PracticeUpdate Dermatology Best of 2018

Best of 2018

VOL. 2 • NO. 4 • 2018

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4702

TOP STORIES 2018 On the Cusp of a Safe and Effective Approach for Androgenic Alopecia? Acne and Venous Leg Ulcers Melanoma Hot Topics Comprehensive Patch Testing for Contact Dermatitis

JOURNAL SCANS Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-Analysis

Association Between Itch and Cancer in 16,925 Pruritus Patients: Experience at a Tertiary Care Center

Age at Diagnosis as a Relative Contraindication for Intervention in Facial Nonmelanoma Skin Cancer

Indication: ILUMYA (tildrakizumab) is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. 1 Recommended dose: 100mg at weeks 0, 4 and every 12 weeks thereafter. 1

6 injections in rst 52 weeks

0 Week

4

8 12

16

20 24

28

32 36

40

44 48

52

Storage: Store at 2°C to 8°C. ILUMYA is stable for up to 30 days at 25°C. 1

PBS Information: Not PBS Listed

Please review Product Information before prescribing available from www.ebs.tga.gov.au or Sun Pharma by calling 1800 726 229 ILUMYA tildrakizumab (rch) 100 mg/1 mL solution for injection in pre-lled syringe. Indications: treatment of adults with moderate- to-severe plaque psoriasis who are candidates for systemic therapy. Contraindications: Hypersensitivity to the active substance or excipients. Clinically important active infections (e.g. active tuberculosis). Precautions: Infections: Chronic or a history of recurrent infections; monitor patients if a serious infection develops Active tuberculosis (TB); evaluate for TB prior to treatment. Consider anti-TB therapy in patients with history of latent or active TB in whom an adequate course of treatment cannot be conrmed. Monitor for TB during and after treatment. Hypersensitivity: Discontinue immediately if a serious reaction occurs and initiate appropriate therapy. Immunisations: Patients should not receive live vaccines during and for at least 17 weeks after treatment. Consider completion of immunisations prior to treatment initiation but if a live vaccine is received, wait at least 4 weeks prior to treatment initiation. Malignancy: Caution should be observed in patients with a history of malignancy or if this develops during therapy. Paediatric Use: not evaluated in under 18yr population. Interactions: Live vaccines. (See full PI). Pregnancy: (Category B1) Adverse effects: Common: diarrhoea, nausea, fatigue, injection site pain nasopharyngitis, sinusitis, arthralgia, back pain and pain in extremity. Dosage and administration: subcutaneous injection (100mg) at weeks 0, 4 and every 12 weeks thereafter. See Consumer Medicines Information for instructions. Storage: store in refrigerator (2ºC-8ºC). Do not freeze. ILUMYA is stable for up to 30 days at 25ºC. Protect from light. Do not shake. Store in original container until ready for use. Date of preparation: August 2018 ▼ This medicinal product is subject to additional monitoring in Australia. This will allow quick identication of new safety information. Healthcare professionals are asked to report any suspected adverse events at https://www.tga.gov.au/reporting-problems References: 1. Approved Product Information Sun Pharma ANZ Pty Ltd ABN 17 110 871 826, Macquarie Park NSW 2113. Ph: 1800 726 229. Fax: +61 2 8008 1639. Med Info and to report Adverse Events: adverse.events.aus@sunpharma.com or 1800 726 229. ILUMYA™ is a trade mark of Sun Pharma ANZ Pty Ltd. IL2018/12PUD1. Date of preparation: November 2018.

NEW

First IL-23 inhibitor with 12-weekly dosing * and results that last † * First IL-23 inhibitor approved with 12 weekly dosing after initial doses at weeks 0 and 4 1 † Of 100mg responders at week 28, 94% and 78% maintained PASI 75 or 90 respectively out to week 52 1

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. 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. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. 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 accordance with the editorial policies of Elsevier’s PracticeUpdate.com. All content 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 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: Hair with skin under microscopic close-up view/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; Clinical Director for Geisinger Dermatology, 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

Jeffrey Scott MD Mohs Micrographic Surgery and Dermatologic Oncology Fellow, Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio

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.

