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A DERMATOLOGY FOUNDATION PUBLICATION SPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC VOL. 33 NO. 2 SUMMER 2014 DERMATOLOGY FOCUS ™ Also In This Issue The DF Turns 50! DF Clinical Symposia: Proceedings 2014–Part II ADVANCES IN DERMATOLOGY The Dermatology Foundation presented its annual 3-day symposia series in February. This highly regarded cutting-edge CME program provides the most clinically relevant knowledge and guidance for making the newest research advances accessible and usable. A daily provocative keynote talk precedes topic-focused, peer-reviewed–caliber presentations. This year’s topics were: Difficult Diseases in Medical Dermatology; Surgery and Aesthetics; Immunologic Skin Diseases; Pediatric Dermatology; How to Avoid Harming Your Patient: Safety Issues in Dermatology; Cutaneous Oncology: Clinical Challenges; Infectious Diseases and the Skin. The Proceedings appear in the Spring (Part I) and Summer (Part II) issues. Janet A. Fairley, MD, and Jack S. Resneck, Jr., MD—Program Co-Chairs KEYNOTE ADDRESS Comparative Effectiveness of Psoriasis Therapies Joel M. Gelfand, MD, MSCE Introduction. Dr. Gelfand explained that efficacy and effectiveness have different and mutually exclusive meanings when evaluating therapeutic modalities. Comparative efficacy research involves the familiar randomized controlled clinical trial, a shortterm and highly controlled format that shows how well a treatment works in an ideal setting. Comparative effectiveness research—of which very little exists so far in dermatology—addresses the far less disciplined realities of daily practice, ie, when the full spectrum of patients (with varied ages, behaviors, treatment histories, and comorbidities) living with a chronic disease are treated by a spectrum of physicians (with varied backgrounds, knowledge, experience, and attitudes) over the long term. The respective results are not interchangeable, yet the randomized controlled clinical trial, 2015 Research Funding Applications Due October 15 DF Welcomes 26 New LS Members despite its obvious limitations, is considered the gold standard— not just for earning FDA approval—but for making evidence-based treatment decisions in real-world settings. Gelfand is among those beginning to create a comparative effectiveness research (CER) data base to support relevant, meaningful treatment decisions— something that is becoming a major public health priority. Effectiveness vs efficacy. In essence, CER asks how well interventions and strategies for preventing, diagnosing, treating, and What Is CER: AHRQ Definition • Comparative effectiveness research is the conduct and synthesis of research comparing the benefits and harms of various interventions and strategies for preventing, diagnosing, treating, and monitoring health conditions in real-world settings. PH Conway and C Clancy. NEJM. 2009;361:328–330. Efficacy • How well does it work in ideal settings (clinical trials)? • Stringent patient selection criteria to optimize safety • Highly motivated patients with strict adherence to research protocol • Highly trained physicianinvestigators with expertise in the study drug • Clinical response determined at arbitrary “short-term” time point • Maximize internal validity Effectiveness well does it work vs • How in real-world use (routine vs vs vs vs vs clinical practice)? • Patient population more susceptible to adverse events • Variations in patient motivation and ability to adhere to prescribed regimen • Variation in experience and knowledge of the drug by prescriber • Clinical response determined in routine clinical visits • Maximize external validity (Continued on page 3) 2015 DF Clinical Symposia ADVANC ES IN D ER M ATO LO GY February 4–8, 2015 The Ritz-Carlton, Naples, Florida Registration Begins in September! Visit www.dermatologyfoundation.org/symposia RAVE REVIEWS “ Chock full of cutting-edge knowledge—the most concentrated presentation of new, pertinent information for dermatology.” “ Great coverage of the modern scope of derm—balance of basic science, clinical, surgical, and cosmetic.” “ Great speakers and latest material in an efficient, high yield setting.” “ Best meeting I attend all year.” COMPELLING TOPICS A spectrum of Mini-Symposia bring the latest advances to benefit your practice: New Perspectives, Old Diseases Melanocytic Lesions Pediatric Dermatology Dermatology and Women CPC Surgical Focus Plus 3 provocative Keynote Talks EXPERT FACULTY David E. Cohen, MD Emma Guttman-Yassky, MD, PhD Misha A. Rosenbach, MD New York University Mt. Sinai School of Medicine University of Pennsylvania Lawrence F. Eichenfield, MD James G. Krueger, MD, PhD Diane M. Thiboutot, MD University of California, San Francisco The Rockefeller University Pennsylvania State University Dirk M. Elston, MD Mark G. Lebwohl, MD Marta J. Van Beek, MD, MPH Mt. Sinai School of Medicine University of Iowa Amy J. McMichael, MD Heidi A. Waldorf, MD Wake Forest University Mt. Sinai School of Medicine Seth J. Orlow, MD, PhD Frank Wang, MD New York University University of Michigan Ackerman Academy of Dermatopathology Andrew T. Goldstein, MD The Centers for Vulvovaginal Disorders The DF Clinical Symposia provides 16 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. 2 Summer 2014 Dermatology Foundation monitoring health conditions work in a real-world practice rather than ideal settings—“real-world information on which interventions are most effective in which patients under which specific circumstances.” A new psoriasis drug in clinical trial, for example, is typically assessed at “the arbitrarily chosen brief interval of 12 weeks. We make our treatment decisions based on this,” yet patients living with a chronic disease are concerned with a drug’s impact “over a broad time frame.” A collaboration of federal and academic organizations has launched a major initiative to generate CER data and disseminate such results to the medical community. The current combined funding pool for this initiative exceeds $4 billion, and the recently established Patient Centered Outcomes Research Institute (PCORI) leads the way in funding and directing effectiveness research. The Institute of Medicine’s top 100 priority list includes treatments for psoriasis and for acne. DCERN and psoriasis. “Because there is almost no comparative data on our increasingly numerous therapeutic options for patients with psoriasis, we have no way of choosing the best treatment for a given patient.” Gelfand is taking the first steps with a substantial challenge grant (from NIAMS) enabling him to establish a CER infrastructure—DCERN, the Dermatology Clinical Effectiveness Research Network—and begin assessing the real-world effectiveness of psoriasis therapies. DCERN involves academic hubs at UPenn and the University of Utah and a network of private practices across the U.S. Currently, Gelfand and his colleagues are creating a detailed, panoramic snapshot of current reality to answer: “how are our patients doing?” Assessment of the ~2,000 patients with moderateto-severe psoriasis seen annually by DCERN’s clinical network includes multiple measures of patient treatment satisfaction and quality of life, plus a variety of physician-reported outcome measures. Gelfand discussed the 713-person subset currently using a systemic treatment (most commonly methotrexate, the TNF inhibitors adalimumab, etanercept, and ustekinumab, and narrow-band phototherapy [NB-UVB]). Average treatment duration was 11 months. Adalimumab achieved the best control. Inappropriate and ineffective treatment was unexpectedly common, eg, 36% of patients on etanercept who were beyond the double-dose period yet still being double-dosed; a large percentage of NB-UVB-treated DERMATOLOGY FOCUS A PUBLICATION OF THE DERMATOLOGY FOUNDATION Sponsored by Valeant Pharmaceuticals North America LLC Editors-in-Chief Mary M. Tomayko, MD, PhD—Assistant Professor of Dermatology Yale School of Medicine, New Haven, CT Heidi A. Waldorf, MD—Director, Laser and Cosmetic Dermatology The Mount Sinai Medical Center, New York, NY Executive Director Sandra Rahn Benz Deputy Executive Director Christine M. Boris Please address correspondence to: Editors-in-Chief Dermatology Focus c/o The Dermatology Foundation 1560 Sherman Avenue, Evanston, Illinois 60201 Tel: 847-328-2256 Fax: 847-328-0509 e-mail: [email protected] Published for the Dermatology Foundation by Robert B. Goetz—Designer, Production Sheila Sperber Haas, PhD—Managing Editor, Writer This issue of Dermatology Focus is distributed without charge through an educational grant from Valeant Pharmaceuticals North America LLC. The opinions