Fortthe Worth, USAlidocaine for symptomatic relief. Revised: December 2014

Discussion

Paradoxical psoriasis Tumor necrosis factor-α (TNF-α) inhibitors are used to treat moderate to severe psoriasis as well as inflammatory bowel disease (IBD), rheumatoid arthritis, and many other conditions. Although these medications have been effective for many patients, there have been more than 200 cases of paradoxical induction or worsening of psoriasis documented with their use.1 References: 1. Stein Gold L, Kircik L, Fowler J, et al; The majorityPhase of psoriasis cases induced by TNF-α inhibitor Ivermectin III Study Group. Efficacy and safety therapy involve1% plaque, pustular, or guttate psoriasis. Most paof ivermectin cream in treatment of papulopustular rosacea: of twoorrandomized, tients haveresults no personal family historydouble-blind, of psoriasis.2 Patients vehicle-controlled pivotal studies. J Drugs with pre-existing psoriasis can have worsening ofDermatol. the disease, and 2014;13(3):316-323. 2. Data on file. Galderma some have changes in the morphology of their skin lesions and Laboratories, L.P. 3. Taieb A, Ortonne JP, Ruzicka T, 1 timeSuperiority to onset after nail changes, as seenPhase in ourIII patient. et al; Ivermectin Study The Group. ofthe initiation of TNF-α inhibitor therapy is variable—from after a ivermectin 1% cream over metronidazole 0.75% cream 2 in treating inflammatory lesions rosacea:ofa therapy. randomized, Cursingle injection to 63 months afterofinitiation investigator-blinded trial. Br J Dermatol. In press.

From the Department of Dermatology, University of Illinois at Chicago College of Medicine, Chicago, IL

All trademarks are the property of their respective Address for Correspondence: Sonoa Au, MD, Universityowners. of Illinois at Chicago College of Medicine, Department of Dermatol©2015 L.P. Room 376 CME, Chicago, IL 60612 • E-mail: sonoaau@gmail.com ogy (MCGalderma 624), 808Laboratories, South Wood Street, Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 IVM-143 Printed in USA 02/15 SKINmed. 2015;13:403–405

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Figure 2. Examination of the buccal mucosa showing a reticulated white plaque consistent with Wickham’s striae in a patient taking etanercept for psoriasis.

Figure 1. Psoriasiform plaques on the patient’s soles after the initiation of adalimumab for Crohn’s disease.

rently, there does not appear to be any predilection for age, sex, type of primary disease treated, or TNF-α inhibitor used.

several immunological signaling pathways, being of particular interest.3

Although there have been many proposed mechanisms, the most well-studied involves plasmacytoid dendritic cells (PDCs) and their production of interferon α (IFN-α).3 TNF-α usually inhibits PDC maturation and hence IFN-α. The inhibition of TNF-α by these medications is believed to cause increased and unregulated production of IFN-α. This theory is somewhat substantiated by increased levels of IFN-α found in and around the vasculature of TNF-α–induced psoriatic lesions when compared with non–TNF-α–treated psoriasitic plaques.4

Some patients were able to continue TNF-α inhibitor therapy by staying on the same medication or by making a within-class substitution.6 Complete resolution was seen in up to 26% of cases without stopping TNF-α inhibitor therapy. Many patients discontinued anti-TNF therapy when the lesions first developed; therefore the true proportion of patients who can tolerate the treatment is unknown.3 It appears that patients who discontinue TNF-α inhibitors do not necessarily show a better response rate than those who continue treatment. A small proportion of reported patients experienced worsening of psoriasis despite stopping TNF-α inhibitors.2

Another possible mechanism comes from studies in patients with rheumatoid arthritis on TNF-α inhibitor therapy who show an increase in TH1 lymphocytes in the peripheral circulation. IFN-α is known to induce the expression of chemokine (C-X-C motif ) receptor 3 (CXCR3) on T cells, which promotes migration of T cells to the skin in susceptible patients.2 There is a disproportionate fraction of de novo cases of the palmoplantar pustulosis variant (more than half in some series).1–3 This is believed to be the result of a difference in expression of TNF-α in the eccrine palmar sweat gland of these patients compared with controls.5 Although the majority of cases have involved anti–TNF-α therapy, there have been case reports of psoriasiform lesions occurring with other biologics. Efalizumab, no longer available in the US market, is one such example, suggesting that cytokines other than TNF-α may be involved. Gene polymorphisms are also being studied with PTPN22, which encodes a protein tyrosine phosphatase that regulates SKINmed. 2015;13:403–405

It is important to counsel patients, particularly those with a personal or family history of psoriasis, of this paradoxical side effect prior to initiation of treatment. TNF-α therapy should be stopped in patients with severe disease and in those who opt to discontinue treatment. In patients with less than 5% body surface area (BSA) involvement and no significant clinical manifestations, continuation of TNF-α therapy is encouraged in conjunction with the treatment of psoriasis. In patients with more than 5% BSA involvement or those with localized palmoplantar pustulosis, an alternative TNF-α antagonist can be considered. Topical corticosteroids, keratolytics, and vitamin D analogs are indicated in all of these situations. UV phototherapy, methotrexate, acitretin, and cyclosporine may also be considered. Consider infections and psoriasis mimickers prior to making decisions regarding whether to continue anti-TNF therapy. Recalcitrant disease calls for either TNF-α inhibitor switch or discontinuation.2,3,6,7

