A DE RMATOL OGY FO UNDA TION PUBLICAT IO N

VOL. 34 NO. 3 SPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC FALL 2015 DERMATOLOGYDERMATOLOGY ™ FOCUS Also In This Issue FOCUS Young Leaders Give Back Dr. Thomas Darling Leads Atopic Dermatitis: Medical & Scientific Committee Annenberg Circle Welcomes Demystifying a Complex New and Sustaining Members Inflammatory Disease

ntil Emma Guttman(-Yassky), MD, PhD, treatments have not yet reached the ap - U dedicated herself to a high-intensity, proval stage, the robust pace and progress Focus on Research focused exploration of atopic dermatitis of her research will be altering clinical prac - Reversing Skin Aging: Endurance (AD) (see box on page 6)—the most com - tice in the very near future. Exercise’s Unexpected Benefit— mon inflammatory skin disease world - In this process of transforming the AD and How Rejuvenated wide—roughly 10 years ago, it had remained landscape, Guttman has firmly established it Mitochondria Make This Happen poorly understood. And treatments, espe - as an immunologically based disease that cially for moderate-to-severe disease, were only secondarily damages the barrier, dis - Mark A. Tarnopolsky, MD, PhD, FRCPC too often inadequate and/or carried con - placing the previously dominant view that Professor, Division of Neuromuscular and cerning side effects. genetic defects in the barrier protein filag - Neurometabolic Disease, Department of Pediatrics; McMaster University, Hamilton, Ontario In this short time, Guttman has suc - grin comprise the pathogenic root, creating ceeded in bringing a paradigm-changing barrier dysfunction that then leads to in - kin had not been clarity to the molecular underpinnings and flammatory damage. At the very start, she S on Tarnopolsky’s pathogenic fundamentals of this highly identified the Th22 T cell that exists uniquely investigative radar until challenging skin disease. Although new in humans. Guttman has been revealing the an astonishing and complexities and subtypes completely unanti- within AD as she has uncov - cipated observation ered the important immuno - roughly five years ago logic differences between opened his eyes to a lesional and nonlesional skin, potent antiaging effect acute and chronic lesions, pe - of endurance exercise diatric and adult lesions, and on murine hair and skin. Western and Asian disease. All At the time, this metabolic genetic neu - of this will translate to accu - rological specialist—who cares for patients rately targeted treatments. with mitochondrial disease and other ge - One in particular—dupilumab, netic disorders—had a long-standing interest which inhibits the Th2 cy - in understanding impaired and healthy tokines IL-4 and IL-13—is in skeletal muscle and developing therapeutic its final data-gathering stages. interventions for patients with muscle-im - Another, the first anti-IL-22 pairing diseases. He had found exercise to monoclonal antibody, is com - be an important modality in this regard. pleting a phase II study in mod - Then aging—in skeletal muscle and eventu - erate-to-severe AD patients ally system-wide—ultimately captured his for which Guttman received in terest as well. Tarnopolsky wanted to un - NIH/NIAMS support. Guttman derstand the fundamental wellspring, and Blocking the IL-4 receptor- ␣. The fully human monoclonal antibody is conducting single-center find ways to slow it down or repair its impact. dupilumab—the first targeted immunotherapy agent in trials with AD studies for treatments targeting It was during an innovative aging inter - patients—shows a significant dose-related improvement in EASI scores in IL-23 and, most recently, IL-17. vention study that the unexpected impact of both patient subgroups. (Reprinted with permission from JD Hamilton et al. J Allergy Clin Immunol. See Suggested Readings for citation details .) (Continued on page 3) (Continued on page 10) DF’s Young Leaders A Foundation for the Future

The DF Board of Trustees welcomes the foresight and generosity shown by these Young Leaders, members who joined the within five years of completing their residencies. Their early-career annuaLle caodmemrsi tSmoecniet toyf $1,500 will help further every aspect of dermatology and patient care.

Alabama Louisiana Ohio Scott Freeman, MD Kim Bui Drew, MD Jennifer Bahner, MD Alexis R. Duke, MD Benjamin Bogucki, MD Arizona Dana A. Marshall, MD Anthony A. Nuara, MD, PhD Frankie G. Rholdon, MD Pennsylvania Brian C. Capell, MD, PhD California Massachusetts Emily Y. Chu, MD, PhD Brooks A. Bahr, MD Erik Domingues, MD Ron A. Birnbaum, MD Alexis Perkins, MD Rhode Island Adrianna Browne, MD Robert Dyer, MD Minnesota Jeffrey B. Cheng, MD, PhD H. William Higgins, II, MD, MBE Caleb Creswell, MD Sabrina G. Fabi, MD Kathryn Gehrig, MD Texas Anna K. Haemel, MD Juan P. Jaimes, MD Ammar M. Ahmed, MD Anubhav N. Mathur, MD, PhD Daniel D. Miller, MD Matthew C. Fox, MD Jeffrey North, MD Sarah Schram, MD Donald A. Glass, II, MD, PhD Susana M. Ortiz-Urda, MD, PhD Megha M. Tollefson, MD Ashley Group, MD Francisco Ramirez-Valle, MD, PhD Catherine L. Kowalewski, DO Mississippi Michael D. Rosenblum, MD, PhD Vineet Mishra, MD William L. Waller, MD Tiffany C. Scharschmidt, MD Gunjan Modi, MD Missouri Paras Ramolia, MD Connecticut Ramona Behshad, MD Christy Riddle, MD Peggy S. Myung, MD, PhD M. Laurin Council, MD Travis W. Vandergriff, MD Richard C. Wang, MD, PhD District of Columbia New Jersey Andrea Morris, MD Marc Meulener, MD Amanda Wolthoff, MD

Florida New York Utah David Casper, MD Tobechi Ebede, MD Chad Tingey, MD Emma Guttman-Yassky, MD, PhD Marie S. Tuttle, MD Georgia Ali Jabbari, MD, PhD Wisconsin Travis Blalock, MD Anthony M. Rossi, MD Alexandra Carley, MD Jonathan H. Zippin, MD, PhD Idaho Yvonne E. Chiu, MD Brock A. Andersen, MD North Carolina Jeremy Cook, MD Alisa Funke, MD Donna A. Culton, MD, PhD Clayton B. Green, MD, PhD Gregory L. Wells, MD William W. Huang, MD, MPH Elizabeth Nietert, MD

