SKINmed - May/Jun, 2018 by jo-ann kalaka-Adams

Chinese Society of Dermatology

Lebanese Dermatological Society

Dermatology Insights and Inquiries

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

African Association for Dermatology

May/June 2018 Volume 16 Issue 3

EDITORIAL Recertification Revisited: A Not So Eleemosynary Tale Lambert and Parish

Chinese Society of Dermatology

COMMENTARY Skin Failure

Dermatology Insights and Inquiries

Coltart and Irvine

ORIGINAL CONTRIBUTIONS Antimicrobial Susceptibility of Cutibacterium acnes Isolated from Ecuadorian Patients with Acne Vulgarisa Solís, Zurita, Velasco, and Dressendorfer

Reticulohistiocytoses: A Unique Nosologic Spectrum of Non-Langerhans Cell Histiocytosis Luz, Rochael, and Ramos-e-Silva

CORE CURRICULUM Behçet Disease: New Developments in the Etiopathogenesis of an Old Silk Road Disease Ozlu and Karadag

DEPARTMENTS NEW THERAPY UPDATE Bavencio® (Avelumab)—A Newly Approved Anti-PD-L1 IgG1 Antibody

Lebanese Dermatological Society

Belarusian Society of Dermatovenereologists and Cosmetologists

North American Clinical Dermatologic Society

The Dermatologic & Aesthetic Surgery International League

HISTORY OF DERMATOLOGY NEWSLETTER Picturing in Dermatology—From Wax Models to Teledermatology, Part 2 Lowenstein

African Association for Dermatology

CASE STUDIES Syringocystadenocarcinoma Papilliferum: A Rare Malignant Sweat Gland Tumor Yao, Cellura, and Phelps

Reticular Telangiectatic Erythema: A Chronic Hematoma Subsequent to Hip Replacement as an Underlying Cause

Beggs, McGuinn, Santoro, Nazarian, and Lee

Bullous Fixed Drug Eruption Caused by Doxycycline

Zaouak, Bacha, Jrad, Jouini, Salah, Sahnoun, Hammami, and Fenniche

Acrodermatitis Enteropathica Presenting with Recurrent Diarrhea and Vomiting in an Infant Reluctant to Breastfeed, and a Peculiar Erythemato-Eczematous Eruption around the Oral and Anogenital Regions Sehgal, Bhattacharya, Sharma, and Singh

Gupta, Versteeg, Abramovits, and Vincent

PHOTO CAPSULE Nevus Lipomatosus Cutaneous Superficialis on the Nape—A Rare Presentation

Kulkarni, Chhabra, Prabha, Hussain, and Bugalia

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TABLE OF CONTENTS May/June 2018 • Volume 16 • Issue 3

EDITORIAL

Recertification Revisited: A Not So Eleemosynary Tale .................................................................151

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

COMMENTARY

Skin Failure ................................................................................................................................155

George Stewart Coltart, BMBCh; Catriona Irvine, MBBS, FRCP

ORIGINAL CONTRIBUTIONS

Antimicrobial Susceptibility of Cutibacterium acnes Isolated from Ecuadorian Patients with Acne Vulgaris ......................................................................................................................159

María Belén Solís, MD; Jeannete Zurita, MD, MSc; Nadyn Velasco, MD; Luz María Dressendorfer, MD

Reticulohistiocytoses: A Unique Nosologic Spectrum of Non-Langerhans Cell Histiocytosis ............167

Flávio Barbosa Luz, MD, PhD; Mayra Carrijo Rochael, MD, PhD; Marcia Ramos-e-Silva, MD, PhD

DEPARTMENTS Core Curriculum

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

Behçet Disease: New Developments in the Etiopathogenesis of an Old Silk Road Disease ..............176

Emin Ozlu, MD; Ayse Serap Karadag, MD

New Therapy Update

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

Bavencio® (Avelumab)—A Newly Approved Anti-PD-L1 IgG1 Antibody ...........................................183

Aditya K. Gupta, MD, PhD, FRCPC; Sarah G. Versteeg, MSc; William Abramovits, MD, FAAD; Kimberly D. Vincent, MD

Photo Capsule

Snejina Vassileva, MD, PhD, Section Editor

Nevus Lipomatosus Cutaneous Superficialis on the Nape—A Rare Presentation ............................189

Sandeep Kulkarni, MBBS, DNB; Namrata Chhabra, MD; Neel Prabha, MD; Nighat Hussain, MD; Amit Bugalia, MD

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

Picturing in Dermatology—From Wax Models to Teledermatology, Part 2 .....................................191

Eve J. Lowenstein, MD, PhD

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TABLE OF CONTENTS May/June • Volume 16 16 • Issue 3 3 May/June 2018 • Volume • Issue

CASE STUDIES

Vesna Petronic-Rosic, MD, MSc, Section Editor

Syringocystadenocarcinoma Papilliferum: A Rare Malignant Sweat Gland Tumor ..........................195

Jonathan L. Yao, MD; A. Paul Cellura, BS; Robert G. Phelps, MD

Reticular Telangiectatic Erythema: A Chronic Hematoma Subsequent to Hip Replacement as an Underlying Cause ..............................................................................................................199

Sarah M. Beggs, MD; Kathleen P. McGuinn, MD; Anthony F. Santoro, MD; Levon N. Nazarian, MD; Jason B. Lee, MD

Bullous Fixed Drug Eruption Caused by Doxycycline ....................................................................202

Anissa Zaouak, MD; Takoua Bacha, MD; Meriem Jrad, MD; Raja Jouini, MD; Meriem Belhaj Salah, MD; Rym Sahnoun, MD; Houda Hammami, MD; Samy Fenniche, MD

Virendra N. Sehgal, MD, FNASc, FAMS, FRAS (Lond); Sambit N. Bhattacharya, MD; Sonal Sharma, MD; Navjeeven Singh, MD

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Volume 16 • Issue 2

ABOUT OUR JOURNAL

MANAGING EDITOR Marla Kipp marla@skinmedjournal.com

SKINmed: Dermatology for the Clinician®, print ISSN 1540-9740, online ISSN 1751-7125, is published bimonthly by Pulse Marketing & Communications, LLC, located at 4 Peninsula Avenue, Sea Bright, NJ 07760.

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Printed in the USA. Authors interested in submitting a paper should refer to the instructions located online at: http://www.skinmedjournal.com/author-info.html. Submissions should be e-mailed to the Editor at: larryderm@yahoo.com

COMPOSITION Paul Bennett

Publishing PUBLISHER Art Kalaka

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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Volume 16 • Issue 3

May/June 2018

EDITOR IN CHIEF

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

DEPUTY EDITORS William Abramovits, MD

Aditya K. Gupta, MD, PhD, FRCPC

W. Clark Lambert, MD, PhD

Vesna Petronic-Rosic, MD, MSc, MBA

Dallas, TX

London, Ontario, Canada

Newark, NJ

Washington, DC

Larry E. Millikan, MD

Marcia Ramos-e-Silva, MD, PhD

Jennifer L. Parish, MD

Cumming, GA

Rio de Janeiro, Brazil

Philadelphia, PA

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

Jasna Lipozencic, MD, PhD Zagreb, Croatia

Virendra N. Sehgal, MD Delhi, India

Ada Lo Schiavo, MD Naples, Italy

Charles Steffen, MD Oceanside, CA

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

Alexander J. Stratigos, MD Athens, Greece

George M. Martin, MD Kihei, HI

James S. Studdiford III, MD Philadelphia, PA

Marc S. Micozzi, MD, PhD Rockport, MA

Robert J. Thomsen, MD Los Alamos, NM

Seung-Kyung Hann, MD, PhD Seoul, Korea

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

Julian Trevino, MD Dayton, OH

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

Oumeish Youssef Oumeish, MD, FRCP Amman, Jordan

María Daniela Hermida, MD Buenos Aires, Argentina

Joseph L. Pace, MD, FRCP Naxxar, Malta

Warren R. Heymann, MD Camden, NJ

Art Papier, MD Rochester, NY

Tanya R. Humphreys, MD Bala-Cynwyd, PA

Johannes Ring, MD, DPhil Munich, Germany

Camila K. Janniger, MD Englewood, NJ

Roy S. Rogers III, MD Scottsdale, AZ

Ayse Serap Karadag, MD Istanbul, Turkey

Donald Rudikoff, MD New York, NY

Abdul-Ghani Kibbi, MD Beirut, Lebanon

Robert I. Rudolph, MD Wyomissing, PA

Andrew P. Lazar, MD Washington, DC

Todd E. Schlesinger, MD Charleston SC

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

Brian Berman, MD, PhD Miami, FL Mark Bernhardt, MD Ft. Lauderdale, FL Jack M. Bernstein, MD Dayton, OH Sarah Brenner, MD Tel Aviv, Israel Henry H.L. Chan, MB, MD, PhD, FRCP Hong Kong, China Joel L. Cohen, MD Greenwood Village, CO Natalie M. Curcio, MD, MPH Nashville, TN Richard L. Dobson, MD Mt Pleasant, SC William H. Eaglstein, MD Menlo Park, CA Charles N. Ellis, MD Ann Arbor, MI Howard A. Epstein, PhD Philadelphia, PA

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

SKINmed. 2018;16:150

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Maria M. Tsoukas, MD, PhD Chicago, IL Graham Turner, PhD, CBiol, FSB Port Sunlight, UK Snejina Vassileva, MD, PhD Sofia, Bulgaria Daniel Wallach, MD Paris, France Michael A. Waugh, MB, FRCP Leeds, UK Wm. Philip Werschler, MD Spokane, WA Ronni Wolf, MD Rechovot, Israel Jianzhong Zhang, MD Beijing, China Matthew J. Zirwas, MD Columbus, Ohio

May/June 2018

Volume 16 • Issue 3

EDITORIAL

Recertification Revisited: A Not So Eleemosynary Tale W. Clark Lambert, MD, PhD;1,2 Lawrence Charles Parish, MD, MD (Hon)3 “The road to hell is paved with good intentions.”—Saint Bernard of Clairvaux

ecertification (together with “Maintenance of Certification” [MOC], which is variously, vaguely, and heterogeneously defined in different sources1,2) is putatively a process by which physician competence, particularly that in specific specialties and subspecialties, is periodically redocumented to assure that the physician remains competent and up to date as he or she ages and medicine continues to evolve. This may sound like a good idea, and in the appropriate context it may be. The rub is that some sort of mechanism is required to bring this about, and this mechanism is subject to abuse, potentially corrupting once honored and even revered medical institutions in the process. THE GOOD INTENTIONS Medical specialty boards, such as the American Board of Internal Medicine (ABIM) and our own American Board of Dermatology, were founded with the noble goal of assuring the public that physicians newly certified by in their respective specialties were properly trained, knowledgeable, and, so far as could be readily determined, competent. With the passage of time, multiple specialty boards have been founded. A combined board, the American Board of Medical Specialties, was formerly chaired by dermatology’s own John Strauss, MD, Professor and Chairman of Dermatology at the University of Iowa. These boards have enjoyed widespread respect among physicians and laymen alike, and today board certification is an important credential by which physicians are evaluated and chosen. Even at the beginning, however, seeds of problems were sewn. Although in most fields a single board was acknowledged to be authoritative, there were subsequent exceptions, such as in Mohs

chemigraphic surgery. Membership on a board gave a physician honor and respect, but also tended to set physicians apart, with board members seen as a cut above the others. Despite the fact that the boards were self-appointed, this was not seen as a cause for concern: there were numerous other ways that physicians could distinguish themselves from their peers, and anyhow the power of board members over others ended when the latter became board certified, with lifetime certification, in their specialty or subspecialty. THE ROAD TO HELL Recertification changed all that. Now, because every physician must be recertified, and recertified by the same board that certified them to begin with, every board-certified physician is forever beholden to his or her respective board. Under this new arrangement, board members may now forever see themselves as a cut above their peers, and with their self-appointed status the whole arrangement begins to resemble a banana republic. Third-party payers, motivated only by fiduciary concerns, are only too willing to reduce, or withhold altogether, payment to physicians who have not recertified or undergone MOC. State medical societies and hospital boards may also come to require recertification. As specialties change (think loss of syphilology and acquisition of dermatologic surgery and cosmetic dermatology in dermatology), their respective specialty boards should, perhaps, change as well. Boards may, or may not, choose to appoint new members accordingly. Finally, board members may appoint new members or replacements influenced by factors other than expertise, credentials, judgment, and wisdom, so that the respective board may eventually come to resemble an “old boys/girls club,” respected by few, but retaining their power over all.

From the Department of Dermatology,1 and Department of Pathology and Laboratory Medicine,2 Rutgers University – New Jersey Medical School, Newark, NJ;1 and the Department of Dermatology and Cutaneous Biology and the Jefferson Center for International Dermatology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA3 Address for Correspondence: Lawrence Charles Parish, MD, MD (Hon), Clinical Professor of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 1845 Walnut Street, Suite 1650, Philadelphia, PA 19103 • E-mail: larryderm@yahoo.com

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ARRIVAL IN HELL At this point, commercialization/corruption raises its ugly head. The more onerous, expensive, and obfuscatory the recertification/MOC process, the more money and power the boards accrue. As we have previously pointed out, the goals of recertification can be achieved cheaply and with minimum fuss,1,2 but a number of boards are pursuing a very different course. Not content with their special status, some boards have decided to financially enrich themselves at the expense of their diplomates.3–5 Significantly, not only board members, but also their hired staffs, including lower echelon personnel, are becoming wealthy at the expense of diplomates and board certification candidates.3 We may be accused, perhaps not entirely without justification, of having practiced a bit of “yellow journalism” in these pages in the past, attacking these issues.1,2 Our efforts pale in comparison to more recent publications by others, however, as a recent issue of Philadelphia Medicine, for example, featured three contributions, including one each by the president and immediate past president of the Pennsylvania Medical Society,3–5 each of which may be gently described as scathing.

gladly or, anyhow, willingly borne by diplomates and board certification candidates in eleemosynary (defined by Webster’s Dictionary as wholly or partially charitable) arrangements, fees of some boards have exploded, as their expenditures have become excessive, sometimes even absurd.3 Diplomates, forced to remain board-certified regardless of the cost, as well as candidates for initial certification, are now forced, unwillingly, to pay exorbitant fees.4 Under present arrangements, there is nothing to restrain boards from even more egregious charges. The whole system is in danger of collapsing.5 OUR SOLUTION We suggest that, instead of trying to reform the behavior of presently involved players, an alternative pathway to recertification be created: introduction of boards that exist only to award recertification to present board diplomates.1,2 We also recommend that “MOC,” whatever that is, be abolished altogether. We recommend that the material upon which recertification is based:

While the ABIM is the immediate target of these presentations, other boards are also mentioned, and their comments may also be applied to the American Board of Dermatology. Charles Cutler, MD, MACP, president of the Pennsylvania Medical Society, admonishes the ABIM to “reign in the wild spending,” citing numerous examples.3 Scott E. Shapiro, MD, immediate past president of the Pennsylvania Medical Society, agrees, referring to the ABIM as “a costly, punitive process that gives the illusion of evaluating physician competence.”4 He notes that the American Medical Association, formerly a supporter, now opposes the ABIM as well as other boards, noting that they “got it wrong.” Westby G. Fisher, MD, after listing a number of egregious examples of fiscally questionable activities of the ABIM, calls for a system “based on integrity, not greed.”5 Presented with an opportunity to respond to these essays, Richard J. Baron, MD, MACP, of the ABIM “respectfully decline[d] at this time.”6 In our view, his response may be gently defined as inadequate. The way back is not easy now, and will rapidly become more difficult with continued inaction as more and more third-party payers become increasingly involved, and hospital privileges and state medical licenses come to be contingent on recertification/ MOC. There is money involved, lots of money; any attempt at reform is certain to be met with expensive and labyrinthine legal challenges. Whereas boards once charged reasonable fees, SKINmed. 2018;16:151–153

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1. be referenced to the time(s) recertification is requested (eg, December 31, 2005 to January 1, 2011); 2. be written in a readily obtained book of limited length (word count) and size font; and 3. be prepared by a committee appointed by a respected organ within that specialty (eg, in dermatology, the American Academy of Dermatology or the American Dermatological Association); and that 4. a separate committee should be appointed by that society charged with creating an examination of reasonable length and difficulty based solely on information within this book; 5. that this examination to be given just before or following the annual meeting of the society or at some other generally convenient time; 6. that it should not to exceed one half-day in length for each 10-year period for which recertification is sought; 7. that the entire process should be of reasonable price and inconvenience, in any case not to exceed one third the annual dues of the society; 8. that there should be no minimum pass rate for the examination—the expected pass rate is expected to approximate 100%; Recertification Revisited: A Not So Eleemosynary Tale

May/June 2018

EDITORIAL

9. that upon passing this examination and providing proof of original certification, the candidate should be recognized by that organ as having been recertified for the period in question; 10. and that state medical boards should be notified of the recertification(s) by the organ, but only in the event recertification is successful.

2 Lambert WC, Parish, LC. Continuing medical education, II: MOC, CME, ABD, ABMS, ACGME, CMS, FSMB, IOM, MOL, PQRS, SMB, et cetera et ad nauseum. [Editorial]. SKINmed. 2013;11:262– 263. 3 Cutler C. A message to the ABIM: Reign in spending and stop turning staff into millionaires. Phila Med. 2016–2017; Winter:7. 4 Scott SE. The ABIM: A costly, punitive process that gives the illusion of evaluating physician competence. Phila Med. 2016– 2017, Winter,:8.

We believe that time is of the essence in establishing this or a similar alternate mechanism for recertification.

5 Fisher WG. Point of view … A broken system – The American Board of Internal Medicine. Phila Med. 2016–2017, Winter:9–10.

REFERENCES

6 Baron RJ. A response from ABIM…. Phila Med. 2016–2017; Winter:10.

1 Lambert WC, Parish LC. Editorial: Contemporary American dermatology: Continuing medical education, I. SKINmed. 2011;8:134–135.

7 Webster’s New Twentieth Century Dictionary of the English Language, Unabridged. 2nd ed. Philadelphia, PA: William Collins; 1980:586.

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Volume 16 • Issue 3

COMMENTARY

Skin Failure George Stewart Coltart, BMBCh;1 Catriona Irvine, MBBS, FRCP2

he skin is the largest organ in the human body by weight and, like all other organs in the body, it can be subject to injury that can impair its normal function. The medical profession as a whole has a good concept of organ failure when it relates to the heart, lungs, liver, kidneys, brain, and even gut, but much less so when it involves the skin. Skin failure is relatively uncommon, but when it does occur, it can be life-threatening, requiring urgent and specialist management.

Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) represent different severities of the same serious eruption of mucocutaneous blistering and epithelial sloughing. This is almost invariably an adverse reaction to certain medications, particularly sulfa-containing drugs (eg, sulfonamides), antiepileptics, and

DEFINITION There are many different definitions of skin failure. Chronically, it may describe loss of any function of the skin, such as through the formation of unavoidable decubitus ulcers, or even the failure of skin to maintain a normal aesthetic appearance.1,2 For the purposes of this commentary, however, we define skin failure as a clinical syndrome, characterized by the acute loss of normal homeostatic and barrier skin function due to a diffuse dermatologic insult.3,4

Table I. Functions of Skin Homeostasis Thermoregulation Prevention of fluid and electrolyte loss Environmental protection Barrier to trauma and microorganisms Immunosurveillance Ultraviolet light protection Endocrine function Vitamin D synthesis Neurological function Sensation of external stimuli

NORMAL SKIN PHYSIOLOGY The many functions of the skin are summarized in Table I. Any loss to the body’s regulation of temperature, fluid and electrolyte management, and ability to defend against infection, can cause an acute deterioration in an affected patient. CAUSES OF SKIN FAILURE Table II lists the most frequent causes of skin failure. After physical burns, the most common cause for skin failure is erythroderma. This condition arises when a dermatologic condition affects more than 90% of the body surface area. It has an incidence of 1 to 2 per 100,000 individuals per year.5 It frequently occurs due to an exacerbation of a preexisting dermatologic condition, such as atopic dermatitis or psoriasis, and may be precipitated by an exogenous trigger, such as infection, sudden cessation of systemic immunosuppression, or initiation of a new medication (eg, lithium, antimalarials).

Table II. Causes of Skin Failure Erythroderma Inflammatory: dermatitis, psoriasis Other dermatoses: pityriasis rubra pilaris, lichen planus, ichthyosis, Sweet syndrome Neoplastic: cutaneous T-cell lymphoma Drug eruptions Infective exanthema Desquamation Burns Stevens-Johnson syndrome/toxic epidermal necrolysis Staphylococcal scalded skin syndrome Epidermolysis bullosa Vesicobullous disorders Pemphigus, pemphigoid Graft-vs-host disease

From the Department of Dermatology, University Hospital of Southampton, Southampton, UK;1 and the Department of Dermatology, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK2 Address for Correspondence: George Stewart Coltart, BMBCh, Department of Dermatology, University Hospital Southampton, Royal South Hants Hospital, Brintons Terrace, Southampton, SO14 0YG, UK • E-mail: g.coltart@nhs.net

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nonsteroidal anti-inflammatory drugs. It is rare, with an incidence of 1 to 6 per million per year, but carries a high mortality—10% for Stevens-Johnson syndrome, to more than 30% for TEN.6–8 Staphylococcal scalded skin syndrome may have a similar appearance to Stevens-Johnson syndrome /TEN, and is caused by a bacterial exotoxin that binds to desmoglein-1 in the skin to cause widespread epidermolysis. This carries a much better prognosis than Stevens-Johnson syndrome /TEN, with mortality of less than 4%.9 Other causes of skin failure that may become apparent in pediatric populations include such severe genodermatoses as epidermolysis bullosa or ichthyosis. Graft-vshost disease is a condition that affects patients after allogenic bone marrow transplant. If not adequately controlled with potent immunosuppressive agents, it too can result in erythroderma and widespread bullous formation.10 COMPLICATIONS OF SKIN FAILURE The physiologic complications of skin failure are summarized in Table III. Patients have significant cutaneous fluid loss; transepidermal water loss has been estimated to be 2.5 liters per day in erythroderma, which is 10 to 20 times the rate that from normal skin.11 In addition, the inflammation of an extensive surface area of skin can cause widespread cutaneous vasodilatation. This results in a significant increase in cardiac output and can cause high-output cardiac failure, especially in patients with a previously impaired myocardium.12 Fluid shifts and their correction are invariably accompanied by electrolyte abnormalities, and in particular, hyper- or hypokalaemia can precipitate life-threatening cardiac arrhythmias.13 Cutaneous thermoregulation is mediated by control of sweating and skin blood flow, and these mechanisms are disturbed in skin failure. Diffuse cutaneous inflammation causes cutaneous vasodilatation, which, when combined with the convective heat loss from transepidermal water loss, can lead to a fall in core body temperature. The compensatory physiologic response causes the patient to shiver, mimicking rigors.

