PracticeUpdate: Dermatology - Winter 2018

VOL. 2 • NO. 3 • WINTER 2018

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4702

Itching to Prescribe the Right Treatment for Scabies: Topical Permethrin or Oral Ivermectin?

International Investigative Dermatology 2018 Meeting

JOURNAL SCANS A Cross-Sectional Study of Clinical Distinctions Between Neuropathic and Inflammatory Pruritus

The Medical Necessity of Comprehensive Patch Testing

Cost-Effectiveness of Skin Cancer Referral and Consultation Using Teledermoscopy in Australia

PracticeUpdate.com is a free online resource for medical information and expert insight.

Our Process Our top medical experts meet weekly to review and discuss all relevant literature (journal articles, news, and current topics) and select the most important content in each specialty. Take-Home Messages Take-home messages are added to articles to highlight key takeaways and findings. Expert commentaries provide additional insights and guidance on important topics to help you identify critical information quickly and easily, freeing up more time for patient care. Our Boards Each PracticeUpdate specialty has its own diverse team of experts who hand select the articles on a weekly basis and give unique multi-specialty perspectives on a single topic. You benefit by receiving several viewpoints on one subject, enabling a more complete and multidimensional learning experience.

Benefits of PracticeUpdate.com • Our experts provide customized, curated research and clinical findings. • Exclusive, free clinical information is scanned, selected, and prioritized. • Unbiased, impartial, independent medical information provided each week. • Stay current in your field with distilled professional research, articles, and education.

PracticeUpdate.com

Join For Free Today at

PRACTICEUPDATE DERMATOLOGY BOARD PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Robert T. Brodell MD, FAAD Professor and Chair, Department of Dermatology, and Professor of Pathology, University of Mississippi Medical Center, Jackson, Mississippi; Instructor in Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, New York

PracticeUpdate® is a registered trademark of Elsevier Inc.

2018 Elsevier Inc. All rights reserved.

ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’s mission is to help medical professionals navigate the vast array of available literature and focus on the most critical information for their patients and practice. All journal articles selected for PracticeUpdate receive a Take-Home Message designed to quickly summarize the key findings and explain the importance of that research within the specialty area. The most critical articles also receive Expert Commentaries from experts who are handpicked by the PracticeUpdate Editorial Board, providing additional context on that research for the reader. Expert Opinion pieces give special highlights to important topics and Conference Coverage captures relevant takeaways from a vast array of medical meetings throughout the year. PracticeUpdate Dermatology provides coverage of key research from leading international conferences, and a collection of top journal articles and accompanying expert commentaries in a convenient print periodical. These and more are also available online at PracticeUpdate.com PracticeUpdate and PracticeUpdate Dermatology are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER PracticeUpdate Dermatology has been developed for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Product Information before prescribing any medication mentioned in this publication. Althoughalladvertisingmaterial isexpected toconform toethical (medical)stand- ards, inclusion in thispublicationdoesnotconstituteaguaranteeorendorsement of the quality or value of such product or of the claims made of it by its manu- facturer. The printing and distribution of this publication has been made possible through paid advertising. The editorial content herein is independently produced by Elsevier with no involvement by the advertiser. It contains content published in accordancewiththeeditorialpoliciesofElsevier’sPracticeUpdate.com.Allcontent printed in this publication can be found on PracticeUpdate.com. CONTENT Abstracts are available when the publisher grants permission from MEDLINE/ PubMed, a database of the US National Library of Medicine. • NLM data are produced by a US Government agency and include works of the United States Government that are not protected by US copyright law but may be protected by non-US copyright law, as well as abstracts originating from publications that may be protected by US copyright law. • NLM assumes no responsibility or liability associated with use of copyrighted material, including transmitting, reproducing, redistributing, or making commercial use of the data. NLM does not provide legal advice regarding copyright, fair use, or other aspects of intellectual property rights. Persons contemplating any type of transmission or reproduction of copyrighted material such as abstracts are advised to consult legal counsel. SALES Fleur Gill fleur.gill@elsevier.com Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng • Designer Jana Sokolovskaja Cover: Scabies/gettyimages.com PracticeUpdate Dermatology is published by Elsevier Australia ISSN 2206-4702 (Print) ISSN 2206-4710 (Online)

Associate Editors

Ashish C. Bhatia MD, FAAD Assistant Professor, Clinical Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Medical Director, Dermatologic Research, DuPage Medical Group, Naperville, Illinois; Co-Director, Dermatologic, Laser and Cosmetic Surgery, The Dermatology Institute – Naperville,

DuPage Medical Group Eliot Mostow MD, MPH

Head, Dermatology Section, Northeast Ohio Medical University; Professor, Northeast Ohio Medical University, Dermatology Section, Rootstown, Ohio; Assistant Professor, Clinical Medicine, Department of Dermatology, Case Western Reserve College of Medicine, Cleveland, Ohio; Chief, Wound Care Research, Akron General Medical Center, Akron, Ohio

Advisory Board

Sarah L. Chamlin MD Professor of Pediatrics and Dermatology, Northwestern University Feinberg School of Medicine; Attending Physician, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois

Jane Grant-Kels MD Professor of Dermatology, Pathology and Pediatrics; Founding Department Chair Emeritus; Vice Chair of the Department of Dermatology; Founding Director Emeritus of the UCONN Dermatopathology Lab and Dermatology Residency program; Director of the Cutaneous Oncology and Melanoma Program; University of Connecticut Health Center and School of Medicine, Farmington, Connecticut Christen Mowad MD Director of Contact and Occupational Dermatitis Clinic, Geisinger Medical Center, Danville, Pennsylvania

Editorial Contributors

Caroline Crabtree MD Dermatology Resident, University of Mississippi Medical Center, Jackson, Mississippi

InYoung Kim MD, PhD Resident, Dermatology, Case Western University Hospital, Cleveland, Ohio

Caitlyn Reed MD Dermatology Resident, University of Mississippi Medical Center, Jackson, Mississippi

Editorial Boards:

Our specialty-focused KOLs meet weekly to review the Editorial Contributors’ selections and to discuss which content is truly the most impactful – identifying which items require additional expert context and commentaries.

