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Vol. 2, No. 5 | May 2021

Delusions of Parasitosis

New Drugs Injectable Harnesses Immune Response against CA Devices for

Ted Talks

Does IKEA Sell Rocking Chairs?

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Columbus, WI Columbus,

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EDUCATIONAL • INTERACTIVE • AUTHORITATIVE

THE Contents www.thedermdigest.com Volume 2, Number 5 | May 2021

2 Ted Talks

Does IKEA sell 18 rocking chairs? Cover Article

Delusional parasitosis: Artful interactions for dealing with a tricky condition 6 Literature Lessons

Research updates in COVID-19, pediatric derma- tology, infectious diseases, atopic dematitis, cutaneous oncology, and more

The Dermatology Digest is Different Our multimedia approach delivers engaging and authoritative content in digestible bites for dermatologists overloaded with information in the emerging virtual environment. A distinct new concept, The Dermatology Digest filters practical and important information from industry meetings and develops original content for identified knowledge gaps in digital (video, podcast) and print formats. Concise, yet comprehensive, our content comes from the views, voices, and visions of leading dermatologists. As such, ours is an informative, educational approach that emphasizes key details in support of safe, efficacious patient results.

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May 2021 | 1 Ted Talks “ The older I grow, the more I distrust the familiar doctrine that age brings wisdom.” —H. L. Mencken

t was a small thing, really. I was in my home study, creating a slideshow to be presented at Ian upcoming meeting. I was designing a table of the various approved agents for the topical treatment of . I had already listed the generic names and was about to include the brand names. To my chagrin and utter frustration, I simply could not recall the trade name of one of the drugs. I looked it up by entering the generic name into my acces- Ted Rosen, MD, FAAD sory brain (Google) and finished my task. But Editor-in-Chief it got me to thinking ... wasn’t it just the prior week that I could not remember the first name This is Ted's take. of a patient I have cared for more than 3 de- What's yours? cades? I could picture her and knew her illness [email protected] and treatment regimen, but I couldn’t remem- ber her first name! I started to worry about later. But dermatologists routinely retire being in mental decline, or worse, early stage 5 years or more after the mean physician dementia. When would I forget how to dose retirement age. So, we traditionally tend to terbinafine? Or maybe forget what terbinafine practice longer into life’s journey. Which even was? Was it my time to research long- brings me to this point: at a certain age, term care facilities and to purchase a comfort- should we all be subject to voluntary—or able rocking chair? even involuntary—periodic cognitive and We all age, and as we do so, some (or all) of physical reassessment? This is much different our capabilities naturally wane and weaken. from taking another iteration of a certifying At what point do our inherent strengths fade board examination or collecting a specified sufficiently for us to conclude our time as number of CME credits annually. What I’m healthcare providers? It has been written in talking about is a comprehensive battery of many corners that physicians, as a group, tests which might measure fine-motor skill, are among the least likely to recognize and motor planning capability, visual acuity and acknowledge their own declining professional pattern recognition, psychomotor efficiency, prowess. Yet it is intuitively obvious that as processing speed under pressure, concentra- professionals dealing with human life, clini- tion, capacity of both long- and short-term cians of all types must possess both the proper memory, interpersonal communication skills, physical and cognitive capacities to safely and executive functioning, among others. By practice medicine. This becomes an especially the way, executive functioning relates to self- pertinent concern for dermatologists. regulation, including foresight and flexibility in executing an organized strategy in response The average age of retirement for American to situational demands. For example, you plan physicians is 65.1 years. Gynecologists retire a excision but the patient arrives to the about a year earlier, cardiologists about a year office complaining of substernal chest pain! continued on page 4 2 | The Dermatology Digest www.thedermdigest.com/TOC

Contents continued from page 1

22 45 General Dermatology Cosmetic Corner Literature Update

Options for hyperhidrosis: 30 Topical corticosteroids and the A review of old and new techniques risk of osteoporosis, fractures What is the risk of vascular occlusion when injecting fillers?

34 All about eyelashes: Your patients' interest is likely increasing

37 New Drugs 50 Cavrotolimod targets PD-1 inhibitor resistance Diagnose this Zebra Drug-induced bullous pemphigoid with a twist 26 41 Pediatrics Integrative Medicine

Primary hyperhidrosis in children: IV therapy addresses energy What we know has changed and other health issues as well as skin aesthetics

52 COVID Concerns

Immunosuppression and COVID-19 outcomes: Is there an effect?