A breakdown of the skin barrier can lead to infectious complications. Skin colonization with Staphylococcus aureus is higher in erythrodermic patients than in the general population.14 This may lead to secondary bacterial infections and sepsis, which can result in multiorgan failure and death if not treated promptly.15 Increased energy requirements result from the catabolic metabolic state associated with wound repair, impaired thermoregulation, and increased metabolic rate.16 In addition, exudate from damaged skin increases cutaneous protein loss and adds to nutritional requirements.17 It is recognized that systemic inflammation, as characterized by raised C-reactive protein and low serum albumin, is associated with an increased risk of venous thromboembolism.18 Additionally, patients with skin failure are frequently in a state of dehydration and immobility, furthering their risk of venous thromboembolism.19 MANAGEMENT Skin failure is a medical emergency, and the systemic disturbances described above require urgent correction and specialist input. A multidisciplinary team approach is essential. Acute internal physicians are best placed to diagnose and manage the most acute systemic complications, such as sepsis, shock, and hypothermia. Patients may require admission to an intensive care unit or high-dependency unit, depending on the degree of other organ involvement.20 Early review by the dermatology team is required to help diagnose and reverse the underlying cause. A cutaneous biopsy may elucidate the cause of the skin failure. All potential triggers should be immediately eliminated. Any unnecessary drugs must be stopped, allergens removed, and potentially causative infections promptly treated. Treatment of the condition underlying skin failure is key to its resolution, and disease-specific management (eg, systemic agents in psoriasis, immunosuppression in graft-vs-host disease) should be commenced as soon as it is safe to do so.21

Table III. Complications of Skin Failure

Skin protection

Infection

Bland topical emollients with a high lipid content, such as 50:50 liquid paraffin, should be applied 2- to 4-hourly to help prevent cutaneous fluid and heat loss. It is important to manage patients’ pressure areas carefully, as they are at high risk of developing pressure ulcers. Nurses must exercise care when repositioning the patient about the bed, as skin can easily shear off in certain conditions (TEN, epidermolysis bullosa).22 Nursing the patient on silk bed sheets is reported to be beneficial for avoiding skin

High-output cardiac failure Hypo-/hyperthermia Pain Electrolyte abnormalities Death SKINmed. 2018;16:155–158

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shearing.23 Intravenous lines, catheters, and other invasive paraphernalia should be kept to a minimum.

feeding should be managed with a nasogastric tube or parenteral supplementation.

Symptomatic management

Venous thromboembolism

Denuded skin can be exquisitely tender. It is important to make the patient as comfortable as possible; analgesia may be required if the areas of affected skin are particularly painful. Itch is a common finding in erythroderma that may be treated with oral antihistamines.21

Patients should be treated with prophylactic low-molecularweight heparin unless otherwise contraindicated.

Thermoregulation Patients should have frequent monitoring of their body temperature. They should be nursed in a constant temperature, preferably 30 to 32°C (86 to 90°F)—this will feel uncomfortably hot for the staff caring for the patient. Hypothermic patients may require thermal convective blankets (such as the Bair Hugger™; 3MTM, St. Paul, MN). Uncontrolled hyper- or hypothermia should be managed in an intensive care unit setting, as it may require cooled or warmed intravenous fluids for temperature correction.24

CONCLUSIONS Skin failure is an uncommon but dangerous condition. Although it can be caused by a wide range of different disease processes, there are common complications that can affect all patients with skin failure and can prove life-threatening. It is vital that clinicians are aware of the causes of skin failure so that they can reverse them as rapidly as possible. They must also be alert to the complications of skin failure so they can protect their patients long enough for their skin to recover. REFERENCES

Fluid balance Patients require intravenous fluids and careful monitoring of their vital signs (blood pressure, pulse), fluid balance, and urine output. If volume overload results in association with high-output cardiac failure, patients may require diuresis and fluid restriction. Conventional heart failure therapy (angiotensin-converting enzyme inhibitors, β-blockers) is only indicated in high-output cardiac failure if the cardiac ejection fraction is less than 40%.25

Electrolyte replacement Fluid losses and shifts cause fluctuations in patients’ electrolyte balance. All patients with skin failure should have electrolytes monitored daily and corrected as appropriate.

Infection Vigilance for signs of local and systemic infection is imperative in patients with skin failure. Patients’ temperature and inflammatory markers should be monitored, although the underlying skin disease can compound their reliability as indicators of infection. Any suspicion of infection should be addressed urgently and will require early treatment with intravenous antibiotics.

Nutrition Energy requirements in patients with TEN have been estimated at 20 to 25k cal/kg per day during the early course of the disease, and 25 to 30 kcal/kg per day during recovery.26 If patients are too unwell to meet their own requirements adequately, their SKINmed. 2018;16:155–158

157

1 Witkowski JA, Parish LC. The decubitus ulcer: Skin failure and destructive behavior. Int J Dermatol. 2000;39:894–896. 2 Ryan TJ. Skin failure 1995;28:171–173.

and

lymphedema.

Lymphology.

3 Irvine C. ‘Skin failure’—a real entity: Discussion paper. J Roy Soc Med. 1991;84:412–413. 4 Inamadar AC, Palit A. Acute skin failure: Concept, causes, consequences and care. Indian J Dermatol Venereol Leprol. 2005;71:379–385. [[Q9]] 5 Sigurdsson V, Steegmans PH, van Vloten WA. The incidence of erythroderma: A survey among all dermatologists in the Netherlands. J Am Acad Dermatol. 2001;45:675–678. 6 Harr T, French LE. Toxic epidermal necrolysis and StevensJohnson syndrome. Orphanet J Rare Dis. 2010;5:39. 7 Yang MS, Lee JY, Kim J, et al. Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis: A nationwide population-based study using national health insurance database in Korea. PloS One. 2016;11:e0165933. 8 Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens–Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133:1197–1204. 9 Patel GK, Finlay AY. Staphylococcal scalded skin syndrome. Am J Clin Dermatol. 2003;4:65–175. 10 Ruutu T, Gratwohl A, De Witte T, et al. Prophylaxis and treatment of GVHD: EBMT–ELN working group recommendations for a standardized practice. Bone Marrow Transpl. 2014;49:168–173. 11 Grice KA, Bettley FR. Skin water loss and accidental hypothermia in psoriasis, ichthyosis, and erythroderma. Br Med J. 1967;4:195–198. 12 Shuster S. High-output cardiac failure from skin disease. Lancet. 1963;281:1338–1340. 13 Lee JW. Fluid and electrolyte disturbances in critically ill patients. Electrolyte Blood Press. 2010;8:72–81.

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COMMENTARY

14 Talpur R, Bassett R, Duvic M. Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome. Br J Dermatol. 2008;159:105– 112.

20 Nates JL, Nunnally M, Kleinpell R, et al. ICU Admission, discharge, and triage guidelines: A framework to enhance clinical operations, development of institutional policies, and further research. Crit Care Med. 2016;44:1553–1602.

15 Green MS, Prystowsky JH, Cohen SR, et al. Infectious complications of erythrodermic psoriasis. J Am Acad Dermatol. 1996;34:911–914.

21 Rothe MJ, Bernstein ML, Grant-Kels JM. Life-threatening erythroderma: Diagnosing and treating the “red man”. Clin Dermatol. 2005;23:206–217.

16 Kien CL, Young VR, Rohrbaugh DK, Burke JF. Increased rates of whole body protein synthesis and breakdown in children recovering from burns. Ann Surg. 1978;187:383–391.

22 Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: Current evidence, practical management and future directions. Br J Dermatol. 2005;153:241–253.

17 Kanthraj GR, Srinivas CR, Devi PU, et al. Quantitative estimation and recommendations for supplementation of protein lost through scaling in exfoliative dermatitis. Int J Dermatol. 1999;38:91–95.

23 Booy R, Tudor-Williams G. Staphylococcal skin sepsis. Curr Paed. 1997;7:42–47.

18 Olson NC, Cushman M, Lutsey PL, et al. Inflammation markers and incident venous thromboembolism: The REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. J Thromb Haemost. 2014;12:1993–2001. 19 Van Haren RM, Thorson CM, Valle EJ, et al. Hypercoagulability after burn injury. J Trauma Acute Care. 2013;75:37–43.

24 Jones WG, 2nd, Minei JP, Barber AE, et al. Bacterial translocation and intestinal atrophy after thermal injury and burn wound sepsis. Ann Surg. 1990;211:399–405. 25 Mehta PA, Dubrey SW. High output heart failure. Q J Med. 2009;102:235–241. 26 Coss-Bu JA, Jefferson LS, Levy ML, et al. Nutrition requirements in patients with toxic epidermal necrolysis. Nutr Clin Pract. 1997;12:81–84.

“Ulcus cruris dext.”, Moulage No. 101, made in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD SKINmed. 2018;16:155–158

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Volume 16 • Issue 3

ORIGINAL CONTRIBUTION

Antimicrobial Susceptibility of Cutibacterium acnes Isolated from Ecuadorian Patients with Acne Vulgaris María Belén Solís, MD;1,2 Jeannete Zurita, MD, MSc;1,2 Nadyn Velasco, MD;2 Luz María Dressendorfer, MD2 ABSTRACT Antimicrobial resistance to Cutibacterium acnes has become a worldwide problem in the last century, but there are no previous studies on antibiotic susceptibility patterns of this bacterium in Ecuador. A total of 129 skin swabs were collected from patients with acne vulgaris (AV) attending the dermatology department of a hospital in Quito, Ecuador, from July to August 2015. The patients selected had received registered antimicrobial therapy on at least one occasion before sampling. Microbiological procedures were performed according to conventional methods. The species of isolates were identified using a mass spectrometer system (matrix-assisted laser desorption ionization time-offlight [MALDI-TOF]). Antibiotic susceptibility tests on isolated Cutibacterium were performed using an anaerobe-sensitive panel (ANO2; Thermo Fisher; TREK Diagnostic Systems Ltd., West Sussex, UK). (SKINmed. 2018;16:159–165)

ropionibacterium spp. were isolated from 71 of 129 patients. Sixty-five organisms were Cutibacterium acnes, three were Propionibacterium granulosum, and three were Propionibacterium acidifaciens. Twenty-one (29.5%) strains were resistant to erythromycin, eight (11.2%) to clindamycin, seven (9.8%) to tetracycline, and two (2.8%) to minocycline. This first study of its kind in Ecuador has therefore shown that C. acnes are highly resistant to erythromycin and less resistant to clindamycin and tetracycline, with susceptibility to minocycline. Antimicrobial resistance in C. acnes in this population has a lower prevalence than in populations in Asia, Australia, and Europe, and a similar pattern to Chile and Colombia.

AV is a chronic inflammatory disease of the sebaceous glands that occurs in approximately 35% to 90% of young people, lasting in some into adulthood.1 This health problem affects the emotional, social, and economic aspects of life for the individuals who have it. The annual cost of consumption of acne products in the United States is approaching $100 million.2

Four factors are involved in the pathogenesis of acne: excess sebum production, bacterial colonization, inflammation, and abnormal keratinization.3 The primary bacteria responsible for AV are Cutibacterium acnes and Staphylococcus epidermidis, which are part of the normal microbiota of the skin. The diagnosis of acne is mainly clinical, with classification according to the morphology and/or severity of the lesions. Dermatologists regularly prescribe antibiotics for AV and other long-term inflammatory dermatoses; however, antibiotic resistance has led to a decreased susceptibility of certain bacterial organisms such as C. acnes. Acne therapy is based on controlling etiopathogenic factors that cause acne by use of anticomedogenic, anti-inflammatory, and antimicrobial medications.2 The susceptibility pattern of C. acnes to antibiotics in Ecuador has previously been unknown. The aim of this study was to determine the resistance trends of commonly used antimicrobials for Cutibacterium strains isolated from patients with AV treated at the dermatology department of a hospital in Quito, Ecuador,

From the Biomedical Research Unit, Zurita & Zurita Laboratories,1 and the Facultad de Medicina, Pontificia Universidad Católica del Ecuador,2 Quito, Ecuador Address for Correspondence: María Belén Solís, MD, Avenida de la Prensa N49-221, Quito, Ecuador 170104 • E-mail: maria.belen04@hotmail.com

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and to discuss clinical management, with the goal of decreasing antibiotic resistance.

incubated at 34°C to 36°C for 46 to 48 hours. After incubation, each plate was viewed with a manual viewer.

MATERIALS AND METHODS

The study population included all patients with a clinical diagnosis of acne who were attending the dermatology department of a hospital in Quito, Ecuador. Acne lesions were evaluated by a dermatologist according to the system of Vyas et al.4 Patients with mild to moderate facial acne were included in the study; those with severe acne were excluded. The information collected included demographic data (age, sex) and information about previous treatment for acne through a review of medical records. The local ethical committee approved the study, and patients voluntarily signed an informed consent.

The minimum inhibitory concentration (MIC) was defined as the lowest antibiotic concentration that completely inhibited bacterial growth. For erythromycin and minocycline, which are not included in the Sensititre panel, the E-test gradient strip (Biomérieux, Marcy-l’Étoile, France) was used. The breakpoints used in this study were obtained from Performance Standards for Antimicrobial Susceptibility Testing M100S January 20165 and Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria M11-A8.6 Resistance to tetracycline was defined at MIC >16 µg/mL, and resistance to clindamycin at MIC >8 µg/mL according to the M100S. Minocycline resistance was defined at MIC >16 µg/mL, and erythromycin resistance at MIC >2 µg/mL according to the M11-A8.

Sample collection

Statistical analysis

After cleansing the facial acne lesions with 70% ethanol, the comedones, papules, and pustules were punctured with a sterile hypodermic needle (25 mm × 35 mm) and then squeezed using a swab. The contents were immediately placed into transport medium (Stuart Transport Medium, Copan™, Italy) and sent to the laboratory. The sample collection was performed between July and August 2015, and all samples were processed within 12 hours of collection.

The data collected from medical records and interviews were tabulated using Excel Microsoft Office 2010 (Impressa Systems, Santa Rosa, CA). Analysis was performed using the Statistical Package for the Social Sciences version 22 (SPSS Inc., Chicago, IL, USA). A percentage distribution of sensitive and resistant strains was made for each antimicrobial tested in the general study group.

Identification of C. acnes

Demographics and treatment history

The swabs were inoculated into thioglycollate broth, placed on phenylethylalcohol plates, and incubated in an anaerobic GasPak system (Becton Dickinson, Sparks, MD) for 5 days at 35ºC under anaerobic conditions. Species of Cutibacterium were identified using a MALDI-TOF mass spectrometer system. After identification, the isolated strains were frozen at −80ºC until susceptibility testing.

A total of 129 patients were recruited for the study between July and August 2015. There were 80 female and 49 male participants, with a mean age of 25 years (range 13 to 38 years). All patients were treated with oral antibiotics available in the hospital and without cost to the patient. A total of 100 patients (77.5%) received tetracycline, 25 patients (19.3%) received erythromycin, and four patients (3.1%) received both antibiotics, according to antibiotic availability in the hospital. Only 17 patients were treated with the combination of peroxide benzoyl or adapalene plus an antibiotic. Monotherapy was the most widely used treatment plan, used in 68.22% of patients. The duration of antibiotic treatment was 12 weeks in 34.8% (n=45) and less than 12 weeks in 65.1% (n=84) of patients.

Patients and data collection

Determination of antimicrobial susceptibility The antimicrobial susceptibility was determined by the Sensititre® Anaerobe MIC Susceptibility system (Trek Diagnostic Systems, Cleveland, OH, USA). Three to five colonies from the phenylethylalcohol agar plate were emulsified in 5 mL Sensititre® Mueller-Hinton broth, and turbidity was adjusted to a 0.5 McFarland standard. Next, 100 µL of the suspension was transferred into a tube of Sensititre®-supplemented Brucella broth and inverted 8 to 10 times. The suspension was transferred to Sensititre® anaerobic plates, and the plates were covered with perforated adhesive. Finally, the plates were anaerobically SKINmed. 2018;16:159–165

RESULTS

Identification of C. acnes Among the 129 samples, 93 showed gram-positive rods, 30 showed classic pleomorphic rods, and 63 showed gram-positive coccobacilli. Cutibacterium spp. were isolated in 71 of 129 patients. Sixty-five of these isolates were identified as C. acnes, three as P. granulosum, and three as P. acidifaciens. Moreover,

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Staphylococcus epidermidis was isolated from 54 of the 129 samples. Cutibacterium and Staphylococcus were identified by MALDI-TOF.

of effective treatment. In addition, physicians who work in public hospitals must prescribe drugs that are on the National Table of Basic Medications (NTBM; available at http://apps.who.int/medicinedocs/documents/ s21672es/s21672es.pdf). The doctors must prescribe drugs that are in this Table, so that the patient can receive the medication free of charge. If the drug is not in this Table the patient is forced to get the medication outside of the hospital and has to pay for the drugs. According to one study,9 minocycline is one the drugs of choice for AV, but although minocycline is available in Ecuador, it is unfortunately not on the NTBM. Therefore patients treated for acne in a public hospital do not have access to this drug.

Resistance pattern of C. acnes Among the 129 specimens collected, 71 strains of Cutibacterium spp. were recovered. Fifty-eight specimens had no growth of Cutibacterium spp. The MICs of the 71 strains are shown in Table I. The patients received tetracycline, erythromycin, clindamycin, and minocycline, and the trends of resistance found in this study were as follows: 21 (30%) strains were resistant to erythromycin, eight strains (11.2%) were resistant to clindamycin, seven strains (9.8%) were resistant to tetracycline, and two isolates (3.2%) were resistant to minocycline. DISCUSSION The prevalence of acne is high in Ecuador, representing the third leading cause of outpatient visits to a dermatologist.7 Acne is a self-limiting disease; hence, the goal of treatment is to control the lesions using antibiotics and incorporating coadjuvant therapies. The ideal treatment plan is the one that causes the fewest adverse effects, to facilitate patient adherence and therefore effectiveness.8 Antibiotic therapy without coadjuvant treatment was the most widely used treatment plan, representing 68.22% of patients in this study. According to the clinical record review, the primary causes of the mishandling of acne can be attributed to the following: 1

There was a lack of an established treatment protocol in the hospital, which caused the use of several treatment plans that differed according to the dermatologist attending the patient.

In public hospitals, the patient cannot choose the dermatologist; thus, in each appointment, the patient is evaluated, treated, and monitored by a different doctor, leading to the treatment being changed according to the criteria of the doctor evaluating the patient at that time.

Follow-up intervals were inconsistent, and could vary from 15 days to a year.

The hospital did not consistently stock the medicines indicated for the management of acne (especially coadjuvants), leading to partial effectiveness or total lack SKINmed. 2018;16:159â&#x20AC;&#x201C;165

The differences in treatment we have found in this study allowed us to construct an algorithm for acne treatment based on the situation encountered in Ecuador. Our proposal for the diagnosis and treatment of AV is shown in the Figure. We consider that this algorithm could also be useful in countries with similar conditions to ours. Since 1979, resistance to erythromycin has been reported to be very high worldwide; thus, this antibiotic is no longer recommended as a first-line option for the treatment of AV.8 In this study, however, 25 patients received erythromycin alone, and resistance to this antibiotic was found to be 29.5%. If we compared the data obtained in Ecuador with other countries in Latin America, we would find different results. The reason for the difference in in vitro antibiotic susceptibility patterns of C. acnes among different countries is not clear, although different antibiotic prescribing habits and/or a different patient ethnicity may contribute to it.10 Needless to say, antibiotics are useful for numerous other systemic infections, and their use in the treatment of AV for prolonged periods leads to cross-resistance to other organisms.11 Clindamycin is the most common of the antibiotics used in the treatment of AV. Countries in Europe and Asia (except Japan) share the same resistance pattern for antibiotics that are frequently used in AV treatment. These countries report isolates with greater than 30% resistance to clindamycin and erythromycin, whereas for oxytetracycline and minocycline, the resistance is less than 25%. Latin American countries such as Ecuador, Chile, and Colombia, however, have isolates with a low resistance to clindamycin (â&#x2030;¤15%) and minocycline (1% to 3%) (Table II). Resistance to antibiotics in the treatment of AV is poorly understood because studies are not routinely performed in most

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SKINmed. 2018;16:159–165

162 45

13 1

Piperacillin/ tazobactam

Erythromycin 10

15 3

>128

Total

0.25

0.5

0.25

0.5

0.12

<0.06

0.5

MIC 50

0.25

0.5

0.25

0.5

0.12

<0.06

0.5

MIC 90

≥16

≥0.5

≥128/4

≥16

≥128

≥2

≥32

≥64

≥8

≥16

≥2

≥64

16//8

≥32/16

CLSI Breakpoint for Resistance

CLSI, Clinical and Laboratory Standards Institute; MIC50, minimum inhibitory concentration required to inhibit the growth of 50% of organisms; MIC90, minimum inhibitory concentration required to inhibit the growth of 90% of organisms.

Mezlocillin

Tetracycline

Piperacillin 5

Ampicillin 8

Chloramphenicol

Metronidazole

Cefoxitin

Clindamycin

Meropenem

Imipenem

Penicillin

Cefotetan Na

0.5

0.25

Amoxicillin/ clavulanic acid

0.12 62

<0.06

Ampicillin/ sulbactam

Antimicrobial

Number of Isolates Inhibited at an MIC (µg/mL) of:

Table I. Minimum Inhibitory Concentrations (MICs) of Various Antibiotics for Strains of Cutibacterium acnes, P. acidifasciens, and P. granulosum Recovered from 71 Samples

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ORIGINAL CONTRIBUTION

Diagnosis of acne

Is it inflamatory acne?