2 Fall 2015 Dermatology Foundation And there will be more to come. This article AD and Psoriasis—Side by Side reviews the highlights of Guttman’s game- The perspective on AD at that time was DERMA TOLOGY changing progress. completely dominated by the view that it was caused by barrier defects due to inher - FOCUS Finding Her Focus ited mutations in the filaggrin gene, and thus A PUBLICATION OF THE DERMATOLOGY FOUNDATION Guttman—in the Department of Der - inflammation was the consequence of a matology at the Icahn School of Medicine dysfunctional and poorly protective barrier. Sponsored by at Mount Sinai in New York—is Director of But as Guttman began to compare Valeant Pharmaceuticals North America LLC the Center for Excellence in Eczema and psoriasis and AD histologically and im - Editors-in-Chief the Occupational/Contact Dermatitis clinic, munologically, intriguing similarities stood Lindy Fox, MD and Director of the Laboratory of Inflam - out. They not only resembled each other his - matory Skin Diseases. Her trajectory to this tologically. She saw many immune infiltrates Associate Professor of Dermatology UC, San Francisco point, and the groundbreaking research in AD—large numbers of T cells and dendritic Mary M. Tomayko, MD, PhD contributions to understanding and treating cells in both the epidermis and dermis. Assistant Professor of Dermatology AD, began many years earlier. Guttman was aware of Donald Leung’s re - Yale School of Medicine, New Haven, CT Guttman’s personal experience had pro - search from the early 1980s and 1990s (see Heidi A. Waldorf, MD voked a precocious awareness of and inter - box on page 8) that had supported an im - Director, Laser and Cosmetic Dermatology est in skin diseases. She is atopic. And as a munologic pathogenesis for AD. And despite The Mount Sinai Medical Center, New York, NY child in Romania and then Israel, she suffered the powerful hold that the barrier hypothesis Executive Director from mild asthma and moderate-to-severe had on thinking about AD, “I began to won - Sandra Rahn Benz AD. Once in medical school, this dominant der if we were going to arrive at the under - interest combined with her highly visual na - standing that AD, too, is driven by cytokines, CDherpisuttiyn eE Mxe. cBuotriivs e Director ture to take her directly to dermatology and and that we will eventually have immune-dri - then immunodermatology. She knew from ven therapeutics for treating our patients,” Please address correspondence to: the start that her career focus would integrate she recalls. The advances in technology and EDdeirtmoarsto-ilnog-Cy hFioecf us her clinical and investigative work. the significantly expanded knowledge of the Guttman came to the immune system since Leung’s c/o The Dermatology Foundation U.S. in 2005 for a 2-year im - early studies—including the 1560 Sherman Avenue Evanston, Illinois 60201 munodermatology postdoc far more complex roster of Tel: 847-328-2256 Fax: 847-328-0509 fellowship at The Rocke - T-cell species and cytokines— e-mail: dfgen@de rmatologyfoundation.org feller University’s Laboratory would enable her to explore for Investigative Dermatol - Published for the this possibility. Dermatology Foundation by ogy. Her plan was to return Robert B. Goetz to Rambam Medical Center IL-22: The Fulcrum Designer, Productio n in Haifa and establish a Psoriasis had been clearly Sheila Sperber Haas, PhD small immunodermatology established as an immune- Managing Editor, Writer unit. Instead, at Rockefeller based inflammatory skin dis - This issue of is distributed and then Mount Sinai, ease driven by IL-23 and Th17. without chargDe ethrmroautgohlo agny Fedoucucas tional grant from she found the stimulating So Guttman’s next step was to Valeant Pharmaceuticals North America LLC. The opinions expressed in this publication do not environment, productive re - examine differences between necessarily reflect those of the Dermatology Foundation sources, and generous men - Emma Guttman-Yassky, MD, PhD psoriasis and AD along this IL- or Valeant Pharmaceuticals North America LLC. tors that she realized would enable her to 23/Th17 immune axis, and establish the rela - © Copyright 2015 by the Dermatology Foundation do her best work. tive frequencies of T-cell subsets in AD. So “I began my fellowship just when major skin biopsies and peripheral blood were col - AD skin was also notable for high con - changes were emerging in understanding lected from 12 patients with chronic AD and centrations of IL-22–producing CD4+ (ma - psoriasis,” Guttman recalls. It had finally 13 patients with psoriasis, and standard tech - ture T-helper cells) and CD8+ (cytoxic T been recognized as an immunologic dis - niques were used to determine the relative cells) populations, and the frequency of this ease, and the immune pathways were even - frequencies of CD4+ and CD8+ T-cell subsets. CD8 T-cell subset correlated with disease tually pinned down to the IL-23/Th17 axis. Peripheral blood did not distinguish between severity. Striking was that—unlike what had (The cytokine IL-23 induces naïve CD4+ the two patient groups, but their skin told the been learned from studying mice—Guttman helper cells to transform into highly patho - story. Frequencies of Th1 and Th17 cells were saw that human T cells are capable of ex - genic Th17 T cells.) Targeted treatments significantly higher in psoriatic skin. (Th1 T pressing IL-22 regardless of IL-17 levels. She were in progress. The Laboratory for Inves - cells produce the inflammatory cytokines realized that this independence of IL-22 and IL-17 in humans pointed to the existence tigative Dermatology was the center of re - IFN- ␥ and IL-2.) And Th2 cells were signifi - search in psoriasis, and ideal for beginning cantly elevated in AD skin. (Th2 T cells pro - of fully independent Th17 and T22 T-cell her exploration of AD by comparing these duce a very different pool of inflammatory populations, each with its own group of two common inflammatory skin diseases. cytokines: IL-4, IL-5, IL-6, IL-10, and IL-13.) expressed cytokines that drive different features of epidermal pathology in inflam - matory skin diseases. Dr. Guttman received a 2011 Physician-Scientist CDA from the DF: “Our findings suggested that novel sub - A Study Evaluating the Immunomodulatory Effects of Narrowband sets of Th22 ( h indicates helper ) and Tc22 Ultraviolet (NB-UVB) Radiation in Patients with Atopic Dermatitis (c indicates cytotoxic ) T cells contribute to the increased IL-22 expression in chronic www.dermatologyfoundation.org Fall 2015 3 DF Medical & Scientific Committee: Heart of the Research Awards Program

The Foundation’s Medical & Scientific Committee is central to the Research 2016 Medical & Scientific Committee Awards Program’s proven success in nurtur - ing progress and leaders in dermatology. Committee Chair Lu Q. Le, MD, PhD UT Southwestern Each member of this key group brings out - Thomas N. Darling, MD, PhD Medical Center standing expertise and understanding to the Uniformed Services University of the Health Sciences committee’s responsibilities—evaluating pro - Delphine J. Lee, MD, PhD Dermatological Center for posed research and applicants, and identify - Committee Members Skin Health ing physician-scientists and investigators Robert P. Dellavalle, MD, PhD, MSPH Denver VA Medical Center Lloyd S. Miller, MD, PhD who will shape the future. Johns Hopkins University Members’ collective experience reflects Johann E. Gudjonsson, MD, PhD University of Michigan Abrar A. Qureshi, MD, PhD the breadth of medical and surgical derma - John E. Harris, MD, PhD Brown University tology, enabling the committee to easily han - University of Massachusetts Eric L. Simpson, MD, MCR dle the comprehensive range of DF award Mayumi Ito, PhD Oregon Health & categories. Members thoroughly evaluate New York University Science University each application, diligently assessing both scientific merit and the applicant’s potential Clinical/Medical/Surgical/Dermatopathology Panel for advancing understanding and care of the skin in health and disease. Panel Chair Pedram Gerami, MD Northwestern University The committee’s effective review process Désirée Ratner, MD is based on the NIH grant review procedure. It Icahn School of Medicine, Mt Sinai Robert S. Kirsner, MD, PhD University of Miami has been refined over the DF’s many years of Panel Members experience to ensure the thorough, equitable, Philip LeBoit, MD Jeremy S. Bordeaux, MD, MPH Univ. of California, and science-based evaluation of all applications. Case Western Reserve University San Francisco The DF is very pleased to present the 2016 Jerry D. Brewer, MD Misha A. Rosenbach, MD Medical & Scientific Committee, and extends Mayo Clinic Uiversity of Pennsylvania deep appreciation for the substantial time, Anna L. Bruckner, MD Julie V. Schaffer, MD effort, and expertise each member contributes University of Colorado, Denver Hackensack University to this year’s Research Awards Program.

AD skin,” Guttman says. This supported defects. Guttman found the explanation for based treatments—narrow-band UVB pho - a Th2/T22 immune axis—or polarity , as this in the large reservoir of chronically ac - totherapy (NB-UVB) or cyclosporine (CsA) — Guttman calls it—in chronic AD compared tivated circulating skin-homing T cells that for 12 weeks. NB-UVB phototherapy was with the dominance of a Th1/Th17 pheno - she observed in AD patients. This may well given 3 times weekly. CsA was dosed at 5 type in psoriasis. It suggests an immune- explain the frequent disease exacerbations mg/kg/d, and biopsies were taken at week driven hyperplasia induced by IL-22, and across different skin regions. 2 as well. All skin biopsies were evaluated fully independent of IL-17. Guttman and her research team also using gene expression and immunohisto - Her data pointed to these newly de - found that patients with severe AD have chemistry studies. fined T22 T cells in AD as a highly promising expanded numbers of specific circulating The immunomodulatory effects of UV future therapeutic target for reversing both T-cell populations within their skin-homing radiation lead to improvement of inflam - the epidermal hyperplasia and the dis - T cells—Th2/Tc2 and Th22/Tc22. matory skin diseases. Guttman’s study turbed terminal differentiation pattern that showed that NB-UVB treatment includes characterize this disease. New Information From strong suppression of the Th2 and Th22 Existing Treatments axes. Because NB-UVB phototherapy Completing the T-Cell Story Having established the potent and clearly reversed the epidermal growth and Psoriasis and AD also differ in the na - unique profile of immune activation in AD, differentiation defects as well as the under - ture of nonlesional skin. In psoriasis, skin Guttman used current molecular tools to ex - lying immune activation, results added sup - that looks normal actually resembles nor - amine baseline and post-treatment lesional port for the hypothesis regarding immune mal skin. But in AD, visibly normal skin ac - and nonlesional skin from patients treated activation as primary, and the epidermal tually harbors broad barrier and immune with either of two broad spectrum immune- changes as a secondary result.

4 Fall 2015 Dermatology Foundation 2016 Committee Chair: Investigates Inherited Tumor Syndromes, Skin Regeneration Thomas Darling, MD, PhD, is looking forward to an investigative career in academic dermatology. to his new role as Chair of the Dermatology Foun - Dr. Darling’s excitement about the specialty dation’s 2016 Medical & Scientific Committee. began during his dermatology rotation in medical “I school. “What fascinated me was how the field en - really enjoy working on this committee and the compasses so many diseases. It was ideal from a grant applications we review because it’s about research perspective, since the extent of disease the future of dermatolovgeyry. We take the review could be monitored visually and patient samples of award applications seriously. It’s so could be readily obtained for study.” important for developing research It was ideal for an aspiring clinician- careers and advancing knowledge investigator. Dr. Darling, now Chair about the skin and skin diseases,” of Dermatology at USUHS, devotes he explains. “It’s exciting to see the his research efforts primarily to un - high quality of the science being derstanding and treating skin hamar - proposed, and how well qualified tomas and to the signaling pathways thesDer . bDuadrldining gk ninovwess ftirigsta-htoarnsd athree .” that promote skin regeneration. powerful career-launching benefit of Dr. Darling brings his understand - a Dermatology Foundation research ing of the necessary ingre-dients for award. After completing his dermatol - gaining extramural research funding, ogy residency at Duke University Med - as well as extensive grant review Thomas Darling, MD, PhD ical Center and additional training at the experience, to his committee respon - NIH’s Dermatology Branch, he joined the faculty at sibilities. He has the highest praise for his col - the Uniformed Services University of the Health Sci - leagues as he prepares for the upcoming grant ences (USUHS). He received his very first research review session. “This committee is such an out - grant that year, a DF Career Development Award to standing group,” he says. study skin tumors. “It was critical for me,” Dr. Darling “The variety of back - recalls. “It gave me the support I needed to start grounds, experience, and science that we my own research program, and a big boost when I represent leads to discussion that really en - began applying for other grants.” Since then, he has ables us to dissect and examine the great things been continuously successful in gaining extramural about each application. As chair, I hope to main - research funding—an essential for anyone devoted tain the high standards and great examples that have been set in previous years.”

