PracticeUpdate Dermatology May 2019

VOL. 3 • NO. 2 • 2019

OUR EXPERTS. YOUR PRACTICE.

ISSN 2206-4702

Biologics and Psoriatic Disease: Have We Finally Detected a Mechanism Linking Treatment to CV Risk Improvement?

Expert Opinion Oral Collagen Supplementation By InYoung KimMD, PhD Tissue-Sparing Properties of Mohs Micrographic Surgery for Infiltrative BCC By Ashish C. Bhatia MD, FAAD Tularemia’s Re-Emergence By Warren R. Heymann MD

American Academy of Dermatology Annual Meeting 2019

JOURNAL SCANS Randomized Trial of Four Treatment Approaches for Actinic Keratosis

Optimizing the Total Body Skin Exam: An Observational Cohort Study

A Retrospective Cohort Study to Evaluate the Development of Comorbidities, Including Psychiatric Comorbidities, Among a Pediatric Psoriasis Population

Are you targeting complete treatment for your psoriasis patients? * *Efficacy of Cosentyx established by achievement of primary endpoints in clinical trials looking at manifestations of psoriatic disease (skin, joint, spine, nail, scalp and palmoplantar) 1–8

Sustained clear skin with 90% of PASI responses maintained over 5 years 8,9 No new safety signals up to 5 years 8,9

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) . Abbreviation: PASI: Psoriasis Area and Severity Index. References: 1 . McInnes IB et al. Lancet 2015;386:1137–46. 2. Bagel J et al. J Am Acad Dermatol 2017;77(4):667–74. 3. Langley RG et al. N Engl J Med 2014;371(4):326–38. 4. Reich K et al. EADV 2016; Vienna, Austria (Poster 2095). 5. Gottlieb A et al. J Am Acad Dermatol 2017;76(1):70–80. 6. Blauvelt A et al. J Am Acad Dermatol 2015;76(1):60–9. 7. Cosentyx Approved Product Information. 8. Bissonnette R et al. Br J Dermatol 2017;177:1033–42. 9. Bissonnette R et al. J Eur Acad Dermatol Venereol 2018;32:1507–14. Cosentyx is a registered trademark of Novartis AG. Novartis Pharmaceuticals Australia Pty Limited. ABN 18 004 244 160. 54 Waterloo Road, Macquarie Park NSW 2113. Ph (02) 9805 3555. April 2019. AU-8989. NODE15897W. See approved Product Information before prescribing. Approved Product Information available on request. For the most up-to-date Product Information, go to: https://www.novartis.com.au/products/healthcare-professionals 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.

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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

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 to 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: Science laboratory test tubes/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

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 EMDN051901

VOL. 3 • NO. 2 • 2019

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 NOW PBS LISTED 1 February 2019 for severe chronic plaque psoriasis 2

PBS Information: Authority required. Refer to PBS Schedule for full authority information

Please review Product Information before prescribing available from www.ebs.tga.gov.au ILUMYA tildrakizumab (rch) 100 mg/1 mL solution for injection in pre-filled 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 confirmed. 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 (2°C-8°C). Do not freeze. ILUMYA is stable for up to 30 days at 25°C. 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 identification 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 2. PBS. Schedule of Pharmaceutical Benefits - Effective 1 February 2019. Department of Health, Canberra. www.pbs.org.au. 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. IL2019/04ELSpbs2. Date of preparation: March 2019.

CONTENTS 5

RESEARCH Editor’s picks 6 Four Treatment Approaches for Actinic Keratosis

COVER 16

Biologics and Psoriatic Disease: Have We Finally Detected a Mechanism Linking Treatment to Cardiovascular Risk Improvement? By Anthony Fernandez MD, PhD

Comment by Martin Weinstock MD, PhD, Meghan E. Beatson BS and Angelica A. Misitzis MD

7 Optimizing the Total Body Skin Exam Comment by Jeffrey Miller MD, Matthew F. Helm MD and Katherine K. Hallock MD

EXPERT OPINION 18 Oral Collagen Supplementation By InYoung Kim MD, PhD 19 Tissue-Sparing Properties of Mohs Micrographic Surgery for Infiltrative BCC By Ashish C. Bhatia MD, FAAD 20 Tularemia’s Re-Emergence By Warren R. Heymann MD

8 Analysis of Readmissions Following Hospitalization for Cellulitis Comment by Lindy Fox MD 9 Herpes Zoster Incidence and Consensus Recommendations on Vaccination in Adults on Systemic Therapy for Psoriasis or Psoriatic Arthritis Comment by Robert T. Brodell MD, FAAD 10 Evaluating the Development of Comorbidities