Advisory Boards: Expert physician Advisory Boards oversee subspecialty areas within each broader topic and provide guidance and context for that content for each specialty area. Editorial Contributors: Each week these teams of specialty-specific physicians scan all of the available literature and hand-select the most impactful and practice changing content for the Editorial Boards to review.

ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 EMDN081801

CONTENTS 5

COVER 20

RESEARCH Editor’s picks 6 Determinants of Patient Satisfaction in a Dermatology Outpatient Clinic Comment by Eliot N. Mostow MD, MPH 7 Clinical Distinctions Between Neuropathic and Inflammatory Pruritus 8 The Medical Necessity of Comprehensive Patch Testing Comment by Salma F. de la Feld MD, FAAD 10 Toxicological Impact of the Sunscreen Ingredient Oxybenzone/Benzophenone-3 Comment by Robert T. Brodell MD, FAAD 11 Cost-Effectiveness of Skin Cancer Referral and Consultation Using Teledermoscopy in Australia Comment by Robin P. Gehris MD 12 Microbiome Associated With Anti-PD-1 Efficacy in Metastatic Melanoma Patients Comment by Robert L. Modlin MD 14 Prevalence of Contact Allergy to Metals in the European General Population With a Focus on Nickel and Piercings Comment by Christen Maria Mowad MD 15 The 9-Valent HPV Vaccine for Treatment of Squamous Cell Carcinomas Comments by Stephen K. Tyring MD, PhD, Uyen Ngoc Mui MD and Ravi Patel MD 16 Silver Absorption and Toxicity Associated With Silver Wound Dressings in Chronic Wounds Comments by Robert S. Kirsner MD, PhD and Ashish C. Bhatia MD, FAAD 17 Safety and Efficacy of Hydrogen Peroxide Topical Solution in Patients With Seborrheic Keratoses 18 A Biologically Based Approach to Acne and Rosacea Comment by Christine Jaworsky MD 19 Antiandrogen Therapy With Spironolactone for the Treatment of Hidradenitis Suppurativa Comment by Paul G. Hazen MD

Itching to Prescribe the Right Treatment for Scabies: Topical Permethrin or Oral Ivermectin? By Warren R. Heymann MD

CONFERENCE 24 International Investigative Dermatology 2018 Meeting By the PracticeUpdate Editorial Team 24 Secukinumab Reduces

CD4-Positive Th17, As Well As CD8- and CD4-Positive Treg Cells in Patients With Plaque Psoriasis

EXPERT OPINION 20 Itching to Prescribe the Right Treatment for Scabies: Topical Permethrin or Oral Ivermectin? By Warren R. Heymann MD 22 25 Two Topical Preparations Show Promise for Eczema 26 Results of Two Studies Point to Potential Treatments for Alopecia Areata 27 Vitamin C and Its Derivatives Suppress Melanogenesis 28 BLZ-100 (Tozuleristide) Shown to Discriminate Between Subtle Molecular Subtypes of Basal Cell Carcinoma 29 After 52 Weeks, Ixekizumab Is Linked to Consistently Higher Responses Than Ustekinumab Across Patient Subgroups With Moderate to Severe Plaque Psoriasis 30 Neutralization of Interleukin 17 Implicated in Inflammatory Skin Diseases Overall and in Psoriasis Specifically

Time for a Churchillian Approach to Idiopathic Guttate Hypomelanosis? By Warren R. Heymann MD

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 6

Determinants of Patient Satisfaction in a Dermatology Outpatient Clinic Journal of the European Academy of Dermatology and Venereology Take-home message • The authors of this prospective survey study of 133 consecutive, newly referred patients assessed the factors that determine patient satisfaction in an outpatient dermatology clinic in Denmark. On a Likert Scale of 1 to 5, with 1 indicating the highest expectations, patients reported very high pre-consultation expectations of their doctor being respectful and helpful (mean values, 1.25 and 1.33, respectively). Increasing age was associated with a greater expectation of receiving a full disease explanation, having a physical examination performed, having diagnostic tests performed, being given a specific diagnosis, and receiving reassurance. In general, patient expectations were not met with regard to the degree of patient involvement in making treatment decisions, receiving detailed explanations about conditions, discussing the benefits, side effects, and complications/risks of treatment, and having diagnostic tests performed. • Patients expect to be provided detailed information about their diagnosis and treatment options and to be actively involved in medical decision-making during their visits. Patient satisfaction improves with increasing age, the feeling of being able to influence the visit, and having expectations met. Jeffrey F. Scott MD

" I am quite sure I don't meet every patient's expectations, but sometimes I appear to be the first person to have told a patient

that I cannot cure his or her disease!