CsA’s broad systemic immunosuppres - barrier abnormalities and/or background acute and chronic lesions in 10 patients and sive effects included minimizing the levels immunologic activation. She and her team created genomic, molecular, and cellular of Th2/Th22 cells, and treatment also re - compared nonlesional skin to skin from profiles. These profiles made it clear that the versed the epidermal alterations in lesional healthy people as well as to same-person le - onset of acute lesions was associated with a skin. Here was further support for immune sional skin. And they learned that the nor - striking increase in a subset of cytokine-in - activation as primary in AD. This enabled mal-looking skin of AD patients is really far duced (meaning from immunologic action) Guttman to hypothesize “that IL-22 is critical from normal—it manifests presence of the terminal differentiation proteins from the in AD’s pathogenesis, and that upregulation same barrier issues and cytokine activation S100 family, along with a significant increase of the Th2 and T22 axis might be the link that characterize lesional skin. The primary in the gene expression levels of the major cy - be tween the immune and epidermal ab - difference is that the immune alterations are tokines produced by Th2, Th22, and also normalities seen in patients with AD.” greater in lesional skin, and increase with Th17 cells. Chronic lesions showed an addi - Both studies also provided biomarkers disease severity. tional important jump in these cytokines, but that would be of value in future studies of Next, Guttman compared acute and the pattern remained the same. Guttman potential therapeutic interventions. chronic AD lesions. She hoped to shed light re garded this “progressive activation of Th2 on the mechanisms responsible for the onset and Th22 immune axis, as well as some Variations on a Theme of new lesions versus those that maintain Th17 activation,” as further evidence for their Guttman’s initial motivation for char - chronic disease. The answers could be criti - value as therapeutic targets. acterizing differences between lesional and cal for developing targeted therapeutics. Guttman’s comparison of patients with nonlesional (or normal-looking) skin was to Guttman and her research team examined extrinsic versus intrinsic AD was stimulated see if there is an intrinsic predisposition to nonlesional skin along with biopsies from (Continued on page 7) www.dermatologyfoundation.org Fall 2015 5 Rex A. Amonette, MD “We Will Always Be Committed to the DF”

Dr. Rex A. Amonette and his wife Johnnie have honored the Dermatology Foundation’s 50 years of service to the specialty with a $50,000 Founder’s Gift.

“Early in my career I realized the importance an important training center for Mohs surgery. of the Dermatology Foundation’s mission to Throughout his career, Dr. Amonette has enable advancements in patient care by helping been a vigorous and steadfast DF member, to develop and retain tomorrow’s teachers and contributing his time and money with notable leaders in dermatology,” Dr. Amonette explains. generosity. He has taken advantage of every “Johnnie and I knew from the start that we opportunity to further the specialty through the would always be committed to this important Foundation, including helping to establish the and great cause,” he adds. Earlier Leaders Society in 1989 as a this year, Dr. Amonette and his wife founding member and then dupli - chose to recognize the Founda - cating this role with the Annenberg tion’s 50th anniversary with a Circle in 1994. Since then, Dr. of $50,000. These Amonette joined the Fitzpatrick cFoonutnridbeurt’iso nGsi fat re earmarked for the Legacy Fund and more recently DF Endowment Fund and amplify became an AC Sustaining mem - the DF’s capacity to provide future ber. The work of the DF has bene - dermatologic research support. fitted from Dr. Amonette’s wisdom When Dr. Amonette established and leadership in various volunteer Dr. Rex A. and the Memphis Dermatology Clinic Mrs. Johnnie Amonette roles. He devoted many hours to in 1972, after completing his resi - the Annenberg Circle committee dency at the University of Tennessee Health as a member and its chair. Dr. Amonette contin - Science Center, he was only the second fellow - ues to serve on the DF’s Board of Trustees. He ship-trained physician in the U.S. to practice the shares that his long-term involvement with the Mohs method of tumor excision. Over the years, Foundation, its members, and volunteers has his practice has grown significantly and become always been “an honor and a pleasure.”

The Board of Trustees is deeply grateful to Dr. and Mrs. Amonette for their exceptional generosity and long-standing dedication to the mission of the Dermatology Foundation.

Atopic Dermatitis—A Thumbnail Sketch AD is characterized by immune activation, marked epidermal hyperplasia, and defective barrier function reflecting underlying alterations in keratinocyte differentiation. This disease affects 4–7% of adults in Western countries, 10% of adults in Asia, and up to 25% of children worldwide. (By comparison, psoriasis— also a common inflammatory skin disease—affects less than 2% of adults.) One-third of patients experience moderate-to-severe disease, and “most of these patients are not well controlled long-term with currently available treatments,” Guttman points out. The broadly immunosup - pressive drug cyclosporin is effective, but long-term use of this systemic agent runs a significant risk of hypertension, kidney disease or damage, and cancers, among others. Corticosteroids are also limited by toxicity and are not long-term systemic treatment options. Narrow-band UVB phototherapy is highly inconvenient because it requires several treatment visits every week. Although it uses a very narrow segment of the UVB spectrum, treatments are of higher intensity than broad-band UVB therapy. Little is known about the side effects of long-term treatment, which is particularly relevant for pediatric patients.