Yes Benzoyl peroxide or adapalene

Noninflamatory acne

Topical retinoids Antimicrobials

1. Tetracyclines

Good response in 6–8 weeks?

No Yes Continue for additional 4–6 months

2. Sulfones

Good response in 6–8 weeks?

Yes 3. Lincosamides

Continue for additional 4–6 months

Good response in 6–8 weeks?

Yes Continue for additional 4–6 months

End of the treatment

Figure. Proposal for diagnosis and treatment of acne vulgaris.

laboratories. Many studies have shown the trend of resistance in several countries around the world. Because sensitivity tests are expensive, the breakpoints for various antibiotics have not been established, there are no standard criteria for their interpretation, and the role of inflammation in acne is unknown, few studies have been pursued this area. In this study, antimicrobial resistance was high for C. acnes, as we expected, especially to erythromycin and tetracycline. This could SKINmed. 2018;16:159–165

be explained by genomic analysis of C. acnes to discover various phylotypes of IA1, IA2, IB, IC, II, and III, and to find out whether there are commensal and pathogenic strains of the bacterium.24 This type of analysis could not, however, be performed in this study. The skin microbiota from each individual and each skin site may harbor good, neutral, and bad strains at the same time, and these may have different growth rates under in vitro culture conditions. It is well known worldwide that C. acnes acquires resistance to most antibiotics if they are used for a sufficiently

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Table II. Worldwide Trends of Antibiotic Resistance Percentages of Cutibacterium acnes Year

Country

ERI

OXI

DOX

TET

MCL

AZI

TMP/SX

201012

Mexico

—

200413

Costa Rica

—

201314

Chile

7.5

12.5

—

26.3

2013

Colombia

—

This study

Ecuador

—

201116

Hong Kong

53.5

20.9

16.3

—

16.3

—

201117

Iran

—

2007

Singapore

>50

>11.5

—

200019

Japan

—

2016

India

90.4

—

44.2

30.8

1.9

100

—

201310

Korea

26.7

—

6.7

3.3

6.7

—

France

—

75.1

9.5

—

55.5

26.4

—

200320

Greece

—

200320

Hungary

—

200320

Italy

—

2003

Spain

—

200320

Switzerland

—

200320

Sweden

—

Australia

—

8.8

—

Latin America

Asia

Europe 201021 2003,19 200222

Australia 201223

AZI, azithromycin; CL, clindamycin; DOX, doxycycline; ERI, erythromycin; MCL, minocycline; OXI, oxytetracycline; TET, tetracycline; TMP/ SMX, trimethoprim/sulfamethoxazole.

long duration; thus, it is time to look beyond antibiotic suppression to modulation of inflammation, with an increased use of nonantibiotics as a means of therapy with adjuvants such as benzoyl peroxide and retinoids. A limitation of this study is that we did not perform the cultures in an anaerobic environmental chamber. Very few laboratories in Ecuador have an anaerobic chamber, and most hospital laboratories use the GasPouch system (Becton, Dickinson and SKINmed. 2018;16:159–165

Company, Sparks, MD); this could limit the recovery of anaerobes that usually live only 15 to 20 minutes after exposition to air and would not occur if an appropriate chamber was used for counting. As long as antibiotics are used, drug resistance will remain a challenge. To prevent the development of antibiotic resistance, the practice of prescribing antibiotics for the treatment of acne must be examined carefully. In particular, antibiotic monotherapy, long-term administration of antibiotics, and

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dosing below the recommended levels promote the development of bacterial resistance.8 Susceptibility among anaerobes differs from species to species, and also from region to region. Although AV was managed here with antibiotics, resistance to tetracycline and clindamycin was less than expected. It is perhaps time to look beyond antibiotic suppression to modulation of inflammation, with an increased use of nonantibiotics as a means of therapy. Improper use of antibiotics in the dermatological setting needs to be evaluated to prevent the increasing prevalence of antibiotic resistance. CONCLUSIONS Management of acne focuses on controlling the factors involved in its pathogenesis, especially inflammation, which is a key factor at the time of treatment. Hence, antibiotics such as tetracycline work on multiple levels to dampen this response, as do other products such benzoyl peroxide and adapalene. Based on the results of this study, our proposal for successful management of AV could be useful, especially in countries with similar risk factors for antimicrobial resistance and limitations on culturing anaerobes. ACKNOWLEDGMENTS Cecibel Gonzalez assisted in the laboratory. This study was supported by Unidad de Investigaciones en Biomedicina, Zurita & Zurita Laboratorios, Project No MIC-008. REFERENCES 1 Ataseven A, Ugur Bilgin A. Effects of isotretinoin on the platelet counts and the mean platelet volume in patients with acne vulgaris. ScientificWorld Journal. 2014;2014:156464. 2 Zouboulis C, Katsambas A, Kligman A. Pathogenesis and Treatment of Acne and Rosacea. Dessau: Springer; 2014;459– 464. 3 Kaminsky A. Acné: Un enfoque global. Colegio IberoLatinoamericano de Dermatología. Buenos Aires: La Rioja 982; 2007:13–33.

8 Humphrey S. Antibiotic resistance in acne treatment. Skin Therapy Lett. 2012;17:1–3. 9 Garner SE, Eady A, Bennett C, et al. Minocycline for acne vulgaris: Efficacy and safety. Cochrane Database Syst Rev. 2012;15:CD002086. 10 Moon SH, Roh HS, Kim YH, et al. Antibiotic resistance of microbial strains isolated from Korean acne patients. J Dermatol. 2012;39:833–837. 11 Fattah A, Darwish Y. In vitro antibiotic susceptibility patterns of Propionibacterium acnes isolated from acne patients: An Egyptian university hospital-based study. J Eur Acad Dermatol Venereol. 2013;27:1546–1551. 12 Gonzalez R, Welsh O, Ocampo J, et al. In vitro antimicrobial susceptibility of Propionibacterium acnes isolated from acne patients in northern Mexico. Int J Dermatol. 2010;49:1003–1007. 13 Rodríguez-Cavallini E, Vargas-Dengo P. Etiología bacteriana y susceptibilidad a antibióticos en pacientes con acné. Rev Biomed. 2004;15:101–106. 14 Schafer F, Fich F, Lam M, et al. Antimicrobial susceptibility and genetic characteristics of Propionibacterium acnes isolated from patients with acne. Int J Dermatol. 2013;52:418–425. 15 Mendoza N, Hernandez PO, Tyring SK, Haitz KA, Motta A. Antimicrobial susceptibility of Propionibacterium acnes isolates from acne patients in Colombia. Int J Dermatol. 2013;52:688– 692. 16 Luk NM, Hui M, Lee HC et al. Antibiotic-resistant Propionibacterium acnes among acne patients in a regional skin centre in Hong Kong. J Eur Acad Dermatol Venereol. 2013;27:31–36. 17 Zandi S, Vares B, Abdollahi H. Determination of microbial agents of acne vulgaris and Propionibacterium acnes antibiotic resistance in patients referred to dermatology clinics in Kerman, Iran. Jundishapur J Microbiol. 2011;4:17–22. 18 Tan HH, Tan AWH, Barkham T, Yan XY, Zhu M. Communitybased study of acne vulgaris in adolescents in Singapore. Br J Dermatol. 2007;157:547–551. 18 Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: Lessons from Europe. Br J Dermatol. 2003;148:467–478. 20 Sardana K, Gupta T, Kumar B et al. Cross-sectional pilot study of antibiotic resistance in Propionibacterium acnes strains in Indian acne patients using 16S-RNA polymerase chain reaction: Comparison among treatment modalities including antibiotics, benzoyl peroxide, and isotretinoin. Indian J Dermatol. 2016;61:45–52.

4 Vyas A, Kumar Sonker A, Gidwani B. Carrier-based drug delivery system for treatment of acne. ScientificWorld Journal 2014; 2014:276260.

21 Dumont-Wallon G, Moyse D, Blouin E, et al. Bacterial resistance in French acne patients. Int J Dermatol. 2010;49:283–288.

5 Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty First Informational Supplement. CLSI document M100-S2. Wayne, PA: CLSI; 2016.

22 Coates P, Vyakrnam S, Eady EA, et al. Prevalence of antibioticresistant propionibacteria on the skin of acne patients: 10-year surveillance data and snapshot distribution study. Br J Dermatol. 2002;146:840–848.

6 Clinical and Laboratory Standards Institute. Methods for Antmicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard–Eighth Edition. CLSI M11-A8. Wayne, PA: CLSI; 2012.

23 Perret LJ, Tait CP. Non-antibiotic properties of tetracyclines and their clinical application in dermatology. Australas J Dermatol. 2014;55:111–118.

7 Santofinio M. Prevalence of Acne in the Population of 12 to 21 Years of the City of Quito (degree thesis). Instituto Superior de Posgrado, Facultad de Ciencias Médicas, Universidad Central del Ecuador, Quito, Ecuador; 2003.

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24 Thiboutot D. Dermatologists do not yet fully understand the clinical significance of antibiotic use and bacterial resistance in patients with acne: Comment on “Antibiotics, acne, and Staphylococcus aureus colonization.” Arch Dermatol. 2011;147:921–922.

Antimicrobial Susceptibility of Cutibacterium acnes

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May/June 2018

Volume 16 • Issue 3

ORIGINAL CONTRIBUTION

Reticulohistiocytoses: A Unique Nosologic Spectrum of Non-Langerhans Cell Histiocytosis Flávio Barbosa Luz, MD, PhD;1 Mayra Carrijo Rochael, MD, PhD;2 Marcia Ramos-e-Silva, MD, PhD3 ABSTRACT It is controversial whether multicentric reticulohistiocytosis (MR), diffuse cutaneous reticulohistiocytoma (DR), and solitary cutaneous reticulohistiocytoma (SR) occupy a spectrum of the same disease or are distinct clinicopathologic entities. The study of these diseases is very important mainly because of their involvement in the differential diagnosis of major diseases, for example some malignant neoplasias, and also, as in the case of MR, because patients frequently present with disfiguring lesions, arthritis mutilans, and/or possible fatal internal organ involvement. This investigation was performed to investigate the nosologic placement of those diseases described as reticulohistiocytosis. We performed a blind analysis of 21 patients (five with MR, three with DR, and 13 with SR), looking at their clinical, histopathologic, and immunohistochemical aspects. The immunohistochemical panel included CD68, MAC387, factor XIIIa, CD1a, CD34, trombomodulin, CD3, and CD8. The cases studied showed characteristic histopathologic and immunohistochemical elements, but their differences were not consistent enough to enable a distinction between them. Consequently, reticulohistiocytosis may be considered a unique spectrum among non-Langerhans cell histiocytosis. (SKINmed. 2018;16:167–174)

eticulohistiocytoses (RHCs) comprise three clinically distinct diseases that share a common histopathology of reticulohistiocytic granuloma: MR, DR and SR. MR usually is a mutilating and disfiguring systemic disease with a preference for the joints and skin, DR exclusively affects the skin and shows multiple lesions, whereas SR is associated with a solitary cutaneous nodule or papule.

A common histopathology does not prove that we are dealing with the same disease, but, conversely, distinct clinical manifestations do not exclude the possibility of diseases having the same nosologic identity. In terms of the features shared by these diseases and their singularities, their nosologic position is still a matter of debate. They may be considered variants of the same disease1 or as distinct, unrelated diseases. In 1994, Zelger et al suggested that the nonsystemic forms (DR, SR) were related to dermatofibroma and xanthogranuloma, considering the latter entities to be unrelated to MR.2

Although very rare, RHCs, particularly MR, can cause considerable morbidity, and major diagnostic and therapeutic difficulties. Additionally, RHCs present with relevant clinicopathologic peculiarities that can suggest the existence of unique etiopathogenic processes related to histiocytes.3 This histopathologic and immunohistochemical clinical study was based on the assumption that histiocytoses can be understood and classified according to the differentiation of the prevailing type of proliferated cells, and that such differentiation can be supported by the cells’ immunohistochemical profile.4 Our aim was to produce a nosologic positioning of RHCs, considering their interrelations and their relations with other histiocytic diseases. METHODS Clinical reports and paraffin blocks of biopsies from lesions were collected for 21 participants with RHC. The blocks were

From the Sector of Dermatology and Post-Graduation Course1 and Department of Pathology,2 School of Medicine and University Hospital, Fluminense Federal University, Niterói, Brazil; and the Sector of Dermatology and Post-Graduation Course in Dermatology, School of Medicine and University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil3 Address for Correspondence: Flávio Barbosa Luz, R. Guapiara, MD, PhD, 78, Rio de Janeiro 20521-180, Brazil • E-mail: flaviobluz@gmail.com

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submitted to histopathologic analyses using hematoxylin and eosin staining and immunohistochemical analyses for antigen immunomarking of CD68, MAC387, XIIIa, CD34, CD1a, thrombomodulin (CD141), CD3, and CD8. Table I lists the substances expressed by histiocytes that function as cell markers and can distinguish the particular cell types that were studied in here.

Table I. Correlation Between the Primary Antibodies Used in This Study and the Main Types of Cell Observed

Evaluation of the hematoxylin and eosin–stained sections focused on following aspects: the types of inflammatory cell, circumscribed nature of the infiltrate, vasculature, overlying epidermis, and presence of fibrosis. The inflammatory cells were separated into histiocytes and other infiltrating cells. The histiocytes were differentiated in accordance with their morphology, as defined by Zelger et al,5 into five mononucleated types (oncocytic, xanthomized, vacuolated, fusiform, stellate) and three giant multinuclear types (giant oncocytic, foreign body type, Touton type). Our results were compared to those available in the literature.

Primary antibody against

Cell types

CD68

Tissue macrophage

MAC387

Activated macrophage, granulocyte

Factor XIIIa

Dermal dendrocyte type I

Thrombomodulin

Thrombomodulin, dermal dendritic cell

CD34

Endothelial cell, bone marrow stem cell, dermal dendrocyte type II

CD1a

Langerhans cell, indeterminate cell, CD1a+ dermal dendritic cell

CD3

T lymphocyte

CD8

T “supressor” lymphocyte

Of the remaining cell types in the inflammatory infiltrate, the presence of lymphocytes, neutrophils, eosinophils, and plasmocytes was assessed. Mastocytes were not included in this analysis as there was insufficient availability of the material required for their special staining. RESULTS

Clinical Multicentric reticulohistiocytosis Of the five patients with MR, three were women and two were men. In four individuals, the lesions were disseminated over almost all the skin (Figure 1); in one, the trunk was spared. All patients presented joint involvement. Three of the participants were white and two were black. Their ages ranged from 42 to 62 years, and an average age of 50.6 years. Spontaneous involution was not described for any of the patients. With the exception of patient 4, who presented hoarseness, no other extracutaneous articular symptomatology or associated disease was reported.

Diffuse cutaneous reticulohistiocytoma The three participants with DR were two men and one woman, all of whom were black, and who varied in age from 28 to 65 years (average 44.3 years). The first patient presented with lesions that had been present for a decade without any remission. Individually, the lesions had each lasted a few months and had had a predictable course, starting as an erythematous macule that progressed to a papule, and then to a small nodule. They then SKINmed. 2018;16:167–174

Figure 1. Multicentric reticulohistiocytosis. Small papules on the face and nose with some clustering around the nostrils.

regressed spontaneously, leaving a discrete hyperpigmented scar. The female patient had had lesions during the entire observation period; contact with her was then lost when she moved away. The third patient was observed for a couple of months, without apparent modification of his lesions during this period (Figure 2).

Solitary cutaneous reticulohistiocytoma Of the 13 participants described, six were men and six women, with one patient’s sex not on file. All those whose skin color had been recorded were white. The ages of all patients ranged from 16 to 67 years, with an average of 44 years.

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ORIGINAL CONTRIBUTION Four lesions were located on the lower limbs (thighs), three on the head (two on the chin and one on the scalp), five on the trunk, three in the armpits, and one on the breast; the position of a further lesion was not specified. In one person, the lesions affected the penis. The lesions were described as papules or nodules that were usually dome-shaped, pinkish with telangiectasia, skin color, or erythematous, with a consistency varying from soft to hard. The evolution periods of the lesions were known for only two patients (1 and 6 months, respectively), and the diagnostic hypotheses previously considered were dermatofibroma (four cases), nevus (four cases), basal cell carcinoma (three cases), cyst (two cases), xanthoma, common wart, pyogenic granuloma, follicular granuloma, and reticulohistiocytic granuloma.

Histopathology Table II outlines the histopathology of nonhistiocytic inflammatory cells.

Figure 2. Diffuse cutaneous reticulohistiocytoma. Similar lesions appear on the face and trunk, but articular disease was not present.

In all cases examined, the histopathologic appearance was that of a prevailing histiocyte infiltrate with variable presence of other inflammatory cells. Histiocytic cells contained transparent eosinophilic material that conferred a “ground-glass” appearance, which provides the main diagnostic criteria for RHCs. Among the nucleated multinuclear histiocytes, the oncocytic type was practically the only found type. Although mitoses were present, they were not a notable finding, with the exception of patient 19 (SR), in which they were frequent, albeit typical. In patient 10 (SR), there was little collagen in between the cells, and in patient 18 (SR), the collagen had been totally replaced by inflammatory cells. In all remaining cases, the infiltrate dissected without destroying the collagen, which was always interspersed with proliferated cells. This feature was particularly evident in patient 17 (SR), in whom a large amount of collagen interspersed with the proliferated cells was found. The infiltrate was limited to the dermis in all cases, in some instances having touched the subcutaneous tissue. The sample from patient 17 showed histiocytes inside the hair erector muscle.

Multicentric reticulohistiocytosis (patients 1 to 5)

Figure 3. Multicentric reticulohistiocytosis. Giant multinucleated and oncocytic histiocytes (hematoxylin and eosin stain, original magnification ×100). SKINmed. 2018;16:167–174

A great number of oncocytic histiocytes was present in all cases, being especially large for patients 1 and 3. Xanthomized and vacuolated histiocytes were present in all sections, with exception of those from patient 3. Stellate histiocytes were not observed in any of the fragments, and fusiform histiocytes were found in patients 3, 4, and 5. Giant cells were always observed, and were especially numerous in samples 1 and 5 (Figure 3), all being oncocytic in patient 1; in patient 3, there were only two or three nuclei present

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Table II. Nonhistiocytic Inflammatory Cells and Other Histopathologic Aspects Cases

Diagnosis

Lymphocytes

Neutrophils

Eosinophils

Plasmocytes

Vasculature

Epidermis

Fibrosis

−

Normal

Absent

−

Normal

Absent

−

Normal

Hyperkeratotic

Absent

−

+++

Normal

Rectified

Deep

−

Normal

Rectified

Absent

+/+++

Normal

Present

−

Normal

Absent

−

Normal

Absent

−

In excess

Rectified, hyperkeratotic, collaret

Absent

−

In excess

Normal

Absent

−

Normal

Rectified

Absent

−

Small increase

Normal

Absent

−

Small increase

Normal

Absent

−

Normal

Absent

−

Normal

Absent

−

In excess

Rectified, hyperkeratotic, collaret

Absent

−

Normal

Present

In excess

Rectified, hyperkeratotic, collaret

Absent

−

In excess

Hyperkeratotic, collaret

Absent

−

In excess

Rectified, hyperkeratotic, collaret

Absent

−

Normal

Absent

inside each multinucleated histiocyte, and the cytoplasm was very abundant and clearly foamy in the periphery, reminiscent of the Touton cells in samples 1 and 4.

epidermis was unchanged in patients 1 and 2, hyperkeratotic in patient 3, and rectified in patients 4 and 5. Fibrosis was observed in the underlying skin in patient 4.

With the exception of patient 4, lymphocytes were always present, albeit in small numbers in patients 1 and 2. There were some neutrophils in samples 3 and 4, as well as numerous plasmocytes in sample 4, but none in the remainder. Rare eosinophils could be observed.

Disseminated cutaneous reticulohistiocytoma (patients 6 to 8)

The lesions varied from mildly to relatively well circumscribed, with a normal number and morphology of blood vessels. The SKINmed. 2018;16:167–174

In patient 6, it was possible to observe a lesion’s progress in time by biopsies taken at different stage of evolution. The number of giant cells, oncocytic histiocytes, and eosinophils increased with maturation of the lesions, whereas the number of vacuolated histiocytes diminished. Oncocytic histiocytes were prevalent

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in the majority of sections examined, with a predominance of xanthomized histiocytes in patient 8. Fibrosis was only present in the older lesions in patient 6. Plasmocytes could be observed in the four fragments from patient 6, and eosinophils in those from patients 6 and 8. Epidermis and vascularization were normal in all sections studied, and in no case was the circumscription very evident. Vacuolated histiocytes and giant cells were always observed, but in variable numbers.

Solitary cutaneous reticulohistiocytoma (patient 9 to 21) Oncocytic histiocytes, although seen in all histologic sections, were present in large numbers in patients 9, 11, 13, and 20, and were extremely abundant in patients 18 and 19. Xanthomized histiocytes were not found in fragment 18 but were seen abundantly in 13, 14, 15, and 17. Vacuolated histiocytes were present in more than half the studied samples but were never numerous. Fusiform histiocytes were associated with the infiltrate in almost half of cases, presenting themselves in great numbers only in sample 21, whereas stellate histiocytes were observed in large quantities in fragment 19. There were no giant cells in sample 18, although they occurred in small numbers in samples 10 and 21. In all other cases, they existed in good numbers, particularly in sections from samples 14, 16, and 19, but presenting few nuclei in samples 13, 20, and 21. Foreign bodyâ&#x20AC;&#x201C; type cells were observed in large numbers in fragment 14. Lymphocytes were present in all cases, with low numbers in samples 12 and 21, and greater numbers in 13, 14, 15, 16, and 19. The only sample in which neutrophils were not seen was fragment 21, and they were very frequent in samples 12 and 20. Eosinophils were abundant in samples 12, 19, and 20, and absent or rare in the remainder. Plasmocytes were only observed in the periphery of sample 18. The lesions were well circumscribed in three cases, clearly limited in four, and poorly circumscribed in one case; in all other samples, the specimen did not allow such assessment. Vascularization was highly increased in six cases, and in the remainder ranged from normal to slightly increased. The epidermis was unchanged in seven patients and rectified in five, showed a collaret in five, and was hyperkeratotic in three. Fibrosis was observed in patient 17.