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LP-Like Eruptions

References

There have been more than 15 cases of LP or LPLE induced by TNF-α antagonists described in the literature. Infliximab and adalimumab are the other TNF-α agents implicated.8 These cases can appear like LP clinically or they can have a nonspecific maculopapular appearance but demonstrate a lichenoid infiltrate histologically. A third variant described looks like psoriasis clinically but shows some lichenoid features on histology.9 Our case appears to have the longest lag in onset following initiation of TNF-α antagonist therapy reported in the English language literature—7 years. A previous study observed a latent period ranging from 3 weeks to 16 months.9 There is no known predilection for sex or age, and the patients were treated for a different conditions including psoriasis, IBD, rheumatologic conditions, and toxic epidermal necrolysis.9,10 LP has been reported to respond to TNF-α antagonist therapy; hence, the mechanism for this paradoxical induction remains unclear. As with paradoxical psoriasis, it is believed that TNF-α inhibition causes increased IFN-α production, leading to an inflammatory response mediated by resident T cells and dendritic cells.4,9 Our patient responded quickly to the discontinuation of etanercept, as others reported in the literature. Discontinuation of TNF-α antagonist therapy leads to improvement and, in many, complete resolution of the lichenoid eruption.8–11 The worsening of our patient’s oral eruption upon rechallenge again supports this diagnosis. Like our patient, some were able to tolerate the LP and continued on the same therapy, with additional treatments directed towards the LP.9,12 Due to the small number of cases reported, there are mixed results with switching to another anti–TNF-α agent, with one case reporting recurrence but none in another.9,13 Rechallenge does not consistently cause recurrences.9 Conclusions TNF-α inhibitors have led to a breakthrough in the treatment of many inflammatory diseases, but these recent observations of the induction of secondary autoimmune diseases show that there is a fine balance of cytokines and inflammatory modulators. Treatment can be challenging due in part to the number and complexity of immunologic pathways. The development of an international database may assist in better understanding these disease processes.

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1 Joyau C, Veyrac G, Dixneuf V, Joliet P. Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effects? Clin Exp Rheumatol. 2012;30:700–706. 2 Wollina U, Hansel G, Koch A, et al. Tumor necrosis factoralpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol. 2008;9:1– 14. 3 Collamer AN, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: clinical features and possible immunopathogenesis. Semin Arthritis Rheum. 2010;40:233–240. 4 de Gannes G, Ghoreishi M, Pope J, et al. Psoriasis and pustular dermatitis triggered by TNF-alpha inhibitors in patients with rheumatologic conditions. Arch Dermatol. 2007;143:223–231. 5 Michaelsson G, Kajermo U, Michaelsson A, et al. Infliximab can precipitate as well as worsen palmoplantar pustulosis: possible linkage to the expression of tumour necrosis factor-alpha in the normal palmar eccrine sweat duct? Br J Dermatol. 2005;153:7:713–714. 6 Collamer AN, Guerrero KT, Henning JS, Battafarano DF. Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: a literature review and potential mechanisms of action. Arthritis Rheum. 2008;59:996– 1001. 7 Ko JM, Gottlieb AB, Kerbleski JF. Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog Treat. 2009;20:100–108. 8 Flendrie M, Vissers WH, Creemers MC, et al. Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther. 2005;7:R666–R676. 9 Asarch A, Gottlieb AB, Lee J, et al. Lichen planus-like eruptions: An emerging side effect of tumor necrosis factor-alpha antagonists. J Am Acad Dermatol. 2009 ;61:104–111. 10 Worsnop F, Wee J, Natkunarajah J, et al. Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus. Clin Exp Dermatol. 2012 ;37:879–881. 11 Battistella M, Rivet J, Bachelez H, et al. Lichen planus associated with etanercept. Br J Dermatol. 2008;158:188– 190. 12 Musumeci ML, Lacarrubba F, Micali G. Onset of lichen planus during treatment with etanercept. Am J Clin Dermatol. 2010;11 suppl 1:55–56. 13 Pontikaki I, Shahi E, Frasin LA, et al. Skin manifestations induced by TNF-alpha inhibitors in juvenile idiopathic arthritis. Clin Rev Allergy Immunol. 2012;42:131–134.