expressed in this publication do not necessarily reflect those of the Dermatology Foundation or Valeant Pharmaceuticals North America LLC. © Copyright 2014 by the Dermatology Foundation patients who were significantly below effective dosing. Controlling for all factors that could influence intertreatment differences showed that biologics are superior to methotrexate based on physician-reported outcomes (such as body surface area affected), but patient-reported outcomes (such as the dermatology life quality index) showed that patients regarded all treatments as equivalent. Deferred Giving: The Benefits of a Bequest to the DF Contributing to the Dermatology Foundation this year is the best way to ensure that today’s new generation of physician-scientists and investigators have the support they need to initiate work that will continue to advance patient care. A simple, effective way to provide this much-needed funding well into the future is a bequest to the Dermatology Foundation. A bequest is your legacy to benefit future generations of dermatologists and patients— and what better time to arrange this future support than the DF’s 50th anniversary year. www.dermatologyfoundation.org By reducing your estate, a bequest also has the potential to reduce estate taxes. Once your attorney and/or financial advisor helps determine the most beneficial option for establishing a bequest, be sure to identify the Dermatology Foundation, a 501(c)3 organization, as the gift recipient in your will or other instrument. Please note that the DF is able to accept only monetary donations. If you have questions about establishing a bequest to the Dermatology Foundation, feel free to address them to Sandra Benz, DF Executive Director, at 847-328-2256 or [email protected]. Summer 2014 3 Adalimumab illustrates “the huge gap” between clinical trials and the real world in physician-assessed treatment success. Although ~80% of patients are clear/almost clear at the end of a 12- to 16-week clinical trial, only ~48% were clear/almost clear during routine follow-up in the real world. “In clinical practice only ~24–48% of patients on systemic treatments are clear/almost clear— even at highly experienced clinical centers.” This actually “overestimates effectiveness” because those experiencing little to no benefit had already stopped using the particular drug and were not in the assessment. Study results also identify phototherapy as “an example of health care gone wrong.” Although it is quite effective, regarded as the safest psoriasis treatment, and cheap compared to the biologics, travel time and co-pays make it costly for patients. “We have to figure out why our safest and cheapest therapy is the most expensive and inconvenient for those who need it.” And only 10% of patients were receiving phototherapy at a frequency (3 times/week) that maximizes efficacy while decreasing toxicity. Gelfand also learned that patients typically stopped TNF inhibitors because they lost effectiveness within a year, not for adverse effects. “This raises a significant issue for a disease requiring good control for a lifetime.” Next, DCERN will explore persistence, the various real-world factors that contribute to long-term treatment success. Conclusion. It is clear that data from 12-week clinical trials can mislead care providers, and that real-world effectiveness data are needed to guide our treatment decisions. The concept of treatment persistence may be the most informative marker for identifying the best drugs. PGA Clearance: Real World vs RCT • Most patients fail to achieve longterm disease control • Durable response rates are much lower in clinical practice compared to short-term RCTs JM Gelfand et al. Arch Dermatol. 2012;148:487. J Takeshits et al. JID. 2013;133:S92. 4-year Drug Survival Rates in Denmark: DERMBIO Database • 4-year survival: – 40% Etanercept – 70% Infliximab • Reasons for stopping treatment: – Loss of effectiveness (75%) – Adverse events (12%) • Protective factors: – Male sex, no prior TNF failure, infliximab R Gniadecki et al. Brit J Dermatol. 2011;164:1091–6. 4 Summer 2014 MINI-SYMPOSIUM: IMMUNOLOGIC SKIN DISEASES Emerging Biologic Therapies for Psoriasis Bruce E. Strober, MD, PhD Introduction. A robust pipeline of self-injectable biologic drugs for psoriasis should give us at least 8 approved biologics within the next 5 years. Dr. Strober discussed 4 monoclonal antibodies in clinical trials. Their 12-week placebo-compared endpoint enables us to “know the drug works better than placebo, and in a significant manner.” Data given are for the highest dose. Inhibiting the IL-17 pathway. Discovery of IL-17’s pathophysiologic role in psoriasis spurred several targeted drugs with similarly high efficacy. Brodalumab blocks the IL-17 receptor (impeding the signaling of all IL-17 isoforms). In phase II data, at week 12 (biweekly dose), 82% achieved PASI-75 and 75% reached PASI-90—“possibly a more relevant metric.” (Phase III trials are in progress, including comparison with the IL-12/23 inhibitor ustekinumab.) Secukinumab and ixekizumab immobilize the primary isoform IL-17A. Phase III data for secukinumab—dosed weekly for 1 month, then taken monthly—included a 12-week placebo arm and a 1-year etanercept arm (TNF inhibitor, administered at its standard, FDA-approved dosing). At week 12 with secukinumab, 77% reached PASI-75, 60% attained PASI-90, and 30% reached PASI-100. It consistently outperformed etanercept. Candida infection is the one notable adverse effect (5% of the high-dose group) observed with this agent (most cases were mild). Week-20 phase II data for ixekizumab show ~82% of patients reached PASI-75, ~70% reached PASI-90. Secukinumab approval is expected within a year; brodalumab and ixekizumab will follow. Anti-IL23 p19 antibody. Tildrakizumab and guselkumab are considered an “improvement” over the less precise ustekinumab. (IL-23 collaborates with IL-17.) Ustekinumab’s target is p40, a molecule shared by both IL-12 and IL-23; tildrakizumab and guselkumab bind exclusively to p19, found only in IL-23. Both of these IL-23 inhibitors demonstrate efficacy in phase II studies that is comparable or better than that of ustekinumab. Whether the more selective drug has better safety is unknown, but may be inconsequential compared to a drug that “already seems pretty clean.” Conclusions. Waning long-term efficacy will continue. Confident safety claims have to await post-marketing data. Because the TNF inhibitors appear to surpass the newer medications for efficacy for psoriatic arthritis, “one of these agents should probably be your first-line biologic for such patients.” Summary: Pipeline Biologic Drugs • IL-17 inhibitors – Selective for IL-17R—brodalumab – Selective for IL-17A—secukinumab, ixekizumab • IL-23 inhibitors – Selective for IL-23 p19—tildrakizumab • High efficacy, self-injectable • Good early data on safety • Likely to have lesser efficacy for psoriatic arthritis than the TNF inhibitors (Continued on page 6) Dermatology Foundation www.dermatologyfoundation.org Summer 2014 5 Vitiligo: What Do I Tell My Patients, and Can I Make Them Better? John E. Harris, MD, PhD Introduction. Vitiligo, an autoimmune disease of the skin, lacks effective treatments because the underlying molecular pathway has long been a mystery (although Dr. Harris is hot on its trail*). “But this does not mean—as I tell my patients—that we cannot help them. There is a lot we can do.” Harris noted basic elements in pigment loss and recovery, then characterized uncommon and rare presentations of vitiligo before describing its basic workup and treatment (all off-label). Vitiligo basics. This relatively common disease (.50–1% of the population) appears before age 20 in half the patients and can create profound emotional distress. Small macules of depigmentation grow to patches that coalesce. Harris described various locations and manifestations. He explained the importance of pigmented hairs for repigmentation during treatment, but noted that glabrous skin can repigment—albeit very slowly. Depigmentation vs Hypopigmentation to 20% in this population. Treatments work best in combination. “Hands down, the most effective” combines narrow-band UVB (NB-UVB) with topical corticosteroids. Harris uses clobetasol on an alternate-week schedule, adding tacrolimus for the off weeks if insurance covers it. Patient limitations are important—some have no time for NB-UVB, some hate applying creams. The good news. Let patients know they appear to be at a lower risk for skin cancers. A recent study found a 3-fold lower risk of melanoma and nonmelanoma skin cancers in this group. Harris sees “a spectrum with