Immunohistochemistry The immunohistochemistry results are shown in Table III. CD68. There was a clear and strongly positive cytoplasmic coloration pattern in all large histiocytes (multi- or mononucleated) in all patients, as well as many small histiocytes in all cases, except in patient 2 (MR). In patient 1 (MR), small histiocytes were only observed at the periphery of the lesion. SKINmed. 2018;16:167â&#x20AC;&#x201C;174

MAC387. Strong positivity was shown in the cytoplasm of many small histiocytes, in well-constituted and more discrete infiltrates, in all cases except patient 12. Frequent immune reactivity was observed in the cells of the Malpighian layer. Factor XIIIa. Scattered, this was detected in cells with two distinct morphologic characteristics: (1) cells with a dendritic appearance, which were located mainly in the papillary dermis, around the vessels and appendages, especially the ducts of the eccrine sweat glands (dermal dendrocytes [DDs]); and (2) cells with abundant cytoplasm that were round or slightly spiny, corresponding, at least in part, to oncocytic cells. Strong cytoplasmic marking was found in countless DDs in the perilesional skin, mainly in the papillary dermis around the vessels and appendages. The pattern seen in perilesional areas was similar to that in nonlesional areas. Cells of dendritic morphology staining for factor XIIIa were seen permeating the infiltrates in practically all participants, albeit in reduced number in relation to the perilesional areas; they were sometimes present in equivalent numbers but never exceeded those observed in the surrounding cells. Lesional histiocytic nondendritic XIIIa+ cells were seen in patient 6 (DR) and in patients 15 and 21 (both SR). Thrombomodulin. There was constant positive marking for this glycoprotein, with an intercellular pattern in the epidermis that was stronger in the suprabasal layer and progressively reduced towards the horny layer. Thrombomodulin was also present in endothelial vascular cells and in the dendritic cells surrounding them. Few dermal cells staining for thrombomodulin were observed in the infiltrate. In practically all the sections studied, there were some giant cells and large histiocytes that presented a cytoplasmic membrane staining pattern. CD34. This marker was positive only in endothelial and myoepithelial cells around the eccrine sweat glands ducts in all patients. CD1a. Langerhans CD1a+ cells were found in the epidermis in all cases, apparently in normal numbers. Such cells were absent from the infiltrate of all cases except patients 4 (MR) and 20 (SR), where dispersed small cells could be observed. CD3. In all sections, CD3 immunomarking was strongly positive in the cytoplasmic membrane of countless lymphocytes, mainly around vessels, with poor marking in some giant and oncocytic cells. CD8. CD8 was present in lymphocytes in all cases. As for CD3, CD8+ lymphocytes seem to correspond to the greater

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Table III. Immunomarking of the 21 Patients Studied Cases

CD68

CD34

FXIIIa

MAC387

Thromb0modulin

CD1a

CD8a

CD3a

H+

Neg

E+, HS+

H+

Neg

H+

Neg

E−, HS+

H+

Neg

E−, HS+

H+

Neg

H+

Neg

E+, HS+, HL+/−

H+

HS+

++b

H+

Neg

E+, HS+

H+

Neg

H+

Neg

H+

E−/+, HS−/+c

HS+

Neg

+++

H+

HS+

Not E, HS+

H+

Neg

E+, HS+

H+

Neg

H+

Neg

E+, HS+

HS+

Neg

H+

Neg

E+, H+

H+

Neg

H+

Neg

E+, HS+

HL+/−

Neg

+++

H+

HS+, HL+/−

H+

Neg

E−, HS+

H+

Neg

H+

Neg

E+, H+

Neg

H+

Neg

H +/−

E−, HS+

H+

Neg

H+

Neg

E+, HS+

HS+

Neg

H+

Neg

E−, HS+

H+

Neg

H+

Neg

E+, HS+

H+

Neg

H+

Neg

E+, HS+

H+

Neg

H+

Neg

E+, HS+

H+

HS+

H+

Neg

H+

E−, HS+

H+

Neg

Diagnosis MR

4 5 6

Abbreviations: DR, diffuse reticulohistiocytosis; E, epidermis; FXIIIa, factor XIIIa; H, histiocytes; L, large; MR, multicentric reticulohistiocytosis; Not, absent; NR, not done; Neg, no reactivity; S, small; SR, solitary cutaneous reticulohistiocystosis; +, reactivity present; −, reactivity absent, +/−, reactivity variable. a The presence of CD3 and CD8 cells was quantified as + (few), ++ (moderate) and +++ (abundant). b Exocytosis present. c Epidermal reactivity, as well as the number of small histiocytes, increased as the lesion matured.

part of the lymphocytic population, with the exception of patient 21 (SR). DISCUSSION The hematoxylin and eosin–stained fragments revealed, as a general pattern, a large number of histiocytic cells, mainly oncocytic, with eosinophilic cytoplasm, and other cells, larger and usually multinucleated, with “ground-glass” material in their interior. Other histiocytic cell types, especially xanthomized, and other inflammatory cells, in general lymphocytes, were almost always seen permeating the infiltrate. SKINmed. 2018;16:167–174

CD68+ cells were present in high numbers in all specimens examined. The majority of these cells were characterized by ample cytoplasm, usually rounded, although some were smaller with sometimes fusiform cytoplasm. All CD68+ cells had clear nuclear membranes and evident nucleoli, which were often multinucleated. The morphology of the CD68+ cells corresponded mainly to that of the oncocytic histiocytes and giant multinucleated cells that characterize RHCs. These findings are in agreement with the published literature and therefore define these cells as macrophage in nature, and the conditions therefore as RHC.

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Small MAC387+ histiocytes were seen in most of the cases studied, possibly representing the precursors of larger CD68+ histiocytes. Double immunomarking for CD68 and MAC387 evidenced small MAC387+ histiocytes, giant CD68+ cells, and oncocytic cells reacting to both antibodies, suggesting a transformation of small MAC387+ histiocytes into multinucleated CD68+ cells.6

present in almost all the cases here studied, not only in dendritic cells, but also in the periphery of numerous histiocytes. This cell population deserves more in-depth study, especially as the present observation only allows the demonstration of a greater identity between RHCs. It is important to emphasize that expression of thromboÂmodulin in other histiocytoses is unknown.

Almost all individuals studied in this investigation presented with XIIIa+ DDs surrounding the lesions, apparently in the same numbers as in the nonaffected skin, and always in smaller numbers in the interior of the lesions. This suggests that XIIIa+ DDs do not perform a central role in the etiopathogenic process of RHC. Perrin et al, based on the expression of XIIIa in one case of MR, suggested a DD lineage for MR.7 Zelger and Orchard attributed this discrepant result to methodologic aspects: the high concentration (1:20) of anti-XIIIa employed, and artifacts in the material frozen by nitrogen.8 Although it is well accepted that factor XIIIa is the main marker of DDs, Zaba et al have suggested that CD11c/BDCA-1 and CD163 could be used as alternative markers to differentiate DDs from macrophages.9

CD34+ dendritic cells, identified by Regezi et al15 and named DD type II by Doval and Toribio,16 were seldom found in the patients we studied, consistent with reports in the literature. These cells seem to be responsible for the cellular proliferation in dermatofibrosarcoma protuberans and solitary fibrous tumor.17,18

Zelger et al analyzed 10 cases of RHC and concluded that the purely cutaneous forms were identical to, or at least strongly related to, adult xanthogranuloma.10 Their results were questioned by Perrin et al,11 and their conclusions are also in disagreement with the present study of 21 patients. The differences in the histopathologic and histochemical characteristics of MR, DR, and SR observed in this investigation were not sufficiently significant to allow a differentiation between the RHCs. Despite being indistinguishable in terms of histopathology and immunohistochemistry, only MR presents a significant association with malignant neoplasia and, apparently, with autoimmune diseases.12 Except for the case described by Perrin et al,7 it was not possible to find a reference linking MR and the presence of relevant XIIIa+ cells. DR or SR cases with XIIIa+ cells are, however, sporadically reported. Thus, the expression of XIIIa in oncocytic histiocytes and giant cells in three individuals in our study, as well as in a few others described in the literature, could represent an intermediate stage between RHC and xanthogranuloma. In xanthogranuloma, however, XIIIa is expressed in dendritic cells in the infiltrate, and not in large histiocytes. It is therefore preferable to accept the possibility of only a sporadic presence of XIIIa in oncocytic histiocytes and giant cells in RHCs, while allowing the possibility that the macrophages proliferating in this disease underwent some differentiation similar to DDs. Cells expressing dermal thrombomodulin cells seem to perform a pertinent role in some diseases.13,14 Thrombomodulin was SKINmed. 2018;16:167â&#x20AC;&#x201C;174

According to the literature, the lack of expression of CD1a in histiocytic cells in almost all the patients studied excludes the possibility that RHCs originate from Langerhans cells or other CD1a+ cells. The presence of small CD1a+ cells in patient 4 (MR) and patient 20 (SR) does not contradict this hypothesis, as such cells may correspond to the subpopulations of dermal dendritic CD1a+ cells identified by Nestle et al and Nestle and Nickoloff.19,20 This can be explained by the recent discovery that monocytes are able to express langerin, suggesting that these langerin-positive monocytes may be potential precursors of CD1+ cells and dendritic cells.21 It was not possible to detect the presence of CD3 or CD8 in the majority of the histiocytic cells we assessed. CD3+ lymphocytes were seen in almost all cases and, by comparing the number of lymphocytes observed in hematoxylin and eosinâ&#x20AC;&#x201C;stained sections, this T-cell population can be considered the most frequent cell type in RHCs. Of the CD3+ lymphocytes, the CD8+ subpopulation seems to be in the majority. It must be emphasized, of course, that this analysis is merely an estimate as double marking for CD3 and CD20, and CD8 and CD4, was not undertaken. CONCLUSIONS RHCs constitute a group of related diseases involving macrophage proliferation that are part of the group of nonLangerhans histiocytoses. Although the purely cutaneous presentations (DR, SR) share similarities with xanthogranuloma and dermatofibroma, they are more closely related to MR. The histopathologic and immunohistochemical characteristics of the RHCs in the individuals we studied did not allow a clinical distinction to be made among the variants (MR, DR, SR), indicating that they represent a nosologic spectrum. ACKNOWLEDGMENT Walter Burgdorf provided fundamental guidance on this work.

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REFERENCES 1 Snow JL, Muller AS. Malignancy-associated multicentric reticulohistiocytosis: A clinical, histological and immunophenotypic study. Br J Dermatol. 1995;133:71–76. 2 Zelger B, Cerio R, Orchard G, Wilson-Jones E. Juvenile and adult xanthogranuloma. A histological and immunohistochemical comparison. Am J Surg Pathol. 1994;18:126–135. 3 Luz FB, Kurizky PS, Ramos-e-Silva M. Reticulohistiocytosis. Dermatol Clin. 2007;25:625–632. 4 Burgdorf WHC, Zelger B. Histiocytosis. In: Elder D, Banchereau J, Schmitt D, eds. Lever’s Histopathology of the Skin. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:667–688. 5 Zelger BWH, Sidoroff A, Orchard G, Cerio R. Non-Langerhans cell histiocytoses: A new unifying concept. Am J Dermatopathol. 1996;18:490–504. 6 Luz FB, Gaspar AP, Ramos-e-Silva M, et al. Immunohistochemical profile of multicentric reticulohistiocytosis. SKINmed. 2005;4:71– 77. 7 Perrin C, Lacour JP, Michiels JF, et al. Multicentric reticulohistiocytosis. immunohistological and ultrastructural study: A pathology of dendritic cell lineage. Am J Dermatopathol. 1992;14:418–425. 8 Zelger B, Orchard G. Reticulohistiocytomas versus multicentric reticulohistiocytosis. Reply [letter]. Am J Dermatopathol. 1995;17:625–626. 9 Zaba LC, Fuentes-Duculan J, Steinman RM, Krueger JG, Lowes MA. Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages. J Clin Invest. 2007;117:2517–2525.

12 Luz FB, Gaspar AP, Kalil-Gaspar, N, Ramos-e-Silva M. Multicentric reticulohistiocytosis. J Eur Acad Dermatol Venereol. 2001;15:524–531. 13 Cuzzi-Maya T, Sidbury R, Epstein WL, Fukuyama K. Thrombomodulin expression on dermal cells in normal and psoriatic skin. Arch Dermatol Res. 1998;290:233–239. 14 Soub CRW, Rochael MC, Cuzzi T. Granuloma anular: Distribuição tecidual dos dendrócitos dérmicos fator XIIIa+, das células dérmicas trombomodulina+ e de macrófagos CD68+. An Bras Dermatol. 2003;78:289–298. 15 Regezi JA, Nickoloff BJ, Headington JT. Oral submucosal dendrocytes: Factor XIIIa+ and CD34+ dendritic cell population in normal tissue and fibrovascular lesions. J Cutan Pathol. 1992;19:398–406. 16 Doval IG, Toribio J. El histiocito: Conceptos actuales. Actas Dermosifiliogr. 1997;88:649–662. 17 Rudolph P, Schubert B, Wacker H-H, Parwaresch R, Schubert C. Immunophenotyping of dermal spindle cell tumors: Diagnostic value of monocyte marker Ki-M1p and histogenetic considerations. Am J Surg Pathol. 1997;21:791–800. 18 Vadmal MS, Pellegrini AE. Solitary fibrous tumor of the vagina. Am J Dermatopathol. 2000;22:83–86. 19 Nestle FO, Zheng X-G, Thompson CB, Turka LA, Nickoloff BJ. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J Immunol. 1993;151:6.535–6.545.

10 Zelger B, Cerio R, Soyer HP, et al. Reticulohistiocytoma and multicentric reticulohistiocytosis. Histopathologic and immunophenotypic distinct entities. Am J Dermatopathol. 1994;16:577–584.

20 Nestle FO, Nickoloff BJ. Dermal dendritic cells are important members of the skin immune system. In: Banchereau J, Schmitt D, eds. Dendritic Cells in Fundamental and Clinical Immunology. New York: Plenum Press; 1995:111-–116.

11 Perrin C, Lacour JP, Michiels JF, Ortonne JP. Reticulohistiocytomas versus multicentric reticulohistiocytosis. Am J Dermatopathol. 1995;17:625–626.

21 Milne P, Bigley V, Gunawan M, Haniffa M, Collin M. CD1c+ blood dendritic cells have Langerhans cell potential. Blood. 2015;125:470–473.

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May/June 2018

Volume 16 • Issue 3

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

Behçet Disease: New Developments in the Etiopathogenesis of an Old Silk Road Disease Emin Ozlu, MD;1 Ayse Serap Karadag, MD2

Behçet disease (BD) is a systemic inflammatory disorder that affects the skin, mucosa, eyes, joints, blood vessels, brain, and gastrointestinal tract. The etiopathogenesis of BD has not yet been fully elucidated, but disorganized immune responses against the stimuli of environmental triggering factors have been considered to play a major role in the pathogenesis of the disease in individuals with genetic susceptibility. Human leukocyte antigen (HLA)-B*51 is known to be the main factor involved in genetic susceptibility to BD. Among the environmental factors, infectious agents in particular are thought to be important. Immunological abnormalities could thus be the cornerstone in the development of BD. Along with cytokines that play a role in disease pathogenesis, numerous other cytokines have been recently identified or have been the focus of recent studies. This contribution sheds light on the etiopathogenesis and immunology of BD in relation to the current literature. (SKINmed. 2018;16:176–181)

D is a type of vasculitis that produces changes in endothelial function by affecting arteries and veins of all sizes. The disease has a very high incidence in countries spanning the ancient Silk Road from Asia to the Mediterranean. It is therefore prevalent in Turkey, Japan, Korea, and China.1 BD is a multifactorial disease, and triggering factors such as oral cavity infections and viruses can induce an inflammatory response in genetically susceptible individuals.2 BD was, furthermore, classified as “variable vessel vasculitis” in the 2012 International Chapel Hill Consensus Conference Nomenclature of Vasculitides, as it can affect arteries and veins of all sizes.3 The disease has a complex pathogenesis that is not fully understood; however, microbial triggers, environmental factors, endothelial dysfunction, genetic predisposition, and immunological abnormalities have been associated with disease pathogenesis.4 The interaction between T lymphocytes (T helper [Th] cell types Th1 and Th17) and activated neutrophils triggered by genetic predisposition (the HLA-B*51 gene and non-HLA genes) and activation of innate and adaptive immunity by various pathogens are thought to be the main factors in

disease pathogenesis.5 The etiopathogenesis that is currently postulated is shown in the Figure. This section will focus on the underlying etiopathogenetic and immunological mechanisms, also considering the current literature. GENETIC FACTORS IN BD The exact etiology of BD is unknown, but recent immunogenetic findings have provided clues to the pathogenesis of the disease. It has been more than four decades since the association between BD and the HLA-B*51 allele was established, and this association has been demonstrated in various populations. Recent studies, however, have suggested an independent association between BD and the major histocompatibility complex class 1 region.6 In addition, HLA-B*15, HLA-B*27, HLA-B*57, and HLA-A*26 have been shown to be independent risk factors for the development of BD, whereas HLA-B*49 and HLA-A*03 class I alleles have been shown to protect against the disease.6 The importance of genetic and environmental factors in disease pathogenesis was highlighted in two recent comprehensive reviews

From the Department of Dermatology, Duzce University School of Medicine, Duzce, Turkey;1 and the Department of Dermatology, Istanbul Medeniyet University School of Medicine, Istanbul, Turkey2 Address for Correspondence: Ayse Serap Karadag, MD, Department of Dermatology, Istanbul Medeniyet University School of Medicine, Apt:14, Kadıkoy, Istanbul, Turkey, 34730 • E-mail: karadagaserap@gmail.com

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Genetic susceptibility MHC complex Non-MHC genes genes – HLA-B*51 – SNP IL-10 – HLA-B*15 – SNP IL-12R – HLA-B*27 – SNP IL-23R – HLA-B*57 – HLA-B*A25

Cytotoxic T cells

INFγ, TNFa

CD4+ T cell activation

CD8+CD56+ CD8+CD56γδ T cells

Th1

INFLAMMATION

IL-8, IL-21 Th27

Environmental factors Bacteria Virus – Streptococcus – Herpes virus sanguis

Neutrophil Tregs

Molecular mimicry – HSP – Other proteins

Figure. Schematic representation of the etiopathogenesis of Behcet’s disease. Abbreviations: HLA, human leucocyte antigen; HSP, heat shock protein; IFNα, interferon-gamma; IL, interleukin; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism; Th, T helper; TNF-α, tumor necrosis factor-alpha; Tregs, regulatory T cells.

on the immunogenetics of BD, and in one review study from INFECTIOUS FACTORS Figure. Schematic representation of the etiopathogenesis of Behcet’s disease. Abbreviations: HLA, human leucocyte antigen; HSP, 2,6,7 2016. BD exhibits autoimmune and autoinflammatory disease heat shock protein; IFNα, interferon-gamma; IL, interleukin; MHC, major histocompatibility complex; SNP, single nucleotide polymor- triggers, the role of infectious agents, Among environmental characteristics. efficacy of factor-alpha; immunosuppressive phism; Th, T helper; The TNF-α, tumor necrosis Tregs, regulatory Tdrugs cells. such particularly the role played by bacteria (streptococci, Helicobacter as azathioprine and cyclosporine, the presence of autoantigens, pylori, Mycoplasma fermentans, mycobacteria, Borrelia and the role played by human heat shock protein (HSP) 60 in burgdorferi) and viruses (herpes simplex virus types 1 and 2, disease pathogenesis reflect the autoimmune nature of the disease; hepatitis virus, cytomegalovirus, varicella-zoster virus, Epsteinsimilarly, the absence of autoantibodies in high titers or antigen- Barr virus, parvovirus B19), has been emphasized.8 specific T cells, the presence of major histocompatibility complex class I molecules, recurrent inflammatory episodes induced by The bacterial hypothesis neutrophils, the possible contribution of M694V MEVF gene Oropharyngeal bacterial agents have gained increasing mutation to the disease, and the therapeutic efficacy of colchicine importance in recent years as being implemented in the reflect the autoinflammatory nature of the disease.6 Genome-wide pathogenesis of BD.9 Streptococci, particularly Streptococcus association studies showed that there were significant associations sanguis, are the most commonly studied bacterial agents. between interleukin (IL)-23R-IL12RB2, IL-10, signal transducer Compared to the control group, S. sanguinis was in one and activator of transcription 4 (STAT-4), chemokine C-C motif study found to be more commonly isolated from oral flora of receptor 1 and 3 (CCR1-CCR3), killer cell lectin-like receptor K4 patients with BD.10 Saliva rich in bacteria was, furthermore, (KLRC4), endoplasmic reticulum aminopeptidase 1 (ERAP1), found to be more sensitive than sterile saliva for producing a tumor necrosis alpha-induced protein 3 (TNFAIP3), and positive pathergy test, and this was suggested to be caused by fucosyltransferase 2 (FUT2) loci, and BD. In addition, targeted oral streptococci.11 The S. sanguis gene Bes-1 has been detected next-generation sequencing has demonstrated nonsynonymous in monocytes within mucocotaneous lesions in individuals variants of IL23R, Toll-like receptor 4 (TLR4), nucleotide- with BD.12 There are also studies suggesting a relationship binding oligomerization domain-containing protein 2 (NOD2), between BD and Streptococcus faecalis, Streptococcus viridans, and familial Mediterranean fever gene (MEVF).6,7 Streptococcus haemolyticus, and Streptococcus salivarius.9 SKINmed. 2018;16:176–181