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September/October 2015

Volume 13 • Issue 5

CASE STUDY

Adult-Onset Blue Rubber Bleb Nevus Syndrome Sudip Kumar Ghosh, MD, DNB;1 Dhurjati Prasad Dutta, MD;2 Megha Agarwal, MBBS;1 Sourav Chhajer, MBBS2

A 64-year-old, nondiabetic, nonhypertensive Indian woman was admitted to our hospital for evaluation of lethargy that had been present for the past 10 months. In addition, she had developed multiple, gradually progressive, bluish nodules scattered over the skin and mucous membranes for the preceding 15 years. There was no history of recent weight loss, vomiting of blood, passing of bloody stool, or any other external bleeding. There was no significant family history and medical and surgical history was noncontributory. She had received iron preparations repeatedly in the past. (SKINmed. 2015;13:406–409)

G

eneral examination revealed pallor and tachycardia. Systemic examination was noncontributory. Mucocutaneous examination revealed a few soft, compressible, bluish nodules of varying size on her left calf and thigh, chest, and neck (Figures 1 and 2). Similar swellings were also seen on the lips. Multiple compressible, bluish nodules with verrucous surfaces were seen on the tongue, causing its architectural deformity. A blue-colored vascular papule was also seen in the bulbar conjunctiva. Ocular examination was otherwise normal. Routine investigations revealed features of iron deficiency anemia (hemoglobin: 7.5 g/dL, erythrocyte: 3 million cells/mcL, mean corpuscular volume: 60 fL, anisopoikilocytosis, ferritin: 4 ng/mL). Ultrasonography of the mucocutaneous lesions revealed slow-flow vascular lesions, suggestive of venous malformations. X-ray examination of the neck region revealed multiple opaque shadows, suggestive of phleboliths (Figure 3). Findings from computed tomography of the brain revealed no intracranial anomaly, but extracalvarial soft tissue swellings suggestive of vascular malformations and nodular calcification indicative of phleboliths were noted (Figure 4). Endoscopy of the gastrointestinal (GI) tract revealed multiple bluish vascular malformations throughout the upper GI tract. Dermatoscopy of the lesions showed a few distinct patterns in the form of vascular arborization, vascular lacunae rimmed by white fibrous septae, steel-blue macules, and verrucous surface

of the lesions (Figure 5). Based on the clinical and laboratory features, a diagnosis of adult-onset blue rubber bleb nevus syndrome (BRBNS) was made. Discussion BRBNS was first described by Gascoyen in 1860; however, the eponym of this condition, Bean syndrome, had been named after William Bennet Bean (1909–1989) who fully explored the condition in 1958.1 The precise pathogenesis of BRBNS remains elusive. The stem cell factor/c-kit signaling axis has been proposed to be involved in the constant growth of venous malformations.2 The condition is usually sporadic; however, autosomal dominant inheritance can also occur.3 The syndrome comprises multiple venous malformations that affect the skin and viscera (usually the GI tract and most often the small intestine). The name originates from the appearance of the skin lesions, which are small bluish protuberances that feel rubbery.4 Three types of cutaneous lesions have been described in BRBNS: (1) blue blood-filled sacs that look and feel like a rubber nipple and that are easily compressible (leaving a ‘‘wrinkled scrotum’’ appearance) only to refill when pressure is released; (2) disfiguring, cavernous, large lesions that may obstruct vital structures; and (3) blue macules.5 Cutaneous lesions may rarely be tender and

From the Department of Dermatology, Venereology, & Leprosy,1 and the Department of Medicine,2 R.G. Kar Medical College, Kolkata, West Bengal, India Address for Correspondence: Sudip Kumar Ghosh, MD, DNB, R.G. Kar Medical College, Department of Dermatology, Venereology, & Leprosy, 1, Khudiram Bose Sarani, Kolkata, 700004, West Bengal, India • E-mail: dr_skghosh@yahoo.co.in

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Figure 3. X-ray findings of the neck revealed multiple opaque shadows, suggestive of phleboliths. Figure 1. Bluish nodules on the upper chest, neck, and tongue.

Figure 4. Findings from computed tomography of the brain showing extracalvarial soft tissue swellings suggestive of vascular malformations and nodular calcifications indicative of phleboliths.

Figure 2. Bluish nodules with verrucous surface on the tongue, causing its architectural deformity (a). A bluecolored vascular papule was also seen in the bulbar conjunctiva (b).

may have overlying hyperhidrosis.5 These vascular lesions can occur all over the body, but are most commonly located on the trunk and arms.5,6 SKINmed. 2015;13:406â&#x20AC;&#x201C;409

The superficial vascular malformations in this condition can be imaged using ultrasonography with Doppler, demonstrating the slow flow in the lesions, as in our case.4 Conversely, GI lesions

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CASE STUDY with exophytic, verrucous surface.8 Another group reported the dermatoscopic pattern of BRBNS in a 2-year-old child. They described homogeneous steel-blue areas that were found in the macular lesions, and red-purple lacunae and homogeneous steelblue areas, some of which were separated by white linear bands, were seen in papular and nodular lesions.9 In conformity with the above-mentioned findings, our patient had a combination of all of these features. Skin lesions of BRBNS are usually present at birth or in childhood. The cutaneous lesions seen in our patient first become obvious in the fifth decade of her life. We have found only a few previous cases of adult-onset BRBNS in the English language literature. There was a reported case of a blue rubber bleb nevus and Maffucci syndrome in which the cutaneous lesions developed between the ages of 19 and 23 years.10 Another patient had adult-onset BRBNS who had periodic pulsating exophthalmos.11 A 74-year-old woman had cutaneous lesions that first developed at the age of 50.12 More recently, a woman presented with a 7-year history of cutaneous lesions.13