6 Fall 2015 Dermatology Foundation by high serum IgE levels in patients only with children with new-onset AD can we gain plains, “I will be able to dissect the possi - extrinsic AD—80% of the AD population— insight into primary pathogenic events.” ble contribution of individual immune despite similar clinical phenotypes. It was Guttman and Paller have learned that chil - axes—Th2, Th17/IL-23, and Th22.” important to clarify whether extrinsic and dren with early-onset disease have a dif - Dupilumab—a fully human mono - intrinsic subtypes represent two points on ferent phenotype than adults with chronic clonal antibody (mAB) targeting the IL-4 re - the same mechanistic spectrum or reflect disease. Adult disease is driven by Th2 and ceptor- ␣—is the agent furthest along. The different pathogenic mecha - initial assessment represents two nisms. That would determine phase I placebo-controlled trials whether they share the same ther - involving 18 patients treated for apeutic target or not. Guttman 4 weeks, with dupilumab given and her team learned that these in either of 2 doses. The AD two variants do share a common transcriptome was exacerbated T-cell–mediated pathogenesis de - in placebo-treated patients, but spite differences in IgE or allergic dupilumab improved the AD gene status. They also learned that in - signature in a dose-dependent trinsic disease is typified by higher manner (see graphs at left and heat levels of IL-17 characteristic of maps on page 8). Expression of psoriasis lesions. So similar thera - genes normally upregulated in AD peutic interventions would be were decreased by 26% with 150- appropriate, but patients with in - mg dosing, and by 65% with 300 trinsic disease may also benefit mg. Expression of genes that are from IL-17–targeting options. downregulated in AD increased The different cytokine profiles by 21% and 32%, respectively. that define Asian versus Western Guttman documented significant subtypes of AD also resulted from reduction in mRNA expression Guttman’s drive to understand AD of genes related to hyperplasia, as fully as possible. AD is most T cells, and dendritic cells, and highly prevalent in Asian coun - potent inhibition of Th2-associ - tries, with a large unmet need for ated chemokines. Th1-associated effective therapeutics. No one had genes were not significantly undertaken a molecular compari - modulated. Improved clinical son of East versus West before this. scores paralleled these molecular Guttman and her co-workers changes (see graph on front found similarities and significant cover), and the epidermal lesional differences. Asian disease shows phenotype of AD was reversed greater epidermal hyperplasia, fre - after the 4 weeks of treatment. quent parakeratosis, and signifi - “These data support AD as an im - cantly higher levels of Th17 and mune-driven disease and establish Th22 cytokines, even though most IL-4 and IL-13 as pathogenic cy - of the Asian patients assessed tokines in patients with AD that had high IgE levels! A Principal regulates epidermal responses,” Component Analysis—designed Guttman explains. to unmask strong patterns in The current phase II trial of datasets—determined that Asian more than 50 adult patients is of AD represents a blended pheno - significantly longer treatment du - type that clusters between Western ration, and Guttman hopes it will extrinsic AD and psoriasis patients. also provide greater insight as to The relative contributions of the Dupilumab improves the AD gene signature. Top: After 4 weeks of treat - whether barrier genes normalize. Th2, Th22, and Th17/IL-23 immune ment, there were significant dose-dependent changes in the AD transcriptome, Pediatric trials of dupilumab will with upregulated genes decreasing and downregulated genes increasing. axes are now being assessed in Placebo-treated patients worsened. Bottom: The molecular differences between hopefully begin next year. clinical trials with appropriate lesional and nonlesional skin were minimized in a dose-dependent manner. While the IL-4/IL-13 pathway is targeted therapeutics. (Reprinted with permission from JD Hamilton et al. J Allergy Clin Immunol. See clearly pathogenic, “we are still in And finally, Guttman has Suggested Readings for citation details.) the process of deciphering the become very involved in comparing pedi - Th22 immune activity, “but early-onset AD other pathways—Th22 and even IL-23 and IL- atric and adult disease. She collaborates in children is restricted to Th2 activation,” 17,” Guttman says. “To obtain a proof of con - with pediatric dermatology specialist Amy Guttman states. And this has important cept for the role of IL-22 in AD, we are W. Paller, MD, Chair of the Department of therapeutic implications. completing a large clinical trial utilizing an Dermatology at the Northwestern Feinberg anti-IL-22 antibody—the first to explore the bi - School of Medicine. “Our current under - The First Targeted Agents ological effects of blocking IL-22 on disease standing of AD pathogenesis derives Carrying the arc of her research to its activity and associated skin pathology,” she mostly from studies in adults with long- goal, Guttman is now leading the way in adds. In addition, Guttman is exploring IL-23– standing disease,” Guttman points out, testing the mechanism of novel treatments inhibiting treatment, and has also begun a explaining that “only by studying young for AD. “Through these studies,” she ex - large study to assess treating AD patients with www.dermatologyfoundation.org Fall 2015 7 secukinumab, an anti-IL-17 agent. And she and Paller have several projects planned for clarifying the initiation of AD in childhood. “It’s really an exciting time,” Guttman says. “I feel that we are actually making history, and I feel very fortunate to be a part of this ther - apeutic development in AD—which we are now beginning to translate to other challeng - ing diseases, such as alopecia areata.” Suggested Readings Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, et al. “IL-22–producing ‘T22’ T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17– producing Th17 T cells.” J Allergy Clin Im - munol. 2009;123:1244–52. Hamilton JD, Suarez-Farinas M, Dhingra N, Cardinale I, et al. “Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.” J Allergy Clin Immunol. 2014;134:1293–300. Czarnowicki T, Esaki H, Gonzalez J, Malajian D, et al. “Early pediatric atopic derm- atitis shows only a cutaneous lymphocyte anti - gen (CL A)+ Th2/Th1 cell imbalance, whereas adults acquire CLA+ Th22/Tc22 cell subsets.” J Allergy Clin Immunol. 2015;136:941–51. Leung DYM, Guttman-Yassky E. “Deci - phering the complexities of atopic dermatitis: shifting paradigms in treatment approaches.” Dupilumab improves a larger AD gene profile. Left: T his heat map shows dose-dependent changes. J Allergy Clin Immunol. 2014;134:769–79. At 300 mg/wk, the transcriptome resembles that of nonlesional skin. Downregulated genes included markers Malajian D, Guttman-Yassky E. “New of epidermal proliferation and multiple inflammatory mediators. Right: This pattern is duplicated in the heat map of an immune gene subset. DEG = differentially expressed genes. (Reprinted with permission from JD pathogenic and therapeutic paradigms in Hamilton et al. J Allergy Clin Immunol. See Suggested Readings for citation details.) atopic dermatitis.” Cytokine. 2015;73:311–8. I

Donald Leung, MD, PhD—Providing Perspective Leung—who heads the Division of Pediatric Allergy and Immunology at National Jewish Health in Denver— has been fascinated with AD since the late 1970s, when he was a Fellow in Allergy and Immunology at Boston Children’s Hospital Medical Center. He adapted the new technology of that day—the first monoclonal anti - bod ies that had just come into clinical use—to peer below the surface of AD lesions to see what evidence he could find of immunologic activity in this inflammatory skin disease. “Those first monoclonal antibodies were being used primarily as cancer therapies in leukemias and lymphomas, which primarily involved T cells,” he explains. “We were able to use them as markers and learn that, in fact, AD lesions and normal-appearing non - le sional AD skin contain a significant T cell presence.” These pioneering results were published in 1981. After that, Leung spent substantial time in that early phase of his career characterizing these T cells, and in the early 1990s “we were able to identify the cytokines being expressed in atopic lesions,” he notes. They found IL-4 and IL-13, “the two key cytokines in early AD lesions and nonlesional skin. And then we showed that adding them to cultures of skin cells and immune cells recapitulated AD.” During that time he published his perspective on the immunologic basis of AD. Then the imminent conceptual dominance of the centrality of a barrier abnormality to the pathology of AD, plus the lack of technologic tools and targeted immunologic treatments for testing his theory in human patients, blocked any further progress. Leung’s research interest eventually shifted to learning why infection drives AD. “We had laid the groundwork by demonstrating the existence of an association between AD and this unique profile of cytokines,” Leung says. “And now Emma has been able to expand this unique profile and show it in hu - mans. She became interested in this field at a time when the technology had become available to allow her to ask these questions and prove my original hypothesis. Neutralizing these cytokines with targeted biologics in a human being with AD results in their skin disease getting better, demonstrating that this is cause and effect.”

8 Fall 2015 Dermatology Foundation 2016 DF Clinical Symposia ADVANCES IN DERMATOLOGY

January 20–24, 2 01 6 The Ritz-Carlton, Naples, Florida

VERY LIMITED SPACE AVAILABLE—REGISTER NO W! www.dermatologyfoundation.org RAVE REVIEWS “Best meeting I attend all year .” “Great coverage of the modern scope of derm .” “Concentrated presentation of new, pertinent information .”

PRACTICE-RELEVANT MINI-SYMPOSIA TOPICS Treatment Innovation and Skin Disease Pediatric Dermatology Errors, Complications, and Patient Safety Difficult Medical Dermatology Conundrums, Including CPC Policy, Ethics, and the Law Evolving Evidence: New Knowledge in Dermatology

EXPERT FACULTY George Cotsarelis, MD Eva A. Hurst, MD Suzanne M. Olbricht, MD University of Pennsylvania Washington University Harvard University Edward Cowen, MD Sewon Kang, MD Junko Takeshita, MD, PhD National Cancer Institute Johns Hopkins University University of Pennsylvania Mary Beth Fasano, MD Peter A. Lio, MD Abel Torres, MD University of Iowa Northwestern University Loma Linda University Maria Garzon, MD Boris D. Lushniak, MD, MPH Ruth Ann Vleugels, MD Columbia University Uniformed Services University Harvard University of the Health Sciences

The DF Clinical Symposia provides 1 7.5 AMA PRA Category 1 Credits ™. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Yale School of Medicine and the Dermatology Foundation. The Yale School of Medicine is accredited by the ACCME to provide continuing medical education to physicians.

www.dermatologyfoundation.org Fall 2015 9 Focus on Research Reversing Skin Aging: Endurance Exercise’s Unexpected Benefit— and How Rejuvenated Mitochondria Make This Happen