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CONTENTS 5

TOP STORIES 2018 6

8 Melanoma Hot Topics By Jane Grant-Kels MD 9 Comprehensive Patch Testing for Contact Dermatitis By Christen Maria Mowad MD EDITOR’S PICKS 10 Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-Analysis Comment by Thomas Horn MD 12 Serlopitant for the Treatment of Chronic Pruritus Comment by Erin E. Boh MD, PhD 13 Maintenance of Skin Clearance With Ixekizumab Treatment of Psoriasis Comment by Mark G. Lebwohl MD and George Han MD, PhD 14 The Medical Necessity of Comprehensive Patch Testing Comment by Salma F. de la Feld MD, FAAD 15 Association Between Itch and Cancer in 16,925 Pruritus Patients Comment by Rebecca J. Chibnall MD 16 Age at Diagnosis as a Contraindication for Intervention in Nonmelanoma Skin Cancer Comment by Joseph F. Sobanko MD and Daniel M. Siegel MD, MS, CPCD 18 Local Anesthesia in Pediatric Dermatologic Surgery Comment by Brandi M. Kenner-Bell MD

EXPERT OPINION 20 Dr. Dirk Elston and the Best of JAAD By Dirk Elston MD, FAAD 22 Pearls From the Fall Clinical Dermatology Meeting 2018: On the Cusp of a Safe and Effective Approach for Androgenic Alopecia? By Robert T. Brodell MD, FAAD 7 Acne and Venous Leg Ulcers By Eliot N. Mostow MD, MPH

24 Highlights From the Society for Pediatric Dermatology Summer Meeting By Sarah L. Chamlin MD

Dr. Albert Yan By Albert C. Yan MD

26 Pearls From the Fall Clinical Dermatology Meeting 2018: Update on Vaccines in Dermatology By Stephen K. Tyring MD, PhD, Uyen Ngoc Mui MD and Ravi Patel MD

23 AAD 2018 Annual Meeting: Dr. Eliot Mostow's Take-Aways By Eliot N. Mostow MD, MPH

CONFERENCES 28 American Academy of Dermatology Annual Meeting 2018 By the PracticeUpdate Editorial Team 28 Janus Kinase Inhibitors May Revolutionize Dermatology 29 Topical Cannabidiol Recommended as Adjunct Treatment for Acne, Eczema, and Psoriasis 30 Do Not Delay Brimonidine When Using Combination Therapy for Rosacea 31 Topical Anticholinergic Offers New Option for the Treatment of Axillary Hyperhidrosis

32 27th European Academy of Dermatology and Venereology Congress By the PracticeUpdate Editorial Team 32 Two JAK Inhibitors Appear to Be Safe and Effective for Alopecia Areata 33 The Anti-TNF α Class Improves Dactylitis and Enthesitis of PsA Better Than Newer Biologics 34 Secukinumab Improves Symptoms of Moderate-to-Severe Hidradenitis Suppurativa

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 6

On the Cusp of a Safe and Effective Approach for Androgenic Alopecia? By Robert T. Brodell MD, FAAD

E very year during the fourth quarter, I write a commentary about my “top story” of the year. I take this very seriously, recognizing that there are 39,000 PracticeUpdate Dermatolog y subscribers from around the world. I always fear offending 38,999 individuals whose article, professor's article, or friend's article I did not choose! Derma- tology is a rapidly expanding field, with major advances this past year in the systemic treatment of atopic eczema, expanding biologic approaches to psoriasis, and amazing advances in targeted therapy for melanoma. This year, I am going to take a “walk on the wild side” and choose two “cosmetic” articles, something quite unusual for this proud medical dermatologist. Both articles discuss using drugs that are relatively safe, inexpensive, and familiar to all dermatologists in a novel manner. In both cases, additional studies are needed to con- firm the authors novel findings. Finally, millions of individuals, most especially women, will be interested in these treatments. The condition is androgenic alopecia. Sinclair RD. Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone. Int J Dermatol 2018;57(1):104-109. • Safety: Low-dose oral minoxidil (0.25 mg/day) plus spironolactone 25 mg/day caused only a 4-mm systolic and 6-mm diastolic decrease in blood pressure with postural hypotension in only 2 of 100 women. Facial hypertrichosis occurred in 4 of 100 women. Urticaria occurred in 2 of 100 women. Only the urticaria patients discontinued treatment. • Mechanism: Minoxidil opens potassium channels causing hyperpolarization of cell membranes leading to dilatation of blood vessels, and, perhaps, delivering more oxygen and nutrients to the hair follicle. It prolongs the anagen phase and increases hair follicle size. Spironolactone suppresses the production of androgen by adrenal glands and ovaries. • Efficacy: This prospective uncontrolled observational study revealed a reduction of hair loss severity and shedding. • Cost: These are both inexpensive generic medications. Rossi A, Campo D, Fortuna MC, et al. A preliminary study on topical cetirizine in the therapeu- tic management of androgenetic alopecia. J Dermatol Treatment 2018;29(2):149-151. • Mechanism: Prostaglandin D2 (PGD2) is a central player in production of androgenic alopecia. Cetirizine (Zyrtec) blocks PGD2. • Safety: Cetirizine is an antihistamine used frequently by all dermatologists. I would not anticipate that topical application would have any significant side effects besides perhaps a little dry mouth. • Efficacy: In all, 85 male and female patients applied cetirizine 1% solution to the scalp and 18 applied the vehicle as a control. The treatment group demonstrated increased total density, terminal hair density, and decreased vellus density after 6 months. • Cost: This is an inexpensive generic drug. I am not able to predict with certainty whether either or both of these approaches to androgenic alopecia will withstand the test of time, but the combination of logical mech- anisms of action and these preliminary results make me quite hopeful. The quality of life of millions of women (and men, in the case of topical cetirizine) could be impacted by these discoveries. www.practiceupdate.com/c/74879