Figure 5. Dermoscopy showing: vascular arborization (a), vascular lacunae rimmed by white fibrous septae (b), steel-blue macules (c), and verrucous surface of the lesions (d).

occur in all patients with BRBNS from the oral mucosa down to the rectum, but the small bowel is the most commonly affected area.6 Cutaneous lesions rarely bleed unpredictably but they are easily traumatized, in contrast to GI lesions, which typically bleed spontaneously in an occult or profuse way. Insidious GI bleeding might result in iron deficiency anemia.3 Involvement of the central nervous system, thyroid, parotid, eyes, oral cavity, musculoskeletal system, lungs, liver, spleen, and bladder can occur. Symptoms may be varied and, besides intestinal bleeding, range from blindness to bone pain.7 Dermatoscopy is an important field to determine the vascular morphology of a cutaneous lesion as well as to differentiate cutaneous entities. To the best of our knowledge, dermatoscopic features in this syndrome were previously described in only two pediatric patients. One group described the dermatoscopic pattern in a 17-year-old boy with BRBNS. Four important dermatoscopic features have been described, including superficial light red arborizing venous pattern or vessel dilations, maculae with nondefined borders predominantly on the palms and soles, red-purple nodules with lacunas separated by a white linear structure corresponding to fibrous demarcations, and lesions SKINmed. 2015;13:406â&#x20AC;&#x201C;409

Oral cavity lesions occur in 59% to 64% of BRBNS cases.14 A large vascular lesion of the tongue, causing its architectural deformity, was a unique finding in our patient. Ocular vascular malformations are rarely reported in BRBNS. Vascular lesions in the conjunctiva, iris, and retina associated with local hemorrhages at the time of birth have been previously described.15,16 Another important question associated with this condition is that the lesions of this disorder have been historically and imprecisely labeled as hemangiomas, when it is evident that the lesions seen in this disorder are in fact venous malformations. Given the nature of these lesions, the term blue rubber bleb venous malformation syndrome should be used instead of blue rubber bleb nevus syndrome.17 Histopathologically, the malformations may be seen at any plane of the skin; however, there is an inclination for them to occur in the deep dermis and subcutaneous tissue. There are large dilated vascular channels lined by flat endothelium. Some vessels might have smooth muscle in their walls and look like dilated veins. Thrombosis may complicate these lesions. Calcification of the walls and phlebolith-like calcific bodies in the lumina may be found.7 Cutaneous lesions of BRBNS may masquerade as multiple glomangiomas,4 Klippel-Trenaunay syndrome, Parkes Weber syndrome, and Maffucci syndrome.3,7 As a result of the multifocal nature of the lesions and the unpredictable clinical presentation, the treatment modalities of BRBNS range from iron replacement therapy with or without

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blood transfusion to extensive resection of the GI tract. If blood loss is significant and localized lesions are recognized in an accessible area, laser photocoagulation (Nd:YAG) is recommended and preferred to other techniques.17,18 Techniques such as sclerotherapy may be performed with some benefit. We referred our patient to our colleagues from the surgical gastroenterology department for further management. Conclusions Dermatoscopy may play a vital role in the early recognition of BRBNS, which is critical to provide appropriate medical interventions and possible genetic counseling. In this report, we further seek to emphasize that vascular lesion of BRBNS can appear even in adults and can be a source of occult or obvious GI blood loss. References 1 Kaur T, Singh S. Blue rubber bleb nevus syndrome: a case report. Indian J Dermatol. 2014;59:98–99. 2 Mogler C, Beck C, Kulozik A, et al. Elevated expression of c-kit in small venous malformations of blue rubber bleb nevus syndrome. Rare Tumors. 2010;2:e36. 3 James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin. 11th ed. Philadelphia, Saunders Elsevier; 2011. 4 Jarrett DY, Ali M, Chaudry G. Imaging of vascular anomalies. Dermatol Clin. 2013;31:251–266. 5 Bedocs PM, Gould JW. Blue rubber-bleb nevus syndrome: a case report. Cutis. 2003;71:315–318. 6 Kamat AS, Aliashkevich AF. Spinal cord compression in a patient with blue rubber bleb nevus syndrome. J Clin Neurosci. 2013;20:467–469. 7 Weedon D. Weedon’s Skin Pathology. 3rd ed. London, England: Churchill Livingstone Elsevier; 2010.