Among Children With Psoriasis Comment by Sarah L. Chamlin MD

11 Deep Learning-Based, Computer-Aided Classifier vs Board-Certified Dermatologists in Skin Tumor Diagnosis 11 Risk Factors for Keratinocyte Carcinoma Skin Cancer in Nonwhite Individuals 12 Early Melanoma Nodal Positivity and Biopsy Rates Before and After Implementation of AJCC 7 Comments by David G. Brodland MD and by John Zitelli MD

CONFERENCE 22 American Academy of Dermatology Annual Meeting 2019 22 Dr. InYoung Kim's Take-Aways By InYoung Kim MD, PhD 24 Dr. Caroline Crabtree’s Take-Aways By Caroline K. Crabtree MD 25 Dr. Ashish Bhatia’s Take-Aways By Ashish C. Bhatia MD, FAAD 26 Dr. Caitlyn Reed’s Take-Aways By Caitlyn T. Reed MD

VOL. 3 • NO. 2 • 2019

EDITOR’S PICKS 6

Four Treatment Approaches for Actinic Keratosis The New England Journal of Medicine Take-home message

" It is a deficiency of our healthcare system that this is the first paper that conducts rigorous and appropriate

• This study investigated the effectiveness of 5% fluorouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL-PDT), or 0.015% ingenol mebutate gel in 624 patients with multiple actinic keratosis lesions. • Fluorouracil treatment showed the highest cumulative probability of remaining free from treatment failure compared with imiquimod, MAL-PDT, or ingenol mebutate at 12 months after the end of treatment. Jeffrey M. Wiisanen MD COMMENT By Martin Weinstock MD, PhD, Meghan E. Beatson BS and Angelica A. Misitzis MD A ctinic keratoses affect about 40 million Americans, are potential premalignant lesions, have been recognized and treated for decades, and consume large quantities of healthcare resources. Actinic insults resulting in actinic keratoses affect areas of skin – hence, the concepts of actinic neoplasia syndrome and field cancerization. Dermatologists must understand how different options compare for treating these conditions. It is a deficiency of our healthcare system that this is the first paper that conducts rigorous and appropriate randomization to compare the major treatment options for this condition. The way forward is to continue designing and executing studies like this one. Dr. Weinstock is Professor of Dermatology and Epidemiology at Brown University in Providence, Rhode Island. Ms. Beatson is Dermatoepidemiology Fellow at Brown University and an M.D. Candidate at George Washington University in Washington, DC. Dr. Misitzis is Dermatoepidemiology Research Fellow at Brown University in Providence, Rhode Island.

Abstract BACKGROUND Actinic keratosis is the most fre- quent premalignant skin disease in the white population. In current guidelines, no clear rec- ommendations are made about which treatment is preferred. METHODS We investigated the effectiveness of four frequently used field-directed treatments (for multiple lesions in a continuous area). Patients with a clinical diagnosis of five or more actinic keratosis lesions on the head, involving one continuous area of 25 to 100 cm 2 , were enrolled at four Dutch hospitals. Patients were randomly assigned to treatment with 5% fluo- rouracil cream, 5% imiquimod cream, methyl aminolevulinate photodynamic therapy (MAL- PDT), or 0.015% ingenol mebutate gel. The primary outcome was the proportion of patients with a reduction of 75% or more in the num- ber of actinic keratosis lesions from baseline to 12 months after the end of treatment. Both a modified intention-to-treat analysis and a per-protocol analysis were performed. RESULTS A total of 624 patients were included from November 2014 through March 2017. At 12 months after the end of treatment, the cumula- tive probability of remaining free from treatment failure was significantly higher among patients who received fluorouracil (74.7%; 95% confi- dence interval [CI], 66.8 to 81.0) than among those who received imiquimod (53.9%; 95% CI, 45.4 to 61.6), MAL-PDT (37.7%; 95% CI, 30.0 to 45.3), or ingenol mebutate (28.9%; 95% CI, 21.8 to 36.3). As compared with fluorouracil, the haz- ard ratio for treatment failure was 2.03 (95% CI, 1.36 to 3.04) with imiquimod, 2.73 (95% CI, 1.87 to 3.99) with MAL-PDT, and 3.33 (95% CI, 2.29 to 4.85) with ingenol mebutate (P≤0.001 for all comparisons). No unexpected toxic effects were documented. CONCLUSIONS At 12 months after the end of treatment in patients with multiple actinic kera- tosis lesions on the head, 5% fluorouracil cream was the most effective of four field-directed treatments. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med 2019 Mar 07;380(10)935-946, MHE Jansen, JPHM Kessels, PJ Nelemans, et al. www.practiceupdate.com/c/80651 randomization to compare the major treatment options for this condition. "