May 2021 | 3 www.thedermdigest.com/TED_TALKS

continued from page 2 THE Taken together, the assessments listed above of 1967). Fourth, objective evidence solidly could determine the ability of a physician to verifying that advancing age predicts or closely reason, interpret, monitor, problem-solve, correlates with poorer clinical outcomes is adapt, and utilize sound medical judgement. scant and somewhat debatable. www.thedermdigest.com As you might expect, this concept is not so Finally, I wonder if the entire proposition far-fetched. In fact, Yale New Haven Hospital, of mandatory cognitive testing for older physi- CORPORATE Intermountain Healthcare, Stanford Hospi- cians doesn’t discount the incredible value AMY AMMON tals and Clinics, Scripps Health Care, Penn of wisdom derived largely from experience. Executive Director, Publisher [email protected] Medicine, and the University of California, I recall a recent case of dyschromia of the back; DON BERMAN San Diego—to name a few—already have my trainees were concerned about macular Executive Director, Digital Strategy [email protected] mandatory assessment programs for clini- amyloid and confluent and reticulated papillo- GEORGE MARTIN, MD cians at and above a certain age. Indeed, it is matosis of Gougerot and Carteaud. In a rather Executive Director entirely realistic to ask: Should such a require- EDITORIAL ment become universal? Needless to say, such TERESA MCNULTY assessment would have to be consistent and I wonder if the entire proposition Print Editor fair, judged against validated normative values of mandatory cognitive testing for ELIZA CABANA reflective of age, and interpreted in terms of Digital Editor relevance to actual clinical duties and respon- older physicians doesn’t discount NANCY BITTEKER Creative Director sibilities. Before limiting or revoking licensure/“the incredible value of wisdom MICHAEL WESTFALL credentials, there must also be a reasonable Product Manager appeal process, perhaps including repeat derived largely from experience.” testing using an alternative methodology. It also would be advisable to include gradations dramatic fashion, I removed a swath of the

Print Circulation: of consequence, varying all the way from no pathology by merely rubbing the skin with 13,500 dermatologists USA change in clinical privileges, to a controlled/ an alcohol swab. Having been in practice a 2,800 dermatological NP/PA’s proctored practice, to removal of licensure/ long time, I had encountered terra firma- The Dermatology Digest ® is published monthly by The Dermatology Digest, credentials. To some degree, many of the cur- forme dermatosis before, whereas all my LLC, 88 N Main Street, Pearl River, NY 10965. rent mandatory periodic assessments include younger colleagues—whose fine-motor co- © 2020 The Dermatology Digest, LLC. these qualifying parameters. ordination and short-term memory are most All rights reserved. No part of this pub- lication may be reproduced or trans- Nonetheless, I am somewhat hesitant to likely superior to mine—simply had not. mitted in any form or by any means, electronic or mechanical including by jump on this bandwagon. Of course, we all I don’t question the sincere and well-meaning photocopy, recording, or information storage and retrieval without permis- want to do what’s best for the very people we intention of those advocating for cognitive sion in writing from the publisher. Authorization to photocopy items for serve—our patients. We want them to receive assessment of older physicians. But I’m not so internal/educational or personal use, or the internal/educational or personal the highest quality of care possible from fully sure that the time and money spent on such use of specific clients is granted by The capable physicians. But the assessment of endeavors is entirely worth it, and might not Dermatology Digest, LLC. For uses beyond those listed above, please aging physicians is fraught with many poten- actually cause some degree of harm to the direct your written request to Amy Ammon, Executive Director, Publisher tial difficulties. First, who determines exactly healthcare system. Before we rush into this at: [email protected]. which tests comprise the screening battery? black hole, we need to carefully consider all POSTMASTER: Please send address changes to The Dermatology Digest Such screening is an inexact and complex sci- the ramifications. You need to think about this LLC, 88 N Main Street, Pearl River, NY 10965. Printed in the U.S.A. ence and legitimate differences of opinion ex- issue, because—if you’re not there yet—some-

The Dermatology Digest ® does not ist. Second, because the prevalence of serious day you, too, will reach Medicare-eligible age. verify any claims or other information cognitive problems is relatively low in the pro- What might you recommend to your state appearing in any of the advertisements contained in the publication and cannot posed population to be tested, false-positive board or clinic or hospital system? take any responsibility for any losses or other damages incurred by readers screenings are bound to occur. Third, targeting By the way, I decided not to buy that rocking in reliance on such content. only physicians above a specific age (60? 65? The Dermatology Digest ® welcomes chair quite yet! unsolicited articles, manuscripts, 70? 75?) is legally questionable, considering photographs, illustrations and other materials, but cannot be held respon- existing legislation against age discrimination sible for their safekeeping or return. (the Age Discrimination in Employment Act