8 Mejía-Rodríguez S, Valencia-Herrera A, Escobar-Sánchez A, et al. Dermoscopic features in Bean (blue rubber bleb nevus) syndrome. Pediatr Dermatol. 2008;25:270– 272. 9 Turk BG, Turkmen M, Karaarslan IK, et al. Blue rubber bleb nevus syndrome: a case report with dermatoscopic features. Clin Exp Dermatol. 2011;36:211–213. 10 Sakurane HF, Sugai T, Saito T. The association of blue rubber bleb nevus and Maffucci’s syndrome. Arch Dermatol. 1967;95:28–36. 11 Rennie IG, Shortland JR, Mahood JM, et al. Periodic exophthalmos associated with the blue rubber bleb naevus syndrome: a case report. Br J Ophthalmol. 1982;66:594– 599. 12 Torchia D, Schincaglia E, Palleschi GM. Blue rubber-bleb naevus syndrome arising in the middle age. Int J Clin Pract. 2010;64:115–117. 13 Pereira AR, Nunes MC, Dos Santos Guadanhim LR, et al. Blue rubber bleb nevus syndrome: late onset in a patient with cutaneous, neurological, and gastrointestinal involvement. Int J Dermatol. 2014 Jun 5. [Epub ahead of print] 14 Suma GN, Ravi Prakash SM, Rao D, Goel S. Blue rubber bleb nevus syndrome: prominent oral findings. Indian J Dermatol Venereol Leprol. 2010;76:168–171. 15 Crompton JL, Taylor D. Ocular lesions in the blue rubber bleb naevus syndrome. Br J Ophthalmol. 1981;65:133– 137. 16 Shields JA, Mashayekhi A, Kligman BE, et al. Vascular tumors of the conjunctiva in 140 cases. Ophthalmology. 2011;118:1747–1753. 17 Akhiani M, Fateh S, Ghanadan A, et al. Extensive blue rubber bleb nevus syndrome with multiple gastrointestinal venous malformations: a case report. Iran J Dermatol. 2009;12:99–102. 18 Wong WM, Cheung CC, Lau KW. A rare cause of gastrointestinal bleeding: blue rubber bleb nevus syndrome. Ann Coll Surg Hong Kong. 2001;5:25–28.

VINTAGE LABEL

Courtesy of BuyEnlarge, Philadelphia, PA SKINmed. 2015;13:406–409

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Volume 13 • Issue 5

correspondence Snejina Vassileva, MD, PhD, Section Editor

Comment on Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergilllus niger Nardo Zaias, MD To the Editor: The recently published article “Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillis niger,” which appeared in the March/April 2015 issue, unfortunately represents a Hallux demonstrating classical changes due to the asymmetric gait nail syndrome (AGNUS),1,2 which results in the majority of cases in onycholysis and skin friction on the tip of the toes (as shown in Figure 1 in the article) that is occupied by the opportunistic fungus noted. As for the second left toe, melanonychia was not proven by showing the fungus in the nail plate matrix

occupied by the responsible melanocytes. One toenail melanonychia is quite common in non-Caucasians. References 1 Zaias N, Rebel G, Casals G, Appel J. The asymmetric gait nail unit signs (AGNUS), fungus negative, produced by an asymmetric walking gait that could be correctable in early life. SkinMed 2012;10:1–5. 2 Zaias N, Rebel G, Escovar S. Asymmetric nail unit syndrome: the most common worldwide toenail abnormality and onychomycosis. SkinMed 2014;12:217–223.

From the Greater Miami Skin and Laser Center, Miami Beach, FL Address for Correspondence: Nardo Zaias, MD, Mount Sinai Medical Center, 4308 Alton Road, Suite 750, Miami Beach, FL 3314073109 • E-mail: nardozaias@aol.com

Response to “Comment on Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger” Carlos Garcia, MD;1 Roberto Arenas, MD2 invaded the nail plate, potassium hydroxide wet mount showed a

To the Editor: We appreciate the comments on our article “Subungual Black Onychomycosis and Melanonychia Striata Caused by Aspergillus niger.” The author is describing nail abnormalities resembling onychomycosis but fungus-free. In our case, however, the fungus

black fungus, and repeated cultures demonstrated A. niger. Still, the author makes a good point in that nail changes due to hallux and AGNUS should be considered in the differential diagnosis of onychomycosis.

From Dawson Medical Group, Oklahoma City, OK;1 and the Department of Dermatology, Section of Mycology, Manuel Gea Gonzalez General Hospital, Mexico City, Mexico2 Address for Correspondence: Carlos Garcia, MD, Dawson Medical Group, 4805 South Western Avenue, Oklahoma City, OK 73109 • E-mail: cg.derm@yahoo.com

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Patient Positioning During Dermatologic Surgery for Optimal Wound Closure Suneel Chilukuri, MD;1 Khari Bridges, MD;2 Dominic Nguyen, BS;1 Sailesh Konda, MD3 To the Editor: Proper surgical positioning is of paramount importance to both the patient and the practioner, especially during dermatologic surgery. Appropriate positioning allows for patient comfort and more efficient excision of lesions with primary closure. Patient positioning in the operating room for other surgical specialties has been discussed in the literature1; however, the benefit of proper patient positioning in the outpatient setting for optimal wound closure has not been adequately highlighted in the dermatologic surgery literature. We describe proper positioning of the in-office dermatologic surgery patient to facilitate closure of wounds on the extremities, back, and face. Accessible Equipment Simple office equipment, such as adjustable surgical trays, pillows, and blankets, can be used to appropriately position the patient to minimize wound tension and allow for primary closure of a wound with minimal tension. When operating on the distal aspect of the arm, a pillow or folded blanket can be placed under the wrist (Figure 1). With the arm in this position, wound tension is minimized, and the dermatologic surgeon can primarily close wounds that otherwise may not have closed with the hand in a dangling position. Similarly, we have found that tension in wounds proximal to the elbow can be minimized by providing proper support to the upper extremity distal to the elbow (Figure 2). If the wound still cannot be closed in this position, reposition the arm on an adjustable surgical tray in a flexed position. Following wound closure, the patient’s arm can be placed in a sling for 1 to 2 weeks, while the skin stretches and the wound gains tensile strength. When operating on the lower extremity, a pillow can be placed under the hamstring or knee to facilitate excision and to minimize wound tension (Figure 3). In addition to helping with wound closure, this position allows for greater comfort in pa-