" …the combination of logical mechanisms of action and these preliminary results make me quite hopeful. The quality of life of millions of women (and men, in the case of topical cetirizine) could be impacted by these discoveries. "

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TOP STORIES 2018 7

Acne and Venous Leg Ulcers By Eliot N. Mostow MD, MPH

A sking anyone to pick just one article for their story of the year is very difficult. It’s been a great year, with all sorts of excellent work informing us about the associations between psoriasis and meta- bolic disorders and links between dermatologic and cardiovascular and psychological diseases, and data to remind us that we might be overdoing the monitor- ing for lab abnormalities in patients on antifungals and those taking isotretinoin. That being said, I’ve picked two stories that I’ve commented on this year, one on a most common disease that can result in permanent disfigurement and the other that begs for more active involvement by all clinicians, especially dermatologists.

" …we all need to recognize that care of acne patients early, and with the goal of “clear or almost clear” (also the relatively new standard for psoriasis care), can have life-changing benefits. "

compression alone. No surprise that it helped, but the key to the importance of this article is that effective cli- nicians are great communicators with their patients. The other important point is that these are patients who really can benefit from multidisciplinary care, including care from dermatologists. I encourage any- one involved in dermatology care to be involved in the care of patients with venous leg (and other) ulcers. Ultimately, any ulcer is simply a problem with the epi- dermis and dermis, and dermatologists should be a key part of the team to optimize treatment for these patients. Effective communication means that we can more fre- quently close the knowledge gap for patients (and collaborating clinicians and ancillary care providers) with respect to their diagnoses and prognoses, and improve compliance with (potentially) beneficial treat- ments. My disclosure is that I often fail in this regard, but I believe in aspirational goals to help me improve the care I deliver to patients and hopefully be a model for trainees and colleagues. Thanks to all for reading my thoughts on articles that “grabbed me” over the last few years. I owe special thanks also to my colleagues Dr. Bob Brodell and Dr. Ashish Bhatia, who inspire me to work hard and contribute to PracticeUpdate , and to the Elsevier team who makes the work accessible to the world. References 1. Borok J, Udkoff J, Vaida F, et al. Transforming acne care by pediatricians: an interventional cohort study. J Am Acad Dermatol 2018;79(5):966-968. 2. Jull A, Slark J, Parsons J. Prescribed exercise with compression vs compression alone in treating patients with venous leg ulcers: a systematic review and meta-analysis. JAMA Dermatol 2018;2018;154(11):1304-1311. www.practiceupdate.com/c/76139