(Continued from cover) healthy people to older adults, and we do longitudinal interventional studies in older people.” Front and center in Tarnopolsky’s explorations of aging has been the increas - ing mitochondrial dysfunction that occurs as we age and how its impact can be atten - uated. He had initially targeted the mito - chondria in aging skeletal muscle, aiming to ameliorate the erosion of physical func - tion and independence. His more recent scope takes in the whole person—and this is what brought him to the PolG mouse, and then the skin. Laying the Groundwork— Mitochondria, Oxidative Stress, Exercise rejuvenated mtDNA mutator mice. At 30 weeks of age, the sedentary mice ( right ) had and Aging in mtDNA Mutator continued their rapid aging while the exercising mice ( left ) were fully rejuvenated. (Reprinted with permission from PNAS. See Suggested Readings for citation details.) Mouse endurance exercise on the skin “really maintain youthful skin and hair. Highly in - Tarnopolsky’s expanded approach inte - jumped out at me,” he recalls. trigued, he wanted to identify the skin vari - grates the facts that all human organs and sys - It appeared to be mediated by mito - ables involved, and what this might imply. tems are affected negatively by aging, that chondria (see box on page 12). Pursuing they are all affected positively by exercise, this in both mice and humans down to its His Path From Aging Muscle and that mitochondria are ubiquitously dis - molecular underpinnings led Tarnopolsky to Aging Skin tributed throughout the body. And it is an - through a series of discoveries establishing Because of Tarnopolsky’s patient pop - chored in the mitochondrial theory of aging a profound, mitochondria-based, relation - ulation—especially those with mitochon- first fully articulated in the early 1970s by the ship between exercise, skeletal muscle, and drial myopathies and muscular dystrophies— research biochemist and biogerontologist skin—one with preventive and therapeutic “I have always been particularly interested Denham Harman, MD, PhD. Harman re - implications. in skeletal muscle function,” he explains. garded the diminishing capabilities of mito - In the experiment that began it all (de - His concurrent focus on exercise reflects chondria as the fundamental cause of aging. tails to follow), Tarnopolsky and his col - the reality that “genetic therapy for these pa - Those who attribute aging to other processes, leagues were working with mtDNA mutator tients may be significantly off in the future, such as telomere shortening or increased in - mouse , also known as PolG mouse (see box and we need ways to help these people flammation, are actually looking at down - on page 12). This mouse model—lacking the today .” Because both exercise and nutrition stream fallout from this primary cause. normal ability to identify and repair mutations seemed to work very well for many of these And there was more. Harman was in its mitochondrial DNA (mtDNA)—had disorders, Tarnopolsky and his research unswervingly convinced that this increasing been developed to open new avenues in team began using animal models to deepen mitochondrial dysfunction is due specifically studying mitochondrial function, especially their understanding of the fundamental its role in aging. Tarnopolsky and his team molecular biology and biochemistry that were hoping to confirm that exercise can “at - enable these interventions to influence tenuate the mitochondrial-induced cumula - skeletal muscle function. They would see tive systemic decline observed in aging,” how their observations translate to healthy looking beyond skeletal muscle to tissues in - humans, and then, hopefully, to treatments cluding heart, brain, adipose tissue, and liver. for specific diseases. Initially using healthy After placing half of their mice on a 5-month young subjects, Tarnopolsky began to in - program of endurance exercise, they clude senior citizens once he realized that achieved that goal—and more. The greatly ac - normal aging recapitulates his patients’ rare celerated aging of these control mice in - genetic mitochondrial diseases. cluded gray, thin hair and sagging skin, Using the healthy elderly not only en - providing a high-contrast visual background abled him to bypass the obstacle posed by for the unchanged youthful hair and skin of patients with diseases so rare that he can - exercising mice (see photos above and right) not gather enough of them for study, it also Exercise rejuvenated mtDNA mutator mice. and wild-type (WT) mice. Tarnopolsky stimulated a new research focus. “It did not At 72 weeks of age, the rapidly aging mice that had was stunned at the possibility that—in ad - take long before we became very inter - been put on active exercise ( right ) were still indistinguishable from healthy wild-type mice ( left ). dition to protecting internal tissues and ested in human aging in and of itself,” (Reprinted with permission from PNAS . See Suggested systems—endurance exercise might also Tarnopolsky notes. “We compare young Readings for citation details.)

10 Fall 2015 Dermatology Foundation to mtDNA damage from local oxidative Next: Putting PolG Mouse duced risk of chronic diseases and extended stress—self-inflicted damage, in a sense. The to Work life expectancy. But until the appearance of mitochondrial production of free radicals is Now Tarnopolsky and Adeel Safdar, PolG mouse—directly and accessibly con - significant to start with, and increases even PhD (then his doctoral student, and now a necting aging mitochondria with phenotypic further in the context of mitochondrial dys - postdoctoral fellow), were ready to use PolG aging—there had been no sure way of know - function. The mtDNA’s close proximity to mice to see if endurance exercise retarded ing whether endurance exercise actually im - these free radicals makes them highly vul - aging by reducing oxidative stress and nor - proves mitochondrial function. nerable to damage from this oxidative stress, malizing the mitochondrial dysfunctions that Because PolG mice are normal except increasing dysfunction yet further. cause aging—ie, targeting its primary cause. for their mitochondria’s inability to repair But some investigators had strongly dis - They had compelling reason to regard en - damage, they fast-forward a detailed portrait agreed that oxidative stress occurs in the durance exercise as a highly promising in - of aging—including osteoporosis, sarcope - mitochondrial environment. One of these tervention. Endurance exercise—known to nia, cataracts, hearing loss, cardiomyopathy, groups claimed victory after they examined be the most potent physiological inducer of anemia—and die at roughly half the age of a homogenates of skeletal muscle from the mitochondrial biogenesis in skeletal mus - normal mouse. “We thought this model of new mtDNA mutator mice, and found no cle—showed profound effects on metabo - premature—or progeroid—aging would be markers of oxidative stress. They insisted that lism in various other organs as well. And informative for biochemically and molecu - aging is due simply to the inevitable accu - human epidemiologic studies showed re - larly determining the role of the mitochon - mulation of mtDNA defects with time. Resolving this discrepancy was crucial SED 20y SED 56y SED 75y to determining the causes of mitochondrial dysfunction, and fully understanding and ameliorating their impact. Tarnopolsky settled this dispute using the mtDNA mutator mouse—his first experi - ence with this new mouse model—by taking a very different approach to assessing mito - chondrial oxidative stress and exposing the fallacy underlying the earlier conclusion. Examining whole muscle homogenates ACT 20y ACT 57y ACT 77y clearly assumed that mitochondrial oxida - tive stress—if it exists—is a global phenom - enon. But Tarnopolsky recognized the critical importance of location and micro- environment. He knew that to cause dam - age, this oxidative stress had to be in close proximity to mtDNA—within the mitochon - drial niche—and thus this is where it had to be looked for and measured. A colleague in Habitual exercise maintains younger skin life-long. ACT (highly active ) individuals had a thinner the Division of Cardiology at the University stratum corneum and thicker stratum spinosum than SED ( sedentary ) individuals. (Reprinted with permission of Pittsburgh—mitochondrial investigator from Aging Cell. See Suggested Readings for citation details.) Brett A. Kaufman, PhD—had developed novel subcellular localization methods en - 1,500 SED abling them to access the mitochondrial ACT niche and measure the oxidative load there. Homing in on the spot where the action was taking place, “we confirmed the fact that mi -

tochondrial dysfunction does cause oxida - A 1,000 tive stress—and specifically as Harman’s N D

theory proposed it,” Tarnopolsky observes. n It is clearly a local, not global, phenome - / A non, that specifically damages the mtDNA N D and perpetuates mitochondrial dysfunc - t tion. Tarnopolsky and his group also found m 500 that antioxidant production, DNA repair en - zymes, and markers of mitochondrial bio - genesis decreased significantly in these mice. “And this presence of oxidative dam - age associated with the premature aging- 0 like phenotypes induced by mitochondrial 20 40 60 80 dysfunction was consistent with the in - Age (y) creased hallmarks of mitochondrial oxida - Habitual exercise maintains larger mitochondrial numbers. Significance is P<0.05, both for an tive damage that we observe in older age effect within the SED group and for an overall group activity effort. (Reprinted with permission from adults,” Tarnopolsky adds. Aging Cell. See Suggested Readings for citation details.) www.dermatologyfoundation.org Fall 2015 11 dria in this process,” Tarnopolsky explains, Mitochondria—Essential to Life “and to see if exercising these mice could effectively counteract this programmed Back in the mists of evolutionary time, our mitochondria—the mitochondrial dysfunction to mitigate their cellular organelles in our cytoplasm that produce our energy and con - premature aging.” tribute substantially to other basic cellular functions—were once in - The Dramatic Surprise— dependently dwelling purple photosynthetic bacteria. As eukaryotes Impact on Skin evolved more than 1 billion years ago, these free-living bacteria became After raising a group of PolG mice under incorporated within them—the process of endosymbiosis—and de - standard conditions for their first 3 months, Tarnopolsky and his team divided them into veloped a mutually dependent relationship. Mitochondria have their 4 groups of 18 mice each. For the next 5 own genome and are rich in fats, proteins, and enzymes, but some of months, PolG-SED males and females con - the proteins essential to their function—such as the enzyme that tinued their increasingly sedentary lifestyle corrects its DNA mutations—are produced by the cells they inhabit. while PolG-END males and females began 45- The mitochondria transform glucose into ATP via cellular respi - minute sessions of forced-endurance tread - mill exercise—15 m/min—3 times a week. ration, and are thus called the “powerhouse of the cell.” But this Every animal was age- and sex-matched with is only part of what they do. “Mitochondria are host to numerous a sedentary WT littermate to determine biosynthetic, bioenergetic, and signaling processes that ultimately whether this endurance exercise interven - couple cellular metabolism to homeostatic regulatory mechanisms,” tion could phenotypically and molecularly bring PolG mice to normalcy. All mice were Tarnopolsky explains. Among other things, they participate in cal - regularly monitored for body weight and cium and hormonal signaling, cellular differentiation, apoptosis, the condition and given a monthly endurance cell cycle, cell growth, and steroid synthesis. Dysfunctional mito - stress test. After 5 months, they were eutha - chondria are responsible for a number of human diseases and condi - nized to permit collection of blood and tissue samples for histological, electron tions, including cardiac pathology. The number of mitochondria per microscopy, and molecular analyses. cell varies widely by tissue, reflecting the local energy demands. Liver The PolG-SED mice aged rapidly, as ex - cells contain roughly 2,000 mitochondria each, and up to 20–25% of pected, but the PolG mice that had spent the the cytoplasmic space. Human myocytes contain close to 7,000 per last 5 months exercising were now indistin - cell, approximately 40% of the cytoplasmic space. Red blood cells are guishable from their healthy WT littermates— inside and out. Tarnopolsky found “dramatic unique in the absence of mitochondria. suppression of the accelerated aging phe - notype and rescue of multisystem degener - ate pathology.” Endurance exercise had reversed the pro - mtDNA Mutator Mouse aka PolG Mouse gressive reduction in body size, attenuated hematologic pathology and splenomegaly, and When the mtDNA mutator mouse was created with knock-in gene mitigated sarcopenia, cardiac pathology, and technology in 2004, it had been known for some time that mitochon - memory loss. It promoted systemic mitochon - drial DNA (mtDNA) accumulates point mutations and deletions in drial oxidative capacity, restored mitochon- drial biogenesis and morphology in all s ystems a variety of tissues during aging in humans and other mammals. But (which included rescuing mtDNA depletion debate had raged about whether or not this accumulating mtDNA in heart and liver), reduced the frequency of damage had a causal role in the aging process. Until then, evidence mtDNA point mutations in skeletal muscle, had been purely correlative. But mtDNA mutator mouse settled this and restored telomere length. Tarnopolsky debate in short order. was not surprised by this all-encompassing normalization of health, but he was gratified This new mouse model contained a defective version of the proof - to see it demonstrated so clearly and tied so reading gene—called polymerase-gamma A or PolG. This enzyme— transparently to restoring healthy mitochon - synthesized in the cell nucleus for the mitochondria—normally dria, including reduced oxidative stress. corrects mtDNA errors. This inability to correct the ongoing produc - He was completely unprepared, though, to witness the drama of aging skin tion of mtDNA errors resulted in mice with a significantly reduced and fur, and then its rejuvenation by exercise lifespan and the rapidly premature onset of such aging-related phe - (see photos on page 10). The rapid pace of notypes as weight loss, alopecia, kyphosis, osteoporosis, reduced aging in these mice produced progressive subcutaneous fat, and heart enlargement. This mouse model—com - loss of hair pigmentation, alopecia, and sag - ging skin remarkably swiftly, and with stark monly called PolG mouse—quickly became valuable in exploring contrast to the WT mice. Then the visually mitochondrial function and dysfunction, and in studying aging in apparent reversal of these changes in the a variety of organs. treadmill-running mice was equally striking.