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EDITOR’S PICKS 7

Optimizing the Total Body Skin Exam Journal of the American Academy of Dermatology Take-home message

COMMENT By Jeffrey Miller MD , Matthew F. Helm MD and Katherine K. Hallock MD I (Jeffrey) remember calling the patient with a newly diagnosed, deeply invasive mel- anoma. I missed the melanoma near his left axilla on my skin exam 12 months earlier. A total body skin examination (TBSE) is an essential component of every dermatol- ogy patient encounter. Despite being our most important physical exam skill, the TBSE receives minimal research focus. Therefore, we set out to critically review our approach to the TBSE by breaking down the component movements to optimize accuracy and efficiency. Penn State is part of the “Big Ten Academic Alliance.” Not only do we have top athletes seeking to improve performance, we have expert bioengineers eager to collaborate on medical projects. In our study, residents and attending physicians were video-recorded while performing total body skin examination on standardized male and female volunteer patients. Each video subsequently underwent biomechan- ical analysis to identify the most efficient and reproducible technique that is easy to teach, saves time, and eliminates missed body areas. We recognize that there is tremendous variation in how seasoned dermatologists perform a TBSE. Our proposed TBSE can serve as a useful template for teaching and modeling a standardized TBSE for medical students and residents. We plan to validate the efficiency and effectiveness of this standardized TBSE with our residents and primary care colleagues. My (Jeffrey) personal goal is simple yet complex – prevent death from melanoma by not missing it on the TBSE. Dr. Miller is Chair and Professor of Dermatology and Associate Dean for Administration at Penn State Milton S. Hershey Medical Center and Penn State College of Medicine in Hershey, Pennsylvania. Dr. Helm and Dr. Hallock are Dermatologists in the Department of Dermatology at Penn State Health Hershey Medical Centre in Hershey, Pennsylvania.

• Video recordings of 5 dermatology faculty and 5 residents conducting total body skin examinations (TBSE) were obtained to optimize TBSE in practice. Exam time, physician movements, patient movements, sequence of body parts examined, and body parts missed were ana- lyzed. From this analysis, an optimal format for a TBSE that is efficient and accurate was identified. • A standardized way of conducting a TBSE may minimize the chance of missing a body area. These findings may be important while teaching TBSE to medical students, residents, and physicians. InYoung Kim MD, PhD Abstract BACKGROUND Total body skin examinations (TBSE) are commonly performed in clinical prac- tice. There is limited research on best practices for performing a TBSE. OBJECTIVE To optimize the TBSE. METHODS We performed an observational cohort study by video recording 5 dermatology faculty and 5 residents conducting their regular TBSE on both a male and female standardized subject. Exam time, physician movements, subject move- ments, sequence of body parts examined, and body parts missed were analyzed using an ana- lytic hierarchy process (AHP) matrix. Differences were evaluated by a t-test of unequal variance. P-values <0.05 were deemed significant. RESULTS We identified a optimal format for con- ducting a TBSE that is efficient and accurate LIMITATIONS: This study was conducted with only healthy examiners and standardized sub- jects, rather than individuals with a variety of physical and mental disabilities. The structure of the study was not hypothesis driven and assumed that engineers observing physicians performing the total body skin examination would identify the most optimal TBSE. CONCLUSION Our results indicate that a standard- ized process of performing a TBSE minimizes the chance of missing a body area. This could also have implications on teaching a standard- ized TBSE to medical students, residents, and physicians. Optimizing the Total Body Skin Exam: An Observational Cohort Study. J Am Acad Derma- tol 2019 Feb 15;[EPub Ahead of Print], MF Helm,

KK Hallock, E Bisbee, JJ Miller. www.practiceupdate.com/c/80268

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EDITOR’S PICKS 8

Analysis of Readmissions Following Hospitalization for Cellulitis JAMA Dermatology Take-home message