Acne The first top story is on acne care. 1 It is important because the study really went to the heart of provid- ing more effective care to patients with acne through more effective education of pediatricians. That a simple intervention with a guided protocol made a differ- ence should remind us of the power of education and intervention at the right point of care (ie, in early adoles- cence, a time when patients are generally seen most often by their pediatricians, who can more effectively intervene with appropriate care early). Of course, I think most pediatricians prefer to have isotretinoin treatment directed by dermatologists, but that can become part of effective triage and improved communication. No doubt, we probably underutilize isotretinoin, a drug that really does have the consistent potential to dra- matically clear even the most severe acne. I just heard a wonderful presentation by Dr. Julie Harper reminding us that we all need to recognize that care of acne patients early, and with the goal of “clear or almost clear” (also the relatively new standard for pso- riasis care), can have life-changing benefits. Common disease with a simple intervention and cost-effective treatments: this is important. Venous leg ulcers My second choice for a top story study relates to patients with venous leg ulcers. 2 Although we don’t know exactly how many patients suffer from this con- dition, we know it’s relatively common, debilitating in many ways, and costly to the healthcare system. The intervention in this study was also simple and essen- tially free…exercise added to compression versus

VOL. 2 • NO. 4 • 2018

TOP STORIES 2018 8

Melanoma Hot Topics By Jane Grant-Kels MD

M elanoma continued to be a hot topic in 2018, with reported successes in new com- binations of targeted therapy and updates regarding the somewhat controversial role of com- plete lymph node dissection after a sentinel lymph node biopsy (SLNB) revealed a micro-metastasis. In my opinion, there were three stories that were the hottest! Those of us treating high-risk melanoma patients have experienced how difficult it has been for patients and their providers to “wait and see” if they will progress after they are discovered to have a positive SLNB. Until recently, systemic targeted therapies were only available to those of our patients with stage IV disease. An article by Eggermont et al published this year was long awaited and changed this scenario dramatically . 1 These authors conducted a phase III double-blinded trial to evaluate pembrolizumab (a PD-1 inhibitor) as adjuvant therapy in randomly selected patients with resected stage III melanoma. Approximately half of the patients received 200mg of pembrolizumab, and the other half received placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. The authors evaluated safety and recurrence-free survival. At a median follow-up of 15 months, pembrolizumab was associated with signif- icantly longer recurrence-free survival than placebo (1-year rate of recurrence-free survival, 75.4–77.1% in the pembrolizumab group and 62.6% in the placebo group). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group but only 3.4% of patients in the placebo group. The authors concluded, much to the applause of melanoma cli- nicians and patients, that 200 mg of pembrolizumab therapy given every 3 weeks for up to a year in high-risk, stage III melanoma patients resulted in significantly longer recurrence-free survival than pla- cebo, with no new toxic effects identified. This is a long-awaited therapy for our stage III patients and far better than let’s “wait and see what happens.” President Jimmy Carter highlighted the horrors of melanoma brain metastases. Despite his newsworthy medical situation, previous studies of nivolumab com- bined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. Consequently, a group of authors decided to evaluate the efficacy and safety of nivolumab plus ipilimumab in patients withmelanomawith untreated, nonirradi- ated brainmetastases in an open-label, multicenter, phase II study . 2 These patients had a brain metas- tasis that was of a tumor diameter between 0.5 and 3 cm without neurologic symptoms. They received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to four doses, followed by nivolumab

(3 mg/kg) every 2 weeks until progression or unac- ceptable toxic effects. The authors then evaluated the percentage of patients who had stable intracranial disease for at least 6 months, a complete response, or a partial response. The rate of intracranial clinical benefit was 57%, including a 26% rate of complete response, 30% rate of partial response, and 2% rate of stable disease. The overall rate of extracranial clin- ical benefit was calculated to be 56%. Grade 3 or 4 adverse events secondary to the therapy were iden- tified in 55% of patients. This safety profile matched that reported in patients with melanoma who do not have brain metastases. The authors therefore con- cluded that nivolumab plus ipilimumab had clinically meaningful intracranial efficacy for our patients with melanoma with untreated brain metastases. Finally, an oral presentation at the 2018 American Society of Clinical Oncology Annual Meeting in Chi- cago, Illinois, this past June reported that c omplete lymph node dissection (CLND) does not improve survival outcomes among patients with malignant melanoma who have a positive SLNB compared with observation or watchful waiting . 3,4 In the phase III DeCOG-SLT study, 473 patients with melanoma thickness of at least 1 mm and a positive SLNB with micro-metastases with a maximum of 2 mm in diam- eter were randomly assigned to undergo CLND (240 patients) or clinical monitoring only (233 patients) between January 2006 and December 2014. The authors evaluated distant metastasis–free survival (DMFS), recurrence-free (RFS), and overall survival (OS). After a median follow-up of 72 months, the fol- lowing were demonstrated: • The 5-year DMFS rate was 67.6% among patients who only underwent monitoring versus 64.9% among patients in the CLND arm. • There were no significant differences in the 5-year OS, with 71.4% in the observation group compared with 72.3% in the CLND group.