tients with lower back pain. For wounds on the back, the patient can be positioned on his or her side, which is also known as the lateral decubitus position (Figure 4). A common mistake is to have the patient lie prone, where the patient usually dangles his or her hand over the lateral aspects of the operating chair. In this position, the wound is actually stretched to maximal tension. If the patient lies on the side contralateral to the wound site, the skin of the back will be optimally relaxed allowing for primary closure of large wounds. Following back surgery, the patient’s ipsilateral arm can be placed in a sling to help to remind him or her of the recent surgery. This technique decreases the chance of wound dehiscence, a possible complication following large excisions ftom the back. When closing wounds on the face, we usually place the patient in a high Fowler’s position, which is sitting upright with the head of the bed at approximately 60 to 90 degrees. This allows the dermatologic surgeon to follow the natural skin tension lines when performing the repair. Alternatively, when the patient is upright, these skin tension lines can be outlined with a surgical marker, and then the patient can be placed in a semi-Fowler’s position at approximately 30 degrees, which may be more comfortable for both the dermatologic surgeon and patient. When a facial wound is closed with the patient lying completely supine, excess tissue at the lateral edges of the wound may be encountered after the patient sits or stands upright and gravity affects the wound. These standing cones of redundant tissue can be avoided by simply having the patient sit in a high Fowler’s or semi-Fowler’s position during wound closure. Conclusions Proper patient positioning is an effective way to minimize wound tension during dermatologic surgery and often allows for closure of even large wounds with careful perioperative planning. There may be exceptions to these general guidelines as respiratory, circulatory, musculoskeletal, or neurologic disorders may preclude

From Refresh Dermatology, Houston, TX;1 Miami Dermatology & Cosmetics, Miami, FL;2 and the Department of Dermatology, University of Florida College of Medicine, Gainesville, FL3 Address for Correspondence: Suneel Chilukuri, MD, Refresh Dermatology, 4914 Bissonnet, Suite 100A, Houston, TX 77401 • E-mail: dermsurg@gmail.com

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Figure 1. Positioning the distal extremity.

Figure 3. Positioning the lower extremity.

Figure 2. Positioning the proximal extremity.

Figure 4. Positioning for wounds on the back.

placement in a particular position for a prolonged period. Additional factors, such as blood pressure, weight, age, and pregnancy, should be taken into consideration. Pregnant patients, in particular, should be placed in a left lateral tilt position with a wedge under the right hip to reduce aortocaval compression.2 While the dermatologic surgeon should understand surgical anatomy, free margins, cosmetic units, and skin tension lines, he or she should also have a knowledge of proper patient positioning for optimal wound closure.

Acknowledgment Ida Orengo, MD assisted with the diagrams. References 1 Spruce L, Van Wicklin SA. Back to basics: positioning the patient. AORN J. 2014;100:298–305. 2 Richards KA, Stasko T. Dermatologic surgery and the pregnant patient. Dermatol Surg. 2002;28:248– 256.

An Epidemiologic Study on the Relationship Between Hand Dermatitis and Antioxidants Yi Chun Lai, BA;1 Yik Weng Yew, MBBS, MPH1,2 To the Editor: Hand dermatitis is chronic relapsing skin disease1 that results from various factors, including oxidative stress. Dietary antioxidants have been shown to be beneficial for atopic dermatitis (AD).2,3 Given the chronic relapsing and debilitating nature of the condition, there has been considerable interest in dietary modifications in the management of hand dermatitis. We aim

to evaluate whether the diagnosis of active hand dermatitis is associated with reduced supplements intake and lower serum levels of micronutrients (vitamins A, C, and E; carotenoids; folate; and selenium) using data from the 2003–2004 US National Health and Nutrition Examination Survey (NHANES). NHANES consisted of randomly selected individuals aged 20 to 59 years from the noninstitutionalized US population. Data on

From T.H. Chan School of Public Health, Harvard University, Boston, MA;1 and the National Skin Centre, Singapore2 Address for Correspondence: Yik Weng Yew, National Skin Centre, 1 Mandalay Road, Singapore 308205 • E-mail: yikweng.yew@mail.harvard.edu