"

COMMENT By Eliot N. Mostow MD, MPH

P atient satisfaction is an obvious goal for every clinical prac- tice, including dermatology practices. While some will bristle at worrying too much about patient satisfaction as a metric of success (ie, isn't it enough to get the diagnosis and treatment right, thereby improving patient outcomes?), the present study and my own bias is that a few simple measures can often make a huge difference in patient satisfaction. Think back to your mentors. Many were exceptionally good clinicians and teachers, but they also demonstrated a knack for properly setting and exceeding patient expectations. I was inspired to do the same. As an inde- pendent physician, I don't have a business entity monitoring my actions via digital survey tools such as Press-Ganey. I am, however, affected by the online world of patient commentary that lets the whole world know "how well I'm doing." The authors rightly point out that meeting patient expectations with courtesy and under- standable explanations/information increases patient satisfaction. Of course, this is not too surprising; however, I'll offer my own com- mentary on this subject. While this forum does not routinely print readers' suggestions, if you have thoughts on this topic, please email me at emostow@neomed.edu. • "Work hard, be nice, accommodate when possible". Mike Rindler was an interim CEO at Akron General (one of our two major adult hospitals a number of years ago), and this was his mantra for institutional success. Space does not allow me to elaborate on the details, but the simplicity of this message is powerful. Each of us is part of a team that delivers healthcare. For more information about Mike Rindler, consider one of his and his colleagues’

books, especially the one on leadership ( www.integrityhospital. com/books/ ). • Jim Rasmussen, MD, was a passionate master clinician at the University of Michigan who often espoused the simple principle of "under-promise and over-deliver." Setting appropriate expec- tations is critical while a consistent message is communicated. I am quite sure I don't meet every patient's expectations, but sometimes I appear to be the first person to have told a patient that I cannot cure his or her disease! For many conditions, patients should expect flares of their skin disease and continue to follow the plans outlined for them to minimize these flares. This approach is vastly different than "curing” a streptococcal sore throat with a course of antibiotics. • Charles Ellis, MD, also at the University of Michigan, was and continues to be passionate about addressing patient satisfac- tion in many ways. He was very astute in teaching dermatology residents about the need to sit down to make sure that patients don’t feel rushed (even if we do) and to make sure our "shoes are shined" (this latter statement was both specific and figurative; that is, he knew the importance of meeting patient expectations regarding their physicians’ appearance). These are simple meas- ures that can prevent undermining confidence in our treatment plan. Of course, like most of us, Dr. Ellis is also excited about making the elusive diagnosis. If this was the ultimate measure of success, however, some patient would be in for a dose of bad news.

PRACTICEUPDATE DERMATOLOGY

EDITOR’S PICKS 7

Clinical Distinctions Between Neuropathic and Inflammatory Pruritus

Journal of the American Academy of Dermatology Take-home message

• The authors of this cross-sectional study of data of 267 adults with pruritus collected from two institutions between 2015 and 2017 investigated the clinical differences between chronic neuropathic and inflam- matory pruritus. Inflammatory pruritus was defined as pruritus resulting from atopic dermatitis or psoriasis. Neuropathic pruritus was defined as pruritus resulting from bra- chioradial pruritus, nostalgia paresthetica, unspecific neuropathic itch, or post-herpetic neuralgia. • Individuals with neuropathic pruritus were older than individuals with inflammatory pruritus (63.0 years vs 48.8 years; P < .001). Compared with individuals with neuropathic pruritus, individuals with inflammatory pru- ritus were also more likely to report their itch being associated with nociceptive symp- toms related to stinging, burning, sunburn, and pain. Jeffrey F. Scott MD Abstract Chronic pruritus has been grouped according to inflam- matory, neuropathic, psychogenic, or systemic origins. Among those with chronic pruritus, between 8% and 15% are classified as suffering from neuropathic itch. Neuropathic itch is a debilitating form of chronic pru- ritus that occurs secondary to damage to afferent itch pathways. The clinical characteristics of neuropathic itch have been suggested to include nociceptive symp- toms, such as burning, tingling, and stinging. Conversely, inflammatory itch is usually not characterized with other nociceptive complaints. However, a recent large study in patients with atopic dermatitis suggests that there may be an association with pain. Distinctions between neuropathic and inflammatory pruritus help guide the diagnostic workup and the selection of the most effica- cious classes of medication. Nociceptive characteristics of neuropathic and inflammatory itch have not been well studied. The purpose of this study was to examine differences in nociceptive characteristics between neu- ropathic and inflammatory itch. We used cross-sectional survey data collected A Cross-Sectional Study of Clinical Distinctions Between Neuropathic and Inflammatory Pruritus. J Am Acad Dermatol 2018 Jun 01;[EPub Ahead of Print], JD Rosen, AC Fostini, YH Chan, et al. www.practiceupdate.com/c/69432

Abstract Patient expectations shape the patient's attitude towards the consultation and the treatment, and are determinants of patient satisfaction. The aim of this study was to investigate the expectations of dermatological patients concerning the doctor, the consultation and the treatment, and to identify factors associated with patient satis- faction in an outpatient setting. Patient Expectations and Determinants of Patient Satisfaction in a Dermatology Out- patient Clinic. J Eur Acad Dermatol Venereol 2018 Jun 19;[EPub Ahead of Print], MB Søndergaard, MN Ghazanfar, SF Thomsen. www.practiceupdate.com/c/70008