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TOP STORIES 2018 9

Comprehensive Patch Testing for Contact Dermatitis By Christen Maria Mowad MD C ontact dermatitis has been identified as the fifth most common skin disease in the US, affecting more than 13 million Amer- icans of all ages and races, and accounting for $1.529 billion in healthcare expenditures. Until the causative allergen is identified, aller- gic contact dermatitis will remain a chronic disease with numerous quality-of-life issues and significant eco- nomic and personal costs to individuals and society. With a delay in diagnosis or an incorrect or incomplete diagnosis, the eruption continues indefinitely. Comprehensive patch testing is essential to accurately identify causative allergens, resulting in resolution and prevention of disease. ACD can be cured in most cases with the identification of the causative allergen and proper education regarding identification and avoidance of these allergens in the environment. Although FDA-approved allergen series with limited, static numbers of aller- gens are available, these can have limited diagnostic capacity and have been shown to detect at best 66% of relevant reactions. Comprehensive patch testing is needed to accurately and more fully identify causative allergens. A paper entitled, “The Medical Necessity of Comprehensive Patch Testing,” outlines the benefits and necessity of compre- hensive patch testing. 1 History, physical examination, and a query of personal care products, work exposures, avocations, as well as other daily contactants, help direct allergen selection for testing. Expanded/supplemental allergen testing series have been shown to improve diagnostic yield, resulting in better chances at a cure of what would otherwise remain a chronic disease. Patch testing is the criterion standard for diagnosing and resolv- ing allergic contact dermatitis. The limitations on the number of allergens tested hinders the ability to identify causative allergens and limits our ability to potentially cure a chronic disease with sig- nificant costs both economically and personally to patients and society. This paper is important as it highlights the value of compre- hensive patch testing and its ability to diagnose and help resolve a significant and costly skin problem. As limitations on this valua- ble tool are increasingly being imposed, this paper outlines why comprehensive patch testing is of significant value and needs to remain a tool for detection and management of one of the most common skin diseases in the United States. Reference 1. Zhu TH, Suresh R, Warshaw E, et al. The Medical Necessity of Comprehensive Patch Testing. Dermatitis 2018;29(3):107-111. www.practiceupdate.com/c/76154 " …comprehensive patch testing is of significant value and needs to remain a tool for detection and management of one of the most common skin diseases… "

• There were no significant differences in the 5-year RFS, with 60.9% in the observation group compared with 59.9% in the CLND group. • A subgroup analysis was performed based on tumor load in the SLNB: x x The DMFS rate differed between those patients with a SLNB tumor load ≤1.0 mm versus those with a SLNB tumor load >1 mm, but not between the observation and CLND treatment groups. x x The 5-year DMFS for those with a SLNB ≤1.0 mm was 72.5% in the observation group versus 68.7% in the CLND group; the data for those with a SLNB with a metastasis of >1mm was 51.7% (observation group) versus 54.7% (CLND group). x x The 5-year lymph-node recurrence-free survival was 65% (observation group) vs 65.9% (CLND group). The authors performed a multivariable analysis, demonstrat- ing that tumor thickness and tumor load in the SLNB were independent prognostic factors for DMFS, OS, and RFS. In the conclusion of the presentation, the authors stated that “immediate CLND in SLNB-positive patients is not superior to observation. We would no longer recommend CLND in patients with micro-metastases.” This is a major change in what was previously recommended and will spare our patients the morbidity of a CLND for those who have a micro-metas- tasis on SLNB. References 1. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 2018;378(19):1789-1801. 2. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 2018;379(8):722-730. 3. Leiter UM, Stadler R, Mauch C, et al. Final analysis of DECOG-SLT trial: survival outcomes of complete lymph node dissection in melanoma patients with positive sentinel node. J Clin Oncol 2018;36(15_suppl):9501. 4. Nam J. Complete lymph node dissection may not improve outcomes in melanoma. Can Ther Adv Published June 4, 2018. Accessed November 5, 2018. www.practiceupdate.com/c/75706

VOL. 2 • NO. 4 • 2018

EDITOR’S PICKS 10

Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-Analysis Journal of the American Academy of Dermatology Take-home message