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Some studies have suggested a higher prevalence of H. pylori infestation in patients with BD, and a relationship between H. pylori and gastrointestinal system involvement.13 Other studies have also suggested a role for M. fermantans, mycobacteria, Prevotella, Fusobacterium, and B. burgdorferi in the pathogenesis of BD; however, there is no strong evidence for the involvement of these bacteria.8 The ımmunopathological response can be stimulated by different microbial products such as HSPs in BD, and these molecules can induce tissue damage. The molecular similarity between bacterial and 65 kDa human HSP is responsible for activation of the pathogenic immune response through HSP-specific T cells against recurrent infections caused by HSP-containing bacteria in genetically susceptible individuals. In patients with BD, antibodies with increased concentrations against the 65 kDa HSP of S. sanguis and Streptococcus pyogenes were found to be similar to micobacterial HSP-65 antigen.5 Recent evidence supports a contribution of intestinal microbiota to the development of extraintestinal immunological diseases.14 Consolandi et al compared fecal microbiota between patients with BD and a control group, and found a significantly reduced production of Roseburia, Subdoligranulum genera, and butyrate in patients with BD.15 Schimizu et al found increases in the genera Bifidobacterium and Eggerthella, but decreases in the genera Megamonas and Prevotella, in the gut microbiota of patients with BD.16 Antimicrobial peptides have also been investigated for their role in the pathogenesis of BD and recurrent aphthous stomatitis. Ciçek et al found decreased concentrations of the antimicrobial peptide hepcidin in individuals with BD and recurrent aphthous stomatitis compared to the control group, suggesting a relationship with the development of oral aphthous ulcers.17

The vıral hypothesıs Herpes simplex virus-1 genes have been detected in oral and genital ulcers in patients with BD. In addition, patients with BD were found to have HSV-1 DNA in leukocytes and blood and saliva samples, and higher serum anti–herpes simplex virus-1 antibody levels compared to a control group.8,9 Baskan et al found higher levels of parvovirus B19 in nonulcerated skin lesions compared to ulcerated lesions and skin of healthy control participants.18 The roles of hepatitis viruses have been investigated in the etiopathogenesis of BD, but no relationship has been demonstrated with hepatitis A, B, C, E, and G viruses.8 Other than these viruses, studies have suggested a relationship with BD and human immunodeficiency virus, varicella-zoster SKINmed. 2018;16:176–181

virus, cytomegalovirus, and Epstein-Barr virus, although such relationships have not been proved.19 IMMUNOLOGICAL FACTORS The immune system plays a key role in the onset and progression of BD. The discovery of T-cell subtypes in recent years has thrown light on the pathogenesis of BD. The T-cell subtypes of γδT cells and cytotoxic T cells, Th1 cells, regulatory T cells (Tregs), and Th17 cells have been shown to be implicated in the pathogenesis of BD.8

Cytotoxic T cells (γδ T cells, CD56+ cells, CD8+ CD56, and CD56+ T cells) Individuals with BD show an increased number of γδ T cells in the blood and in mucosal lesions, and this increase was found to be associated with disease activity. γδ T cells express CD25, CD29, and CD69 in patients with BD, and mediate production of inflammatory cytokines such as interferon gamma, tumor necrosis factor-alpha, and IL-8. Increases in IL-12 levels are elevated in BD and this results in proliferation of γδ T cells.19 Infliximab, a chimeric monoclonal antibody against tumor necrosis factor-alpha that is used in the treatment of BD, has been shown to suppress in vivo and in vitro γδ T-cell activation and cytotoxic activity.8 Natural killer T cells have been demonstrated in aqueous humour of patients with uveitis, and in cerebrospinal fluid of patients with untreated neuro-BD.8 Natural killer cells are the components of innate immunity that show cytotoxic activity, and increased levels have been detected in the peripheral blood of patients with active BD. The ratio of natural killer types 1 and 2 cells shifts towards type 2 in inactive BD, and this has been found to be associated with disease remission.19

Cytokines associated with BD The serum of individuals with BD has been shown to contain elevated levels of proinflammatory cytokines such as IL-1, IL6, IL-8, IL-12, IL-15, IL-18, tumor necrosis factor-alpha, and interferon-gamma.19 The efficacy of the IL-1 receptor antagonist anakinra in some patients with resistant BD supports the role of IL-1 in disease pathogenesis.20 Studies have reported elevated IL-6 levels in the cerebrospinal fluid of patients with neuro-BD, and IL-6 concentrations have been reported to correlate with long-term outcomes and disease activity.8 Other studies have investigated antibodies raised against IL-6 receptors in BD patients with neurological involvement.20 Increased IL-8 levels were reported in the serum, skin lesions, and endothelial cells of patients with BD, and this was found

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to correlate with disease activity and vascular involvement.8 Elevated serum IL-12 levels have been found in individuals with BD and active uveitis, and in other manifestations of active disease.14 Elevated IL-15 levels have been demonstrated in the peripheral blood and cerebrospinal fluid of patients with BD with neurological involvement; however, no correlation with disease activity has been shown.8 The previous study21 reported that IL-23 levels were associated with uveitis and neuro-BD, and increasing IL-23 levels have been found to correlate with disease activity.Ustekinumab, which acts via IL-12 and IL-23, has shown therapeutic efficacy in BD.22 The cytokine IL-37 has inhibitory effects on innate immunity;23 significantly lower IL37 levels have been reported in patients with BD compared to control groups, and the decreased levels were more marked in active disease.24 İn vitro studies have, furthermore, found that IL37 supplementation in patients with BD significantly suppresses levels of proinflammatory cytokines.25 Lightman et al reported that interferon-alpha 2 use has significantly reduced the use of corticosteroids and improved the quality of life of patients with BD.26

Neutrophil abnormalities have been comprehensively investigated in BD.8 Increased levels of reactive oxygen species in BD indicate neutrophil activation, which represents the role of neutrophils in disease pathogenesis. Studies have reported increased levels of intercellular adhesion molecule-1, CD11, and CD18 in BD, which play a role in the adhesion of neutrophils to endothelial cells.19 Recent evidence suggests that the neutrophil/lymphocyte ratio could be a simple and cheap marker to indicate disease activity in BD. This ratio could be used as a marker of endothelial dysfunction and inflammation, and some studies have suggested its use to evaluate disease activation.30,31

Th1 T-cell subpopulation

ENDOTHELIAL DYSFUNCTION AND THROMBOSIS

A shift towards Th1 has been shown in the Th1/Th2 ratio in patients with BD.12 In addition, evidence suggests a relationship between the severity of the Th1-mediated immune response and disease activity.19 Elevated levels of Th1 cytokines such as IL-12, IL-18, tumor necrosis factor-alpha, and interferon-gamma have been found in skin lesions and peripheral blood of patients with active BD.8,12

Endothelial activation and dysfunction have been shown in BD. Elevated blood levels of thrombomodulin, selectins, and endothelium-derived von Willebrand factors have been demonstrated in patients with the condition.8 Studies have reported increased homocysteine levels in patients with BD and accompanying thrombosis, and this has been suggested to be a risk factor for the development of thrombosis.8 Other studies have evaluated the relationship between genetic mutations and thrombosis in BD, but current data are insufficient to explain their conclusions.32,33 Current data suggest that thrombosis in individuals with BD is not caused by coagulation abnormalities.34

Th17 T-cell subpopulation Th17 cells are associated with various autoimmune and inflammatory diseases, and induce IL-17 production. IL-17 promotes neutrophil influx and regulates the neutrophilmediated inflammatory response.8 Studies have found that IL21 levels in the peripheral blood of patients with BD increase in relation to disease activity, and stimulation of CD4+ T cells by IL-21 promotes leukocyte differentiation towards Th17 and Th1 cells, with reduced differentiation to Tregs.8,27 Studies have reported a high Th17/Treg cell ratio in the peripheral blood of patients with active BD, and in the cerebrospinal fluid of patients with neuro-BD.8

Tregs Tregs have been the focus of recent research into their roles in the pathogenesis of BD. Gündüz et al28 reported decreased levels of Tregs in patients with clinically active BD. Another subgroup of Tregs express high levels of CD52 glycoprotein; SKINmed. 2018;16:176–181

the humanized monoclonal anti-CD52 antibody alemtuzumab causes a relative increase in the number of Tregs by causing a profound depletion of T cells. Alemtuzumab has been successfully used in patients BD refractory to other therapies, and in one study partial or complete remission was observed in 27 out of 32 (84%) patients.29

Neutrophils

OTHER POSSIBLE FACTORS IN ETIOPATHOGENESIS OF BD Fecal calprotectin is a cytosolic protein usually found in neutrophils and macrophages that exerts its antimicrobial effects by binding to calcium.35 Studies have demonstrated significantly increased fecal calprotectin levels in patients with intestinal BD.35,36 Bae and Lee found increased intraocular levels of vascular endothelial growth factor and monocyte chemotactic protein 1 in patients with BD and retinal vasculitis refractory to treatment.37 One of the topics that has attracted attention in recent years is the immunomodulatory role of vitamin D; studies have suggested that decreased vitamin D levels could be associated with BD.38,39

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CORE CURRICULUM and biomarkers in Behcet’s disease. In: Gonul M, Kartal SP, eds. Behçet’s Disease. London: InTechOpen; 2017:27–60.

CONCLUSIONS BD is an inflammatory disease of unknown cause that is characterized by episodes of acute multisystem vasculitis. The disease has a complex pathogenesis, but a genetic predisposition (mainly HLA-dependent), the activation of adaptive and innate immunity by various pathogens, and the subsequent interaction between T lymphocytes (mainly Th1 and Th17) and activated neutrophils are the main elements in its pathogenesis. Advances in the fields of immunology and genetics have significantly contributed to our understanding of its immunopathogenesis, but this still remains largely a mystery. Further comprehensive studies on the immunological pathways involved in BD would contribute new developments in targeted therapies. REFERENCES 1 Mazzoccoli G, Matarangolo A, Rubino R, et al. Behçet syndrome: From pathogenesis to novel therapies. Clin Exp Med. 2016;16:1–12. 2 Gül A. Pathogenesis of Behçet’s disease: Autoinflammatory features and beyond. Semin Immunopathol. 2015;37:413–418. 3 Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1–11. 4 Park UC, Kim TW, Yu HG. Immunopathogenesis of ocular Behçet’s disease. J Immunol Res. 2014;2014:653539. 5 Emmi G, Silvestri E, Squatrito D, et al. Behçet’s syndrome pathophysiology and potential therapeutic targets. Intern Emerg Med. 2014;9:257–265. 6 Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet’s disease: A comprehensive review. J Autoimmun. 2015;64:137–148. 7 Hatemi G, Seyahi E, Fresko I, et al. One year in review 2016: Behçet’s syndrome. Clin Exp Rheumatol. 2016;34:10–22. 8 Pineton de Chambrun M, Wechsler B, Geri G, et al. New insights into the pathogenesis of Behçet’s disease. Autoimmun Rev. 2012;11:687–698. 9 Hatemi G, Yazıcı H. Behçet’s syndrome and microorganisms. Best Pract Res Clin Rheumatol. 2011;25:389–406. 10 Mumcu G, Inanc N, Aydin SZ, et al. Association of salivary S. mutans colonisation and mannose-binding lectin deficiency with gender in Behçet’s disease. Clin Exp Rheumatol. 2009;27:S32– S36. 11 Togashi A, Saito S, Kaneko F, et al. Skin prick test with selfsaliva in patients with oral aphthoses: A diagnostic pathergy for Behcet’s disease and recurrent aphthosis. Inflamm Allergy Drug Targets. 2011;10:164–170. 12 Neves FS, Spiller F. Possible mechanisms of neutrophil activation in Behçet’s disease. Int Immunopharmacol. 2013;17:1206– 1210. 13 Hatemi G, Seyahi E, Fresko I, et al. Behçet’s syndrome: A critical digest of the 2013-2014 literature. Clin Exp Rheumatol. 2014;32:S112–S122. 14 Adeeb F, Khan MU, Stack AG, et al. Etiology, immunopathogenesis

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15 Consolandi C, Turroni S, Emmi G, et al. Behçet’s syndrome patients exhibit specific microbiome signature. Autoimmun Rev. 2015;14:269–276. 16 Shimizu J, Kubota T, Takada E, et al. Bifidobacteria abundancefeatured gut microbiota compositional change in patients with Behcet’s disease. PLoS One. 2016;11:e0153746. 17 Ciçek D, Daglı AF, Aydin S, et al. Does hepcidin play a role in the pathogenesis of aphthae in Behçet’s disease and recurrent aphthous stomatitis? J Eur Acad Dermatol Venereol. 2014;28:1500–1506. 18 Baskan EB, Yilmaz E, Saricaoglu H, et al. Detection of parvovirus B19 DNA in the lesional skin of patients with Behçet’s disease. Clin Exp Dermatol. 2007;32:186–190. 19 Keseroglu HO, Kaya Akıs H, Gonul M. Behçet hastalgının etyopatogenezi. In: Ekiz O, ed. Behçet Hastalıgı Tanı ve Tedavi. Ankara, Turkey: Derman Medical Publishing; 2015:7–23. 20 Zhou ZY, Chen SL, Shen N, et al. Cytokines and Behcet’s disease. Autoimmun Rev. 2012;11:699–704. 21 Gheita TA, Gamal SM, Shaker I, et al. Clinical significance of serum interleukin-23 and A/G gene (rs17375018) polymorphism in Behçets disease: Relation to neuro-Behçet, uveitis and disease activity. Joint Bone Spine. 2015;82:213–215. 22 Baerveldt EM, Kappen JH, Thio HB, et al. Successful long-term triple disease control by ustekinumab in a patient with Behcet’s disease, psoriasis and hidradenitis suppurativa. Ann Rheum Dis. 2013;72:626–627. 23 Nold MF, Nold-Petry CA, Zepp JA, et al. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol. 2010;11:1014– 1022. 24 Bouali E, Kaabachi W, Hamzaoui A, et al. Interleukin-37 expression is decreased in Behçet’s disease and is associated with inflammation. Immunol Lett. 2015;167:87–94. 25 Hamzaoui K, Hamzaoui A. The anti-inflammatory activity of interleukin-37 in Behçet’s disease. Inflamm Cell Signal. 2016;3:e1452. 26 Lightman S, Taylor SR, Bunce C, et al. Pegylated interferon-α2b reduces corticosteroid requirement in patients with Behçet’s disease with upregulation of circulating regulatory T cells and reduction of Th17. Ann Rheum Dis. 2015;74:1138–1144. 27 Alpsoy E. Behçet Hastalıgı: Etyopatogenezde Güncel Bilgiler. Turk J Dermatol. 2013;7:41–45. 28 Gündüz E, Teke HU, Bilge NS, et al. Regulatory T cells in Behçet’s disease: Is there a correlation with disease activity? Does regulatory T cell type matter? Rheumatol Int. 2013;33:3049– 3054. 29 Mohammad AJ, Smith RM, Chow YW, et al. Alemtuzumab as remission ınduction therapy in Behçet disease: A 20-year experience. J Rheumatol. 2015;42:1906–1913. 30 Yuksel M, Yildiz A, Oylumlu M, et al. Novel markers of endothelial dysfunction and inflammation in Behçet’s disease patients with ocular involvement: Epicardial fat thickness, carotid intima media thickness, serum ADMA level, and neutrophil-to-lymphocyte ratio. Clin Rheumatol. 2016;35:701–708. 31 Acikgoz N. The neutrophil-lymphocyte ratio and Behcet disease. Angiology. 2016;67:297.

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32 Adeeb F, Tayel M, El Kaffash DM, et al. Janus kinase 2 V617F mutation and thrombotic events in Behcet’s disease: The Alexandria experience. Eur J Rheumatol. 2016;3:73–74. 33 Ar MC, Hatemi G, Ekizoglu S, et al. JAK2 (V617F) mutation is not associated with thrombosis in Behcet syndrome. Clin Appl Thromb Hemost. 2012;18:421–426.

36 Hatemi I, Hatemi G, Çelik AF. Systemic vasculitis and the gut. Curr Opin Rheumatol. 2017;29:33–38. 37 Bae JH, Lee SC. Effect of intravitreal methotrexate and aqueous humor cytokine levels in refractory retinal vasculitis in Behcet disease. Retina. 2012;32:1395–1402.

34 Seyahi E, Yurdakul S. Behçet’s syndrome and thrombosis. Mediterr J Hematol Infect Dis. 2011;3:e2011026.

38 Can M, Gunes M, Haliloglu OA, et al. Effect of vitamin D deficiency and replacement on endothelial functions in Behçet’s disease. Clin Exp Rheumatol. 2012;30:S57–S61.

35 Özseker B, Sahin C, Özseker HS, et al. The role of fecal calprotectin in evaluating ıntestinal ınvolvement of Behçet’s disease. Dis Markers. 2016;2016:5423043.

39 Khabbazi A, Rashtchizadeh N, Ghorbanihaghjo A, et al. The status of serum vitamin D in patients with active Behcet’s disease compared with controls. Int J Rheum Dis. 2014;17:430–434.

RASH DECISIONS MARK BERNHARDT, MD, SECTION EDITOR Is the perfect[ly legal] the enemy of the [morally] good? Scenario 1 Patient N.P. has been going to another dermatologist who annually renews her prescription for tretinoin which she uses for wrinkles. She now comes to you and not only wants you to renew her prescription but tell her insurance company she is using it for indicated medical reasons. What do you do? Scenario 2 Patient R.K.’s acne as always responded to minocycline, but his new insurance won’t cover it unless he has tried and failed other formulary medicines. Do you simply say that he has done so before he came to you, knowing that he didn’t? Scenario 3 Patient A.H. has severe psoriasis and wants to begin a new medicine she saw advertised on the television. Her insurance will only pay for the new medicine if she first tries methotrexate. A.H. does not want to take methotrexate due to its side effects. Do you write a prescription for methotrexate, advise A.H. to fill it but not actually take it and then have her follow up so you can document that she tried methotrexate and it did not work? Your actions in each scenario could legally be fraudulent, but are they morally justifiable? In the first instance you are merely continuing a course that predates your care. If you refuse to renew N.P.’s prescription, there is a good chance she will simply find another dermatologist who is willing to do what she wants. In the second scenario, you are a more active participant by stating that something took place when you know it did not. In the last scenario you are even more complicit because you are now initiating, aiding, and abetting the deceit. You know that N.P. will appreciate your cooperation in scenario one. If the past predicts the future, R.K. will clear up faster than if he was forced to try other drugs on his insurance formulary first. You respect A.H.’s desire to avoid the potential side effects of methotrexate but you don’t know if she will even respond to the new medicine. I’ve been in each scenario and know how I responded. How about you? 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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Volume 16 • Issue 3

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

Bavencio® (Avelumab)—A Newly Approved Anti-PD-L1 IgG1 Antibody Aditya K. Gupta, MD, PhD, FRCPC;1,2 Sarah G. Versteeg, MSc;2 William Abramovits, MD, FAAD;3,4,5 Kimberly D. Vincent, MD6

Bavencio® (Avelumab) is a newly approved therapy for treatment of Merkel cell carcinoma (MCC), an aggressive form of skin cancer. Avelumab has shown promising results in MCC patients, reporting complete response rates and partial response rates from 9.1% to 11.4% and 21.6% to 22.7%, respectively. Treatment-related adverse events were frequently found among avelumab-treated patients (67%) with seven warnings highlighted in the product insert. It is recommended that intravenous infusions are administered at 10 mg/kg over 60 minutes every 2 weeks. Other potential uses of avelumab include: urothelial carcinoma, metastatic or locally advanced solid tumors and nonsmall cell lung cancer. (SKINmed. 2018;16:183–187)

erkel cell carcinoma (MCC) is a rare and uniquely aggressive form of skin cancer,1,2 with approximately 0.2 to 1.6 cases per 100,000 person-years in the United States. It is considered the second leading cause of skin cancer deaths.1,2 MCC typically presents as a firm, quick-growing tumor that often appears on actinically damaged skin. There are three subtypes of MCC, with the intermediate subtype (stage II regional lymph node involvement) being the most prevalent; this commonly affects elderly people, sun-exposed fair-skinned individuals, and those who are immunocompromised.2–5 MCC is associated with a high mortality rate, with a 5-year relative survival rate ranging from 75% to 25% depending on severity (stage I localized to skin and stage III distant metastasis, respectively).4 Proposed etiologies include ultraviolet radiation and Merkel cell polyomavirus infection.3 Traditionally, surgery, radiation, and chemotherapy have been used to treat MCC.6 Varying levels of control can be achieved with these therapies; chemotherapy often lacks durable responses.7,8 The US Food and Drug Administration recently approved therapy with Bavencio® (avelumab, initial US approval April 25,

2017; EMD Serono, Inc., Rockland, MA; Merck KGaA, Darmstadt, Germany) to combat MCC in patients aged 12 years and older. Avelumab can also be used to treat patients with advanced or metastatic urothelial carcinoma, whose disease has progressed during or after 12 months of platinum-containing chemotherapy (monotherapy, neoadjuvant, or adjuvant treatment).9,10 MECHANISM OF ACTION Evidence suggests that programmed death-ligand 1 (PD-L1) can be expressed on Merkel carcinoma cells and tumor-infiltrating immune cells.11 Receptors found on T cells and antigen-presenting cells (eg, program death receptor-1 [PD-1] and B7.1) can bind to these PD-L1 ligands, creating a favorable environment for tumor growth through the suppression of T-cell proliferation, cytokine production, and cytotoxic T-cell activity.12 Avelumab is a human IgG1 monoclonal antibody that inhibits this PD-1 interaction by binding to PD-L1, restoring immune responses (antitumor immune response, etc), and decreasing tumor growth.13 In addition, avelumab can induce antibody-dependent cell-mediated cytotoxicity, triggering the lysis of tumor cells.14–16

From the Division of Dermatology, Department of Medicine, University of Toronto School of Medicine, Toronto, Ontario, Canada;1 Mediprobe Research Inc., London, Ontario, Canada;2 Department of Medicine, Baylor University Medical Center,3 Departments of Dermatology and Family Practice, University of Texas Southwestern Medical School,4 and the Dermatology Treatment and Research Center, Dallas, TX;5 and Belle Meade Dermatology, Nashville, TN6 Address for Correspondence: Aditya K. Gupta, MD, PhD, FRCPC, 645 Windermere Road, London, Ontario, Canada N5X 2P1 • E-mail: agupta@execulink.com

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Table I. Overall Response to Avelumab as Defined by the Response Evaluation Criteria in Solid Tumors Guidelines (RECIST, version 1.1)17 Study

Description

Complete Response

Partial Response

Stable Disease

Progressive Disease

Merkel cell carcinoma Kaufman et al (2016)8

≥6 months of follow-up

8/88=9.1%

20/88=22.7%

9/88=10.2%

32/88=36.4%

Kaufman et al (2018)18

≥1 year of follow-up

10/88=11.4%

19/88=21.6%

9/88=10.2%

32/88=36.4%

Urothelial carcinoma Apolo et al (2017)23

Initial cohorta

5/44=11.4%

3/44=6.8%

15/44=34.1%

Patel et al (2018)24

Efficacy expansion cohortb

9/161=5.6%

18/161=11.2%

37/161=23.0%

67/161=41.6%

Complete response: disappearance of all target lesions. Partial response: ≥30% decrease in the sum of target lesion diameters. Stable disease: cannot be categorized as a partial response (insufficient shrinkage) or progressive disease (insufficient increase). Progressive disease: ≥20% increase in the sum of target lesion diameters. a Initial cohort: patients with urothelial carcinoma progressing after platinum-based chemotherapy (n=44). b Efficacy expansion cohort: initial cohort used in a 2017 study,23 plus cisplatin-ineligible patients who were previously treated or were platinumnaive (n=161).