Abstract IMPORTANCE Cellulitis commonly results in hos- pitalization. Limited data on the proportion of cellulitis admissions associated with readmis- sion are available. OBJECTIVE To characterize the US national read- mission rate associated with hospitalization for treatment of cellulitis. DESIGN, SETTING, AND PARTICIPANTS This retro- spective cohort analysis of cellulitis admissions from the nationally representative 2014 Nation- wide Readmissions Database calculated readmission rates for all cellulitis admissions and subsets of admissions. The multicenter population-based cohort included adult patients admitted for conditions other than obstetrical or newborn care. Data were collected from Janu- ary 1 through November 30, 2014, and analyzed from February 1 through September 18, 2018. Bivariate logistic regression models were used to assess differences in readmission rates by patient characteristics. Costs were calculated for all readmissions after discharge from hos- pitalization for cellulitis (hereinafter referred to as cellulitis discharge) and by readmission diagnosis. EXPOSURES Admission with a primary diagnosis of cellulitis. MAIN OUTCOMES AND MEASURES Proportion of cellulitis admissions associated with nonelec- tive readmission within 30 days, characteristics of patients readmitted after cellulitis discharge, and costs associated with cellulitis readmission. RESULTS A total of 447 080 (95% CI, 429 927-464 233) index admissions with a primary diagnosis of cellulitis (53.8% male [95% CI, 53.5%-54.2%]; mean [SD] age, 56.1 [18.9] years) were included. Overall 30-day all-cause nonelective readmis- sion rate after cellulitis discharge was 9.8% (95% CI, 9.6%-10.0%). Among patients with cellulitis, age (odds ratio for 45-64 years, 0.78; 95% CI, 0.75-0.81; P = .001) and insurance status (odds ratio for Medicare, 2.45; 95% CI, 2.33-2.58; P< .001) were associated with increased read- mission rates. The most common diagnosis of readmissions included skin and subcutaneous tissue infections. The total cost associated with nonelective readmissions attributed to skin and subcutaneous infections within 30 days of a cel- lulitis discharge during the study period was $114.4 million (95% CI, $106.8-$122.0 million). CONCLUSIONS AND RELEVANCE Readmission after hospitalization for cellulitis is common and costly and may be preventable with improved diagnostics, therapeutics, and discharge care coordination. Analysis of Readmissions Following Hospitali- zation for Cellulitis in the United States. JAMA Dermatol 2019 Feb 27;[EPub Ahead of Print], JM Fisher, JY Feng, SY Tan, A Mostaghimi. www.practiceupdate.com/c/80506

• This retrospective analysis utilizing the Nationwide Readmissions Database included data from 447,080 admissions with a primary diagnosis of cellulitis from January 1 through November 30, 2014. The overall all-cause nonelective readmission rate for the 30 days following discharge was 9.8%, which was most commonly associated with a diagnosis of skin and subcutaneous tissue infections (29.7%), followed by diseases of the heart (8.3%), and bacterial infection (8.0%). The readmission rate observed in this study was slightly lower than the reported national readmission rate after index admissions for any diagnosis, which is estimated to be 14.5%. • Patients 65 years of age or older and those insured by Medicare or Medicaid were more likely to be readmitted. Overall healthcare costs for readmissions after discharge for cellulitis was estimated at USD$553.3 million, with USD$114.4 million attributable to skin and subcutaneous tissue infections. Caitlyn T. Reed, MD

COMMENT By Lindy Fox MD T his study used data collected from the 2014 Healthcare Cost and Utilization Project Nationwide Readmissions Database (from January 1 to November 30, 2014) to evaluate the rate of, risk factors for, and costs associ- ated with non-elective readmission within 30 days after an initial hospitalization for cellulitis. Cellulitis accounted for the admission diagnosis in 2.2% of all patients admitted (447,080 of 19,882,317) dur- ing the study time period. The all-cause readmission rate was 9.8%. Risk factors significantly associated with readmission included age ≥65 years and insurance with Medicare or Medicaid (compared with private insurance). The most com- mon readmission diagnosis was skin and subcutaneous tissue infection. The second most common reason for read- mission was diseases of the heart. The total cost of readmission was USD$533.3 million, with the cost of skin and subcu- taneous tissue infection accounting for USD$114.4 million. The authors propose that one possible reason (among others) for readmission for cellulitis is misdiagnosis, as 30% of

patients admitted through the emer- gency room for cellulitis actually have an alternate diagnosis. Correctly identifying cellulitis and its mimickers is one area where dermatologists are indispensable. Including our expertise in the evaluation of such patients has positive impacts on the healthcare system, the patients it serves, and the reputation of dermatology in the house of medicine. serves, and the reputation of dermatology in the house of medicine. " " Correctly identifying cellulitis and its mimickers is one area where dermatologists are indispensable. Including our expertise in the evaluation of such patients has positive impacts on the healthcare system, the patients it

Dr. Fox is Associate Professor of Clinical Dermatology, Director of Hospital Consultation Service, and Director of Complex Medical Dermatology Fellowship in the Department of Dermatology, University of California in San Francisco, California.