COMMENT By Thomas Horn MD T his article describes ameta-analysis of reports on the use of intralesional immunotherapy to treat warts, con- cluding that the treatment works, with PPD and MMR being the most effec- tive immune stimulants. Good to know. I have often wondered about the wisdom of using therapeutically employed anti- gens in this setting, fearing that repeated administration over short periods of time may alter their immunogenicity later on. Still, any single antigen or mix of antigens stimulating the immune system in thewart milieu ought to have benefit. In countries using BCG as a tuberculosis-prevention strategy, I would predict good success in treating warts with it – some evidence exists already. The idea for this came to me during the darkest days of the HIV epidemic, before HAART. The explosion of HPV-induced disease across its entire spectrum as T-cell counts fell was insur- mountable. At the time, studies were being published exploring the value of injecting patients with skin test antigens to stimulate T-cell proliferation, postu- lating that any T-cell was a good T-cell, under the circumstances. Although that didn’t pan out, the notion of draw- ing T-cells into HPV-infected tissue to generate HPV-reactive effector cells in immunocompetent patients seems to have found its place in our (incredibly varied) treatment toolbox.

• These authors performed a review andmeta-analysis of 17 randomized controlled trials investigating various intralesional immunotherapeutic treatments for warts. Compared with placebo, purified protein derivative (PPD), measles, mumps, and rubella (MMR), and INF-β were most effective in terms of complete recovery at the primary site (OR, 39.56, 17.46, and 15.55, respectively). Compared with placebo, autoinoculation, PPD, and MMR were significantly superior to placebo at the distant site (OR, 79.95, 42.95, and 15.39, respectively). MMR was most effective in reducing same-site recurrence. • Intralesional injections, in particular PPD and MMR, may be effective for wart clearance at primary and distant sites, as well as for local recurrence reduction. Immunotherapeutic injections may enhance host cell–mediated immunity against the virus and thus have efficacy beyond the local injection site. InYoung Kim MD, PhD

Dr. Horn is Vice Chair of the Department of Dermatology at Massachusetts General Hospital in Boston, Massachusetts.

Abstract BACKGROUND Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging. OBJECTIVE Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities. METHODS We included randomized controlled trials (RCTs) comparing intralesional immuno- therapeutic modalities to cryotherapy, placebo or imiquimod. All outcomes were presented as odds ratio (OR) with 95% confidence-interval. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments.

RESULTS Network meta-analysis of 17 RCTs (1676 patients) showed that PPD (OR=39.56), MMR (OR=17.46) and INF-β (OR=15.55) had the high- est efficacy in terms of complete recovery at the primary site, compared to placebo. Regarding complete recovery at the distant site, autoinoc- ulation (OR=79.95), PPD (OR=42.95) and MMR (OR=15.39) were all statistically superior to pla- cebo. According to the P-score, MMR was more effective than other modalities in reducing recur- rence rate at the same site. LIMITATIONS Relatively-small sample size in some comparisons and variability in baseline characteristics. CONCLUSION PPD and MMR were the most effec- tive in achieving complete primary and distant

recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site, compared to cryotherapy and other immunotherapeutic modalities. Intralesional Immunotherapy for the Treatment of Warts: A Network Meta-Analysis. J Am Acad Dermatol 2018 Jul 09;[EPub Ahead of Print], S Salman, MS Ahmed, AM Ibrahim, et al. www.practiceupdate.com/c/70845

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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.

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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 12

Serlopitant for the Treatment of Chronic Pruritus Journal of the American Academy of Dermatology Take-home message

" This study also demonstrates that more research is needed in evaluating the basic pathophysiology of pruritus. " COMMENT By Erin E. Boh MD, PhD C hronic pruritus poses a signifi- cant burden on society in terms of healthcare cost and treatment challenges. Additionally, many systemic diseases are also known to be associated with pruritus. Currently, the pathophysiology of pruritus is unclear, but we do know that the substance P/neurokinin 1 recep- tor (NK1R) pathway is critical in chronic pruritus. In this original article, the authors eval- uated the safety and efficacy of novel agent serlopitant, an NK1R antago- nist, for treatment of chronic pruritus in patients with disparate dermatologic diseases and idiopathic pruritus. In this study, serlopitant treatment resulted in a dose-dependent decrease in pruritus in all groups as well as improvement in the DLQI (quality-of-life assay). Nearly 45% of patients had a pri- mary dermatologic disease. However, it should be noted that improvement in pruritus occurred in the treatment group regardless of the underlying der- matologic disease. This is particularly exciting as treatments for chronic pruri- tus are not particularly helpful. This was a small patient population, and the high placebo rates should not detract from the potential significance of this study. This study also demonstrates that more research is needed in evaluating the basic pathophysiology of pruritus. If we are able to discover the key players and pathways in pruritus, we will be able to construct drugs that can target these pathways to block its effects. Dr. Boh is Chairman & Professor of Dermatology at Tulane University Health Sciences Center in New Orleans, Louisiana.