EFFICACY OF AVELUMAB FOR MCC Complete and partial responses have been achieved with avelumab in MCC patients previously treated with chemotherapy (Table I). In an open-label, phase II trial, avelumab (10 mg/kg) was investigated in 88 MCC patients who were refractory to chemotherapy.8 Avelumab was administered through intravenous infusion (1 hour) once every 2 weeks, with H1 antihistamine and acetaminophen given 30 to 60 minutes before treatment.8 In patients with a complete response, treatment was continued for a minimum of 6 months, extending beyond 12 months based on an investigator assessment of potential benefit.8 Partial (≥30% decrease in the sum of target lesion diameters17) and complete (disappearance of all target lesions17) responses were achieved in 22.7% (20/88) and 9.1% (8/88) of patients, respectively (Table I), with the majority of responses observed at week 7 (22/28=78.6%).8 Upon followup ≥1 year after treatment (JAVELIN Merkel 200 trial, the number of patients achieving a complete response increased to 11.4% (10/88), whereas the number of patients achieving a partial response decreased to 21.6% (19/88).18 Durable response, defined as the proportion of patients with a response lasting ≥6 months, was estimated to be 29.0%, with a 69.0% and 52.0% overall survival rate at 6 and 12 months, respectively.8,18 SKINmed. 2018;16:183–187

When questioned before avelumab treatment (n=19), patients reported that MCC had negatively affected their lives (eg, psychologic effects).19 After avelumab treatment, the observed response (tumor reduction) was positively associated with increased quality of life.20 Most patients (62/88=70.4%) experienced treatment-related adverse events (TRAEs), such as fatigue (21/88=23.9%) and infusion-related reactions (15/88=17.0%) (Table II), with five grade 3 TRAEs reported (Table III).8 Treatment-emergent antitherapeutic antibodies were found in three patients (3/79=3.8%).8 SAFETY PROFILE The incidence of TRAEs across phase I and II studies (JAVELIN solid tumor and JAVELIN Merkel 200 trials) is high, with 67.0% (1164/1738) of patients reporting a TRAE;21 the most commonly reported included fatigue (307/1738=17.7%), infusion-related reactions (295/1738=17.0%), and nausea (150/1738=8.6%).21 Infusion-related reactions (15/1738=0.9%), pneumonitis (11/1738=0.6%), pyrexia (6/1738=0.3%), and adrenal insufficiency (5/1738=0.3%) were among the serious TRAEs reported, occurring in 6.2% of patients (108/1738).21 Serious immune-related adverse events were reported in 2.5% (43/1738) of patients,

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Table II. Mild Treatment-Related Adverse Events (Grades 1 and 2) Reported in Patients with Merkel Cell Carcinoma and Urothelial Carcinoma Adverse Events

Merkel Cell Carcinoma

Urothelial Carcinoma

Kaufman et al (2016)8

Apolo et al (2017)23

Patel et al (2018)24

21/88=23.9%

9/44=20.5%

36/249=14.5%

15/88=17.0%

9/44=20.5%

73/249=29.3%

Diarrheaa

8/88=9.1%

4/44=9.1%

14/249=5.6%b

Nauseaa

8/88=9.1%

5/44 = 11.4%

Astheniaa

7/88=8.0%

4/44=9.1%

11/249=4.4%

Eruption

6/88=6.8%

4/44=9.1%b

36/249=14.5%b

Decreased appetite

5/88=5.7%

1/44=2.3%

10/249=4.0%

Maculopapular eruption

5/88=5.7%

NRd

Blood creatine phosphokinase increase

1/88=1.1%

0/249 = 0.0%

Hypothyroidismb

3/88=3.4%

3/44=6.8%

10/249=4.0%

Hyperthyroidismb

2/88=2.3%

2/249=0.8%

1/88=1.1%

1/44=2.3%

4/249=1.6%

1/88=1.1%

3/44=6.8%

NRd

Elevated aspartate aminotransferaseb

3/88 = 3.4%c

1/44=2.3%

1/249=0.04%

Elevated alanine transaminaseb

3/88 = 3.4%c

1/44=2.3%

1/249 = 0.04%

Rheumatoid arthritisb

1/44=2.3%

1/249 = 0.04%

Uveitisb

1/44=2.3%

1/249 = 0.04%

Fatigue Infusion-related reactions

Pneumonitisb Type 1 diabetes mellitus

Pruritusb

Includes signs and symptoms of an infusion-related reaction (fever, chills, etc). Reported as a potential immune-mediated/immune-related treatment-related adverse event. c NR, not reported as a potential immune-mediated/immune-related treatment-related adverse event. d Results of this adverse event were not reported individually. a

and included thyroid disorder (98/1738=5.6%) and eruptions (90/1738=5.2%).21 TRAEs were considered the primary cause of death in 0.2% of the total number of deaths reported (4/1738).21 Phase III safety data have yet to be determined.22 OTHER USES FOR AVELUMAB In a phase Ib, dose-expansion, cohort study, avelumab (10 mg/ kg) was investigated in patients with metastatic urothelial carcinoma that had progressed after platinum-based chemotherapy (n=44).23,24 After an antihistamine and acetaminophen had been given, avelumab was administered through an intravenous infuSKINmed. 2018;16:183â&#x20AC;&#x201C;187

sion (1 hour) once every 2 weeks until the criterion for withdrawal occurred. TRAEs such as infusion-related reactions (73/249=29.3%) and fatigue (36/249 = 14.5%) were common (Tables II and III).23,24 One treatment-related death occurred due to pneumonitis, and three grade 4 TRAEs were observed (Table III).23,24 Evidence suggests that avelumab may be useful in other types of cancers, such as metastatic or locally advanced (previously treated) solid tumors and nonsmall cell lung cancer.25,26 Based on preliminary results, avelumab 10 mg/kg once every 2 weeks is the

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Table III. Severe Treatment-Related Adverse Events (Grade ≥3) Reported in Patients with Merkel Cell Carcinoma and Urothelial Carcinoma Adverse Events

Merkel Cell Carcinoma

Urothelial Carcinoma

Kaufman et al (2016)8

Apolo et al (2017)23

Patel et al (2018)24

Blood creatine phosphokinase increase

1/88=1.1%

1/44=2.3%

1/249=0.04%a

Lymphopenia

2/88=2.3%

Blood cholesterol increase

1/88=1.1%

Asthenia

0/88=0.0%

1/44=2.3%

2/249=0.08%

Decreased appetite

0/88=0.0%

1/44=2.3%

1/249=0.04%

Elevated aminotransferasea

1/88=1.1%

1/44=2.3%

1/249=0.04%

Fatigue

0/88=0.0%

0/44=0%

4/249=1.6%

Eruption

0/88=0.0%

0/44=0%

1/249=0.04%

Diarrheaa

0/88=0.0%b

0/44=0%

1/249=0.04%

Pneumonitis

0/44=0%

2/249=0.08%

Elevated lipase

2/249=0.08%

Hypophosphatasemia

2/249=0.08%

Reported as a potential immune-mediated/immune-related treatment-related adverse event. NR, not reported as a potential immune-mediated/immune-related treatment-related adverse event.

recommended dose for these cohorts.25 Avelumab may also be useful in combination with near-infrared photoimmunotherapy, a novel modality that has prolonged survival in tumor-bearing mice models.27 WARNINGS AND PRECAUTIONS Immune-mediated pneumonitis, immune-mediated hepatitis, infusion-related reactions, and embryo-fetal toxicity are among the seven warnings highlighted in the product insert for avelumab.10 Similar warnings have been reported for other approved checkpoint inhibitors such as pembrolizumab.28 If severe or life-threatening pneumonitis, hepatitis, colitis, nephritis, renal dysfunction, or infusion-related reactions occurs, it is recommended that avelumab treatment be permanently discontinued.10

ommends that intravenous infusions be given at 10 mg/kg over 60 minutes every 2 weeks.10 Avelumab is a significant advance in the treatment of MCC. Dermatologists should consider incorporating it in treatment plans for patients with this aggressive tumor who are not curable through traditional means. It may of value to study it in the prevention of metastatic disease. REFERENCES

CONCLUSIONS Complete and partial responses can be achieved with avelumab in patients with MCC, and responses are typically observed between weeks 7 and 13.8,18,23,24 Before the first four avelumab infusions, it is recommended that premedication with acetaminophen and antihistamine be used. The Food and Drug Administration recSKINmed. 2018;16:183–187

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1 Paulson KG, Park SY, Vandeven NA, et al. Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018;78:457–463. 2 Baker M, Cordes L, Brownell I. Avelumab: A new standard for treating metastatic Merkel cell carcinoma. Expert Rev Anticancer Ther. 2018;18:319–326. 3 Amaral T, Leiter U, Garbe C. Merkel cell carcinoma: Epidemiology, pathogenesis, diagnosis and therapy. Rev Endocr Metab Disord. 2017;18:517–532. 4 Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;49:832– 841. 5 Coggshall K, Tello TL, North JP, et al. Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging. J Am Acad Dermatol. 2018;78:433–442.

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6 Tello TL, Coggshall K, Yom SS, et al. Merkel cell carcinoma: An update and review: Current and future therapy. J Am Acad Dermatol. 2018;78:445–454. 7 Cassler NM, Merrill D, Bichakjian CK, et al. Merkel cell carcinoma therapeutic update. Curr Treat Options Oncol. 2016;17:36. 8 Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–1385. 9 U.S. Food and Drug Administration. FDA Grants Accelerated Approval to Avelumab for Urothelial Carcinoma. 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ ucm557162.htm. Accessed October 12, 2017. 10 U.S. Food and Drug Administration. BAVENCIO® (avelumab) injection, for intravenous use. 2017. https://www.accessdata.fda.gov/scripts/cder/daf/index. cfm?event=overview.process&ApplNo=761078. Accessed October 12, 2017. 11 Lipson EJ, Vincent JG, Loyo M, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: Association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res. 2013;1:54–63. 12 Hahn AW, Gill DM, Agarwal N, et al. PD-1 checkpoint inhibition: Toxicities and management. Urol Oncol. 2017;35:701–707. 13 Vandeveer AJ, Fallon JK, Tighe R, et al. Systemic immunotherapy of non-muscle invasive mouse bladder cancer with avelumab, an anti-PD-L1 immune checkpoint inhibitor. Cancer Immunol Res. 2016;4:452–462. 14 Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res. 2015;3:1148–1157. 15 Khanna S, Thomas A, Abate-Daga D, et al. Malignant mesothelioma effusions are infiltrated by CD3+ T cells highly expressing PD-L1 and the PD-L1+ tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab. J Thorac Oncol. 2016;11:1993–2005. 16 Fujii R, Friedman ER, Richards J, et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget. 2016;7:33498–33511. 17 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–247.

18 Kaufman HL, Russell JS, Hamid O, et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer. 2018;6:7. 19 Kaufman HL, Dias Barbosa C, Guillemin I, et al. Living with merkel cell carcinoma (MCC): Development of a conceptual model of MCC based on patient experiences. Patient. 2018 Mar 6. [Epub ahead of print] 20 Kaufman HL, Hunger M, Hennessy M, et al. Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma. Future Oncol. 2018;14:255– 266. 21 Kelly K, Infante JR, Taylor MH, et al. Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Cancer. 2018;124:2010–2017. 22 Gaiser MR, Bongiorno M, Brownell I. PD-L1 inhibition with avelumab for metastatic Merkel cell carcinoma. Expert Rev Clin Pharmacol. 2018;11:345–359. 23 Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an antiprogrammed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017;35:2117–2124. 24 Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): Pooled results from two expansion cohorts of an openlabel, phase 1 trial. Lancet Oncol. 2018;19:51–64. 25 Heery CR, O’Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): A phase 1a, multicohort, dose-escalation trial. Lancet Oncol. 2017;18:587–598. 26 Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): Dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol. 2017;18:599– 610. 27 Nagaya T, Nakamura Y, Sato K, et al. Near infrared photoimmunotherapy with avelumab, an anti-programmed death-ligand 1 (PD-L1) antibody. Oncotarget. 2017;8:8807–8817. 28 U.S. Food and Drug Administration. KEYTRUDA® (pembrolizumab) for injection, for intravenous use KEYTRUDA® (pembrolizumab) injection, for intravenous use. 2017. h t t p s : / / w w w. a c c e s s d a t a . f d a . g o v / d r u g s a t f d a _ d o c s / label/2017/125514s031lbl.pdf. Accessed February 14, 2018.

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Volume 16 • Issue 3

PHOTO CAPSULE Snejina Vassileva, MD, PhD, Section Editor

Nevus Lipomatosus Cutaneous Superficialis on the Nape—A Rare Presentation Sandeep Kulkarni, MBBS, DNB; Namrata Chhabra, MD; Neel Prabha, MD; Nighat Hussain, MD; Amit Bugalia, MD

28-year-old man presented with multiple, skincolored, grouped, papulonodular lesions over the nape that had been present for 1 year. The lesions had begun as asymptomatic skin-colored papules and nodules that grew insidiously over the next year to be multiple grouped lesions. Examination revealed several fleshy to opalescent groups of oval to oblong papules and nodules ranging from 2 mm to

15 mm in diameter. These were distributed on lower part of the nape and involved an area 50 mm in diameter (Figure 1). The smaller lesions were soft to firm and nonpulsatile on palpation, whereas the larger lesions were cerebriform and negative for the “button hole” sign. Histologic examination of the biopsy revealed ectopic and mature adipocytes surrounding the dermal blood vessels and appendages (Figure 2). A diagnosis

Figure 2. Histologic section showing normal epidermal architecture along with a dermal collection of mature ectopic adipocytes appearing as vacuolated areas (magnification ×40).

Figure 1. Multiple, variably sized, grouped, skin-colored to fleshy cerebriform papulonodules on the nape.

From the Department of Dermatology, Venereology and Leprology and Department of Pathology, All India Institute of Medical Sciences, Raipur, Chattisgarh, India Address for Correspondence: Sandeep Kulkarni, MBBS, DNB, Department of Dermatology, AIIMS, Raipur, 492010, India • E-mail: sak235@gmail.com

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of nevus lipomatosus cutaneous superficialis was made, and the patient was referred to the plastic surgery team for excision of the lesion. Nevus lipomatosus cutaneous superficialis), first described by Hoffman and Zurhelle in 1921,1 usually presents as aggregates of multiple nodules in a linear or zosteriform configuration (the classic form). It is mostly unilateral, but bilateral distribution also has been reported.2 Usually, it involves the sacrum, buttocks, and posterior aspect of the thighs.1 The two most common clinical variants of nevus lipomatosus cutaneous superficialis are classic and solitary. The classic form usually presents on the lower region of the back or buttocks, at birth or in early childhood. The solitary form presents later in life as a domeshaped or sessile papule, and tends to involve several other sites apart from the lower area of the back. The classic morphology with an atypical site of involvement (nape of the neck) were remarkable features associated with our case. One such case

with classical lesions on the left side of the neck was reported in 2006 from Kolkata, India.2 CONCLUSIONS The differential diagnoses include multiple acrochordons, lymphangioma, lipofibromas, neurofibromas, trichoepitheliomas, and angiolymphoid hyperplasia. Malignant transformation has not been reported, and excision usually eliminates the condition.3 REFERENCES 1 Hoffmann E, Zurhelle E. Ubereinen nevus lipomatodes cutaneous superficialis der linkenglutaalgegend. Arch Dermatol Syph. 1921;130:327–333. 2 Das JK, Sengupta S, Gangopadhyay AK. Nevus lipomatosus superficialis over neck, an atypical site. Indian J Dermatol Venereol Leprol. 2006;72:66–67. 3 Yap FB. Nevus lipomatosus superficialis. Singapore Med J. 2009;50:161–162.

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Volume 16 • Issue 3

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

Picturing in Dermatology—From Wax Models to Teledermatology, Part 2 Eve J. Lowenstein, MD, PhD

he 2018 meeting of the History of Dermatology Society was held on February 15, 2018 in San Diego, CA. The main topic was the tools used in the 18th to19th centuries to view and study skin disease. “A good picture is equivalent to a good deed” —Vincent van Gogh The 2018 meeting of the History of Dermatology Society represented a continuation of the subject considered a year previously, focusing on images, color atlases, and moulages.1

INTRODUCTORY PRESENTATIONS Mauricio Goihman-Yahr (Caracas, Venezuela) opened the meeting with a discussion of the Jacobi and Pringle Atlas of Dermatology (1904 edition, English translation), pointing out its timeless features and beauty. Next, the 1883 edition of the complete works of the Duke of Rivas (an outstanding Spanish poet) was discussed, again with a sense of timelessness and durability. Finally, Goihman described Barbara Tuchman’s 1966 book The Proud Tower: A Portrait of the World Before the War, 1890–1914, which is a collection of essays describing economic and other aspects of society, some (eg, confidence and stability) not yet restored. The title of the book was derived from the 1845 Edgar Allan Poe poem The City in the Sea, its epigraph reading: “While from a proud tower in the town, death looks gigantically down.” Richard Spielvogel (Philadelphia, PA) described the most important historical contributions to the technique of dermatoscopy and the technical development of dermatoscopes. The first recorded usage of capillary microscopy was by Johan Christophorus Kolhaus in 1663. The use of immersion oil in microscopy by Zeiss and the application of immersion oil with

magnification to the skin were described by Paul Gerson Unna (1850 to 1929) in 1893. Johan Saphier’s extensive skin studies in Munich, Germany, in the 1920s, with a bulky binocular microscope and a lateral illumination source, led to the term “dermatoskopie.” Leon Goldman’s (1906 to 1997) 1950s’ skin studies in the United States, along with the term “dermoscopy,” and, most importantly, Rona MacKie’s (b. 1940) publications from Scotland in the early 1970s confirmed the advantages of dermoscopy (or dermatoscopy) in the differential diagnosis of pigmented lesions, allowing for more precise separation of benign and malignant lesions. Clinical usage has gradually increased significantly over the last 40 years, initially in Europe, and then in the United States. Eve Lowenstein (Brooklyn, NY) discussed how doctors have pictured themselves throughout the ages: from magic to medical error, from hubris to humility. Physicians’ self-perception and role have changed over time, impacted by culture, ethics, and the tools available (science). Early physicians used little or no science and relied heavily on mystery and magic. Such medical practice, based on little knowledge, was accompanied by unbridled hubris. Awareness of a distinction between magic and science in medicine surfaced in the Middle Ages, and, in parallel with developing civilization and religions, medical ethics evolved. With scientific development, more proof was required to accept diagnoses and treatment recommendations. With increasing knowledge and tools, physicians developed greater admission of limitations and greater consciousness of ignorance—the only way to safeguard against error is to embrace it! Humility is both a by-product of and instrumental in our progress. Marjon Vatanchi (Brooklyn, NY) presented “An Odyssey Into Color Exploration.” The isolated Fugate family of Troublesome Creek, Kentucky, had blue skin secondary to a rare asymptomatic

From the Department of Dermatology, SUNY Health Science Center at Brooklyn, Brooklyn, NY Address for Correspondence: Eve J. Lowenstein, MD, PhD, Department of Dermatology, SUNY Health Science Center at Brooklyn, Box 46, 450 Clarkson Avenue, Brooklyn, NY 11203 • E-mail: evlow13@yahoo.com