(Continued on page 15) 12 Fall 2015 Dermatology Foundation * STEALING THE SHOW? FIGHT IT AT THE SITE OF INFECTION1

*For the treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes.

JUBLIA allows some patients to have clearer toenails grow back. LARGER Individual results may vary. mL INDICATION JUBLIA (efinaconazole) topical solution, 10% is indicated for the topical size treatment of onychomycosis (tinea unguium) of the toenail(s) due to 8 Trichophyton rubrum and Trichophyton mentagrophytes. AVAILABLE Rx Only IMPORTANT SAFETY INFORMATION • JUBLIA is for topical use only and is not for oral, ophthalmic, or intravaginal use. • Patients should be instructed to contact their health care professional if a reaction suggesting sensitivity or severe irritation occurs. • The most common adverse reactions (incidence >1%) were (vs vehicle): ingrown toenail (2.3% vs 0.7%), application-site dermatitis (2.2% vs 0.2%), application-site vesicles (1.6% vs 0%), and application-site pain (1.1% vs 0.2%). • JUBLIA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, and should be used with caution in nursing women. The safety and effectiveness in pediatric patients have not been established. Please see Brief Summary of full Prescribing Information on the adjacent page. Reference: 1. JUBLIA [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2015. Find out more by visiting www.JubliaRx.com.

®/TMs are trademarks of Valeant Pharmaceuticals International, Inc. or its affi liates. Any other product or brand names and logos are the property of their respective owners. © 2015 Valeant Pharmaceuticals North America LLC DM/JUB/15/0180 Printed in US BRIEF SUMMARY OF PRESCRIBING INFORMATION Subcutaneous doses of 1, 5, and 10 mg/kg/day e naconazole were administered during the period of organogenesis (gestational days 6-19) to pregnant female This Brief Summary does not include all the information needed to use rabbits. In the presence of maternal toxicity, there was no embryofetal toxicity or JUBLIA safely and effectively. See full prescribing information for JUBLIA. malformations at 10 mg/kg/day (154 times the MRHD based on AUC comparisons). In a pre- and post-natal development study in rats, subcutaneous doses of ® JUBLIA (e naconazole) topical solution, 10% 1, 5 and 25 mg/kg/day e naconazole were administered from the beginning of organogenesis (gestation day 6) through the end of lactation (lactation day 20). In For topical use the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup Initial U.S. Approval: 2014 mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (17 times the MRHD INDICATIONS AND USAGE based on AUC comparisons). No effects on postnatal development were noted at JUBLIA (e naconazole) topical solution, 10% is an azole antifungal indicated 25 mg/kg/day (89 times the MRHD based on AUC comparisons). for the topical treatment of onychomycosis of the toenail(s) due to Trichophyton rubrum and Trichophyton mentagrophytes. Nursing Mothers It is not known whether e naconazole is excreted in human milk. After repeated DOSAGE AND ADMINISTRATION subcutaneous administration, e naconazole was detected in milk of nursing rats. Apply JUBLIA to affected toenails once daily for 48 weeks, using the integrated Because many drugs are excreted in human milk, caution should be exercised ow-through brush applicator. When applying JUBLIA, ensure the toenail, the when JUBLIA is administered to nursing women. toenail folds, toenail bed, hyponychium, and the undersurface of the toenail plate, are completely covered. Pediatric Use Safety and effectiveness of JUBLIA in pediatric subjects have not been established. JUBLIA is for topical use only and not for oral, ophthalmic, or intravaginal use. Geriatric Use CONTRAINDICATIONS Of the total number of subjects in clinical trials of JUBLIA, 11.3% were None. 65 and over, while none were 75 and over. No overall differences in safety and ADVERSE REACTIONS effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identi ed differences in responses Clinical Trials Experience between the elderly and the younger subjects, but greater sensitivity of some Because clinical trials are conducted under widely varying conditions, adverse older individuals cannot be ruled out. reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reect the NONCLINICAL TOXICOLOGY rates observed in practice. Carcinogenesis, Mutagenesis, Impairment of Fertility In two clinical trials, 1227 subjects were treated with JUBLIA, 1161 for at least A 2-year dermal carcinogenicity study in mice was conducted with daily topical 24 weeks and 780 for 48 weeks. Adverse reactions reported within 48 weeks of administration of 3%, 10% and 30% e naconazole solution. Severe irritation was treatment and in at least 1% of subjects treated with JUBLIA and those reported noted at the treatment site in all dose groups, which was attributed to the vehicle in subjects treated with the vehicle are presented in Table 1. and confounded the interpretation of skin effects by e naconazole. The high dose group was terminated at week 34 due to severe skin reactions. No drug-related Table 1: Adverse Reactions Reported by at Least 1% of Subjects Treated neoplasms were noted at doses up to 10% e naconazole solution (248 times the for up to 48 Weeks MRHD based on AUC comparisons). JUBLIA Vehicle E naconazole revealed no evidence of mutagenic or clastogenic potential based Adverse Event, n (%) N = 1227 N = 413 on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosome aberration assay) and one in vivo genotoxicity test (mouse Ingrown toenail 28 (2.3%) 3 (0.7%) peripheral reticulocyte micronucleus assay). No effects on fertility were observed in male and female rats that were Application site dermatitis 27 (2.2%) 1 (0.2%) administered subcutaneous doses up to 25 mg/kg/day e naconazole (279 times the MRHD based on AUC comparisons) prior to and during early pregnancy. Application site vesicles 20 (1.6%) 0 (0.0%) E naconazole delayed the estrous cycle in females at 25 mg/kg/day but not at Application site pain 13 (1.1%) 1 (0.2%) 5 mg/kg/day (56 times MRHD based on AUC comparisons). PATIENT COUNSELING INFORMATION DRUG INTERACTIONS See FDA-Approved Patient Labeling (Patient Information). In vitro studies have shown that JUBLIA, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with JUBLIA in pregnant women. JUBLIA should be used during pregnancy only if the potential bene t justi es the potential risk to the fetus. Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 2, 10 and 50 mg/kg/day e naconazole were administered during the period of organogenesis (gestational days 6-16) to Manufactured for: pregnant female rats. In the presence of maternal toxicity, embryofetal toxicity Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 USA (increased embryofetal deaths, decreased number of live fetuses, and placental Manufactured by: effects) was noted at 50 mg/kg/day [559 times the Maximum Recommended Kaken Pharmaceutical Co. Ltd, Shizuoka, Japan Human Dose (MRHD) based on Area Under the Curve (AUC) comparisons]. No Product of Japan embryofetal toxicity was noted at 10 mg/kg/day (112 times the MRHD based on AUC comparisons). No malformations were observed at 50 mg/kg/day U.S. Patents 8,039,494; 7,214,506 (559 times the MRHD based on AUC comparisons). Based on 9391902 DM/JUB/15/0076 Issued: 02/2015

DF Welcomes Annenberg Circle and Sustaining Members

As of December 1, 2015 The Dermatology Foundation welcomes its newest They join more than 600 of their colleagues in pledging $25,A0n0n0 eton bperorgv idCeir cfulen d(AinCg )t hmaet mis binesrstr.umental in launching the careers of tomorrow’s investigators, teachers, and master clinicians.