• Tim Johnson, MD, also at the University of Michigan, taught and modeled the importance of treating every patient as if he or she were your family member. It's a simple thing, although not always easy; but I find it makes for improved satisfaction in my day. We all recognize that some patients or problems are not as easy to address as others, but my line to our team is that "everyone can love the puppy dog" – meaning that it's easy to give love and care to the cute kid or funny kind elderly patient, but smiling and giving that same care to someone who is not so "cute" is the mark of a professional and part of our job. • Meeting expectations from the start to finish of the patient encounter is key. This study looked mostly at the clinician encounter, but I believe the process works best if you recognize that this is a team effort. I tell my staff that everyone has the option to “pull the emergency brake” if they see that a patient does not understand what is going on (eg, needs to have the diagnosis or treatment information repeated). It is always best to avoid a phone call back to the office when the patient arrives home. I know that many clinicians have a policy of treating just a limited number of problems at each visit. While I recognize the need to move patients efficiently in and out and know that there are some patients/problems requiring rescheduling for another visit, I would rather deal with as many of a person’s concerns as possible at the time that that person is with me. Rescheduling for something that I can address fairly quickly while we are together seems much less efficient and takes away from another patient who has not been able to schedule a convenient appointment in a reasonable amount of time. Let me close by assuring everyone who has read this far that I do not meet the expectations of every patient, but I try and try to improve the process on a regular basis.

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 8

The Medical Necessity of Comprehensive Patch Testing Dermatitis Take-home message • Allergen identification is crucial in the management of allergic contact dermatitis (ACD). The commercially available T.R.U.E Test screening panel (36 allergens) is reported to have a detection rate of, at most, 66.0% of the clinically relevant reactions identified by the North American Contact Dermatitis Group (NACDG). Notably, up to 50% of allergens causing occupational dermatitis aremissed. Studies show that 21% to 34% of ACD diagnoses would be missed by the NACDG screening series without the use of supplemental allergens. Comprehensive testing with supplemental allergens beyond a screening series may increase the diagnostic yield and the likelihood of achieving a cure for ACD. • The authors emphasize the need to integrate the patient's medical history, exami- nation findings, and environmental exposure history to implement comprehensive and customized allergen testing in the management of ACD. InYoung Kim MD, PhD

COMMENT By Salma F. de la Feld MD, FAAD C ontact dermatitis has a significant impact on patients’ quality of life and, as the fifth most prevalent skin disease in the United States, it has a high burden of medical cost at over $1 billion. This article highlights the impor- tance of utilizing comprehensive patch testing to effectively diagnose and cure patients of allergic contact dermatitis. Although “limited” patch testing with 36 allergens can seem easier, it misses up to one-third of the diagnoses found on comprehensive patch testing and misses up to 50% of the causes of occu- pational dermatitis. The time involved with this labor-intensive, 1-week pro- cedure can be a barrier to utilization. However, in the long-run, proper accu- rate diagnosis and counseling with patch testing can avert subsequent office visits and additional unnecessary treatment (decreasing the economic impact of this disease) as well as ulti- mately improving patients’ quality of life. " Although “limited” patch testing with 36 allergens can seem easier, it misses up to one-third of the diagnoses found on comprehensive patch testing and misses up to 50% of the causes of occupational dermatitis. " Comprehensive patch testing is an underuti- lized and helpful tool that should be considered in the evaluation and treatment of allergic contact dermatitis. Patients will often come in saying that they already had “allergy testing” and not realize that they actually had prick or intradermal testing instead, which evaluates for different dis- eases (such as immediate, IgE-mediated type I hypersensitivities). Patch testing eval- uates for delayed-type hypersensitivity and allergic contact dermatitis, and it is important to make this distinction when approaching patients.

Abstract Allergic contact dermatitis is associated with significant disease and economic burden in the United States. To properly manage allergic contact dermatitis, it is important to accurately identify the substance(s) implicated in the der- matitis to prevent disease recurrence. The commercially available T.R.U.E Test (36 aller- gens) screening panel has been reported to have a conservative hypothetical allergen detec- tion rate of 66.0%, at most. Importantly, these calculations are based on the 78% of patients who had clinically relevant reactions to allergens present on the North American Contact Der- matitis Group screening series (70 allergens), without the use of supplemental allergens.

Testing with supplemental allergens beyond a screening series can more fully evaluate an individual's environmental and occupational exposure, which may significantly increase diag- nostic accuracy. Comprehensive patch testing with additional allergens in sunscreens, cosmet- ics, and fragrances, for example, may increase the diagnostic yield as well as the likelihood of achieving a cure if the dermatitis is chronic and recalcitrant. The Medical Necessity of Comprehensive Patch Testing. Dermatitis 2018 Apr 02;29(3)107- 111, TH Zhu, R Suresh, E Warshaw, et al. www.practiceupdate.com/c/68157

Dr. de la Feld is an Assistant Professor at Emory University Department of Dermatology in Atlanta, Georgia, where she is also Co-Director of the Patch Testing Clinic and Director of the Sub-I medical student rotation.

PRACTICEUPDATE DERMATOLOGY

LOOKS CAN BE DECEIVING

IN ATOPIC DERMATITIS

While lesions and itch represent the primary signs and symptoms of atopic dermatitis, hidden signs of inflammation have been shown to persist, even after a flare has subsided. Current evidence suggests that patients’ skin, including nonlesional skin, suffers from chronic subclinical inflammation, a process which is driven by the key Th2 cytokines IL-4 and IL-13. 1–5 Discover what’s really going on beneath the surface.