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EDITOR’S PICKS 9

Herpes Zoster Incidence and Consensus Recommendations on Vaccination in Adults on Systemic Therapy for Psoriasis or Psoriatic Arthritis Take-home message • This systematic review of 41 studies assessed the risk of herpes zoster in patients with psoriasis and/or psoriatic arthritis receiving systemic treatment. Treatments that are associated with an increased herpes zoster risk include systemic corticosteroids (strong evidence), tofacitinib (strong evidence), and combination therapy with biologic and conventional synthetic disease-modifying antirheumatic drugs (weak evidence). There is insufficient evidence to evaluate the risk associated with apremilast or interleukin 12/23, 17, and 23 inhibitors. • Recombinant zoster vaccine is recommended for all patients with psoriasis and psoriatic arthritis who are >50 years old and for younger patients at an increased risk, including those on tofacitinib, systemic steroids, or combination systemic treatment. InYoung Kim MD, PhD Journal of the American Academy of Dermatology

Abstract BACKGROUND Herpes zoster (HZ) incidence is linked to immunosuppression. Patients with psoriasis (PsO) and/or psoriatic arthritis (PsA) on systemic therapy may be at increased risk for HZ. OBJECTIVE To assess HZ risk in patients with PsO/ PsA by systemic treatment and provide recom- mendations regarding HZ vaccination. METHODS A systematic literature search was performed of HZ in patients with PsO/PsA. HZ vaccination guidelines were reviewed and the medical board of the National Psoriasis Foun- dation made consensus recommendations in PsO/PsA patients based on graded evidence. RESULTS 41 studies met inclusion criteria. Sys- temic corticosteroids (strong, 1), tofacitinib (strong, 1), and combination therapy with biologic and conventional synthetic disease modifying antirheumatic drugs (weak, 2a) carry increased HZ risk while monotherapy does not. There is insufficient evidence to determine risk with inter- leukin 12/23, 17, and 23 inhibitors, or apremilast (weak, 2a). Recombinant zoster vaccine is rec- ommended for all PsO/PsA patients >50 years old and to patients <50 years old on tofacitinib, systemic steroids, or combination systemic treat- ment. Vaccination of patients <50 years old on other systemic therapies may be considered on a case-by-case basis. LIMITATIONS There was significant heterogeneity between studies. CONCLUSIONS HZ risk depends on disease severity and treatment class. Recombinant zoster vaccine should be given to all PsO/PsA patients >50 years old and younger patients at increased risk. A Systematic Review of Herpes Zoster Inci- dence and Consensus Recommendations on Vaccination in Adult Patients on Systemic Ther- apy for Psoriasis or Psoriatic Arthritis: From the Medical Board of the National Psoriasis Foun- dation. J Am Acad Dermatol 2019 Mar 15;[EPub Ahead of Print], E Baumrin, A Van Voorhees, A Garg, et al. www.practiceupdate.com/c/81555

COMMENT By Robert T. Brodell MD, FAAD C onsidering all patients with psoriasis “who” are seen in the dermatol- ogist’s office, the authors of this study have done a good job determining who should get the recombinant zoster vaccine prior to initiating therapy: • All patients being treated with a bio- logic over the age of 50. In any event, it has been recommended that all immunocompetent individuals should get the vaccine at this age. • Patients being treated with systemic corticosteroids, tofacitinib, and com- bination therapy with a traditional systemic psoriasis drug and a biologic at any age because of their increased risk of shingles. They also discuss “why” this should be done: • To prevent shingles when possible in at-risk patients • To reduce the severity of shingles when it is not prevented. The problem is “how” to get this done! The barriers: • The cost of the vaccine is more than USD$200. Physicians can charge about USD$20 more than this, but if only 1 in 10 patients does not pay his/her bill, the dermatology office loses money trying to do what is right. Response: I would recommend that patients be referred to their pharmacy to get their vaccine, but many will not adhere to this approach.

• Busy physicians who are well-meaning may forget to place the order for zoster vaccination. Response: A systemmust be put into place to remind the phy- sician to place the order. This might be a simple checklist reminder, which could include laboratory tests, and a reminder to dispense educational material. • Some patients may resist all vaccina- tions. Response: Education materials can be prepared, and providers, if over the age of 50, can administer the vaccine to themselves. Thus, they can tell their patients, “I took it myself!” In fact, there is a science behind convincing patients to take vaccines that is rooted in characterizing the reasons the individuals are refusing the vaccine (Table 1). 1 However, it is certainly impossible to convince some “non-vaccinators” to accept vaccines of any kind. Table 1: Reasons Patients Refuse Vaccines 1 • Complacency • Inconvenience • Lack of confidence (this would include a subset of anti-vaccinators who are fervently against vaccines of all kinds) • Rational calculation of pros and cons Reference 1. Betsch C, Bohm R, Chapman G. Using behav- ioral insights to increase vaccination policy effectiveness. Policy Insights Behavi Brain Sci 2015;2(1):61-73.