Steven A. Binnick, MD Karen A. Lund, MD Ellen H. Frankel, MD Andrew L. Ondo, MD Jack L. Lesher, Jr, MD Laura McNeely Tamburin, MD

The DF extends sincere appreciation to its AC members who have increased their support of dermatology’s future still further. After completing their original pledge, these Sustaining AC members chose to expand their giving with a $5,000 annual gift. Some pledge to maintain this annual support into the future. Below, each new member’s cumulative AC contributions—including current and pledged annual Sduosntaatiinoinsg —are recognized.

$75,000 Ronald R. Brancaccio, MD * Eugene Mandrea, MD * Mark G. Cleveland, MD, PhD * Kim B. Yancey, MD * $50,000 Joseph C. Kvedar, MD* Marta J. Petersen, MD* $30,000 Thomas W. Andrews, MD Ronald E. Grimwood, MD William F. Cosulich, MD Renée J. Mathur, MD *New multi-year pledge

“What really jumped out at us from the Human Skin Under The ber—was lower in the skin of older adults start,” Tarnopolsky recalls, “was how terri - Microscope—Exercise and IL-15 compared to younger ones.” ble the skin and hair of PolG mice began to Studies of healthy human subjects Next, they searched for an interaction look. And then how completely restored began with Justin D. Crane, PhD, then one of between age and exercise—and found it in they were when the mice exercised. So we Tarnopolsky’s doctoral students (now in the both retrospective and prospective designs. biopsied their skin,” he continues, “and it Department of Biology at Northeastern Uni - First, subjects were grouped by activity was dramatically different.” The skin from versity). They began with the basics, com - level— ACT (habitually active lifestyle: ≥4 sedentary PolG mice resembled aging paring skin samples—from non-sun-exposed hours/week of high-intensity aerobic exer - human skin, with a very thin dermis and a buttock skin—across the lifespan from ages cise) and SED (sedentary lifestyle: ≤1 stratum corneum that was thick and ex - 20 to 86 y. Buccal swabs and plasma and hour/week of exercise). ACT subjects at every tremely irregular. But those changes had serum samples were also collected. “We re - age had a thinner stratum corneum than their been completely eradicated in the exercis - capitulated what was known,” Tarnopolsky SED counterparts (see photos on page 11), ing mice. “That got us thinking,” Tarnopol - says, “that as we age, the stratum corneum and those 65–86 y had significantly less thin - sky says. “There was no previous evidence becomes thicker and the reticular dermis ning of the stratum spinosum. mtDNA copy that exercise impacts skin—yet it was one of thins out.” Then he and his team asked if number in their skin and buccal cells was the most dramatic effects in our mice. Skin there was mitochondrial dysfunction in greater (see graph on page 11), and basal lev - is the largest organ in the human body and these samples. In the older humans—as in els of buccal cell mitochondrial genes were the primary physical barrier against infec - the sedentary mutator mice—the answer was maintained with age only in ACT subjects. tion and disease—and we decided to start yes. “Every metric of mitochondrial func - Then a subset of these elderly SED looking at it.” tion—including mitochondrial copy num - adults (65–86 y) spent 3 months in a twice- www.dermatologyfoundation.org Fall 2015 15 weekly aerobic training program involving specific exercise-mediated serum samples IL-15—Endocrine a cycle ergometer and working up to 45- were prepared—each one missing the activ - Muscle-to-Skin Signaling minute sessions at 75% of maximum heart ity of one of these four candidates—and Tarnopolsky was breaking new ground rate. And after just 3 months, these previ - added to a fibroblast culture. Only the ver - with his investigation of muscle-induced IL- ously sedentary elderly had clear indicators sion lacking IL-15 activity made a difference. 15. Until then it had been known as a cy - of skin rejuvenation. Their thickened stra - Mitochondrial biogenesis came to a com - tokine that affects T-cell activation and tum corneum was becoming more normal, plete halt. Then adding recombinant human proliferation similarly to IL-2. Now he and his and both collagen content and skin mtDNA IL-15 restored it. group were in the midst of discovering its copy number had increased. “It was pretty Returning to WT mice and assessing unique role as the very first example of en - remarkable to see,” Tarnopolsky said. Under them 1 hour after completing a single ses - docrine signaling from muscle to skin. Up a microscope, their skin “looked like that of sion of treadmill running, Tarnopolsky’s until their explorations in mice and humans, a much younger person—and all that they group found transiently elevated levels of “the regulation of muscle-derived IL-15 and had done differently was exercise.” Pgc-1 ␣ in their skeletal muscle and skin, its physiological consequences in skin had Next, Tarnopolsky found that ACT in - as well as significant IL-15 present in their remained unclear,” Tarnopolsky points out. dividuals produce a unique mitochondrial serum. Then injecting mice with an IL-15- The basic reality is that “muscle-derived IL- response to exercise. His first clue came neutralizing antibody before and after 15 is an exercise-stimulated hormone that when he and his team measured expres - their exercise—and thus taking this circu - mediates the health of skin tissue.” And by sion of the master regulator of mitochon- lating IL-15 out of action—created a sce - the time these studies were finished, thera - drial biogenesis just before and immediatel y nario “indicating that IL-15 partially peutic implications had become apparent. after acute exercise. This master regulator mediates exercise-stimulated mitochon - is Pgc-1 ␣, the critical PPAR ␥ coactivator. drial biogenesis in skeletal muscle and AMPK—Completing a (PPAR ␥, part of a family of transcription skin,” Tarnopolsky says. Strong Portrait factors, causes insulin sensitization and IL-15’s role ultimately turned out to be Tarnopolsky eventually demonstrated enhances glucose metabolism.) Pgc-1 ␣ even more fundamental, not limited just to that a given subject’s acute exercise capa- expression was unchanged in the SED mediating mitochondrial effects of exercise city actually predicts the degree of his/her group right after exercise. But in the ACT in skin and skeletal muscle. It is actually es - exercise-induced cutaneous benefits. And group it had increased significantly. And sential for basic mitochondrial function in this pointed to a role for the energy-sensing only post-exercise serum from ACT subjects both tissues. Mice that were engineered to molecule that regulates exercise capacity. increased the mitochondrial content of cul - lack the system-wide ability to express IL-15 This highly influential molecule is muscle tured fibroblasts. showed impaired mitochondrial activity in AMPK (adenosine monophosphate-acti - Screening ACT pre- and post-exercise skin and skeletal muscle. In particular, cy - vated protein kinase). Because Tarnopolsky plasma samples for cytokines that might be tochrome c oxidase (COX)—a critical factor wanted to find out if it is involved in exer - inducing this increase in Pgc-1 ␣ identified in mitochondrial production of ATP—was cise’s impact on inducing and/or express - four possibilities. Then four versions of ACT- significantly reduced. ing IL-15, he collaborated with McMaster’s colleague Gregory R. Steinberg, PhD—in both the Division of Endocrinology and Me - DF Annual Meeting Events: 2 01 6 tabolism and Department of Biochemistry and Biomedical Sciences—who had created mice lacking functional AMPK only within Friday, March 4 – Sunday, March 6 skeletal muscle. Although these mice ap - pear normal at rest, they turn out to be ex - Walter ED. FW Easxhiinbgito Bno Coothn v#e1n5ti0o0 n Center ercise intolerant. The cause was traced to a # # # # pair of skeletal muscle defects—significantly fewer mitochondria and impaired contrac - tion-stimulated glucose uptake. Because IL- Saturday, March 5 15 expression is stimulated in part by DF AnnuaMl Marerieottitn Mg aorfq Muise mHobteerls, hMiapr &qu Aisw Baarldlrso oPmre 5sentations contractile muscle activity, this impairment reduced muscle IL-15 mRNA expression 5:30 – 6:30 pm and plasma IL-15 levels. In skin tissue, mito - # # # # chondrial COX activity was diminished. Then a variety of additional studies in mice Sunday, March 6 all contributed confirmation that muscle Leadership Recognition Reception AMPK regulates muscle production of IL-15. National Museum of Women in the Arts The broader recognition gained from this series of explorations is that skeletal muscle 7:30 – 9:00 pm metabolism can regulate skin morphology Co-sponsored by: (see illustration on page 17). Amgen Inc. IL-15: Therapeutic Potential Novartis Pharmaceuticals Corporation With IL-15 apparently the regulatory Valeant Pharmaceuticals North America LLC linchpin in exercise-stimulated mitochon- (By invitation only—tickets required) drial signaling in both skin and skeletal mus - cle, it was time to clarify its therapeutic

16 Fall 2015 Dermatology Foundation as you train. Then during an individual ex - 100 ercise session there is an acute release—or † pulse—of these pre-existing stores.” It is clear to them that this release is partially depend - 90 * ) ent on muscle-specific AMPK, because of %