VISIT THE WEBSITE TO FIND OUT MORE AND REGISTER FOR FURTHER INFORMATION .

atopicdermatitisexposed.com.au

References: 1. Gittler JK, et al. J Allergy Clin Immunol 2012;130(6):1344–1354. 2. Leung DYM, et al. J Clin Invest 2004;113(5):651–657. 3. Suárez Fariñas M, et al. J Allergy Clin Immunol 2011;127(4):954–964. 4. De Benedetto A, et al. J Allergy Clin Immunol 2011;127(3):773–786. 5. Mollanazar NK, et al. Clinic Rev Allerg Immunol 2015. doi:10.1007/s12016-015-8488-5. ©2018 Sanofi. Sanofi-Aventis Australia Pty Ltd trading as Sanofi Genzyme, ABN 31 008 558 807. Talavera Corporate Centre, Building D 12-24 Talavera Road, Macquarie Park, NSW 2113. www.sanofigenzyme.com.au. GZANZ.DUP.17.10.0192 Date of preparation May 2018. SAG0151.

Sanofi Genzyme and Regeneron are committed to providing resources to advance research in dermatology in areas of unmet medical needs among patients with poorly controlled moderate-to-severe atopic dermatitis.

EDITOR’S PICKS 10

Toxicological Impact of the Sunscreen Ingredient Oxybenzone/Benzophenone-3 Journal of Cosmetic Dermatology Take-home message • The environment effects of commonly used organic UV filters have become a pressing topic. Organic UV filters have been identified in water sources worldwide, with oxybenzone noted as the most frequently detected in the largest concentrations. Organic filters are prevalent in waste from sunscreen and cosmetic manufacturing facilities. These filters are not easily removed by common waste treatment plant techniques. Oxybenzone has also been shown to contribute to coral reef bleaching. Further- more, 4-methylbenzylidene camphor, oxybenzone, octocrylene, and octinoxate have been identified in various species of fish worldwide, which may have consequences for the food chain. • These authors suggest potential solutions to reduce environmental toxic effects of organic UV filters, which include seeking shade; wearing photoprotective clothing, wide-brimmed hats and sunglasses; and using sunscreens with inorganic filters (titanium dioxide and zinc oxide).

COMMENT By Robert T. Brodell MD, FAAD T his article was certainly stimulating! Written by a national leader in this field, Henry Lim, MD, it details the facts: 1) oxybenzone from sunscreen use and manufacture is detectable in oceans, swimming pools, and lakes; 2) oxyben- zone can destroy coral by bleaching; and 3 4-methylbenzylidene camphor, oxybenzone, octocrylene, and octinoxate have been identified in fish. With regard to coral, studies have shown damage to coral in the immediate vicinity of beaches where sunscreens have been worn by thousands of swimmers. However, the concen- trations after dilution in the ocean should not affect the Great Barrier Reef…the type of destruction that would be expected to seriously harm the ecosystem. There is no evidence that these chemicals in sunscreen are harming humans in the concentrations to which we are exposed. Still, should we err on the side of caution and ban the use of these products? I believe that would be premature. The alter- native physical block sunscreens are hard to rub onto the skin and leave a white residue. There have been fears raised about the nanoparticles in these agents. On the other hand, the phys- ical sunscreens do not get into the eyes with sweating, causing stinging and burning like many of the chemical sunscreens. The evidence is not all in; but, for now, it is abundantly clear that sunscreens, as part of a multimodal effort, can reduce actinic keratoses, skin cancer, wrinkles, and solar lentigines. I will continue to recommend to my patients that they wear a hat, use an umbrella and other sun-protectant shelters, and wear the sunscreen SPF 30 or greater that they like best. I believe that the difficulties with patient adherence to the use of sun- screens make this the best approach for now. For individuals worried about their vitamin D levels, I also recommend 2000 international units (IU) of vitamin D daily. Finally, the Food and Drug Administration (FDA) should rapidly consider the safety and efficacy of broad spectrum chemical sunscreens available in Europe so that American consumers have as many options as possible should evidence lead to elim- ination of oxybenzone/benzophenone-3 from the marketplace.

Abstract Oxybenzone (Benzophenone-3) is an emerging human and environmental contaminant used in sunscreens and personal care products to help mini- mize the damaging effects of ultraviolet radiation. The Center for Disease Control fourth national report on human exposure to environmental chemicals demonstrated that approximately 97%of the people tested have oxybenzone present in their urine, and independent scientists have reported various con- centrations inwaterways and fishworldwide. Oxybenzone can also react with chlorine, producing hazardous by-products that can concentrate in swimming pools and wastewater treatment plants. Moreover, adverse reactions could very well be increased by the closed loop of ingesting fish contaminatedwith oxybenzone and/or washing the ingredient off our bodies and having it return in drinking water as treatment plants do not effectively remove the chemi- cal as part of their processing protocols. In humans, oxybenzone has been reported to produce contact and photocontact allergy reactions, implemented as a possible endocrine disruptor and has been linked to Hirschsprung's dis- ease. Environmentally, oxybenzone has been shown to produce a variety of toxic reactions in coral and fish ranging from reef bleaching to mortality. Lastly, with the rise in skin cancer rates and the availability of more effective sunscreen actives such as micronized zinc oxide and titanium dioxide, seri- ous doubts about the relative prevention benefit of personal care products containing oxybenzonemust be raised and comparedwith the potential neg- ative health and environmental effects caused by the accumulation of this and other chemicals in the ecosystem. Dermatological and Environmental Toxicological Impact of the Sun- screen Ingredient Oxybenzone/Benzophenone-3. J Cosmet Dermatol 2018 Feb 01;17(1)15-19, JC DiNardo, CA Downs. www.practiceupdate.com/c/70634