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hand dermatitis diagnosis, questionnaire, and laboratory parameters on serum levels of micronutrients were analyzed. The study was approved by the US National Center for Health Statistics ethics review board. All study participants had standardized photographs taken of the dorsal and palmar views of the hands. These photographs were read by two dermatologists for the diagnosis of hand dermatitis. Both dermatologists were blinded to other information of the participants. Information on supplement use for the past month from the questionnaire was also included in the analysis. Serum concentrations of micronutrients such as retinoids (retinol, retinyl palmitate, retinyl stearate), carotenoids (lutein, zeaxanthin, α-cryptoxanthin, β-cryptoxanthin, trans-lycopene, cis-lycopene, α-carotene, trans-β-carotene, cis-β-carotene, ciscombined lutein/zeaxanthin, phytoene, and phytofluene), vitamin E (α-, δ-, and γ-tocopherols), vitamin C, and selenium were measured. Variables such as age, sex, occupational groups, atopic diathesis, and body mass index (BMI) were included as possible confounding factors. Multivariate logistic regression analysis was performed to adjust for possible confounding factors. Results A total of 2688 study participants were included in the analysis. There were 42 (1.56%) diagnosed cases of active hand dermatitis. The demographic characteristics of our population are summarized in Table I. Intake of vitamins, minerals, or other

dietary supplements for the preceding 1 month was associated with lower odds of having active hand dermatitis (odds ratio: 0.363; 95% confidence interval: 0.178–0.741; P=.0037). However, this association was not significant after adjusting for age, sex, occupational groups, atopic diathesis, and BMI (odds ratio: 0.610; 95% confidence interval: 0.277–1.343; P=.219). Median serum levels of five carotenoids (α-, cis-β-, trans-β-carotenes and α- and β-cryptoxanthins), vitamin C, and folate were significantly lower in patients with active hand dermatitis (Table II). Lower serum levels of three carotenoids and folate remained significantly associated with active hand dermatitis after adjusting for the aforementioned confounders with multivariate logistic regression (Table III). Discussion In this study, active hand dermatitis was significantly associated with lower serum levels of carotenoids and folate, although this association was not observed in retinoids and vitamin E. Studies have reported that intake of foods rich in vitamins A and C decreased the risk of developing AD.4 A Korean study reported that folate, vitamin A, and vitamin C were frequently deficient in patients with AD.5 A recent study reported that the blood levels of vitamins A, C, and E were significantly decreased in AD patients, compared with healthy controls.6 Relative dietary deficiency of antioxidants has been suggested to shift T-helper

Table I. Characteristics of Patients With Hand Dermatitis Characteristics

Hand Dermatitis

No Hand Dermatitis

Odds Ratio

95% Confidence Interval

P Value

Age, mean, y

40.4

37.7

.129

Male

38 (2.9)

1263 (97.1)

10.4

(3.70–29.2)

<.0001

Female

4 (0.3)

1383 (99.7)

1.00

(4.03–32.6)

<.0001

Sex, No. (%)

Occupation groups, No. (%) Frequent manual/ wet work

31 (3.8)

777 (96.2)

11.47

Minimal manual/ wet work

4 (0.3)

1150 (99.7)

1.00

29.5

28.5

.328

(0.19–0.95)

.0322

Body mass index, mean, kg/m2

Atopy diathesis, No. (%) Yes

7 (0.8)

852 (99.2)

0.42

No

35 (1.9)

1794 (98.1)

1.00

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Table II. Supplement Intake and Serum Vitamin Levels of Study Participants With and Without Hand Dermatitis Hand Dermatitis

No Hand Dermatitis

P Value

Yes

10 (0.8)

1223 (99.2)

.004

No

32 (2.2)

1419 (97.8)

α-Carotene

1.235

2.375

<.001

Trans-β-carotene

7.215

10.115

<.001

Cis-β-carotene

0.540

0.830

<.001

α-Cryptoxanthin

2.155

2.505

.022

β-Cryptoxanthin

5.950

7.295

.041

Retinol

55.22

54.08

.428

Retinyl palmitate

0.505

0.670

.587

Retinyl stearate

0.215

0.220

.775

α-Tocopherols

1093

1118

.769

δ-Tocopherols

6.50

5.00

.415

γ-Tocopherols

240.0

216.5

.153

0.555

0.930

.001

Characteristics Dietary supplement intake, No. (%)

Median serum carotenoid levels, ug/dLa

Median serum vitamin A levels, ug/dL

Median serum vitamin E levels, ug/dL

Median serum vitamin C levels, mg/dL Median serum folate levels, ng/mL

8.20

10.70

.005

Median serum selenium levels, ug/L

132.00

134.00

.611

Median serum levels of other carotenoids were not significantly different between patients with and without hand dermatitis.

a

Table III. Adjusted Odds Ratio After Adjusting for Potential Confoundersa in a Multivariate Logistic Regression Model β

EXP (β)b

95% CI for EXP(β)