4 | The Dermatology Digest THE

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EDITORIAL BOARD

EDITOR-IN-CHIEF

TED ROSEN, MD JIM TREAT, MD SANDY TSAO, MD Houston, Texas Philadelphia, Pennsylvania Boston, Massachusetts

STEPHEN TYRING, MD, PhD ASSOCIATE EDITORS CONTRIBUTING EDITORS Houston, Texas

BRIAN BERMAN, MD, PhD LUCIA DIAZ, MD GUY WEBSTER, MD, PhD Miami, Florida Austin, Texas Philadelphia, Pennsylvania

JOEL COHEN, MD HAYES GLADSTONE, MD Greenwood Village, Colorado San Ramon, California CONTRIBUTORS

SEEMAL DESAI, MD MICHAEL GOLD, MD NEAL BHATIA, MD Plano, Texas Nashville, Tennessee San Diego, California

SHEILA FRIEDLANDER, MD MITCHEL GOLDMAN, MD CHERYL BURGESS, MD San Diego, California San Diego, California Washington, DC

DAVID OZOG, MD ADITYA GUPTA, MD, PhD SUNEEL CHILUKURI, MD Detroit, Michigan Toronto, Canada Houston, Texas

MATT ZIRWAS, MD RAJANI KATTA, MD RISA GOLDMAN LUKSA Columbus, Ohio Bellaire, Texas San Diego, California

MARK KAUFMANN, MD RAEGAN HUNT, MD EDITORIAL BOARD New York, New York Houston, Texas

HILARY BALDWIN, MD ARTHUR KAVANAUGH, MD NEIL KORMAN, MD, PhD New York, New York San Diego, California Cleveland, Ohio

VALERIE CALLENDER, MD ROB KIRSNER, MD, PhD DAVID LAUB, MD Glenn Dale, Maryland Miami, Florida Mill Valley, California

LARRY EICHENFIELD, MD HENRY LIM, MD GEORGE MARTIN, MD San Diego, California Detroit, Michigan Kihei, Hawaii

WHITNEY HIGH, MD, JD NATASHA MESINKOVSKA, MD WENDY ROBERTS, MD Aurora, Colorado Irvine, California Rancho Mirage, California

SUZANNE KILMER, MD DANIEL SIEGEL, MD REENA RUPANI, MD Sacramento, California New York, New York New York, New York

BRUCE STROBER, MD, PhD LINDA STEIN GOLD, MD JONATHAN SILVERBERG, MD Cromwell, Connecticut Detroit, Michigan Washington, DC

May 2021 | 5 Off-label Pearl

By Ted Rosen, MD, FAAD, Editor-in-Chief

Pentoxifylline for treatment of claudication Pentoxifylline is an oral xanthine derivative FDA-approved for the treatment of claudication. Pentoxifylline increases deformability of red blood cells, decreasing blood viscosity and enhancing tissue oxygen- ation. As a phosphodiesterase inhibitor, it inhibits platelet microvascu- lar adhesion and aggregation, and exerts vasodilation. In aggregate, these properties allow pentoxifylline to help resolve stubborn venous stasis ulcers, with or even without compression. Dose is 400 mg TID. Side effects are mild and uncommon, including GI distress, headache, and dizziness. This is an old but seemingly forgotten paper: Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2012 Dec 12;12:CD001733. https://pubmed.ncbi.nlm.nih.gov/23235582 Literature Lessons

ROSACEA

An investigator-blinded prospective study (N=97) demonstrated that once-daily SARECYCLINE (1.5 mg/kg) was statistically superior to a multivitamin placebo for the treatment of moderate-to-severe papulopustular . Sarecycline was tolerated by subjects during this 12-week study. TO READ MORE: Rosso J, et al. Oral sarecycline for treatment of papulopustular rosacea: results of a pilot study evaluation of effective- ness and safety. J Drugs Dermatol. 2021; 20(4):426-431. https://pubmed.ncbi.nlm.nih.gov/33852248 (Editor’s note: Although a larger scale study is advisable, this pilot investigation was very promising.)

6 | The Dermatology Digest www.thedermdigest.com/LITERATURE_LESSONS

PEDIATRIC DERMATOLOGY

CANDIDA BLOOD STREAM INFECTIONS, often associated with disseminated cutaneous papules, are seen among immunocompromised children and in the neonatal intensive care unit. This year, a retrospective study done in New England demonstrated that anti-fungal drug resistance was minimal: 96.7% of isolates were fluconazole, 99% were micafungin, and all were amphotericin susceptible. TO READ MORE: Piqueras A, et al. Trends in pediatric candidemia: epidemiology, anti-fungal susceptibility, and patient characteristics in a children’s hospital. J. Fungi. 2021;7(2):78; doi:10.3390/jof7020078