PRACTICEUPDATE DERMATOLOGY

EDITOR’S PICKS 11

Cost-Effectiveness of Skin Cancer Referral and Consultation Using Teledermoscopy in Australia JAMA Dermatology Take-home message

Abstract IMPORTANCE International literature has shown that teledermoscopy referral may be a via- ble method for skin cancer referral; however, no economic investigations have occurred in Australia. OBJECTIVE To assess the cost-effectiveness of teledermoscopy as a referral mechanism for skin cancer diagnosis and management in Australia. DESIGN, SETTING, AND PARTICIPANTS Cost-effec- tiveness analysis using a decision-analytic model of Australian primary care, informed by publicly available data. INTERVENTIONS We compared the costs of teledermoscopy referral (electronic referral containing digital dermoscopic images) vs usual care (a written referral letter) for specialist der- matologist review of a suspected skin cancer. MAIN OUTCOMES AND MEASURES Cost and time in days to clinical resolution, where clinical resolution was defined as diagnosis by a der- matologist or excision by a general practitioner. Probabilistic sensitivity analysis was performed to examine the uncertainty of the main results. RESULTS Findings from the decision-analytic model showed that the mean time to clinical resolution was 9 days (range, 1-50 days) with teledermoscopy referral compared with 35 days (range, 0-138 days) with usual care alone (dif- ference, 26 days; 95% credible interval [CrI], 13-38 days). The estimated mean cost difference between teledermoscopy referral (A$318.39) vs usual care (A$263.75) was A$54.64 (95% CrI, A$22.69-A$97.35) per person. The incremen- tal cost per day saved to clinical resolution was A$2.10 (95% CrI, A$0.87-A$5.29). CONCLUSIONS AND RELEVANCE Using teleder- moscopy for skin cancer referral and triage in Australia would cost A$54.64 extra per case on average but would result in clinical resolution 26 days sooner than usual care. Implementation recommendations depend on the preferences of the Australian health system decision mak- ers for either lower cost or expedited clinical resolution. Further research around the clinical significance of expedited clinical resolution and its importance for patients could inform imple- mentation recommendations for the Australian setting. Cost-Effectiveness of Skin Cancer Referral and Consultation Using Teledermoscopy in Australia. JAMA Dermatol 2018 May 09;[EPub Ahead of Print], CL Snoswell, LJ Caffery, JA Whitty, et al. www.practiceupdate.com/c/68079

• This study compared the estimated cost as well as time to clinical resolution of patients referred to dermatologists by a traditional referral letter versus a teleder- moscopic referral. Clinical resolution was defined as either clinical diagnosis by a dermatologist or excision of the lesion in question by a general practitioner (GP). Referral via teledermoscopic images resulted in clinical resolution 26 days faster than traditional referral. However, teledermoscopic referral cost an average of AUD 54.64 more per case than traditional referral. The authors suggested that additional costs were likely avoided using teledermoscopic referral by preventing unnecessary excisions by GPs as well as better triaging patients who needed to be managed by a dermatologist versus those who could be managed well by their referring GP. • The authors found that teledermoscopic referrals to dermatologists by general practitioners can result in faster clinical resolution but higher referral costs for patients with suspicious skin lesions. Caitlyn T. Reed MD

COMMENT By Robin P. Gehris MD T his article acknowledges the need to more accurately triage dermatol- ogy referrals. Because melanoma represents more than 10% of all reported cancers in Australia, this was an ideal study population. This was also a great place to study the cost-effectiveness of teledermoscopy because the govern- ment health system places a high value on teledermatology, reimbursing live interactive tele-visits at a rate of 1.5% higher than in-office visits. The goal of teledermoscopy is to expedite in-office evaluation and man- agement of potentially atypical skin lesions and avoid wasting precious der- matology schedule slots for patients with benign-appearing skin lesions. Even though preferential reimbursement does not yet exist for asynchronous, or store- and-forward visits, the authors chose to use a store-and-forward system initiated by the primary care provider because of its efficiency. Dermoscopic images were sent along with clinical information to the dermatologist. The measurable endpoint they used was clinical resolution either by dermatology diagnosis or by excision of the lesion by the primary physician. In concordance with many other studies of

teledermoscopy, there was an increased cost per patient of $54. The study did succeed, however, in reducing the time to clinical resolution by a mean of 26 days. The other cost savings proposed, but not quantified, was the avoidance of biop- sying or excising benign-appearing skin lesions in the primary care offices. It is imperative to stress to government and private payers that a delay in diag- nosis or excision of almost 1 month could lead to poorer clinical outcomes. This would be expected to lead to an increase in morbidity to the patient and costs to the system. This must be weighed against not only the cost of teledermoscopy noted above but also the cost of training and providing dermatoscopes to primary care physicians. Thus, studies considering a broader range of costs and benefits will be needed before teledermoscopy can be broadly recommended.

Dr. Gehris is Chief of Pediatric Dermatology, Medical Director of Pediatric Teledermatology and Founding Member of the Pediatric Melanoma Group at UPMC Children’s

Hospital of Pittsburgh in Pittsburgh, Pennsylvania.