P Value

α-Carotene

–0.112

0.894

0.767–1.043

.154

Trans-β-carotene

–0.107

0.899

0.833–0.969

.005

Cis-β-carotene

–1.766

0.171

0.057–0.516

.002

α-Cryptoxanthin

–0.364

0.695

0.487–0.991

.044

β-Cryptoxanthin

–0.062

0.940

0.875–1.009

.086

Vitamin C, mg/dL

–0.719

0.487

0.207–1.015

.101

Folate, ng/mL

–0.104

0.901

0.818–0.993

.036

Serum Vitamin Levels Carotenoids, ug/dL

Abbreviation: CI, confidence interval. Adjusting for potential confounders such as age, sex, work occupation, atopic diathesis, and body mass index. b Odds of having hand dermatitis for every unit increase in serum micronutrients. a

cell differentiation toward Th2 phenotype.7 Investigators indicated that low serum folate level may aggravate symptoms of AD by an altered Th1/Th2 equilibrium caused by the inhibition of homocysteine re-methylation.5 SKINmed. 2015;13:410–415

In our study, significantly more men were afflicted with active hand dermatitis, which is generally more common in women. This sex discrepancy can be partly explained by the fact that the diagnosis of hand dermatitis relied on assessment of stan-

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dardized photographs by two dermatologists. Although this is a specific diagnostic method, it may be less sensitive to detect cases of hand dermatitis that are mild or infrequently relapsing. Therefore, cases of identified hand dermatitis likely represented a more severe and persistent form, which may be more common in men (who are more likely to be involved in manual/wet work) than women.

References

Conclusions This study provides indirect evidence that reactive oxygen species may play an important role in hand dermatitis. Given the crosssectional nature of this study, however, results may be subjected to recall bias and reverse causation. Further studies including a detailed dietary history and serial antioxidants measurements could be considered. Physicians should be cognizant that patients with persistent hand dermatitis may have relative deficiency in certain antioxidants.

1 Meding B, Swanbeck G. Prevalence of hand eczema in an industrial city. Br J Dermatol. 1987;116:627–634. 2 Harik-Khan RI, Muller DC, Wise RA. Serum vitamin levels and the risk of asthma in children. Am J Epidemiol. 2004;159:351–357. 3 Fogarty A, Lewis S, Weiss S, et al. Dietary vitamin E, IgE concentrations, and atopy. Lancet. 2000;356:1573–1574. 4 Kim J, Kwon J, Noh G, et al. The effects of elimination diet on nutritional status in subjects with atopic dermatitis. Nutr Res Pract. 2013;7:488–494. 5 Cui HS, Ahn IS, Byun YS, et al. Dietary pattern and nutrient intake of Korean children with atopic dermatitis. Ann Dermatol. 2014;26:570–575. 6 Sivaranjani N, Rao SV, Rajeev G. Role of reactive oxygen species and antioxidants in atopic dermatitis. J Clin Diagn Res. 2013;7:2683–2685. 7 Li-Weber M, Giasisi M, Trieber MK, et al. Vitamin E inhibits IL-4 gene expression in peripheral blood T-cells. Eur J Immunol. 2002;32:2401–2408.

Editorial

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

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Publishing PUBLISHER Art Kalaka

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Copyright: © 2015 Pulse Marketing & Communications, LLC. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or by any means without the prior permission in writing from the Publisher. Requests should be addressed to the Permissions Editor at: Pulse Marketing & Communications, LLC, 4 Peninsula Avenue, Sea Bright, NJ 07760.

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Associate Publisher James R. Adams jadams@skinmedjournal.com

415

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

African Association for Dermatology

Hand Dermatitis and Antioxidants

The Dermatologic & Aesthetic Surgery International League


September/October 2015

Volume 13 • Issue 5

RETRACTION

Notice of Retraction: Duplicate Publication in Sehgal VN, Chatterjee K, Chaudhuri A, Chatterjee G. “Acquired/post-traumatic ectopic nail: onychoheterotopia.” Skinmed. 2014;12:306–307. Content presented in the paper “Acquired/post-traumatic ectopic nail: onychoheterotopia” by Virendra N. Sehgal, MD; Kingshuk Chatterjee, DNB; Anita Chaudhuri, MD; and Gautam Chatterjee, MS, which was published in the September-October 2014 issue of SKINmed Dermatology for the Clinician, comprised material previously published in other copyrighted sources.1 As a result, we retract this presentation from the literature. Lawrence Charles Parish, MD, MD(Hon) Editor-in-Chief, SKINmed Dermatology for the Clinician Reference 1 Chatterjee K, Chaudhuri A, Chatterjee G. Onychoheterotopia: a unique case. Indian J Dermatol. 2013;58:150–151.

Smallpox (Vaiolo umano florido all’apice dell’eruzione pustolosa): Courtesy of Museo delle Cere Anatomiche L. Cattaneo, University of Bologna, Italy. Photo by Cristian Mancini. Submitted by Diana Garrisi, London, UK. SKINmed. 2015;13:416

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© 2015 Pulse Marketing & Communications, LLC


IMPORTANT INFORMATION ABOUT

SOOLANTRA®

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

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

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

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

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

All trademarks are the property of their respective owners. ©2015 Galderma Laboratories, L.P. Galderma Laboratories, L.P. 14501 N. Freeway, Fort Worth, TX 76177 SOL-254 Printed in USA 06/15


TREATING INFLAMMATORY LESIONS OF ROSACEA CAN BE TOUGH…

PRESCRIBE

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

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


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