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Evaluating the Development of Comorbidities Among ChildrenWith Psoriasis Pediatric Dermatology Take-home message

conditions were higher for patients with pediatric psoriasis compared with patients without pedi- atric psoriasis, and similar between patients with moderate-to-severe and mild pediatric psoriasis. A Retrospective Cohort Study to Evaluate the Development of Comorbidities, Including Psychiatric Comorbidities, Among a Pediatric Psoriasis Population. Pediatr Dermatol 2019 Feb 21;[EPub Ahead of Print], AS Paller, J Schen- feld, NA Accortt, et al. www.practiceupdate.com/c/80304 Although these screening recommen- dations may be time-consuming and seemingly outside the usual toolbox of a dermatologist, pediatric patients with psoriasis are seeing their dermatologist much more often than their primary care providers. We are in an important front- line position to identify comorbidities early in this vulnerable population. COMMENT By Sarah L. Chamlin MD C ompared with adults with pso- riasis, limited data exist for the comorbidities associated with pediatric psoriasis in the United States. This claims-based retrospective study describes comorbidities for children with psoriasis. Of note, the study used a control group and the mean age in the group with psoriasis was 12.9 years. Obesity, juvenile idiopathic arthropa- thy, and serious infections were more common in the psoriatic group. In addi- tion, ulcerative colitis, Crohn’s disease, and psychiatric comorbidities, such as depression, anxiety, and suicidal idea- tion, were also more common. Findings are consistent with the comor- bidities seen in adults with psoriasis, and children with psoriasis should also be screened yearly for overweight/obe- sity using BMI percentile, hypertension starting at 3 years of age, and type 2 diabetes every 3 years starting at age 10. Universal lipid screening should be performed as well. Depression and anx- iety screening is suggested yearly as well as substance abuse screening for patients over 11 years of age.

• This retrospective study assessed the prevalence and incidence of comorbidities, including psychiatric comorbidities, in children with psoriasis. As compared with children from a matching non-psoriasis cohort, those in the psoriasis cohort had higher prevalence and incidence rates of obesity, serious infection, and juvenile idiopathic arthropathy. Psychiatric comorbidities, ulcerative colitis, and Crohn’s disease were also more common in the psoriasis cohort. • There were no significant differences in the incidence of comorbidities between the two subsets after stratifying the psoriasis cohort according to the severity of disease. InYoung Kim MD, PhD

Abstract BACKGROUND/OBJECTIVE Compared with the adult psoriasis population, knowledge about the inci- dence of comorbidities in the pediatric psoriasis population is limited. The objective of this study was to assess the prevalence and incidence of comorbidities, including psychiatric comorbidi- ties, in patients with pediatric psoriasis. METHODS In this claims-based, retrospective cohort study, patients with pediatric psoriasis were matched 1:3 with a nonpsoriasis cohort based on age, sex, and index date (the earliest of inpatient claims or the latter of two outpatient claims).

RESULTS Obesity, serious infection, and juvenile idiopathic arthropathy had higher prevalence and incidence rates in the psoriasis cohort than the nonpsoriasis cohort. Psychiatric comorbid- ities were also more common in the psoriasis cohort than the nonpsoriasis cohort, as were ulcerative colitis and Crohn disease. Stratifying the psoriasis cohort by disease severity-mild and moderate-to-severe-found no differences in incidence rates of comorbidities between the two subsets. CONCLUSION The incidence rates ofmany comorbid