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methemoglobinemia caused by a hereditary diaphorase deficiency; this resulted in blue skin color that vanished with exposure to methylene blue. Marjon Vatanchi recounted the history of development of the color recognition system known as the Pantone® matching system. Finally, she placed the topic in perspective around the photographer Angélica Dass, who has developed the Humanae project to demonstrate the irrationality of racism based on skin color. Christine Totri (Brooklyn, NY) spoke about Carl Heitzman (1836 to 1896), one of the most important Jewish physicians and artists of the 19th century. He was insightful and observant, the first to describe the blood cell precursor the hematoblast, before Georges Hayem (1841 to 1933), who was originally credited with the discovery. Although he had no formal art training, Heitzman’s work as an artist is more frequently quoted in medical literature than are his scientific papers. He coillustrated Hebra’s Atlas of Skin Diseases with watercolor images. Even today, his images remain good learning tools. The Kaposi sarcoma illustration he created was one of the earliest used by Kaposi in his original contribution on the condition. WAX MODELS Michelle Xu (Charleston, SC) spoke about the techniques involved in creating wax models and moulages. Early moulage techniques were considered trade secrets and not publically shared. The current era still finds use for wax modeling for education and forensic study, with modern moulage techniques described. Lawrence Charles Parish (Philadelphia, PA) discussed Joseph Towne (1806 to 1879), born into poverty in Cambridge, UK. At age 17, with little education, he created a skeleton model that led to his becoming a modeler at Guy’s Hospital in London. During a half century, he produced more than 1000 realistic models, half of which represented skin diseases, such as pemphigus, ichthyosis, and leprosy. His models were so realistic that audiences were often afraid to touch them for fear of catching the disease. His techniques are speculated upon and largely unknown as he kept them secret. His works were, however, exhibited and won awards, with two catalogues created for the Guy’s Hospital Collection. Many of his models were purchased by buyers abroad, although the largest extant collection still exhibited is housed at the Gordon Museum of Pathology at the Guy’s campus of King’s College London. Natalie Curcio (Nashville, TN) discussed the moulage museum in Madrid, the El Museo Olavide collection. José Eugenio Olavide (1836 to 1901), known as the father of Spanish dermatology, established the large wax moulage collection there. The principle SKINmed. 2018;16:191–193

sculptor, Enrique Zofio Dávila (1840 or 1843 to 1915), created a large collection and was unusual in that he shared his techniques with trainees. The collection was at that point housed in the Hospital San Juan de Dios. Beginning in the Spanish Civil War, Franco wanted to suppress any remnant of his detractors and destroy the moulages. During the Forgotten Period (1940 to 2005), many were hidden away in hospital warehouses, only recently to have been fortuitously found and salvaged. Since 2005, several artists have been dedicated to the restoration, recovery, cataloguing, and restoration of this collection of 603 figures. Many models are life size, with full medical histories. The New Museo Olavide in Madrid, Spain, is open to show them again to the public. ATLASES W. Clark Lambert (Newark, NJ) spoke about “Confusion, Error, and Omissions with 19th Century Atlases.” Considering how much was deduced without a knowledge of histology, these atlases bear witness to impressive insights. Lambert told about the significant collection of atlases in the library of Rutger’s University, Piscatway, NJ, that were recently rescued from imminent destruction. He discussed whether we are better off now with photography than with artistic renditions of disease. He gave an example where the camera angle profoundly impacted one image’s perspective, making an individual look child-, adolescent-, and adultlike in photographs taken minutes apart. Daniel Wallach (Paris, France) presented the atlas Clinique Photographique de l’Hôpital San Louis (1868) by Alfred Hardy (1811 to 1893) and Arthur de Montméja (1841 to 1910). Hardy was an internist who worked at l’Hôpital San Louis, known for clinical lessons on skin disease. He authored two books featuring skin diseases and their treatments. Hardy developed unique disease classifications including on dartrous diatheses, not well understood in his time. de Montméja founded a clinical photographic journal with Désiré-Magloire Bourneville, a French neurologist who described many features of tuberous sclerosis, also known as Bourneville-Pringles disease. The moulages being developed in Paris were expensive, and de Montmeja concurrently began developing his collection of black and white colorized photographs. Characteristic and striking to note is that his images portrayed real-life presentations of clothed patients, displaying them with sensitivity to their circumstance and suffering. Pezhman Mobasher (Irvine, CA) presented on the Photographic Review of Medicine and Surgery (1872), established by Francis Fontaine Maury (1840 to 1879) and Louis A. Duhring (1845 to 1913), from Philadelphia, PA. Maury was a very talented American surgeon who earned his MD at age 21 from the University of

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Pennsylvania and died at 39 from tuberculosis, a few weeks after his wife’s demise from the disease. Duhring would become the first professor of dermatology at the University of Pennsylvania (1875), and famously described dermatitis herpetiformis. Together, they authored this outstanding pictorial journal. Gerd Plewig and Johannes Ring (Munich, Germany) discussed The Atlas of Syphilis by Leo Ritter von Zumbusch (1874 to 1940). Von Zumbush was an early identifier of lichen albus (now known as lichen sclerosus), as well as pustular psoriasis and several other skin diseases. His atlas, with 63 color photographs, used revolutionary techniques in colorized photography, the 1913 Colcin process being the first to use color additive methods. A highly respected physician, von Zumbush was forced into involuntary retirement due to his resistance to the Nazi regime. Von Zumbusch was very active and involved in German medical politics, and his vocalized anti-Nazi opinion resulted in his exile from the medical establishment in Nazi Germany. When he died in exile in 1940, not a single colleague attended his funeral. Robert Thomsen (Los Alamos, NM) presented a comparison of illustrations and figures from five circa-1900 dermatology textbooks by Shoemaker, Radcliffe-Crocker, Kaposi, Hyde and Montgomery, and Stelwagon (1903). Shoemaker’s book, A Practical Treatise on Diseases of Skin, published in 1888 by Appleton and Co. of New York, was the only one to credit the illustrators and creator of the woodcuts, the others rarely acknowledging sources. Photomicrographs prepared with camera obscura and camera lucida techniques were discussed. Although microscopic images were predominantly illustrations, photographs were beginning to be included in textbooks at that time.

English translation of 1955 included plates that were printed in France, with translated text in English, for the five volumes. The detailed images were exemplary and excellent learning tools. CONCLUSIONS Three quotations seem to sum up the main emphases of this meeting: “The farther backwards you can look, the farther forwards you can see” (Winston Churchill)2—This year’s sessions gave perspective to how we view the science of color, the role of humility in accepting our role in medical error, and an everevolving understanding of disease today. The 17th-century proverb “One man’s trash is another man’s treasure”3—Several speakers presented artistic treasures (atlases and moulages) that had been rescued from the trash heap. “There are always two people in a picture: the photographer and the viewer” (Ansel Adams)4—The role of the perspective of the photographer or artist in how we perceive a photographed or recreated disease was expanded upon. A better understanding of how we arrived at today’s perspective and tools for education was achieved through this year’s meeting. REFERENCES

Finally, Mark Valentine (Everett, WA) presented the Color Atlas of Dermatology by Graciansky, Boulle, Sulzberger, and DobkevitchMorrill. The original book having been written in French, the

1 Lowenstein EJ. Picturing in dermatology – From wax models to teledermatology, Part II. SKINmed. 2017; 15:209–210. 2 Winston Churchill Quotes. https://www.brainyquote.com/ quotes/winston_churchill_136790. Accessed June 20, 2018. 3 StackExchange. English Language & Usage. https://english. stackexchange.com/questions/60429/origin-of-one-manstrash-is-another-mans-treasure. Accessed June 20, 2018. 4 BrainyQuote. Ansel Adams Quotes. https://www.brainyquote. com/search_results?q=There+are+always+two+people+in+a +picture%3A+the+photographer+and+the+viewer%E2%80% 9D+. Accessed June 20, 2018.

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May/June 2018

Volume 16 • Issue 3

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

Syringocystadenocarcinoma Papilliferum: A Rare Malignant Sweat Gland Tumor Jonathan L. Yao, MD;1 A. Paul Cellura, BS;1 Robert G. Phelps, MD2

A 73-year-old Hispanic woman presented to the clinic with an erythematous, friable 3.0 cm × 2.7 cm × 0.7 cm mass located on the posterior vertex of the scalp (Figure 1). The lesion had been present since birth but had recently begun to bleed intermittently, prompting evaluation. A biopsy was obtained, revealing a tumor with irregular, complex papillomatous invaginations lined by a two-layered epithelium. Atypical and crowded columnar cells lined the luminal aspect, while cuboidal cells lined the epithelium adjacent to the stroma (Figure 2). Decapitation secretion was noted in several areas on the luminal surface. (SKINmed. 2018;16:195–197)

he epithelial cells showed marked nuclear and cellular atypia, loss of polarity, pleomorphism, and multiple mitotic figures (Figure 3). The atypia was confined mainly to the lining of the papillae. Pagetoid spread of neoplastic cells and geographic necrosis were not present. Areas of adjacent benign-appearing papillary projections were also present within the tumor (Figure 4). A diffuse and brisk plasmacytic and lymphocytic infiltrate was present within the stroma of the papillae. The tumor extended to all margins of the biopsy. Based on the histopathologic features, the diagnosis of in situ syringocystadenocarcinoma papilliferum (SCACP) was made. The tumor was completely excised with no subsequent disease recurrence.

cases have been identified. There does not appear to be a clear sex predilection among cases. The age of presentation has ranged from 46 to 86 years old, with the majority of patients presenting in the seventh decade of life. The head and neck region, especially the scalp, has been the most common site of occurrence, as was seen in our case; however, other sites of occurrence have been documented, such as the upper and lower extremities, 2 suprapubic area, 3 auricle, 4 penis, 5 axilla, 6 eyelid,7 and perianal region. 8 The size of reported lesions has been variable, ranging from 1.5 to 13 cm.

DISCUSSION

It is thought that the majority of SCACP lesions arise from its benign counterpart, syringocystadenoma papilliferum. Many cases report SCACP arising from a preexisting long-standing lesion that had suddenly changed in appearance and behavior; however, there have been isolated reports of the abrupt onset of an initial lesion.9 When viewed histologically, a good number of SCACP cases also displayed a benign component among the malignant tumor, as our case demonstrated, which provides credence to the notion that these tumors may arise from preexisting syringocystadenoma papilliferum. Several reports have also shown an association with nevus sebaceous. Of note, Hoekzema et al reported a case of SCACP arising within a linear nevus verrucosus.10

SCACP is a very rare malignant sweat gland tumor, first described in 1980. 1 After review of the literature, 24 previous

Histopathologically, SCACP shares many histopathologic charac teristics with syringocystadenoma papilliferum, differentiated by

Immunohistochemical studies revealed an α-smooth muscle actin— positive stroma. Pankeratin staining was also positive, with less intense staining occurring within the inner cell layer. Cytokeratin-7 staining showed similar changes to those of pankeratin staining, indicating the presence of squamous and adnexal differentiation. Epithelial membrane antigen stain was focally positive, primarily on the luminal surface, confirming the presence of glandular elements. Staining for p63 was positive only along the basal layer.

From the Department of Dermatopathology, Mount Sinai Medical Center, New York, NY;1 and Sidney Kimmel Medical College at, Thomas Jefferson University, Philadelphia, PA2 Address for Correspondence: Jonathan L. Yao, MD, Department of Dermatopathology, Annenberg Building, 3rd Floor, Dermatopathology Suite Rooms 3-08 through 3-14, Mount Sinai Medical Center, New York, NY 10029 • E-mail: Jonathan.Yao@mountsinai.org

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Figure 1. A 3.0 x 2.7 x 0.7 cm flesh-colored warty indurated plaque with well-defined borders.

Figure 3. Atypical and crowded columnar cells revealing hyperchromatic nuclei and pleomorphism. The atypical cells additionally are crowded and the normal bilayer architecture is lost.

Figure 2. Complex papillary projections of the tumor with fibrovascular core. Numerous plasma cells are also noted within the fibrovascular core. The luminal cells are atypical, showing hyperchromasia and pleomorphism.

Figure 4. Adjacent to the malignant adenocarcinoma component there is retained benign syringocystadenoma papilliferum.

nuclear and cellular atypia, loss of polarity, and abnormal mitotic figures. The malignancy may be either invasive or in situ. A twolayered epithelium consisting of columnar cells lining the luminal aspect and cuboidal cells adjacent to the stroma is appreciated in both conditions. The presence of decapitation secretion provides evidence of underlying apocrine differentiation. An abundance of lymphocytes and plasma cells is often seen within papillae. Pagetoid spread of neoplastic cells has been reported in a minority SKINmed. 2018;16:195â&#x20AC;&#x201C;197

of cases.11 Concomitant squamous cell carcinoma has also been reported in a few cases.2 The histopathologic differential diagnosis includes cutaneous metastases of gastrointestinal, breast, and thyroid cancer, as well as hidradenoma papilliferum.4 There is no specific immunohistochemisty profile for the diagnosis of SCACP. Certain markers may be of use when considering SCACP in the

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differential diagnosis. SCACP is often positive for cytokeratin, carcinoembryonic antigen, human milk fat globules-2, gross cystic disease fluid protein-15, epithelial membrane antigen, and p63.8 One case of SCACP on the penis tested positive for human papillomavirus, although more investigation is required to determine if any relationship exists between human papillomavirus and SCACP.5 The prognosis of SCACP is favorable, with only three reported cases demonstrating regional lymphatic metastases.12 When concomitant invasive squamous cell carcinoma is present, risk for local metastasis may be increased.13 No confirmed cases of extensive disseminated metastases have been reported. Treatment of SCACP consists of surgical removal of the tumor. In one case, Mohs micrographic surgery was shown to be an effective treatment.4 Utility of sentinel lymph node biopsy has not been established, although some authors have recommended the procedure when there is suspicion of local spread, such as in the presence of overt lymphadenopathy.12 CONCLUSIONS SCACP is an exceedingly rare tumor and is believed to arise from long-standing nevus sebaceous. Its benign counterpart is syringocystadenoma papilliferum, and the diagnosis of the malignant form is based on cytological atypia, abnormal mitotic figures, and loss of polarity. REFERENCES 1 Dissanayake RV, Salm R. Sweat-gland carcinomas: Prognosis related to histological type. Histopathology. 1980;4:445–466. 2 Sroa N, Zirwas M. Syringocystadenocarcinoma papilliferum. Dermatol Surg. 2010;36:261–263.

3 Park SH, Shin YM, Shin DH, Choi JS, Kim KH. Syringocystadenocarcinoma papilliferum: A case report. J Korean Med Sci. 2007;22:762–765. 4 Chi CC, Tsai RY, Wang SH. Syringocystadenocarcinoma papilliferum: Successfully treated with Mohs micrographic surgery. Dermatol Surg. 2004;30:468–471. 5 Plant MA, Sade S, Hong C, Ghazarian DM. Syringocystadenocarcinoma papilliferum in situ of the penis. Eur J Dermatol. 2012;22:405–406. 6 Abrari A, Mukherjee U. Syringocystadenocarcinoma papilliferum at unusual site: Inherent lesional histologic polymorphism is the pathognomon. BMJ Case Rep. 2011 June 30. doi: 10.1136/ bcr.05.2011.4254. 7 Hoguet AS, Dolphin K, McCormick SA, Milman T. Syringocystadenocarcinoma papilliferum of the eyelid. Ophthal Plast Reconstr Surg. 2012;28:e27–e29. 8 Ishida-Yamamoto A, Sato K, Wada T, Takahashi H, Iizuka H. Syringocystadenocarcinoma papilliferum: Case report and immunohistochemical comparison with its benign counterpart. J Am Acad Dermatol. 2001; 45:755–759. 9 Leeborg N, Thompson M, Rossmiller S, et al. Diagnostic pitfalls in syringocystadenocarcinoma papilliferum: Case report and review of the literature. Arch Pathol Lab Med. 2010;134:1205– 1209. 10 Hoekzema R, Leenarts MF, Nijhuis EW. Syringocystadenocarcinoma papilliferum in a linear nevus verrucosus. J Cutan Pathol. 2011;38:246–250. 11 Kazakov DV, Requena L, Kutzner H, et al. Morphologic diversity of syringocystadenocarcinoma papilliferum based on a clinicopathologic study of 6 cases and review of the literature. Am J Dermatopathol. 2010;32:340–347. 12 Aydin OE, Sahin B, Ozkan HS, Gore O. A rare tumor: Syringocystadenocarcinoma papilliferum. Dermatol Surg. 2011;37:271–274. 13 Arslan H, Diyarbakrl M, Batur S, Demirkesen C. Syringocystadenocarcinoma papilliferum with squamous cell carcinoma differentiation and with locoregional metastasis. J Craniofac Surg. 2013;24:e38–e40.

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May/June 2018

Volume 16 • Issue 3

CASE STUDY

Reticular Telangiectatic Erythema: A Chronic Hematoma Subsequent to Hip Replacement as an Underlying Cause Sarah M. Beggs, MD;1 Kathleen P. McGuinn, MD;1 Anthony F. Santoro, MD;1 Levon N. Nazarian, MD;2 Jason B. Lee, MD1

A 78-year-old woman with a history of bilateral hip replacements presented with an ill-defined erythematous plaque with foci of reticulated and indurated areas on the left thigh. Initially, a few weeks after her surgery, a small area of erythema appeared overlying the incision site. Over a 6-month period, the erythema slowly expanded before stabilizing in size (Figure 1). There was no pruritus, pain, or warmth. Orthopedic evaluation found no evidence of infection or malfunction of the hip prosthesis. A skin biopsy revealed telangiectasia of the superficial vessels. Based on the clinical and histopathologic findings, a diagnosis of reticular telangiectatic erythema (RTE) was established. An ultrasound scan revealed a greater trochanteric bursa distended by a chronic, organized hematoma measuring 12 cm at greatest dimension, secondary to a full-thickness tear of the left gluteus minimus (Figure 2), establishing the underlying cause of the RTE in this patient. (SKINmed. 2018;16:199–200)

TE is a rare cutaneous reaction pattern reported to occur in the skin overlying implanted devices. Cardiac devices, such as pacemakers and defibrillators, are most frequently associated with RTE. Intrathecal infusion pumps, spinal cord stimulators, orthopedic joint prostheses, and suture material have also been reported as an underlying cause.1–6 Clinically, RTE presents as an asymptomatic, erythematous, reticulated, and blanchable patch, usually overlying a surgical scar. The onset of RTE from device implantation is highly variable and ranges from days to years.1,4 The diagnosis of RTE can be made by correlation of the physical examination and, most importantly, the patient’s history of previous surgery to the area involving an implantable device. A skin biopsy is frequently performed due to the rarity, lack of awareness, and desire to rule out other entities. Histopathology is nonspecific and usually shows increase telangiectasias.1,4

The differential diagnosis of RTE includes morphea, cellulitis, and allergic contact dermatitis.1,4 Morphea can be ruled out by

skin biopsy. Infectious etiologies are the most important to consider and can usually be excluded clinically. There may be concern for an allergic contact dermatitis to the underlying device; however, patch testing reportedly fails to produce a relevant antigen.4,5 The pathogenesis of RTE is not fully understood. A few mechanisms have been proposed: mechanical obstruction of venous flow, heat, and electric or magnetic fields.1–3,5 The most accepted theory is that a foreign body causes a mechanical obstruction or change in the vasculature leading to the development of telangiectasias. Providing support for this theory are case reports of RTE resolving after removal or repositioning of the underlying device.2,4,5 The case above represents the development of RTE precipitated by a hematoma secondary to a tear of the gluteal minimus. Although hematomas have not been described in the literature as a cause of RTE, none of the reported cases included imaging modalities that would exclude this entity. The development of a hematoma, especially one of an extensive size as seen in our case,

From the Department of Dermatology and Cutaneous Biology,1 and the Department of Radiology,2 Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA Address for Correspondence: Jason Lee, MD, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College at Thomas Jefferson University, 833 Chestnut St, Suite #740, Philadelphia, PA 19107 • E-mail: Jason.Lee@jefferson.edu

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CASE STUDY can theoretically lead to mechanical obstruction of venous flow causing changes in the microcirculatory environment. RTE is a benign condition. There are cases of spontaneous resolution of RTE, as well as cases where RTE remains unchanged for years.4 Removal or repositioning of the causative agent may lead to resolution of RTE, but this is unnecessary unless there is another clinical indication. The patient reported here was monitored clinically, as the hematoma was organized and not likely to expand. CONCLUSIONS When considering the diagnosis of RTE, the practitioner should consider sonography to evaluate for hematoma formation or other underlying pathology of the surgical site. REFERENCES 1 Beutler BD, Cohen PR. Reticular telangiectatic erythema: Case report and literature review. Dermatol Pract Concept. 2015;5:71–75.

Figure 1. Erythematous indurated plaque overlying a left hip replacement site.

2 Kint A, Vermander F. Reticular telangiectatic erythema after implantation of a pacemaker. Dermatologica. 1983;166:322– 324. 3 Inzinger M, Tilz H, Komericki P, et al. Heat-triggered reticular telangiectatic erythema induced by a spinal cord stimulator. Mayo Clin Proc. 2013;88:117–119. 4 Aneja S, Taylor JS, Billings SD, Honari G, Sood A. Post-implantation erythema in 3 patients and a review of reticular telangiectatic erythema. Contact Dermatitis. 2011;64:280–288. 5 Mercader-García P, Torrijos-Aguilar A, de La Cuadra-Oyanguren J, Vilata-Corell JJ, Fortea-Baixauli JM. Telangiectatic reticular erythema unrelated to cardiac devices. Arch Dermatol. 2005;141:106–107.

Figure 2. Ultrasound imaging shows a greater trochanteric bursa distended by a chronic, organized hematoma measuring 12 cm at greatest dimension secondary to a full-thickness tear of left gluteus minimus.

6 Armengot-Carbo M, Sabater V, Botella-Estrada R. Reticular telangiectatic erythema: A reactive clinicopathological entity related to the presence of foreign body. J Eur Acad Dermatol Venereol. 2016;30:194–195.

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Edward L. Keyes Resident Contest for Outstanding Case Reports 14th World Congress of the International Academy of Cosmetic Dermatology Lima, Peru, March 28 – 30, 2019 Abstract deadline: December 31, 2018 To be awarded for the best Case Report submitted by a physician in training (resident, fellow, or registrar) for presentation at the 14th World Congress of the International Academy of Cosmetic Dermatology in Lima, Peru from March 28 – 30, 2019. We invite you to submit original Case Reports that reflect the presentation of new ideas and original observations to the Academy membership and other attendees of the Congress. The case may be medical, surgical, and cosmetic (or combined) in nature. The author whose abstract receives the highest score during the review process will receive a scholarship by the IACD to present the full paper at the 14th World Congress of the International Academy of Cosmetic Dermatology in Lima, Peru, March 28–30, 2019. The scholarship will provide reasonable travel expenses, lodging for 3 nights, the Congress registration fee, and a basic spending stipend.