vitiligo at one end and melanoma on the other, with most people somewhere in the middle.” *M Rashighi et al. “CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo.” Sci Transl Med. 2014;6. doi: 10.1126/scitranslmed.3007811. MINI-SYMPOSIUM: PEDIATRIC DERMATOLOGY Recognizing Nutritional Deficiencies in Children James R. Treat, MD Vitiligo + Progressive Macular Hypomelanosis Combination Therapy Is Most Effective Introduction. Significant nutritional deficiencies in children occur in varied contexts: parents overzealously withdrawing possibly allergenic foods, children with autism spectrum disorders who reject many foods, metabolic disorders, malabsorption, eating disorders, and certain drugs. Dr. Treat discussed cases for which the skin can aid the diagnosis. Treatment is repletion; improvement is often rapid and dramatic. Case discussions. Case 1: kwashiorkor. An 11-monthold with atopic dermatitis (AD) has a widespread dry and cracked scaling rash that does not reflect AD, is somewhat edematous, and is failing to thrive. The parents claim milk, soy, peanut, egg, and wheat allergies. “As this child is failing to thrive, has a very restrictive diet, and widespread dry, cracked skin—consider a nutritional deficiency.” The parents were using rice milk as his “formula,” ie, sufficient nutrition, insufficient protein. Case 2: zinc deficiency. An 8-month-old has a 2-month history of diaper and facial eruption unresponsive to nystatins, zinc oxide, or substituting fragrance-free diaper wipes. The eroded, crusted rash that is poorly responsive to treatment is the primary clinical clue to zinc deficiency. Other clinical clues include diarrhea, irritability, and photosensitivity. Low alkaline phosphatase—a zinc-dependent protein—is a rapid test, justifying initiating oral zinc while waiting for zinc level results. Case 3: carotenemia. A 3-year-old with trisomy 21 is fluorescent orange, yet his diet is exclusively spaghetti without tomato sauce, chicken nuggets, and a multivitamin. The child’s carotene levels were 10 times normal due to Ascorbic Acid Deficiency (Scurvy) *NOTE: There are no FDA-approved treatments for vitiligo. ALL treatments are used off-label. T Lotti et al. Dermatol Ther. 2008;21 Suppl 1:S24. Workup and treatment. The workup is clear and straightforward, as there are few other possibilities. The Woods lamp is indispensable in highlighting depigmentation. A review of systems looks for coincident autoimmunity. Thyroiditis is increased from 3% 6 Summer 2014 • Often seen in patients with eating disorders, autism spectrum disorders, or with extreme malnutrition • Presenting signs of bleeding gums, gum hypertrophy, perifollicular hemorrhage • Can also have boney findings and pain as their presenting sign (periosteal lifting, osteopenia) • Repletion is rapidly beneficial • Pediatric Bottom Line: Ask about diet, as there has to be severe malnutrition to get scurvy Dermatology Foundation hypothyroidism (which impairs the conversion of carotene to retinol), fairly common with trisomy 21. Case 4: phrynoderma. A colleague’s young patient with Crohn's disease had follicular hyperkeratosis. These widespread scaly papules indicate phrynoderma, ie, severe vitamin A deficiency. GI illnesses and malabsorption easily affect absorption of vitamins A, D, E, and K. Case 5: scurvy. A child with autism spectrum disorder was diagnosed with vasculitis and sent to the emergency room for confirmation. He had red papules on his arms and legs and refused to walk. A close look also showed perifollicular hemorrhage and bleeding gums—all consistent with scurvy. The child would eat only popcorn and chocolate milk, and was seriously vitamin C-deficient. Testing for vitamin C is the sole assessment. Nutritional Deficiencies: Bottom Line • Remember not only underserved populations, but also those with restrictive diets—happens in autism spectrum disorders, extreme or over-diagnosed food allergies, eating disorders—and malabsorption • Testing and therapy are extremely satisfying— it just has to be on your differential diagnosis! Neonatal Dermatology: Case-based Challenges Ilona J. Frieden, MD Introduction. Dr. Frieden discussed neonatal cases that are relevant to the management of older patients. Candidiasis. Although congenital and neonatal candidiasis may involve features resembling those seen in immunocompromised hosts, some presentations are truly unique. Although congenital candidiasis usually presents with a widespread scaly eruption on face and torso, this is one of the few eruptions characterized by small pustules where the palms and soles are typically involved. Thus when this occurs, it can be particularly helpful in diagnosis. Risk factors include prematurity, maternal history of vaginal candidiasis, and amniotic rupture (overt or subclinical) that creates a “Candida albicans bath.” Frieden discussed a spectrum of disease in neonates, including the potential for life-threatening disease in very preterm infants. Face mask pressure-induced necrosis. A 32-week gestational age infant 7 weeks after birth had an area of skin necrosis from face mask CPAP, which is being increasingly used in NICUs. Mask CPAP is used commonly in adults and while reports of skin effects are rare, they are probably under-recognized. Subcutaneous fat necrosis (SCFN). Frieden discussed a patient with extensive SCFN following therapeutic hypothermia for perinatal asphyxia. Therapeutic hypothermia is a very important treatment to improve neurologic outcome in asphyxiated newborns, but creates “the perfect storm” for SCFN risk because both asphyxia and cold can each induce SCFN. Consider this diagnosis if you see a newborn (or adult) who had this treatment. Extensive SCFN requires monitoring for hypercalcemia for 4 to 6 months. Perinatal scalp injury. Chronic scalp dermatitis can arise after perinatal birth injury and in certain rare ectodermal dysplasias such as Rapp-Hodgkin and Hay-Wells syndromes. These scalp dermatoses resemble so-called erosive pustular dermatosis seen in elderly actinic-damaged scalps. In young infants, we hypothesize that abnormal or damaged hair follicles act as a foreign antigen and provoke an intense inflammatory reaction. Potent topical antiinflammatory medications can be helpful, as in the elderly. www.dermatologyfoundation.org Candida Infection in Newborns • Most common–diaper or other skin folds • Nail dystrophy • Congenital candidiasis–widespread erythema, pustules, and scale – Present at birth or within 1–3 days • Palmar pustules common • Invasive candida in preemies–serious! Cooling and SCFN: Take-home Points • Cold temperatures cause SCFN • Asphyxia is main risk for SCFN • Asphyxia treated with cold could worsen SCFN risk and extent of disease • Therapeutic hypothermia used in older children/adults: ? potential for injury TP Wiadrowski et al. Austral J Dermatol. 2001;42: 217–9. YM Liu et al. J Burn Care Res. 2014;35:e1846. Perinatal Scalp Injury: Take-Home Points • Erosive pustular dermatosis in elderly actinicdamaged scalps gave clues to infants • Probable common pathway – Damaged follicles/scarring/anatomic chaos leading to strong inflammatory reaction • Anti-inflammatory medications helpful in improving process KEYNOTE ADDRESS Update on Melanoma Genetics Hensin Tsao, MD, PhD Introduction. “The molecular revolution is bringing about a sea change” in the way we think about melanoma, and thus its treatment, Dr. Tsao observed. Before this, we held overly simplified notions of cutaneous melanoma and its genetic causality. And until 3 years ago, only 3 major genes—p16, CDKN2A, and CDK4—had been identified in familial melanoma (10% of melanoma tumors), discovered 20 years earlier. But in the past 5 years, advances in the reach and speed of technology have enabled a vast jump shift in assessing the DNA from melanoma families. In the last 3 years, 3 major new familial genes have been identified (some also relevant to sporadic melanoma) that fundamentally expand our awareness of the locus where mutations can reside, and illuminate cutaneous melanoma’s connections to other cancers. The concept of melanoma heritability goes beyond cutaneous melanoma to melanoma and mixed cancer syndromes, and molecular patterns are replacing morphology in defining them. We are moving from phenotype to genotype in identifying high-risk individuals. These new genes are TERT (telomerase reverse transcriptase), BAP1 (BRCA1-associated protein-1), and MITF (microphthalmia-associated transcription factor). Tsao discussed them and the lessons we are learning from them. TERT. Telomerase is encoded by the TERT gene. Telomerase maintains the caps at chromosome ends to ensure proper