• The authors assessed the safety and efficacy of serlopitant in patients with chronic pruritus associated with dermatologic and non-dermatologic conditions. Patients were randomized to receive either placebo (n=64), or serlopitant 0.25 mg (n=64), 1 mg (n=65), and 5 mg (n=64). No adverse events were detected. After 6 weeks, patients receiving 1 mg or 5 mg of serlopitant had a marked decrease in pruritus scores compared with patients receiving placebo. Differences emerged at 3 weeks after treatment initiation and remained at final follow-up visit 4 weeks after completing treatment. • The results suggest that serlopitant is well-tolerated and reduces pruritus in patients with severe chronic pruritus from several dermatologic and non-dermatologic conditions that were refractory to antihistamines and corticosteroids. Jeffrey F. Scott MD

Abstract BACKGROUND The substance P/neurokinin 1 receptor (NK1R) pathway is critical in chronic pruritus; anecdotal evidence suggests antag- onism of this pathway can reduce chronic itch. OBJECTIVE To assess the safety and efficacy of the NK1R antagonist serlopitant in treating chronic pruritus. METHODS Eligible patients with severe chronic pruritus who were refractory to antihistamines or topical steroids were randomized to serlopitant 0.25, 1, or 5 mg, or placebo, administered once daily for 6 weeks as monotherapy or with mid- potency steroids and emollients. The primary efficacy end point was percentage change in Visual Analog Scale (VAS) pruritus score from baseline. RESULTS Serlopitant treatment resulted in a dose-dependent decrease in pruritus. Mean percentage decreases from baseline VAS

pruritus scores were statistically significantly larger for the 1- and 5-mg doses of serlopitant (P = .022 and P = .013) versus placebo at week 6. No significant safety or tolerability differences were detected among the groups. LIMITATIONS The sample size was insufficient for subgroup analyses of the efficacy of serlopi- tant for chronic pruritus based on underlying conditions. CONCLUSIONS Serlopitant 1 mg and 5 mg daily was associated with a statistically significant reduction in chronic pruritus and was well tolerated. Serlopitant for the Treatment of Chronic Pruritus: Results of a Randomized, Multicenter, Placebo- Controlled Phase 2 Clinical Trial. J Am Acad Dermatol 2018 Feb 17;[EPub Ahead of Print], G Yosipovitch, S Ständer, MB Kerby, et al. www.practiceupdate.com/c/64715

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EDITOR’S PICKS 13

Maintenance of Skin Clearance With Ixekizumab Treatment of Psoriasis Journal of the American Academy of Dermatology Take-home message

• This study reports on the long-term efficacy and safety of ixekizumab in patients with psoriasis treated for 3 years in the UNCOVER-3 study. Of the 385 participants originally randomized to receive ixekizumab every 2 weeks for 12 weeks and then every 4 weeks thereafter, 77.9% completed the total of 156 weeks, among whom the percentage with PASI 75, 90, and 100 at week 156 were 80.5%, 66.0%, and 45.1%, respectively. Clinical responses were also maintained by participants with nail, scalp, and palmoplantar involvement of their psoriatic disease at baseline. Infections, including viral and upper respiratory tract infections, were the most commonly reported adverse events reported over the course of the study. • Ixekizumab demonstrated sustained clinical efficacy over 3 years, with a safety profile consistent with that reported with other psoriasis treatments. Jeffrey F. Scott MD

" The current paper now allows us to also say that the response

COMMENT By Mark G. Lebwohl MD and George Han MD, PhD W hen a drug is first approved after phase III time-limited stud- ies, patients and physicians