VOL. 2 • NO. 3 • 2018

EDITOR’S PICKS 12

Microbiome AssociatedWith Anti-PD-1 Efficacy in Metastatic Melanoma Patients Science Take-home message

Abstract Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients' microbiome, which has been shown to affect antitumor immunity and immunother- apy efficacy in preclinical mouse models. We analyzed baseline stool samples from meta- static melanoma patients before immunotherapy treatment, through an integration of 16S ribo- somal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative poly- merase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus fae- cium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. Our results suggest that the commen- sal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients. The Commensal Microbiome Is Associated With Anti-PD-1 Efficacy in Metastatic Melanoma Patients. Science 2018 Jan 05;359(6371)104- 108, V Matson, J Fessler, R Bao, et al. www.practiceupdate.com/c/69998

• In this study, the authors investigated whether microbiome heterogeneity in met- astatic melanoma patients was associated with their response to anti-PD-1–based immunotherapy. The microbiome composition in baseline stool samples of patients before immunotherapy was significantly associated with clinical responses. Patients who responded to immunotherapy had increased abundance of Bifidobacterium longum , Collinsella aerofaciens , and Enterococcus faecium . Moreover, microbial reconstitution of germ-free mice with fecal material from responding patients improved tumor control and augmented T-cell responses in mice. • The results indicate that the composition of the commensal microbiome was sig- nificantly associated with a response to anti-PD-1 therapy in metastatic melanoma patients. The microbiome might affect antitumor immunity in cancer patients. InYoung Kim MD, PhD

COMMENT By Robert L. Modlin MD A major breakthrough in the treat- ment of melanoma and other cancers is based on the finding that expression of the programmed death-1 (PD-1) receptor on tumor cells prevents the activation of T cells that recognize the tumor and have the capacity to attack it. Administration of antibodies that block PD-1 (so-called checkpoint inhibitors) to patients with metastatic melanoma has resulted in unprecedented clinical responses, yet therapeutic efficacy varies among individuals. We now know that the composition of microbes in our intestine has a global influence on our immune sys- tem and could therefore be one variable that affects the response to immuno- therapy. The Gajewski lab measured the

that fecal matter from melanoma patients who responded to checkpoint blockade enhanced both the clinical and immune responses to anti-PD-1 therapy in mice as compared with that from non-responders. Therefore, it may be possible to awaken the unresponsive T cell to attack tumor cells with a little poop from your friends.

gut microbiota in patients undergoing anti-PD-1 therapy, finding 10 bacterial spe- cies that were differentially expressed in responders vs non-responders – 8 were greater in responders and 2 were greater in non-responders. These findings raise the possibility of fecal transplant to alter the gut micro- biome, given that this intervention is already being performed clinically to treat Clostridium difficile infection that causes pseudomembranous enterocol- itis. To evaluate the potential efficacy of fecal transplantation as an adjuvant to immunotherapy in melanoma, the Gajew- ski lab transplanted human fecal matter from melanoma patients into a mouse melanoma model. They demonstrated

Dr. Modlin is Klein Professor of Dermatology, Distinguished Professor of Medicine and Microbiology of Immunology and Molecular Genetics, Chief of the Division of

Dermatology, and Vice Chair for Cutaneous Medicine and Dermatological Research at the David Geffen School of Medicine in Los Angeles, California.

PRACTICEUPDATE DERMATOLOGY

‘I am so much more than my psoriasis’ 1 Cosentyx patient Cosentyx improved psoriasis on average by 90% through 5 years. Mean improvement in mean absolute PASI from baseline to Year 5 was 90.1%. 2

See approved Product Information before prescribing. Approved Product Information available at https://www.novartis.com.au/products/healthcare-professionals

COSENTYX ® (secukinumab) Indication: Treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. Treatment of adult patients with active psoriatic arthritis when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. Treatment of adult patients with active ankylosing spondylitis. Dosage and administration: Plaque psoriasis: The recommended dose is 300 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3, and 4 followed by the same dose every month . Each 300 mg dose is given as two subcutaneous injections of 150 mg. Psoriatic arthritis: The recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3, and 4 followed by the same dose every month . For patients who are anti-TNF α inadequate responders or patients with concomitant moderate to severe plaque psoriasis, the recommended dose is 300 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3, and 4 followed by the same dose every month . Each 300 mg dose is given as two subcutaneous injections of 150 mg. Ankylosing spondylitis: The recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, 3, and 4 followed by the same dose every month . Contraindications: Severe hypersensitivity reactions to the active substance or to any of the excipients. Clinically important, active infections. Precautions: Infections: Caution in patients with chronic or history of recurrent infection. If a patient develops a serious infection, the patient should be closely monitored and Cosentyx should not be administered until the infection resolves. Anti-tuberculosis therapy should be considered prior to initiation in patients with latent tuberculosis. Cosentyx should not be given to patients with active tuberculosis. Crohn’s disease: Caution should be exercised, when prescribing to patients with inflammatory bowel disease. Exacerbations, in some cases serious, occurred during clinical trials in plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. In addition, new onset inflammatory bowel disease cases occurred in clinical trials. Patients should be monitored for signs and symptoms of inflammatory bowel disease. Hypersensitivity reactions: Rare cases of anaphylactic reactions have been observed during clinical trials. Administration should be discontinued immediately and appropriate therapy initiated if an anaphylactic or other serious allergic reaction occurs. Latex-sensitive individuals: The removable cap of the Cosentyx prefilled syringes/pen contains a derivative of natural rubber latex. Vaccinations: Cosentyx should not be given concurrently with live vaccines. Pregnancy: Cosentyx should be used during pregnancy only if the benefits clearly outweigh the potential risks. Lactation: Caution should be exercised when Cosentyx is administered to a woman who is breast-feeding. Interactions: Live vaccines should not be given concurrently with Cosentyx. In a study in subjects with plaque psoriasis, no clinically relevant pharmacokinetic interaction was observed between secukinumab and midazolam (CYP3A4 substrate) . Side effects: Very common (≥10%): nasopharyngitis. Common (≥1 to ≤10%): upper respiratory tract infection, rhinitis, pharyngitis, oral herpes, diarrhoea, urticaria, rhinorrhoea, headache, nausea, hypercholesterolemia. Uncommon (≥0.1 to ≥1%): sinusitis, tonsillitis, oral candidiasis, neutropenia, tinea pedis, otitis externa, conjunctivitis. Frequency not known: mucosal and cutaneous candidiasis. In clinical trials, major adverse cardiovascular events were rarely observed in patients receiving secukinumab. In the overall secukinumab program, the exposure adjusted incidence rates of adjudication-confirmed cases per 100 patient-years for secukinumab was 0.40 versus 0.39 for placebo. Elevations (mainly CTCAE Grade 1 and Grade 2) in cholesterol, triglycerides and hepatic transaminases were also observed during clinical trials in patients with psoriatic arthritis and ankylosing spondylitis. ( cos140518m) . Abbreviations : PASI: Psoriasis Area and Severity Index. References: 1 . Novartis Data on File. 2 . Bissonnette R et al. J Eur Acad Dermatol Venereol 2018 Feb 14. doi: 10.1111/jdv.14878. Cosentyx is a registered trade mark of Novartis AG. Novartis Pharmaceuticals Australia Pty Limited.ABN 18 004 244 160. 54Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555.AU-6295. August 2018. NODE14051W/PUD. Ward6.