chromosome division, and thus appropriate cell longevity. With too little Summer 2014 7 New Members Add Support for Dermatology’s Future The Dermatology Foundation extends a warm welcome to the 26 newest Leaders Society members. Their decision to participate at this level to help advance the specialty’s future is especially important in our environment of dramatically decreased federal research funding. Each of these dermatologists contributed $1,500 this year to support the early research of those individuals who can make a difference. out to have a father with ocular melanoma and a brother with both melanoma and kidney cancer. Their search led his team to BAP1, which appears to be mutated in families with cutaneous and ocular melanoma, and often mesothelioma. BAP1 is an important housekeeping enzyme. Normally, the cell’s “trash collection system” places an ubiquitin tag on individual proteins earmarked for destruction; BAP1 removes ubiquitin groups to prevent inappropriate protein destruction. If BAP1 does not work properly, there may be overdestruction of growth-restraining proteins, insufficient removal of growth-promoting proteins, or altered synthesis of these cancer genes (ubiquitination may also be involved in transcription regulation). Having studied close to 300 melanoma families now, Tsao Known Mutations (As of July 22, 2014) Neera Agarwal-Antal, MD Christine Ambro, MD Saundrett G. Arrindell, MD Barbara S. Bopp, MD Alexandra Cameli, MD Janet F. Cheng, MD Jeri Beth Foshee, MD Scott D. Glazer, MD Noah Gratch, MD Earl G. Gross, MD John E. Harris, MD, PhD Suzanne P. Hess, MD Kevin P. Hogan, MD, PhD Tony Hsu, MD William W. Huang, MD Anne W. Lucky, MD Gregory A. Nikolaidis, MD Jeffrey North, MD Gregory G. Papadeas, DO Laura B. Pincus, MD Elizabeth Faircloth Rostan, MD Sarah K. Short Sarbacker, MD Jeffrey B. Travers, MD, PhD Eduardo H. Tschen, MD Travis W. Vandergriff, MD Caroline S. Wilkel, MD telomerase, cells undergo senescence or chromosomal instability. In a recent study, an upregulating TERT mutation was found to cosegregate with melanoma patients from one German family. Carriers also developed other cancers—ovarian, kidney, bladder, and breast cancers—thereby defining “a multi-cancer melanoma complex.” This TERT variant sits in the promoter region of the TERT gene and creates a new transcription factor binding site, which triggers the heightened telomerase production. Tsao and others have since found a variety of telomerase-upregulating changes “everywhere within TERT” in 74% of melanoma cell lines, one-third of primary melanomas, and in a small number of liver and thyroid cancers—but in no other cancers. And in 10% of melanomas, TERT itself is also amplified, driving telomerase overproduction even higher. It is clear that alterations outside the coding region can upregulate protein expression. BAP1. The family that stimulated Tsao’s gene hunt involved a young woman with superficial spreading melanoma who turned 8 Summer 2014 Melanoma Risk Alleles Progress in Melanoma Genetics • New concepts in melanoma heritability – Melanoma/mixed cancer syndromes – New mechanisms of cancer predisposition – Gain of expression promoter variants (TERT) – Altered ubiquitination (BAP1) – Altered epigenetic reprogramming (MITF) • NextGen sequencing will be game-changing – Novel discovery strategies needed for the deluge of variants – “Missing heritability” may result from a large number of low-prevalence mutations Dermatology Foundation The Thomas B. Fitzpatrick Legacy Fund The Powerful Gift That Keeps on Giving Established a decade ago to honor a DF founder, these $100,000 gifts empower the future that Dr. Fitzpatrick set out to build. Contributing to the Fitzpatrick Legacy Fund during this 50th anniversary year is an especially meaningful way to recognize what the DF has already done while ensuring its full future potential. And those 70½ or older this year can benefit from tax-free directfrom-IRA contributions capped at $100,000. Contact Sandra Benz at the DF office for more information: 847.328.2256. et al. have found a higher rate of inactivating BAP1 mutations in families with mixed ocular and cutaneous melanoma—including the one just described. Metastatic disease was common, and had developed very quickly. “If BAP1 mutation carriers can be shown to be at higher risk for metastatic, lethal ocular melanoma, I can envision a scenario in which mutation carriers may need to be screened more aggressively.” Tsao has now identified a “new sort of syndrome” that links ocular and cutaneous melanoma with mesothelioma and renal cell carcinoma. “When we gather a family history of melanoma, it must be broader than just cutaneous disease.” MITF. A small region on chromosome 3—focally amplified in melanoma tumors—contains the MITF gene, an epigenetic transcription factor that modifies the functions of existing proteins in melanocytes and in retinal pigment cells. Mutant MITF can alter or substitute the protein targets that are regulated. Since amplified MITF was found in roughly 4% of melanomas, Tsao’s group became part of an international consortium that identified a disease-causing variant in MITF. This variant predisposes carriers to cutaneous melanoma and/or renal cell carcinoma, with moderate risk. Conclusion. To be determined: how exactly these mutations cause cancer, and if there is a relationship between these mutations and UV exposure. Tsao also noted the search for a larger percentage of our melanoma families and a greater range of the genetic factors accounting for melanoma heritability. MINI-SYMPOSIUM: CUTANEOUS ONCOLOGY: CLINICAL CHALLENGES High-Risk Squamous Cell Carcinoma Marc D. Brown, MD Introduction. “The skin cancer keeping me awake at night more than anything else—one I’ve seen change tremendously over my 30 years in practice—is high-risk squamous cell carcinoma,” Dr. Brown said. Metastasis occurs in 2–5% of all SCC, but in 20% of highrisk disease. The 10–15% lifetime risk for SCC is dramatically higher past age 70, and in immunosuppressed patients. Defining high risk. Tumor size and depth of invasion are the two most important criteria. “Size matters”—tumors 4–6 mm deep, or down to the deep subcutaneous tissue or beyond. Worrisome locations are the ear, lip, genitalia, cheek areas overlying the parotid gland, balding scalp, back of the hand, and burn sites. Worrisome histology includes poor differentiation and perineural invasion. Recurrent SCC www.dermatologyfoundation.org Current Members Rex A. Amonette, MD Susan V. Bershad, MD Gordon J. Dow, PharmD Harley A. Haynes, MD James J. Leyden, MD Robert L. Roschel, MD Jonah Shacknai Charles W. Stiefel Eugene J. Van Scott, MD Ruey J. Yu, PhD, OMD Anonymous Donor can be more aggressive. SCC in the immunosuppressed population are typically high risk, intensely so in organ transplant patients. Immunosuppression. This includes significant numbers of patients living a lot longer with HIV or chronic lymphocytic leukemia (CLL), and anyone on immunosuppressive medication— which makes the organ transplant population especially vulnerable. This population has a 65-fold increase in SCCs, with tumors Characteristics of SCC in Organ Transplant Recipients (OTRs) • Incidence ratios of skin cancer in OTRs – Squamous cell carcinoma: 65-fold increase – SCC of lip: 20-fold increase – Basal cell carcinoma: 10-fold increase – Melanoma: 3.4-fold increase • Occur on an average of 30 years earlier • More frequently multiple • Increased rate of recurrence • Increased rate of metastasis • May have more rapid rate of growth • Some patients with a tremendous number of tumors Final Thoughts 1. Incidence of cSCC is increasing. 2. More patients with high risk SCC. 3. Predicting a patient’s risk for metastatic spread is difficult—but assessment of defined risk factors may help identify this subset. 4. Aggressive surgical excision with clear margins is treatment of choice. 5. SLN Bx may provide prognostic and therapeutic value, but is not well studied. 6. In high-risk patients, electively treating first echelon nodes may improve survival, but high level data are lacking. 