Please submit your case report abstract via email to VPRosic@ChicagoBooth.edu before noon, CDT, December 31, 2018. The abstract should be no longer than 2,500 characters including spacing. Material that was previously presented, published, or submitted for publication should not be offered. Applications will be graded based upon the educational value of the abstract and the extent to which it presents new and significant work. The Review Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will be eligible if it has already been, or is in consideration for publication elsewhere at any time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in SKINmed: Dermatology for the Clinician, an official publication of the International Academy of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed: Dermatology for the Clinician first-rights of refusal for publication through December 31, 2019. 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 January 31, 2019. Vesna Petronic-Rosic, MD, MSc, MBA Chair, Resident Contest Committee Professor and Chair Georgetown University MedStar Washington Hospital Center Department of Dermatology Tel: +1(302) 455-7546 VPRosic@ChicagoBooth.edu

May/June 2018

Volume 16 • Issue 3

CASE STUDY

Bullous Fixed Drug Eruption Caused by Doxycycline Anissa Zaouak, MD;1 Takoua Bacha, MD;1 Meriem Jrad, MD;1 Raja Jouini, MD;2 Meriem Belhaj Salah, MD;2 Rym Sahnoun, MD;3 Houda Hammami, MD;1 Samy Fenniche, MD1

A 50-year-old woman presented to our dermatology clinic with pruritic lesions on her hands that had appeared 24 hours earlier. The clinical manifestations had started 24 hours after taking 100 mg of doxycycline for acute bronchitis. She had no history of allergic disease or allergic reactions to drugs. The dermatologic examination revealed multiple erythematous, purplish annular patches with overlying bullae with hemorrhagic content on both palms (Figure 1). The patient had no fever, and the rest of the physical examination did not reveal any abnormalities. Results of laboratory tests were within normal limits. A skin biopsy was performed, showing hydrophic degenerations of the basal membrane, a superficial perivascular infiltrate consisting of lymphocytes and eosinophils, and red blood cells in the dermis (Figure 2). A pharmacovigilance investigation was conducted, and doxycycline was confirmed as the agent responsible for the bullous fixed drug eruption (FDE) in our patient. (SKINmed. 2018;16:202–203)

ral steroids were prescribed for 5 days. The patient’s lesions resolved after 10 days, leaving residual hyperpigmentation. After 8 weeks, a patch test was performed using 10% of doxycycline in petrolatum applied in Finn chambers to lesional and nonlesional skin. Patch test reactions were read at 48 and 96 hours after application and graded according to the International Contact Dermatitis Research Group’s scoring system; they were strongly positive only in lesional skin. Hence, the patient was advised to avoid taking doxycycline in the future. Doxycycline is a synthetic, long-acting, broad-spectrum antimicrobial drug that is commonly prescribed to treat respiratory tract infections such as pneumonia and bronchitis, rickettsial infections, skin infections, and sexually transmitted infections, and for prophylaxis of malaria. The most common adverse effects of doxycycline are phototoxicity, skin eruptions, abdominal pain, diarrhea, nausea, and discoloration of the teeth.1

FDE due to doxycycline is an uncommon adverse effect that has been reported only in isolated cases, mostly as cross-reactivity between tetracycline and minocycline.2,3 In our patient, there was no history of previously use of either of these two drugs.

Figure 1. Two ill-defined violaceous plaques with overlying tense bullae, located on the palms.

The implication of doxycycline in the genesis of this bullous fixed drug eruption was confirmed with an intrinsic imputation score calculated as I3, meaning a likely relationship in the face of a suggestive delay of occurrence of an FDE, regression of erythema

From the Department of Dermatology,1 and Department of Anatomopathology,2 Habib Thameur Hospital; and the National Center of Pharmacovigilance,3 Tunis, Tunisia Address for Correspondence: Anissa Zaouak, MD, 8 Street Ali Ben Ayed, Montfleury 1008, Tunis, Tunisia • E-mail: anissa_zaouak@yahoo.fr

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CASE STUDY by the drug tested, as noted in our patient, although a negative test does not exclude this.5 In our patient, use of the Naranjo Adverse Drug Reaction Probability Scale6 also indicated a probable relationship (Naranjo score=8) between the bullous FDE and doxycycline therapy. The skin biopsy done in our patient was also useful for the diagnosis of FDE; histological examination usually shows hydrophic degeneration of the basal membrane, necrotic keratinocytes in the epidermis, and a superficial perivascular lymphocytic infiltrate in the dermis.1,2 CONCLUSIONS Doxycycline is a commonly prescribed antibiotic that is infrequently responsible for FDE. This case illustrates an uncommon adverse effect of this drug, which reminds us that it should be prescribed carefully. REFERENCES 1 Podder I, Chandra S, Das A, Gharami RC. Doxycycline induced generalized bullous fixed drug eruption. Indian J Dermatol. 2016;61:128. 2 Nitya S, Deepa K, Mangaiarkkarasi A, Karthikeyan K. Doxycycline induced generalized bullous fixed drug eruption – A case report. J Young Pharm. 2013;5:195–196.

Figure 2. Presence of a subepidermal bullae containing fibrinous material with few eosinophils. Necrotic keratinocytes in the epidermis in association with hydrophic degenerations of the basal membrane. The superficial dermal and perivascular inflammatory infiltrate is composed of lymphocytes and eosinophils (hematoxylin and eosin stain, magnification x40).

3 Walfish AE, Sapadin AN. Fixed drug eruption due to doxycycline and metronidazole. Cutis. 2002;69:207–208. 4 Miremont-Salamé G, Théophile H, Haramburu F, Bégaud B. Causality assessment in pharmacovigilance: The French method and its successive updates. Therapie. 2016;71:179–186.

after drug withdrawal, the suggestive semiology typical of an FDE, and a positive patch test to doxycycline.4 It is important to stress that a positive patch test reaction involving the lesional skin site is considered to be a strong argument that the FDE is caused

5 Shiohara T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316–321. 6 Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.

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May/June 2018

Volume 16 • Issue 3

CASE STUDY

A 6-month-old, 4-kg, dehydrated girl, an Indian native, was admitted with recurrent episodes of diarrhea that had occurred since age 2 months. She had stopped breastfeeding. She had also had concomitant vomiting and loss of appetite. Later, the mother noticed progressively increasing erythematous eruptions around the anogenital and the oral region. The baby had been born to a short-stature mother and was delivered by lower segment cesarean section. Regular antenatal follow-up was normal. (SKINmed. 2018;16:205–207)

xamination of the skin surface showed erythematous macules and/or plaques of dry, scaly skin. A few of these were eczematous, crusted vesicles and pustules. They were multiple, distributed around the mouth (Figure 1) and anogenital region (Figure 2), and also affected the hands, feet, and scalp. Suppurative inflammation of the nail fold surrounding the nail plate—paronychia—was a prominent feature. Loss of hair (alopecia) from the scalp, eyebrows, and eyelashes was an associated feature.

The total leukocyte count was 150–400 x 109/L and a differential leukocyte count revealed 25% neutrophils, 70% lymphocytes, 1% eosinophils, 4% monocytes, and no basophils. The platelet count was 310000 x 109/L. Erythrocyte sedimentation rate was 31 mm in the first hour (Westergren method). Serum values were as follows: blood urea nitrogen 13.6 mg/dL, ionized calcium 1.18 mmol/L (normal range, 1.12 to 1.32 mmol/L), total calcium 2.2 to 2.7 mmol/L, creatinine 0.15 mg/dL (normal

range, 0.5 to 0.9 mg/dL), C-reactive protein 11.9 mg/L (normal, <3.0 mg/L), sodium 133 mmol/L (normal range, 135 to 145 mmol/L), potassium 4.0 mmol/L (normal range, 3.5 to 5.5 mmol/l), and zinc 54.54 µg/dL (normal range, 70 to 120 µg/dL). A single blood culture (BactecTM , Becton, Dickinson and Company, Franklin Lakes, NJ; whole blood) did not show any growth after 5 days of incubation. Ultrasonography examination of the whole abdomen did not reveal any abnormality, and radiography of the chest was normal. A Mantoux/tuberculin skin test measured <10 mm. Hematoxylin and eosin–stained sections prepared from the representative skin biopsy showed denuded epithelium lying separately from the other skin layers in fragmented fashion. The epidermis showed parakeratosis with neutrophilic abscesses. Hypogranulosis and atrophy of the epidermis was apparent. The dermis showed a mild mononuclear perivascular inflammatory infiltrate (Figure 3).

From the the Dermato-Venereology (Skin/VD) Center, Sehgal Nursing Home, Panchwati-Delhi, India1 the Department of Dermatology and STD2 and the Department of Pathology3, University College of Medical Sciences, and Associated Guru Teg Bahadur Hospital, Shahdara, Delhi, India Address for Correspondence: Virendra N. Sehgal MD, FNASc, FAMS, FRAS (Lond), Dermato-Venerology (Skin/VD) Center, Sehgal Nursing Home, A/6 Panchwati, Delhi-110 033, India • E-mail: drsehgal@ndf.vsnl.net.in

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Figure 1. Erythematovesicular scaly lesions around the mouth. A

Figure 2. Depicting scaly, erythematous well-defined macules and/or plaques, a few showing eczematous change, affecting the anogenital region.

The baby was given fluids by slow intravenous infusion. These comprised Nirdex-45 (Baxter Healthcare Corporation, Deerfield, IL) (N/2) 500 mL each, 100 mL of which contained sodium chloride 0.45% plus dextrose 5% anhydrous injection, at a dose of 100 ml 2-hourly, along with Nirlyte-P (Aculife Healthcare Pvt. Ltd. Sachana, Gujrat, India) 500 mL, a preparation containing multiple electrolytes and dextrose, at a dose of 100 mL 4-hourly. Each 100 mL of Nirlyte-P contained anhydrous dextrose Indian pharmacopoeia (IP) 5 g, potassium chloride IP 0.13 g, sodium acetate IP 0.32 g, diabasic potassium phosphate USP 0.026 g, magnesium chloride IP 0.031 g, electrolytes (in mmol/500 mL: sodium11.5, potassium 10, magnesium 0.75, chloride 10, acetate 11.5, phosphate 0.75, Kcl/L-170, mOsmol/L-367). In addition, vancomycin hydrochloride USP (available as injections of vancomycin 500 mg) was given. An injection of Arachitol (Abbott; vitamin D3; cholecalciferol IP 3,00000 IU) was given in a dose of 10 mg/kg slow intravenous infusion 6-hourly, intramuscularly, and an injection of Neurobion (Merck Pharma; vitamin B1 10 mg, vitamin B6 2 mg, and vitamin B12 300 μg) was given in the dose of 1 ml intramuscularly. Z&D-20 (elemental zinc, 20 mg/5 mL) SKINmed. 2018;16:205–207

Figure 3. (A) Section showing exposed dermis with a mild mononuclear inflammatory infiltrate in upper dermis (hematoxylin and eosin stain, magnification ×100). (B) Strips of pale denuded epidermis, with parakeratosis and neutrophils (hematoxylin and eosin stain, magnification ×400).

dry syrup was given in a dose of 0.5 mL four times a day. Other medications given included Ondem (Alkem; ondestron) syrup (2 mg/5 mL three times a day to control vomiting), Enterogermina oral suspension (Torrent Pharmaceuticals Ltd.; Bacillus clausil spores, 2 billion/5 mL; one vial three times a day), and the topical immunomodulator tacrolimus (0.03%). DISCUSSION Acrodermatitis enteropathica is a well-known entity of early infancy heralded by incessant diarrhea, vomiting, and anorexia, the salient prelude to its early diagnosis. The infant is reluctant to breastfeed. The progressive nature of the disease may prompt inquisitive parents to seek medical advice from a pediatrician, who may take appropriate measures to treat only the diarrhea.

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Ultimately, the infant may develop the cardinal cutaneous features, characterized by erythematous macules and/or plaques of dry, scaly skin. The lesions are eczematous, studded with crusted vesicles, bullae, or pustules, and classically distributed around the mouth and in the anogenital region. However, in older children, failure to thrive, anorexia, alopecia, paronychia/nail dystrophy, and repeated infections are frequent.1–3 Prompt diagnosis and early treatment is, therefore, warranted to check the possible progression of the life-threatening disease.

titis enteropathica. The salient features are erythematous macules and/or plaques of dry, scaly skin, acral dermatitis, and alopecia. The anogenital and perioral regions are predominantly affected. Acrodermatitis enteropathica is an inborn error of zinc metabolism, inherited as an autosomal recessive trait. Thorough investigations and treatment are paramount to manage the condition successfully. REFERENCES

A fresh case of the disease is being reported here in early infancy, highlighting the investigative path and step-by-step management strategy, with the aim of serum electrolyte replenishment coupled with administration of elemental zinc. Subsequently, the latter may have to be administered as a maintenance therapy. Acrodermatitis enteropathica is an inborn error of zinc metabolism that is inherited as an autosomal recessive disorder. A mutation of the SLC39A4 gene on chromosome 8q24.3 seems to be responsible for the disorder.4–6 This gene encodes a transmembrane protein that acts as a zinc uptake protein, resulting in zinc deficiency in infants weaned from breast milk; this has led to speculation that human milk contains a substance that helps promote the uptake of zinc.7,8 CONCLUSIONS Recurrent/incessant diarrhea, vomiting, anorexia, and reluctance to breast feed in an infant should arouse suspicion of acroderma-

1 Azemi M, Berisha M, Kolgeci S, et al. Acrodermatitis enteropathica. Med Arh. 2012;66:137–139. 2 Sehgal VN, Jain S. Acrodermatitis enteropathica. Clin Dermatol. 2000;18:745–748. 3 Kumar S, Sehgal VN, Sharma RC. Acrodermatitis enteropathica. J Dermatol. 1997;24:135–136. 4 Küry S, Dréno B, Bézieau S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet. 2002;31:239–240. 5 Michalczyk A, Varigos G, Catto-Smith A, et al. Analysis of zinc transporter, hZnT4 (Slc30A4), gene expression in a mammary gland disorder leading to reduced zinc secretion into milk. Hum Genet. 2003;113:202–210. 6 Santiago F, Matos J, Moreno A, et al. Acrodermatitis enteropathica: A novel SLC39A4 gene mutation found in a patient with an early-onset. Pediatr Dermatol. 2011;28:235–236. 7 Coromilas A, Brandling-Benett H, Morel K, et al. Novel SLC39A4 mutation in acrodermatitis enteropathica. Pediatr Dermatol. 2011;28:697–700. 8 Gehrig K, Dinulos J. Acrodermatitis due to nutritional deficiency. Curr Opin Pediatr. 2010;22:107–112.

“Vaccine.”, Moulage No. 43, made in the Clinic for Dermatology Zurich. Museum of Wax Moulages Zurich, www.moulagen.ch Courtesy of Michael Geiges, MD

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Botulinum Toxins:

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masseter hypertrophy

Levulan® Kerastick® (aminolevulinic acid HCl) for Topical Solution, 20% Initial U.S. approval: 1999

INDICATIONS AND USAGE The LEVULAN KERASTICK for Topical Solution, a porphyrin precursor, plus blue light illumination using the BLU-U® Blue Light Photodynamic Therapy Illuminator is indicated for the treatment of minimally to moderately thick actinic keratoses of the face or scalp. CONTRAINDICATIONS The LEVULAN KERASTICK for Topical Solution plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is contraindicated in patients with cutaneous photosensitivity at wavelengths of 400-450 nm, porphyria or known allergies to porphyrins, and in patients with known sensitivity to any of the components of the LEVULAN KERASTICK for Topical Solution. WARNINGS AND PRECAUTIONS Photosensitivity During the time period between the application of LEVULAN KERASTICK Topical Solution and exposure to activating light from the BLU-U Blue Light Photodynamic Therapy Illuminator, the treatment site will become photosensitive. After LEVULAN KERASTICK Topical Solution application, patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to blue light treatment. Exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread the LEVULAN KERASTICK Topical Solution outside the treatment site to eye or surrounding skin. Application of LEVULAN KERASTICK Topical Solution to perilesional areas of photodamaged skin of the face or scalp may result in photosensitization. Upon exposure to activating light from the BLU-U Blue Light Photodynamic Therapy Illuminator, such photosensitized skin may produce a stinging and/or burning sensation and may become erythematous and/or edematous in a manner similar to that of actinic keratoses treated with LEVULAN KERASTICK Photodynamic Therapy. Because of the potential for skin to become photosensitized, the LEVULAN KERASTICK should be used by a qualified health professional to apply drug only to actinic keratoses and not perilesional skin. If for any reason the patient cannot return for blue light treatment during the prescribed period after application of LEVULAN KERASTICK Topical Solution (14 to 18 hours), the patient should call the doctor. The patient should also continue to avoid exposure of the photosensitized lesions to sunlight or prolonged or intense light for at least 40 hours. If stinging and/or burning is noted, exposure to light should be reduced. Irritation The LEVULAN KERASTICK Topical Solution contains alcohol and is intended for topical use only. Do not apply to the eyes or to mucous membranes. Excessive irritation may be experienced if this product is applied under occlusion. Coagulation Defects The LEVULAN KERASTICK for Topical Solution has not been tested on patients with inherited or acquired coagulation defects. ADVERSE REACTIONS In Phase 3 studies, no non-cutaneous adverse events were found to be consistently associated with LEVULAN KERASTICK Topical Solution application followed by blue light exposure. Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning, itching, erythema and edema as a result of LEVULAN KERASTICK Topical Solution plus BLU-U treatment was observed in all clinical studies of LEVULAN KERASTICK for Topical Solution Photodynamic Therapy for actinic

keratoses treatment. Stinging and/or burning subsided between 1 minute and 24 hours after the BLU-U Blue Light Photodynamic Therapy Illuminator was turned off, and appeared qualitatively similar to that perceived by patients with erythropoietic protoporphyria upon exposure to sunlight. There was no clear drug dose or light dose dependent change in the incidence or severity of stinging and/or burning. In two Phase 3 trials, the sensation of stinging and/or burning appeared to reach a plateau at 6 minutes into the treatment. Severe stinging and/or burning at one or more lesions being treated was reported by at least 50% of the patients at some time during treatment. The majority of patients reported that all lesions treated exhibited at least slight stinging and/or burning. Less than 3% of patients discontinued light treatment due to stinging and/or burning. In the Phase 3 trials, the most common changes in lesion appearance after LEVULAN KERASTICK for Topical Solution Photodynamic Therapy were erythema and edema. In 99% of active treatment patients, some or all lesions were erythematous shortly after treatment, while in 79% of vehicle treatment patients, some or all lesions were erythematous. In 35% of active treatment patients, some or all lesions were edematous, while no vehicle-treated patients had edematous lesions. Both erythema and edema resolved to baseline or improved by 4 weeks after therapy. LEVULAN KERASTICK Topical Solution application to photodamaged perilesional skin resulted in photosensitization of photodamaged skin and in a photodynamic response (see Warnings and Precautions). Other Localized Cutaneous Adverse Experiences: Table 1 depicts the incidence and severity of cutaneous adverse events in Phase 3 studies, stratified by anatomic site treated.

•

After LEVULAN KERASTICK Topical Solution is applied to the actinic keratoses in the doctor’s office, the patient will be told to return the next day. During this time the actinic keratoses will become sensitive to light (photosensitive). Care should be taken to keep the treated actinic keratoses dry and out of bright light. After LEVULAN KERASTICK Topical Solution is applied, it is important for the patient to wear light-protective clothing, such as a wide-brimmed hat, when exposed to sunlight or sources of light.

•

Fourteen to eighteen hours after application of LEVULAN KERASTICK Topical Solution the patient will return to the doctor’s office to receive blue light treatment, which is the second and final step in the treatment. Prior to blue light treatment, the actinic keratoses will be rinsed with tap water. The patient will be given goggles to wear as eye protection during the blue light treatment.

•

The blue light is of low intensity and will not heat the skin. However, during the light treatment, which lasts for approximately 17 minutes, the patient will experience sensations of tingling, stinging, prickling or burning of the treated lesions. These feelings of discomfort should improve at the end of the light treatment.

•

Following treatment, the actinic keratoses and, to some degree, the surrounding skin, will redden, and swelling and scaling may also occur. However, these lesion changes are temporary and should completely resolve by 4 weeks after treatment.

LEVULAN, KERASTICK, BLU-U and DUSA are registered trademarks of DUSA Pharmaceuticals, Inc., a Sun Pharma company. Sun Dermatology is a division of Sun Pharmaceutical Industries, Inc. © 2016 Sun Pharmaceutical Industries, Inc. All rights reserved. US

Patents: 5,954,703,

Manufactured for: DUSA Pharmaceuticals, Inc.® 25 Upton Drive, Wilmington, MA 01887 For more information please contact: 1-877-533-3872 or 1-978-657-7500 www.dusapharma.com Adverse Experiences Reported by Body System: In the Phase 3 studies, 7 patients experienced a serious adverse event. All were deemed remotely or not related to treatment. No clinically significant patterns of clinical laboratory changes were observed for standard serum chemical or hematologic parameters in any of the controlled clinical trials. OVERDOSAGE LEVULAN KERASTICK Topical Solution Overdose LEVULAN KERASTICK Topical Solution overdose has not been reported. In the unlikely event that the drug is ingested, monitoring and supportive care are recommended. The patient should be advised to avoid incidental exposure to intense light sources for at least 40 hours after ingestion. The consequences of exceeding the recommended topical dosage are unknown. BLU-U Light Overdose There is no information on overdose of blue light from the BLU-U Blue Light Photodynamic Therapy Illuminator following LEVULAN KERASTICK Topical Solution application. Information for Patients: LEVULAN KERASTICK Photodynamic Therapy for Actinic Keratoses. •

The first step in LEVULAN KERASTICK Photodynamic Therapy (PDT) for actinic keratoses is application of the LEVULAN KERASTICK Topical Solution to actinic keratoses located on the patient’s face or scalp.

LAB-1442AW Rev D

REDISCOVER

FOR MORE INFORMATION CONTACT US AT (877) 533-DUSA Please see full prescribing information on adjacent page. LEVULAN, KERASTICK, BLU-U and DUSA are registered trademarks of DUSA Pharmaceuticals, Inc., a Sun Pharma company. Â©2016 DUSA Pharmaceuticals, Inc. All rights reserved.

MKT-1790AW Rev C