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Deep Learning-Based, Computer-Aided Classifier vs Board-Certified Dermatologists in Skin Tumor Diagnosis Take-home message • A deep convolutional neural network (DCNN) was trained using 4867 clinical images of benign and malignant dermato- logic neoplasms to determine whether this technology could be used to develop an efficient skin cancer classification system. The DCNN was then tested against board-certified dermatologists and dermatology trainees for accuracy of first-level (benign vs malignant), second-level (epithelial vs melanocytic), and third-level (specific diagnosis, such as melanocytic nevus, basal cell carcinoma) diagnosis. The accuracy of the DCNN in first-level classification was 93.4%, which was significantly higher than the board-certified der- matologists (85.3%) and dermatology trainees (74.4%). • Although, the DCNN outperformed board-certified derma- tologists in third-level classification of neoplasms as well (74.5% vs 59.7%), the authors speculate that dermatologists would likely achieve higher diagnostic accuracy if provided with more clinical information. However, these findings suggest that DCNN may play a role in aiding primary care physicians when evaluating dermatologic lesions. Caitlyn T. Reed MD Abstract BACKGROUND Application of deep-learning technology to skin cancer clas- sification can potentially improve the sensitivity and specificity of skin cancer screening, but the number of training images required for such a system is thought to be extremely large. OBJECTIVES To determine whether deep-learning technology could be used to develop an efficient skin cancer classification system with a rel- atively small dataset of clinical images. METHODS A deep convolutional neural network (DCNN) was trained using a dataset of 4867 clinical images obtained from 1842 patients diagnosed with skin tumours at the University of Tsukuba Hospital from 2003 to 2016. The images consisted of 14 diagnoses, including both malignant and benign conditions. Its performance was tested against 13 board-cer- tified dermatologists and nine dermatology trainees. RESULTS The overall classification accuracy of the trained DCNN was 76·5%. The DCNN achieved 96·3% sensitivity (correctly classified malig- nant as malignant) and 89·5% specificity (correctly classified benign as benign). Although the accuracy of malignant or benign classification by the board-certified dermatologists was statistically higher than that of the dermatology trainees (85·3% ± 3·7% and 74·4% ± 6·8%, P < 0·01), the DCNN achieved even greater accuracy, as high as 92·4% ± 2·1% (P < 0·001). CONCLUSIONS We have developed an efficient skin tumour classifier using a DCNN trained on a relatively small dataset. The DCNN classified images of skin tumours more accurately than board-certified dermatologists. Col- lectively, the current systemmay have capabilities for screening purposes in general medical practice, particularly because it requires only a single clinical image for classification. Deep-Learning-Based, Computer-Aided Classifier Developed With a Small Dataset of Clinical Images Surpasses Board-Certified Dermatolo- gists in Skin Tumour Diagnosis. Br J Dermatol 2019 Feb 01;180(2)373-381, Y Fujisawa, Y Otomo, Y Ogata et al. www.practiceupdate.com/c/79798 The British Journal of Dermatology

Risk Factors for Keratinocyte Carcinoma Skin Cancer in Nonwhite Individuals Journal of the American Academy of Dermatology Take-home message • In this retrospective chart review, squamous cell carcinoma (SCC) was the most common skin cancer in blacks and Asians and basal cell carcinoma was the most common skin cancer in Hispanics among a population of individuals who received a biopsy-proven diagnosis of skin cancer between June 2008 and June 2015. The majority of the SCC in blacks occurred in sun-protected areas (in particular, the anogenital region). Current smokers were diagnosed with skin cancer an average of 12.27 years earlier than former smokers and 9.36 years earlier than nonsmokers. • Although rates of skin cancer overall are higher in the white population, nonwhite individuals may experience greater associated morbidity and mortality. Photoprotec- tion and skin cancer screening are recommended for nonwhite patients, as is active examination of sun-pro- tected areas. Smoking cessation should be part of dermatologic counseling of all patients. InYoung Kim MD, PhD Abstract BACKGROUND As the majority of the U.S. population will consist of non- white individuals by the year 2043, it is essential that both physicians and patients are educated about skin cancer in nonwhite individuals. OBJECTIVE To update the epidemiology, investigate specific risk fac- tors, and facilitate earlier diagnosis and intervention of KC in nonwhite individuals METHODS RB-approved retrospective chart review of all non-white indi- viduals who had received a biopsy-proven diagnosis of skin cancer at Drexel Dermatology from June 2008 to June 2015. RESULTS Squamous cell carcinoma (SCC) was the most commonly diagnosed skin cancer in Black and Asian populations, while basal cell carcinoma (BCC) was the most common skin cancer in Hispan- ics. Blacks exhibited the majority of their SCC lesions in sun-protected areas, particularly the anogenital area. On average, current smokers were diagnosed with skin cancer 12.27 years earlier than former smok- ers and 9.36 years earlier than nonsmokers. LIMITATIONS Single-center design and inter-practitioner variability of skin examination CONCLUSIONS The importance of photoprotection in nonwhite individ- uals should not go overlooked. However, emphasis should also be placed on active examination of sun-protected areas in nonwhites and recognition of the relationship between HPV and genital SCC lesions. Smoking cessation should be integrated in dermatologic counseling of all patients. Interventions tailored to each of these eth- nic groups are needed. Risk Factors for Keratinocyte Carcinoma Skin Cancer in Nonwhite Individuals: A Retrospective Analysis. J Am Acad Dermatol 2019 Jan 28;[EPub Ahead of Print], KS Nadhan, CL