7. Patients with metastatic nodal disease should receive surgery and radiation. Summer 2014 9 that occur an average of 30 years earlier, are significantly more aggressive, and far more likely to recur and to metastasize. Treatment. Brown relies on Mohs surgery with margins of 5– 10 mm instead of 2 mm. Radiation is suggested for patients who are not surgical candidates. Roughly 50% of patients with clinically detectable nodal disease will die from metastatic disease, accounting for at least 2,500 deaths annually in the U.S. There is no best treatment option. “We still do not have a good answer.” Brown noted appropriate situations for adjuvant radiation, discussed elective lymph node dissection and sentinel lymph node biopsy, and noted modest benefit at best with systemic drugs (retinoids, oral 5-FU, cetuximab). Unusual Presentations of Cutaneous Lymphomas Laura B. Pincus, MD Case #1. A 29-year-old otherwise healthy woman with a 9-year history of discrete small (1–5 mm) erythematous papules on her forehead, bilateral temples, and chin was diagnosed with acne/rosacea. Treatment was ineffective. Although a small biopsy 3 years after diagnosis showed a dense B-cell infiltrate pointing to a low-grade B-cell lymphoma, a definitive diagnosis could not be made in part because of the biopsy’s small size. Once the request for further sampling was eventually agreed to, H&E and then immunostaining confirmed the diagnosis of B-cell lymphoma, follicle center type. Lesson: Add follicle center lymphoma to your differential diagnosis of new-onset acne in an adult. Case #2. A 54-year-old man saw his PCP for a nondescript erythematous patch on his thigh. It was diagnosed as a reaction to new medication. Several months later, the patient developed nasal congestion that was unresponsive to treatment for allergic rhinitis (his PCP), then for suspected polyps (ENT). Several months afterward, a 3.5-cm intranasal mass was detected and diagnosed as NK T-cell lymphoma, nasal type, which is an aggressive T-cell lymphoma. The thigh lesion was deemed unrelated—until body-wide papules and nodules erupted after radiation for ostensible stage II disease. It had in fact been his first manifestation of NK T-cell lymphoma, nasal type in the skin. The patient actually had stage IV disease, and should have received chemotherapy, not radiation. Lesson: Be aware that this T-cell lymphoma can present with a subtle erythematous patch. During staging, biopsy anything nonordinary or relatively new. Case #3. A biopsy of a long-standing rash on a 76-year-old man showed a granulomatous infiltrate in a nodular configuration, for which the patient was diagnosed with sarcoidosis. Pincus saw the pa- tient and discovered papules and plaques across his body, highly suspicious for MF. But “sarcoidosis is a great mimicker of MF,” so additional biopsies were taken. These more typically combined findings of conventional MF with the granulomatous infiltrate, confirming a diagnosis of granulomatous MF. Lessons: When granulomas form the bulk of the histopathologic findings, added biopsies can be helpful. Such cases are often misdiagnosed as granulomatous dermatitis. Management of Challenging Pigmented Lesions Hensin Tsao, MD, PhD Introduction. Dr. Tsao discussed atypical Spitz tumors, noting the concern and uncertainty they engender. He noted that there is no one way to manage an atypical Spitz tumor, and outlined what he knows and what he does. Spitz Tumors—Clinical Spectrum Clinical Feature Age Location Size Shape Border Surface Color Classic Spitz Nevi <10 yrs old extremities, face, neck <5–6 mm diameter symmetric, dome-shaped well-defined smooth pink/reddish S Luo et al. JAAD. 2011;65:1073–84. Pathologic Spectrum Atypical Spitz Tumors Case #1: Follicle center lymphoma • Can present as acneiform morphology on the face • Excellent prognosis • On the ddx of an adult acneiform eruption • Follicular MF also on ddx of acneiform eruption Case #2: NK T-cell lymphoma, nasal type • Can present with erythematous patches • Suspicious clinical lesions should be biopsied • Ensure biopsy adequate for clinical lesion Case #3: Granulomatous MF • Granulomas present in biopsies • Clinically indistinguishable from conventional MF • Additional biopsies can be helpful • Cases often misdiagnosed as sarcoid 10 Summer 2014 Classic Haphazard, infiltrative Asymmetric Poorly circumscribed Disrupted, ulcerated epidermis Absent or few Kamino bodies Lack of junctional clefting Atypical Spitz Subcutaneous involvement Prominent, single-cell pagetoid spread, beyond epidermal nests Confluence, dense cellularity Lack of zonation Persistent, expansile deep nests Mitoses ≤2–6/mm2 Take Home Points Atypical Spitz Tumors 10–20 yrs old back >1 cm diameter increasing asymmetry irregular irregular, ulcerated irregular More heterogeneous cell types Granular, dusty cytoplasm High nuclear-to-cytoplasmic ratio Hyperchromatism Large eosinophilic nucleoli Spitzoid Melanoma S Luo et al. JAAD. 2011;65:1073–84. Summary: Atypical Spitz Tumors • Appear to metastasize more often in general • Different genetics 씮 different biology 씮 different outcome – Malignancy (lethality) ≠ Cancer (metastases) – Borderline tumors 씮 developmental anomalies? • Adult melanomas 씮 genetically injured melanocytes? • Better survival than predicted with adults with similar melanomas • Re-excise to prevent local recurrence Dermatology Foundation What we know. Compared to common Spitz nevi, atypical tumors involve an older population, larger size, asymmetry, greater depth, and increased cellularity and mitotic rate. Although alterations in the HRAS gene had been described years ago, more recent analyses have pinpointed activating translocations, rather than point mutations, of receptor tyrosine kinases as common inciting events. Similar rearrangements occur in both Spitz tumors and spitzoid melanomas, “and we do not understand how the same oncogenes lead to these different phenotypes.” Despite a 40% chance of a positive SLNB, actual metastasis is rare. And when Tsao et al. followed all Spitz and atypical Spitz tumors at MGH for at least 10 years, only 7 melanomas developed, always in addition to the Spitz tumor rather than evolving from it. “So the Spitz tumor is behaving more like a marker than a precursor,” and appears to confer an 8-fold increase in risk for melanoma. What we do—the Users Manual. Tsao avoids needless anxiety for patients and parents, calling it simply “a lesion of interest” that is genetically distinct from melanoma. Re-excision is essential to prevent recurrence. Tsao clears a 5 mm–1 cm margin, depending on size and degree of atypia. “Although there was a period of time when SNLB was performed on atypical Spitz tumors, we’ve backed off on doing nodal sampling given the wave of recent articles documenting a high microscopic nodal disease rate but low survival impact.” Tsao avoids these procedures in children because of completion dissection that ensues, and also the use of interferon in young children espoused by many medical oncologists. “SNLB does not appear to predict outcome, nor has interferon ever been shown to alter the outcome of metastatic Spitz tumors.” Conclusion. “I have gone from an enthusiastic molecular geneticist who really believed in SNLB to a primary focus on trying to reassure the parents, and making sure the tumor is re-excised. We do very little for thin melanomas that do have a much higher lethal potential, so why are we exaggerating what we do with these atypical Spitz tumors?” Recurrent SSTI. The poorly understood pathophysiology of recurrent SSTIs and the paucity of good data for guidance makes them “very tough to treat.” There is a complex and mystifying relationship between host, pathogen, and the household environment. Decolonization data do not support bleach baths or chlorhexidine washes. Schwartz has “had some reasonable results” with using twice daily nasal mupirocin for 1 week/month. Systemic therapy is generally a last resort. Non-tuberculous mycobacteria (NTM). A woman with multiple erythematous papules on her face after full-face fractional laser treatment failed all treatments until a rapid-growing, acid-fast bacillus was cultured post-biopsy and identified as NTM. NTM skin infections have increased substantially in the past 30 years, especially recently. Half of Schwartz’s cases are post-procedure (cosmetic or biopsy); half follow a traumatic injury. Antibiotic treatment alone may be effective, but surgical debridement is often needed. Azithromycin plus TMP/SMX was curative in this case. MINI-SYMPOSIUM: INFECTIOUS DISEASES AND THE SKIN Incidence of Cutaneous Non-tuberculous Mycobacteria Infection (NTM) 1980–2009 Microbiology of Purulent SSTIs GJ Moran et al. NEJM. 2006;355:666–74. Skin Infections: The Perspective From an Infectious Disease Specialist Brian S. Schwartz, MD Introduction. Dr. Schwartz emphasized that “there is no one right way to treat many of these skin and soft tissue infections (SSTI).” Representative cases introduced the important issues for purulent, nonpurulent, and recurrent SSTIs, and he discussed the literature and his treatment choices. Purulent SSTI. A 32-year-old afebrile man had a 3-day-old painful, enlarging thigh lesion—attributed