( the diminished benefit from exercise in Dr. * n 80 Steinberg’s AMPK knockout animals. Now e

g they are studying the other molecular path - a l l ways that contribute to this release. There is o 70 C

always the potential that elucidating these l

a additional pathways will produce additional

m 60 r therapeutic candidates. e

D Tarnopolsky also alludes to their dis - 30 covery of yet another novel way in which ex - ercise restores mitochondrial health. His 0 initial studies of mtDNA mutator mice had re - 5 mo. 23 mo. vealed that damaged mtDNA was in fact IL-15 injection in mice mimics effects of exercise. Both IL-15 injections ( blue ) and endurance exercise being repaired—even though the only known (dark green ) increased dermal collagen content in old mice, partically reversing the effects of aging seen in the repair pathway did not exist. He and his re - control mice ( brown ). (Reprinted with permission from PNAS. See Suggested Readings for citation details.) search team realized that there had to be an as-yet unrecognized repair pathway at work behind the scenes in the exercising mtDNA mutator mice. They succeeded in tracking it down and characterized it, and these studies are awaiting publication. Conclusions In both mice and humans, Tarnopol - sky and his team have demonstrated that exercise not only keeps skin younger, it also appears to reverse skin aging in peo - ple who begin exercising late in life. This occurs via the pathways that result in the release of IL-15 stored in skeletal muscle, which then directly affects the skin as well as the muscle itself. IL-15 acts to maintain the status of healthy mitochondria, and also to repair damaged mitochondria, ex - pand their number, and increase mito - From exercise to collagen. This schematic illustrates the trajectory of molecular events beginning with chondrial oxidative capacity. Addressing the expression of AMPK in skeletal muscle, initiating IL-15 release that migrates to skin and induces healthier the mitochondria themselves is the ideal fibroblast function and tissue. (Reprinted with permission from Aging Cell. See Suggested Readings for citation details.) intervention to mitigate negative effects of aging—in the skin as elsewhere. “And our potential. Tarnopolsky and his lab team level of spontaneous cage activity and their data clearly support endurance exercise as worked with young (5 months) and old (23 higher oxygen use indicated a partial a medicine and a lifestyle approach to im - months) mice that did not exercise, and in - restoration of physical function. proving local and systemic mitochondrial stead dosed half of each group with daily in - Expanding the spectrum to assess the function—critical for reducing morbidity travenous injections of recombinant mouse impact of these daily IL-15 injections on in - and mortality across the lifespan,” IL-15 (rmIL-15) to mimic the endogenous flammation—an important hallmark of aging Tarnopolsky points out. And if exercise is physiologic elevation of IL-15 that follows and metabolic dysfunction—“we measured not a sufficient option, he has established acute exercise. (Other than that, their living plasma cytokines from each treatment the therapeutic value of IL-15. conditions and diet were identical to those group and found that rmIL-15 and exercise for control mouse groups.) The basic impact treatment both reduce circulating levels of Suggested Readings on skin and skeletal muscle in both young the inflammatory cytokines IL-6 and MCP-1,” Safdar A, Bourgeois JM, Ogborn DI, Lit - and old mice was the same as if they had ex - Tarnopolsky points out. tle JP, et al. “Endurance exercise rescues ercised—significantly higher COX activity progeroid aging and induces systemic mito - and mtDNA copy number. And among the Works in Progress chondrial rejuvenation in mtDNA mutator old mice, rmIL-15 treatment was able to du - The fact that the post-exercise increase mice.” PNAS. 2011;108:4135–40. plicate some of the rejuvenating effects of ex - in circulating IL-15 is so immediate indicates Crane JD, MacNeil LG, Lally JS, Ford ercise training on aging skin and skeletal a standing reservoir of readily secretable IL- RJ, et al. “Exercise-stimulated interleukin- muscle metabolism—the stratum spinosum 15. “We have already shown that this pool is 15 is controlled by AMPK and regulates thickened and dermal collagen content in - in skeletal muscle,” Tarnopolsky states, “and skin metabolism and aging.” Aging Cell. creased (see graphs above). Their improved we believe that you build up these reservoirs 2015;14:625–34 . I www.dermatologyfoundation.org Fall 2015 17 Membership Opportunities Every Contribution Supports the Future of the Specialty

As you plan your charitable contributions DF Memberships: this year, consider the membership options the DF has available to ensure the future Scholars Circle of the specialty—one of them is just right $250 for you. The need for DF support is critical— Scienti$fi7c5 0Society more so than ever in today’s constrictive economic environment. The specialty’s Leade$r1s,5 S00ociety newest physician-scientists and investiga - tors are starting their careers at a time Annenberg Circle when research dollars are at historic lows. $25,000 commitment, Every one of them will look to the Derma - payable over 5 years tology Foundation for much needed early career support to launch their careers. Up to $10,000 in Leaders Society contributions may be applied. Join or increase your membership contribution before the year is over! AnnuaAl cCo nStruibsuttaioinn ionfg $ 5,000 Visit www.dermatologyfoundation.org or call 847-328-2256. Help fill the urgent need for research For Annenberg Circle members who have dollars. completed their $25,000 pledge.

In Memoriam: Frederick D. Malkinson, MD, DMD, Former DF President

DF president Dr. Michael Tharp describes Dr. Malkinson was Dr. Malkinson as a renaissance man. “Fred deeply dedicated to was incredible—he was known worldwide as medical research and an innovative researcher, especially in the education, and was in - area of radiation medicine, a pre-eminent strumental in expand - journal editor, and a top educator.” For the ing the Dermatology latter, he was honored with the DF’s Lifetime Dr. Malkinson Foundation’s impact Career Educator Award. He was a membero onf the Bspoaercdi aolft yT.r ustees Dr. Malkinson settled in Chicago after from 197 9–1991, and served as the Founda - completing his residency at the University of tion’s Secretary-Treasurer, Vice President, Chicago in 1955, and later joined their faculty. In and President during his tenure. Dr. Malkinson 1968 he founded the Department of Dermatol - was also a founding member of the Leaders ogy at Rush University Medical School, which Society and an early member of the Annen - he chaired for over 20 years. The DF is grateful berg Circle. for his leadership and service to the specialty.

18 Fall 2015 Dermatology Foundation 201 4 Corporate Honor Society Partners in Shaping Dermatology’s Future

The Dermatology Foundation is grateful to the following corporations for their generous contributions last year. Their support furthers the DF’s mission to develop and retain tomorrow’s leaders in the specialty, enabling advancements in patient care.

($500,000 or more ) Cornerstone Benefactor

($200,000 or more ) Platinum Benefactor

($50,000 or more ) Silver Benefactor

AbbVie DUSA Pharmaceuticals

Ranbaxy Laboratories, Inc. Stiefel, a GSK company

www.dermatologyfoundation.org Fall 2015 19 Dermatology Focus c/o Dermatology Foundation Non-Profit U.S. Postage 1560 Sherman Avenue PAID Evanston, Illinois 60201 -4808 Permit No. 236 Melrose Park, IL ADDRESS SERVICE REQUESTED

Giving Bac k— Profile of a DF Volunteer “Something We All Need To Do”

Clinical dermatologist Dr. Misty Caudell This year, Dr. Caudell brought her enthusiasm became a member only three for the specialty to the DF’s cam - years afterL ceoamdpelrest iSnogc hieetry residency at the paign in Nevada. She invitesL heeard ecorsll eSaogcuieetsy to join University of South Florida and two years after the DF by sharing concrete examples of award finishing a year-long cosmetic surgery fellowship recipients and research that have contributed to at the University of Pittsburgh Medical Center. advancing the specialty. Dr. Caudell also points to Joining the DF had been a priority for her own experience when she had a her from the start. “I learned about the practice in Georgia. She referred her Dermatology Foundation and its im - patients with complex rashes to im - portance when I was still a resident. munodermatologist Dr. Robert Swer - I knew that joining the DF was some - lick, chair of dermatology at Emory thing I needed to do once I was able.” University. “I was so thankful to have Dr. Caudell recalls that her der - access to his knowledge and ex - matology rotation in medical school pertise for my most challenging pa - at the Medical College of Georgia tients.” She learned only later that “was my absolute favorite. I was Dr. Swerlick was a DF awardee inspired by the mentors there and early in his career, which strength - really enjoyed the patients. My resi - ened her dedication to the Founda - dency convinced me that dermatol - Misty D. Caudell, MD tion’s mission to support the ogists have the ability to improve development of tomorrow’s experts patients’ quality of life.” Today, she enjoys it all— and teachers. the procedural aspects of her work, the lasting “The DF has been so directly and trusting relationships she builds with her helpful to me as a clinical dermatologist—and patients, and the cosmetic procedures she ultimately benefits the care all dermatologists includes in her general practice. aplrl ovide. Giving to the DF is something we need to do.” The DF is exceptionally grateful to its many volunteers who give so generously of their time to keep dermatology at the forefront of medicine. A DE RMATOL OGY FO UNDA TION PUBLICAT IO N

VOL. 34 NO. 3 SPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC FALL 2015