PBS Information: Section 85 Authority Required for the treatment of severe chronic plaque psoriasis, active ankylosing spondylitis and severe psoriatic arthritis. Refer to PBS Schedule for full Authority information.

EDITOR’S PICKS 14

Prevalence of Contact Allergy to Metals in the European General Population With a Focus on Nickel and Piercings Contact Dermatitis Take-home message • The EDEN Fragrance Study randomly selected a group of 3119 people aged 18 to 74 years from five European countries to undergo patch testing. This current study evaluated the prevalence of nickel allergy and its association with age, gender, nationality, and number of piercings. Overall, females had the higher prevalence of nickel allergy (22.0%). Of the countries represented, Sweden had the lowest prevalence (2.9%), likely reflecting the country’s early institution of laws regulating the nickel content of jewelry. Likewise, younger women were less likely to have a nickel allergy compared with those 31 to 45 years of age and 46 to 60 years old, possibly due to more recent regulation of jewelry nickel content across the rest of Europe. Nickel allergy was positively correlated with number of piercings, with a prevalence of 27.6% in those individuals who had three or more piercings versus 6.4% in those who never had a piercing. • The prevalence of nickel allergy correlates positively with number of piercings; however, rates of nickel sensitization seem to be declining with stricter regulation of jewelry nickel content across Europe. Caitlyn T. Reed MD

Abstract BACKGROUND Studies on sensitization to metals in the general population are scarce. OBJECTIVES To determine the prevalence of sen- sitization to metals in the general population, and factors associated with nickel sensitization. METHODS In 5 European countries (The Nether- lands, Germany, Italy, Portugal and Sweden), a random sample (N =3119) from the general pop- ulation (aged 18-74years) was patch tested and interviewed by use of a questionnaire on expo- sure to metals, piercing, and jewellery. RESULTS Overall, the age-standardized prev- alences of sensitization to nickel, cobalt and chromium were, respectively, 14.5%, 2.1%, and 0.8%. The highest prevalence of nickel sensitiza- tion was seen in Portugal (18.5%) and the lowest (8.3%) in Sweden. The prevalence of cobalt sensitization varied between 3.8% (The Neth- erlands) and 0.9% (Italy), and the prevalence of chromium sensitization varied between 1.3% (Portugal) and 0.2% (Sweden). Significant asso- ciations were observed between nickel allergy and female sex (odds ratio [OR] 5.19; 95% confi- dence interval [95%CI]: 3.99-6.74), past piercing use (OR 3.86; 95%CI: 2.85-5.24), and currently having ≥3 piercings (OR 5.58; 95%CI: 4.02-7.76). CONCLUSIONS The prevalence of sensitization to metals in the European general population was high, mostly because of nickel. The lowest prev- alence of contact allergy to nickel and chromium observed in Sweden supports the effectiveness of long-standing regulation. Prevalence of Contact Allergy to Metals in the European General Population With a Focus on Nickel and Piercings: The EDEN Fra- grance Study. Contact Derm 2018 Jul 01;79(1)1-9, MLA Schuttelaar, RF Ofenloch, M Bruze, et al. www.practiceupdate.com/c/69477

COMMENT By Christen Maria Mowad MD

N ickel is the most common allergen to cause allergic contact dermatitis on patch testing. This study sought to determine the prevalence of allergy to nickel, cobalt, and chromium in the general population in Europe. The researchers found that nickel allergy was the most prevalent, at 14.5%, followed by cobalt at 2.1% and chromium 0.8%. Nickel allergy more commonly affected female patients and was associated with past piercings and multiple piercings (>3). Variations in metal allergy were significant across different countries. Nickel allergy was lowest in Sweden, which adopted the EU nickel directive earlier than other European countries. Nickel regu- lation limits the amount of nickel permitted in products that come into direct contact with the skin. Younger, versus older, women also had a lower rate of sensitization, likely due to the nickel directive being implemented. As nickel allergy remains high in the United States, we could learn from our European colleagues by instituting limits on nickel exposure in this country as well.

PRACTICEUPDATE DERMATOLOGY