to a spider bite—that appeared to be an abscess or furuncle. Data show no significant benefit from adding antibiotic therapy to incision and drainage (I&D). “To be a good antimicrobial steward,” Schwartz typically omits antibiotics for a first infection (with exceptions), using them only with a recurrence. Because 75% of the pathogens causing purulent SSTIs are S. aureus, predominantly MRSA, he advises that empiric regimens include something active against MRSA. Nonpurulent SSTI. An afebrile young woman presented with a 2-day-old erythema of her left foot, an apparent cellulitis. Schwartz opted to begin with cephalexin 500 mg QID, and add TMP/SMX if no response occurred. He described the recent data supporting -hemolytic strep as the primary pathogen in uncomplicated cellulitis, justifying the lack of MRSA coverage unless clearly needed. www.dermatologyfoundation.org AB Wentworth et al. Mayo Clin Proc. 2013;88:38–45. Cellulitis & Pseudocellulitis Daniela Kroshinsky, MD, MPH Introduction. Although Dr. Kroshinsky discussed cellulitis, noting diagnostic challenges in both typical and variant presentations, her primary focus was on “when it’s not cellulitis.” Her intense interest in cellulitis mimickers was sparked when she began as a dermatology hospitalist at Massachusetts General Hospital. She was struck by “the significant number of consults for cases of cellulitis that remained stubbornly unresponsive to treatment.” Reviewing records, she found Summer 2014 11 Why Are You a Leader? Tiffany C. Scharschmidt, MD: “The DF Grows Our Specialty” Dr. Scharschmidt describes the Dermatology Foundation as “a community of dermatologists who give of their personal time and resources to further the specialty. Those of us who become DF members give to grow our specialty into the best that it can be,” says Dr. Scharschmidt, a Young Leader* and dermatologist at the University of California, San Francisco who splits her time between the research lab and clinic. “I feel so fortunate to be a part of this specialty and a DF research award recipient. It means a lot to me to have a way to give back to the Foundation early in my career.” Dr. Scharschmidt completed her residency in 2012, joined the Leaders Society in 2013, and became a new volunteer this year to encourage other young dermatologists in her area to join her in leadership giving. “When I was approached about helping to bring in new members, it was an obvious decision to say yes. My time as a new mother is valuable to me and I don’t take on every opportunity that is offered, but this is one I definitely wanted to be part of.” Dr. Scharschmidt believes DF funding is critical—it supports early research experience and data that are essential to compete successfully for diminishing federal funds. “Dermatologists in my generation have seen exciting advances over the course of our training—including new biologics for psoriasis and targeted treatments for melanoma. Continued research progress is growing more dependent on nontraditional funding sources. I see the DF as an extremely important resource in launching the careers of new faculty members who want to make biomedical research part of their career mission.” Dr. Scharschmidt knew early on that she liked science and medicine. As a kid, she loved spending time in her physician-scientist dad’s lab and regularly visiting her dermatologist mother’s clinic. Then time in a complex medical dermatology clinic during her third year of medical school awakened her recognition that dermatology was perfect for her. “It’s a beautiful specialty. You can see the skin to diagnose it. And for someone interested in research—you have easy access to tissue samples. The skin tells you so much about the human body.” Dr. Scharschmidt is personally grateful for her recent research support from the DF. She received a 1-year fellowship followed by a Career Development Award to identify the cutaneous immunologic mechanisms that enable us to live symbiotically with the commensal organisms residing on our skin. She is now preparing her first NIH grant application—and as a Leaders Society member, is giving her resources and time to help those who follow. *The DF’s Leaders Society is an effective way to give back to the specialty, with an impact lasting well into the future. A new Young Leader is a physician who begins this commitment within 5 years of completing residency. that “85% of these calls turned out to be other diagnoses.” This inspired a 6-month retrospective study of all cellulitis cases that had presented to the hospital (excluding abscesses and atypical infections). Kroshinsky summarized her results, then provided extensive examples and guidance from cellulitis mimickers she has seen. Cellulitis overview. “As we do not have a good gold standard diagnostic technique, we use our clinical criteria.” Be prepared for many variants and exceptions. Kroshinsky discussed the common pathogens, immunosuppressed patients, predisposing traumas (including IV drug use), chronic ulcers and infection, and several variants. Cellulitis mimickers. In the 6-month retrospective review of all hospital admissions for cellulitis, ~18%—“probably a conservative estimate”—were ultimately found to be other diagnoses. In the internal medicine hospitalist service, cellulitis was the 15th 12 Summer 2014 reason for admission but the #1 reason for readmission within 30 days. In the outpatient setting, 80% of the cellulitis diagnoses turned out not to be cellulitis. When Kroshinsky and her colleagues were called in to the outpatient setting for concern with unresponsive cellulitis, “we were able to reduce antibiotic use by 82%.” She added that “this is an arena where we perform better than all other specialties in being able to prevent morbidity and unnecessary hospital admission for patients who really have other skin diseases, and not cellulitis.” Examples. For infections, Kroshinsky discussed tinea faciei incognito, erysipelas, Lyme’s disease, erythema migrans, early zoster, brown recluse spider bite, osteomyelitis, and dental sinus. Patients with noninfectious underlying conditions included subcutaneous fat necrosis of the newborn, erythema nodosum, and Well’s syndrome. (Continued on page 15) Dermatology Foundation FOR INTERDIGITAL TINEA PEDIS DUE TO TRICHOPHYTON RUBRUM AND EPIDERMOPHYTON FLOCCOSUM IN ADULT PATIENTS INTRODUCING LUZU LU Z U FA ST: 2 W E E KS, 14 D O SE S Efficacy demonstrated at 4 weeks post-treatment The only topical azole antifungal approved to treat interdigital tinea pedis with once-daily dosing over a 2-week period Indications and Usage LUZU (luliconazole) Cream, 1% is indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum in patients 18 years of age and older. Important Safety Information • LUZU is indicated for topical use only and is not indicated for ophthalmic, oral or intravaginal use. • LUZU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Caution should be exercised when LUZU is prescribed for nursing mothers. Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies. © 2014 Valeant Pharmaceuticals North America LLC. DM/LUZ/13/0004 • The most common adverse reactions in clinical trials were application site reactions, which occurred in less than 1% of subjects in both LUZU and vehicle arms. Most adverse reactions were mild in severity. Please see full Brief Summary of Prescribing Information on adjacent page. Reference: LUZU [prescribing information]. Bridgewater, NJ: Medicis, a division of Valeant Pharmaceuticals; 2013. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION FOR LUZU (luliconazole) This Brief Summary does not include all the information needed to use LUZU safely and effectively. See full Prescribing Information for LUZU. LUZU (luliconazole) Cream, 1% for topical use Initial U.S. Approval: 2013 Rx Only INDICATIONS LUZU (luliconazole) Cream, 1% is an azole antifungal indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older. DOSAGE AND ADMINISTRATION For topical use only. LUZU Cream, 1% is not for ophthalmic, oral, or intravaginal use. When treating interdigital tinea pedis, a thin layer of LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for two (2) weeks. When treating tinea cruris or tinea corporis, LUZU Cream, 1% should be applied to the affected area and approximately 1 inch of the immediate surrounding area(s) once daily for one (1) week. CONTRAINDICATIONS None ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice. In three Phase 3 clinical trials, 616 subjects were exposed to LUZU Cream, 1%: 305 with interdigital tinea pedis and 311 subjects with tinea cruris. Subjects with interdigital tinea pedis or tinea cruris applied LUZU Cream, 1% or vehicle cream once daily for 14 days or 7 days, respectively, to affected and adjacent areas. During clinical trials with LUZU Cream, 1% the most common adverse reactions were application site reactions which occurred in less than 1% of subjects in both the LUZU and vehicle arms. Most adverse reactions were mild in severity. Post-Marketing Experience The following adverse reactions have been identified during post-marketing use of luliconazole cream, 1%: contact dermatitis and cellulitis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. DRUG INTERACTIONS The potential of luliconazole to inhibit cytochrome P-450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 was evaluated in vitro. Based on in vitro assessment, luliconazole at therapeutic doses, particularly when applied to patients with moderate to severe tinea cruris, may inhibit the activity of CYP2C19 and CYP3A4. However, no in vivo drug interaction trials have been conducted to evaluate the effect of luliconazole on other drugs that are substrates of CYP2C19 and CYP3A4. Luliconazole is not expected to inhibit CYPs 1A2, 2C9 and 2D6 based on in vitro assessment. The induction potential of luliconazole on CYP enzymes has not been evaluated. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C. to pregnant female rats. No treatment related effects on maternal toxicity or malformations were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Increased incidences of skeletal variation (14th rib) were noted at 25 mg/kg/day. No treatment related effects on skeletal variation were noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). Subcutaneous doses of 4, 20 and 100 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. No treatment related effects on maternal toxicity, embryofetal toxicity or malformations were noted at 100 mg/kg/day (24 times the MRHD based on BSA comparisons). In a pre- and post-natal development study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered from the beginning of organogenesis (gestation day 7) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes and increased postnatal pup mortality) was noted at 25 mg/kg/day. No embryofetal toxicity was noted at 5 mg/kg/day (0.6 times the MRHD based on BSA comparisons). No treatment effects on postnatal development were noted at 25 mg/kg/day (3 times the MRHD based on BSA comparisons). Nursing Mothers It is not known whether luliconazole is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when LUZU Cream, 1% is administered to women who are breastfeeding. Pediatric Use The safety and effectiveness of LUZU Cream, 1% in pediatric patients have not been established. The number of pediatric patients ≥12 years of age were too small to adequately assess safety and efficacy. Geriatric Use Of the total number of subjects in clinical studies of LUZU Cream, 1%, 8 percent were 65 and over, while 1.4 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies to evaluate the carcinogenic potential of LUZU Cream, 1% have not been conducted. Luliconazole revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames assay and Chinese hamster lung cell chromosomal aberration assay) and one in vivo genotoxicity test (mouse bone marrow micronucleus test). In a fertility study in rats, subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered prior to and during mating and through early pregnancy. Treatment related effects on reproductive function were noted in females (decreased live embryos and decreased corpus luteum) at 5 and 25 mg/kg/day and males (decreased sperm counts) at 25 mg/kg/day. No treatment related effects on fertility or reproductive function were noted at 1 mg/kg/day (0.1X MRHD based on BSA comparisons). PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Inform patients that LUZU Cream, 1% is for topical use only. LUZU Cream, 1% is not intended for intravaginal or ophthalmic use. Manufactured for: Medicis, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ 08807 There are no adequate and well-controlled studies of LUZU Cream, 1% in pregnant women. LUZU Cream, 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The animal multiples of human exposure calculations were based on daily dose body surface area (BSA) comparisons (mg/m2) for the reproductive toxicology studies described in this section and in Section 13.1. The Maximum Recommended Human Dose (MRHD) was set at 8 g 1% cream per day (1.33 mg/kg/day for a 60 kg individual which is equivalent to 49.2 mg/m2/day). Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 1, 5 and 25 mg/kg/day luliconazole were administered during the period of organogenesis (gestational days 7-17) Manufactured by: DPT Laboratories, Ltd., San Antonio, TX 78215 Product of Japan Issued: 11/2013 140127 DM/LUZ/13/0005(1) Cellulitis • Deep skin and subcutaneous fat infection • Poorly demarcated erythema, warmth, tenderness, edema – Rubor, calor, dolor, tumor: inflammation • 2.2% of all general practitioner office visits • 400,000 bed days per year in the English National Health Service, cost of £96 million ($157.2 million) – U.S.: $98 million for U.S. hospitalization for mouth cellulitis alone • One of the most common infections resulting in hospitalization – Diagnostic criteria are poorly defined, variably applied Pseudocellulitis • Dozens of clinical mimickers of cellulitis: ‘pseudocellulitis’ • Very little literature on pseudocellulitis, prevalence or outcome measures • Empiric use of aggressive antibiotics 씮 rising rates of resistance in soft tissue infections – ‘98–’04: MRSA soft tissue infections 26.2 씮 47.4% Cellulitis: Bullous Variant Case 4: A 10-year-old had fever, severe conjunctivitis, urethritis, and crusted lips (the bottom lip had fully necrosed). It was Stevens Johnson syndrome induced—not by a drug—but by a mycoplasma infection. Because it was limited to mucosa, steroids were helpful. Case 5: A 6-year-old presented with a thick crust on his scalp. Soaking it in saline to remove it allowed Treat to identify underlying alopecia and “a really exuberant kerion,” an inflammatory fungal infection that mimics bacterial infection. Oral antifungal therapy is effective. Case 6: An immunosuppressed 10-year-old girl undergoing induction chemotherapy for new acute lymphoblastic leukemia presented with an asymptomatic purple area on the back of one heel that resembled irritation from her shoe. A biopsy with frozen section showed a cutaneous mold infection. Because there is no inflammatory response to the pathogen, the infected area can be much larger than initially thought. She also had other risk factors for mold infections, and “you want to make your diagnosis immediately, treat broadly, then if possible—restore the person’s immune system.” Case 7: A 3-year-old returned from Costa Rica with his family with what looked like impetigo. It turned out to be leishmaniasis. ■ Cutaneous Mold Infections Patient Factors • Prolonged neutropenia • Prematurity • Bone marrow transplant High risk locations • IV sites • Areas of trauma • Tape occlusion Diagnosis/Treatment • Emergent tissue for histopathology and culture • Broad spectrum coverage including fungal • Evaluation for surgical debridement if localized • Consideration for granulocyte infusion or GMCSF Leishmaniasis Unusual Infections in Children James R. Treat, MD Introduction. Dr. Treat illustrated and discussed an extensive variety of unusual infections in his patients. Case Discussions. Case 1: A 6-month-old with atopic dermatitis presented with a widespread vesicular eruption. The vesicles were all different sizes, which would be unusual for eczema herpeticum, and it was also on his buttocks. He was diagnosed with enterovirus A6, a type of Coxacki virus, that affects hand, foot, mouth and buttocks. Many viruses can superinfect atopic dermatitis, including herpes, Coxackie virus, or varicella. Case 2: A 4-hour-old healthy newborn in the nursery, after a vaginal birth following prolonged rupture of the membranes, had developed congenital Candidiasis after exposure to Candida-filled amniotic fluid for >24 hours. Case 3: A 14-year-old with fevers, chills, malaise, and solitary enlarging ulcerated plaque had impressive lymphadenopathy in his axillary area. Biopsy with culture diagnosed ulceroglandular tularemia infection from an insect bite (a tick) that had initiated a localized lymphadenopathy. IV gentamicin, then ciprofloxacin, were effective. www.dermatologyfoundation.org • Ask about travel! • Parasite transmitted by sandflies • 3 typical clinical presentations—cutaneous, mucocutaneous, visceral—depending on the type of Leishmania, which depends on geography • Diagnosis is difficult! – Special media, PCR – Send to Walter Reed or CDC • Endemic areas include: – Middle East (Iran/Iraq/Afghanistan) – South/Central America (Costa Rica, Brazil, – Peru, Bolivia) – India • Treatment is typically antimony for noncutaneous disease, but in children amphotericin may have better safety profile. S Sundar et al. J Glob Infect Dis. 2010;2:159–66. Summer 2014 15 . 