Abstract BACKGROUND Psoriasis, a chronic disease, may require long-term treatment. Ixekizumab, a high-affinity monoclonal antibody that selec- tively targets interleukin-17A, is an approved therapy for patients with moderate-to-severe plaque psoriasis. OBJECTIVE To evaluate efficacy and safety of ixekizumab through 156 weeks from the UNCOVER-3 study in patients who received the recommended dose regimen [160 mg at Week 0, 80 mg every 2 weeks (IXE Q2W) to Week 12, and 80 mg every 4 weeks (IXE Q4W) thereafter. METHODS Patients randomized to IXE Q2W, IXE Q4W, etanercept twice weekly, or placebo were switched to IXE Q4W during long-term extension period. Efficacy data were summarized using as-observed, multiple imputation (MI), and mod- ified nonresponder imputation (mNRI) methods. RESULTS At Week 156, response rates were 80.5%, 66.0%, and 45.1% for PASI 75, 90 and 100 using mNRI method, respectively, and 97.2% and 86.2 for PASI 75 using as-observed and MI methods, respectively. Similar response rates were observed in patients with baseline scalp, nail, or palmoplantar involvement. No new safety signals were identi ed through Year 3. LIMITATIONS No placebo or active comparison after Week 12. CONCLUSION Ixekizumab sustained high responses with clearance of skin and nail lesions, with no new safety concerns through 3 years. Maintenance of Skin Clearance With Ixeki- zumab Treatment of Psoriasis: Three-Year Results From the UNCOVER-3 Study. J AmAcad Dermatol 2018 May 24;[EPub Ahead of Print], C Leonardi, C Maari, S Philipp, et al. www.practiceupdate.com/c/69091 is durable and that the safety of the drug does not appear to change with long-term use. "

and 45.1% of patients achieved PASI 90 and PASI 100, respectively, using the mod- ified non-responder imputation analysis. The observation that only 3% of patients discontinued because of lack of effi- cacy is further evidence of the durability of response seen with this drug. Equally impressive was the durability of response for scalp and nails; but, perhaps most impressive, was the improvement in pal- moplantar psoriasis. The PP PASI 100 rate by modified non-responder imputation at week 156 was 60.5%. Using other statisti- cal analyses such as “as observed,” 84.7% of patients achieved PP PASI 100 at week 156, a response rate never seen before for palmoplantar psoriasis. It should be pointed out that this response rate might not be seen in patients with predomi- nant palmoplantar psoriasis in contrast to palmoplantar lesions in patients with pre- dominant generalized plaque psoriasis. In summary, previous studies have shown the high degrees of efficacy and the speed of response achieved by ixeki- zumab. The current paper now allows us to also say that the response is durable and that the safety of the drug does not appear to change with long-term use.

naturally ask a number of questions. The first and most important questions include the following: 1) Will the drug continue to be safe with long-term use; and 2) will the drug continue to be effective with long- term use? The paper by Leonardi et al answers both of those questions with a resounding “yes.” Rare side effects may not become evident until a drug has been used in thousands of patients for many years, but it is comforting to know that over 1000 patients have been followed for 3 years without the emergence of any new unexpected side effects. When fol- lowing 1274 patients for 3 years, adverse events certainly occur, but the frequency of malignancies, respiratory infections, and cerebrocardiovascular events were not greater than one would expect in the general population. Candida infec- tions, which were noted in early trials of ixekizumab, certainly did occur in 4.6% of patients, and there were 4 patients (0.3%) who developed Crohn’s disease; how- ever, these had been noted in early trials of all of the drugs that block IL-17. And patients born with mutations in IL-17 or its receptor develop chronic mucocuta- neous candidiasis, so the development of monilial infections was anticipated. The durability of response in patients treated with the approved dosing of ixeki- zumab was particularly noteworthy. Using a rigorous modified non-responder impu- tation method, at 3 years 80.5% of patients had maintained PASI 75. Overall, 66.0%

Dr. Lebwohl is Professor and Chairman of the Department of Dermatology at Mount Sinai School of Medicine in New York.

Dr. Han is Chair of the Department of Dermatology at Mount Sinai Beth Israel in New York.

VOL. 2 • NO. 4 • 2018

EDITOR’S PICKS 14

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 are missed. 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 underutilized and helpful tool that should be considered in the evaluation and treatment of allergic contact derma- titis. 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 diseases (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 in the Department of Dermatology at Emory University in Atlanta, Georgia.

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