Chung, EM Buchanan, et al. www.practiceupdate.com/c/79417

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Early Melanoma Nodal Positivity and Biopsy Rates Before and After Implementation of AJCC 7 JAMA Dermatology Take-home message • This cross-sectional study included 86,846 patients diagnosed with T1 melanoma prior to the AJCC 7th edition (AJCC 7) and 54,434 patients diagnosed after AJCC 7 implementation. Results demonstrated that, after the addition of elevated mitotic rate to the AJCC 7 criteria, 3.8% fewer nodal evaluations overall were performed for T1 melanomas (P < .001), although a significantly higher proportion of patients with T1b tumors underwent nodal evaluation (48.8% vs 62.2%; P < .001), and a clinically significant change in nodal positivity rates was not observed. Most of the nodal evaluations were indicated because of a mitotic rate of 1 or more, which appeared to be associated with lymph node involvement in this study (OR, 1.93; P < .001). • Although mitotic rate was eliminated from the AJCC 8 as a differentiator between T1a and T1b melanomas, these data support continued attention to mitotic rate in patients with thin melanomas when deciding whether a sentinel lymph node biopsy should be performed.

Abstract IMPORTANCE There has been a continued increase in the incidence of newly diagnosed melanomas, most of which are T1 melanomas. The associations between changes in tumor staging, implemented with the 7th edition of the AJCC Cancer Staging Manual (AJCC 7), and sentinel lymph node biopsy rates and nodal pos- itivity rates remain to be seen. OBJECTIVE To evaluate the change that the imple- mentation of the AJCC 7 had on staging criteria

COMMENT By David G. Brodland MD T his article reviews two old AJCC melanoma staging systems, AJCC6 and AJCC7, to compare them and ostensibly sug- gest that mitosis was useful as a staging criterion. However, since January 2018, the staging system in use has been AJCC8, which notoriously dropped mitosis as a staging criterion. The defi- nitions in AJCC8 of T1a and T1b have been revised so that T1a melanomas include those <0.8 mmwithout ulceration, whereas T1b melanomas include those 0.8–1.0 mm with or without ulceration and those <0.8 mm with ulceration. The importance of assignment to T1b is that these patients, according to the NCCN guidelines, should “discuss and consider” SLNB. AJCC6, 7, and 8 all use ulceration as a criterion for T1b classifi- cation. The AJCC6 used Clark’s level IV and V as an upstaging criterion for thin melanomas (<1 mm). Clark’s level criterion was replaced by mitosis in AJCC7. In essence, the presence of a single mitosis in a “hot spot” identified on pathologic examination could qualify a person with thin melanoma for SLNB who, in absence of that single cell, would not have qualified. The obvious criticism of this systemwas that the identification of that single cell was subject to how intensely and compulsively it was searched. It is evident that significant mitotic activity is associated with more aggressive melanomas. However, the AJCC elected to drop it as a criterion, which in my opinion was a good thing. To summarize this paper, the National Cancer Data Base, which is based on hospital registries, was used comparing AJCC6 with AJCC7 patients’ rate of nodal evaluation and of nodal positiv- ity. They report a 3.8% decrease in nodal evaluation rates and a decrease in node positivity per surgery of 1%, which although, statistically significant, the authors state was clinically insignifi- cant. They conclude that continued attention to mitotic rates is warranted when deciding on the use of SLNB for thin melanoma.

In comparing Clark’s level alone, ulceration alone, and both crite- ria together for AJCC6 versus mitotic rate alone, ulceration alone, and both criteria for AJCC7 as a positively predictive criterion for nodal involvement, AJCC7 was less effective at identifying patients who would have a positive lymph node compared with AJCC6 in each comparison. Based on that, and with the understanding that increased Clark’s levels were previously deemed insufficient as a criterion for upstaging melanoma, my take-home message was that mitosis, as an upstaging criterion, was not that good and that its elimination from AJCC8 is understandable. What I did learn is that ulceration in combination with either Clark’s level IV or V or significant mitotic activity was effective at positively identifying individuals at risk for lymph node metastasis (28.3–32.8%). Perhaps one could interpret that to mean that the presence of either mitoses or greater Clark’s level verifies that the ulceration is “real” and not an incidental ulcer- ation due to abrasion, excoriation, or other nonbiological cause. What this paper doesn’t touch on is the very basic question of what SNLB is useful for. A recent paper has called into question its value in prognostication. 1 Since SLNB has been made an inte- gral part of staging, this essential but very key question is rarely discussed and the literature focuses instead on criteria to qual- ify for SLNB, overlooking whether it truly serves the purpose we hope it does. Dr. Zitelli addresses this subject below. Reference 1. Stiegel E, Xiong D, Ya J, et al. Prognostic value of sentinel lymph node biopsy according to Breslow thickness for cutaneous melanoma. J Am Acad Dermatol 2018;78(5):942-948.

Dr. Brodland is a Dermatologic Surgeon at Zitelli & Brodland PC, Skin Cancer Center in Pittsburgh, Pennsylvania.

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