16 Summer 2014 Dermatology Foundation 2013 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. Cornerstone Benefactor ($500,000 or more) Platinum Benefactor ($200,000 or more) A DIVISION OF VALEANT PHARMACEUTICALS Gold Benefactor ($100,000 or more) The Allergan Foundation Silver Benefactor ($50,000 or more) Avon Products, Inc. DUSA Pharmaceuticals Inc., a Sun Pharma company Ranbaxy Laboratories, Inc. Stiefel, a GSK company www.dermatologyfoundation.org Summer 2014 17 2015 DF Research Funding APPLICATIONS NOW BEING ACCEPTED Deadline: October 15, 2014 The outstanding impact of the Dermatology Foundation’s Research Awards Program is nationally recognized. They are effective and essential funding opportunities for advancing the early research efforts and careers of talented new physician-scientists and investigators. The dramatically cut federal grant programs makes these unique awards more essential than ever. The DF’s program offers multi-year career development awards and one-year fellowships and grants supporting research in all areas of modern dermatology and cutaneous biology. Recipients have the capacity and desire to further the future of dermatology and patient care. These awards are made possible by the generosity of the Foundation’s many members and industry supporters. Charles & Daneen Stiefel Scholar Award This award was introduced last year and is designed to support outstanding investigators committed to elucidating the basis, pathophysiology, clinical manifestations, and/or treatment of autoimmune and/or connective tissue diseases affecting adults and/or children. A generous gift from Charles & Daneen Stiefel has made possible an ample $100,000 in funding for each of three years, and represents the first Dermatology Foundation award intended for early to mid-career investigators. Career Development Awards (CDAs) The nine categories of CDAs are designed to enable physician-scientists and investigators to transition from fellowship to established researcher. These highly competitive and effective awards provide an annual stipend of $55,000 for up to three years of support. Physician-Scientist CDA Fellowships Two one-year fellowships are offered—the Dermatologist Investigator Research Fellowship and the Fellowship in Pediatric Dermatology. They provide salary stipends of $30,000 and $45,000, respectively. Research Grants These one-year grants offer $20,000 in seed money for research projects in a variety of concentrations, including patient-directed investigation, basic dermatologic research, and dermatopathology. This year, special funding is also available in the basic research grant category for dermatopharmacology projects. Program Development Grant This unique grant provides $10,000 to further the scientific infrastructure of an existing dermatology division or department that has not successfully competed for DF funding within the last five years. Clinical CDA in Dermatologic Surgery Clinical CDA in Health Care Policy/Public Health Dermatopathology Research CDA Medical Dermatology CDA Science of Human Appearance CDA Women’s Health CDA Pediatric Dermatology CDA Research CDA 18 Summer 2014 APPLY NOW! Proposals are being accepted through October 15th for the funding year beginning July 1, 2015. Visit dermatologyfoundation.org/rap for everything you need: eligibility criteria, application instructions, and downloadable forms. Questions are welcome: 847.328.2256 or [email protected] Dermatology Foundation CLINICAL SYMPOSIA 2014 FACULTY Proceedings—Part I Marc D. Brown, MD Professor Departments of Dermatology and Oncology University of Rochester Ilona J. Frieden, MD Professor Departments of Dermatology and Pediatrics University of California, San Francisco Joel M. Gelfand, MD, MSCE Associate Professor Department of Dermatology University of Pennsylvania John E. Harris, MD, PhD Assistant Professor Division of Dermatology University of Massachusetts Corporate Supporters 2014 DF Clinical Symposia Diamond Supporter ($100,000) Galderma Laboratories, LP Medicis, a Division of Valeant Pharmaceuticals Merz, Inc. Emerald Supporters ($50,000) Daniela Kroshinsky, MD, MPH Assistant Professor Department of Dermatology Harvard Medical School Ranbaxy Laboratories Inc. Laura B. Pincus, MD Assistant Professor Departments of Dermatology and Pathology University of California, San Francisco Sapphire Supporters Brian S. Schwartz, MD Assistant Clinical Professor Division of Infectious Disease University of California, San Francisco Bruce E. Strober, MD, PhD Associate Professor & Vice Chair Department of Dermatology University of Connecticut Health Center ($25,000) Amgen Inc. Bayer HealthCare DUSA Pharmaceuticals Inc., a Sun Pharma company Taro Pharmaceuticals U.S.A., Inc., a Sun Pharma company James R. Treat, MD Assistant Professor Departments of Pediatrics and Dermatology University of Pennsylvania Hensin Tsao, MD, PhD Associate Professor Department of Dermatology Harvard Medical School PROGRAM CO-CHAIRS Janet A. Fairley, MD Professor and Head Department of Dermatology University of Iowa Jack S. Resneck, Jr., MD Associate Professor and Vice Chair Department of Dermatology Core Faculty, Philip R. Lee Institute for Health Policy Studies University of California, San Francisco www.dermatologyfoundation.org The DF is pleased to recognize Unilever for their educational grant of $300,000 supporting the 2014 DF Clinical Symposia Resident Program. 2014 DF Clinical Symposia Faculty Disclosures (Part II) Marc D. Brown, MD: None. Ilona J. Frieden, MD: Anacor, Pierre Fabre Dermatology. Joel M. Gelfand, MD, MSCE: AbbVie, Inc., Amgen, Eli Lilly, Jansen, Merck, Novartis, Pfizer. John E. Harris, MD, PhD: AbbVie, Inc., Combe, Inc., Sanofi/Genzyme. Daniela Kroshinsky, MD, MPH: None. Laura B. Pincus, MD: None. Brian S. Schwartz, MD: None. Bruce E. Strober, MD, PhD: AbbVie, Amgen, Celgene, Janssen, Lilly, Maruho, Merck, Novartis, Pfizer, UCB Pharma. James R. Treat, MD: None. Hensin Tsao, MD, PhD: None. Summer 2014 19 Dermatology Focus c/o Dermatology Foundation 1560 Sherman Avenue Evanston, Illinois 60201-4808 Non-Profit U.S. Postage PAID Permit No. 236 Melrose Park, IL ADDRESS SERVICE REQUESTED Giving Back—Profile of a DF Volunteer “The Best Use of Our Money” “I truly believe that if research in dermatology doesn’t continue to move forward, we won’t have the progress we need Ali Moiin, MD to improve our field and the care we provide our patients,” Troy, Michigan dermatologist Dr. Moiin asserts. “Research funding has decreased so substantially that we have to step up to the plate and help our specialty. This is why I support the DF, and why I give my time to encourage other dermatologists to do the same.” Dr. Moiin’s support of the DF as a member and a volunteer began early in his career as a practitioner. He found it an easy decision to join the Leaders Society in 2001, and the following year volunteered to invite his colleagues to join him. Then in 2010 he became an Annenberg Circle member, and soon joined the Annenberg Circle Committee to focus on increasing membership at this level of giving. Dr. Moiin explains that while his schedule is full, his volunteer work allows him to give even more to the specialty. He shares that he comes from a family of physicians and has wanted to be a dermatologist since he was 16 years old. This clinical dermatologist now runs a busy private practice, is Clinical Associate Professor in Dermatology at Wayne State, and is the chairman of medical education for the Michigan Dermatological Society. Dr. Moiin stresses to his colleagues that “young investigators cannot apply for any federal funding without having research experience and solid early results. And funding for this initial effort comes from the DF.” He notes that many early-career DF research awards have enabled significant progress, including fundamental insights on the hair follicle, the systemic nature of psoriasis, and the cutaneous impact of cancer drugs. “Funding from the DF was the crucial first step. Giving to the DF is the best use of our money.” The DF is exceptionally grateful to its many volunteers who work hard and give generously of their time to keep dermatology at the forefront of medicine. A DERMATOLOGY FOUNDATION PUBLICATION SPONSORED BY VALEANT PHARMACEUTICALS NORTH AMERICA LLC VOL. 33 NO. 2 SUMMER 2014