In a one-year, open-label, multi-center prospective study (N=62, age 6-16), DAILY TOPICAL EFINACONAZOLE 10% solution for 48 weeks led to 40% COMPLETE CLINICAL CURE 65% MYCOLOGIC CURE

The best take-away from this comprehensive review is that a “NO-NIT” policy, Topical efinaconazole 10% appears to be a good still common in parts of the US and Canada, is “without medical or public health option for mild-to-severe onychomycosis in the merit” and that expulsion of children from camp, daycare, or school based solely pediatric population. on the presence of nits after treatment “may harm the child’s self-esteem and TO READ MORE: Eichenfield LE, et al. Efinaconazole impose unnecessary burdens on the parents.” 10% topical solution for the treatment of onychomy- TO READ MORE: Mumcuoglu KY, et al. International recommendations for an cosis in pediatric patients: Open-label phase 4 study. effective control of head louse infestations. Int J Dermatol. 2021;60:272-80. J Am Acad Dermatol. 2021;84(4):1140-1142. https://doi.org/10.1111/ijd.15096 https://pubmed.ncbi.nlm.nih.gov/32622145/

May 2021 | 7 INFECTIOUS DISEASES

As part of the never-ending search for the “best” INTRALESIONAL THE ANTIFUNGAL AGENT T-2307 appears to be IMMUNOTHERAPY FOR VERRUCAE, a cohort of 150 periungual wart patients particularly useful for Candida species (including was randomized to treatment every 2 weeks for a maximum of 5 sessions with C. auris) and the 2 major species of Cryptococcus. 0.1 ml of either Candida antigen, MMR, or PPD. All agents performed well: The agent works via a novel mechanism of action, namely by interfering with mitochondrial membrane WART CLEARANCE OCCURRED IN potential, thereby inhibiting proper mitochondrial function. % % % TO READ MORE: Wiederhold NP. Review of T-2307, 80 74 70 an investigational agent that causes collapse of of the Candida of the MMR group of the PPD group fungal mitochondrial membrane potential. J. Fungi. antigen group 2021:7(2),130; doi:10.3390/jof7020130 Most importantly, the authors also demonstrated distant response of untreated warts. Local side effects were acceptable, and a flu-like syndrome occurred in 10% of those treated with Candida, 4% with MMR, and 6% with PPD. After 6 months of follow-up, patients who had cleared did not have recurrences. TO READ MORE: Nofal A, et al. Intralesional antigen immunotherapy in the treatment of periungual warts. J Cutan Med Surg. 2021;Jan 27: doi:10.1177/1203475420988859

Continuing once-daily application of efinaconazole 10% solution to nails affected by ONYCHOMYCOSIS longer than the currently recommended 12 months leads to continued increase in mycological cure and effective therapy (<10% involvement of the target toenail). No new safety issues appeared during the planned 24 months of continuous treatment. TO READ MORE: Gupta AK, Cooper Ea. Long-term efficacy and safety of once- daily efinaconazole 10% topical solution (Jublia) for dermatophyte onychomycosis: an interim analysis. Skin Ther Lett. 2021;26(1):5-10. https://pubmed.ncbi.nlm.nih.gov/33539062 2404 men enrolled in a 3-year study comparing INCIDENT STD before and after initiation of pre- exposure prophylaxis (PreP). Although the frequency of STD testing rose following the onset of PreP, there was no significant increase in STD test positivity rates. TO READ MORE: McManus H, et al. Comparison of trends in rates of sexually transmitted infections before vs after initiation of HIV pre-exposure prophylaxis among men who have sex with men. JAMA Netw Open. 2020;3(12):e2030806. doi:10.1001/jamanetworkopen.2020.30806 (Editor’s note: In other words, initiating PreP in demographic groups at risk for HIV acquisition doesn’t lead to more STD.)

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CONTACT SUPPRATIVA

While ADALIMUMAB can offer significant improvement in disease burden for HS patients, British investigators found that nearly 32% of patients experienced drug-related adverse events, including worsening mental health status. TO READ MORE: Muralidharan V, et al. Real life data on the biopsychosocial effects of Adalimumab in the management of : A multicenter cross sectional analysis and consideration of a multisystem monitoring approach to follow up. Dermatol Ther. 2021 Jan;34(1):e14643. doi: 10.1111/dth.14643.

A retrospective chart review, enhanced by telephone interviews, assessed the benefit of intralesional injections of high concentration (20 or 40 mg/ml) TRIAMCINOLONE ACETONIDE during active outbreaks of HS. THE MAJORITY OF PATIENTS NOTICED INCREASED MOBILITY BETTER SLEEP DECREASED DRAINAGE 59% 50% 69% A large cohort of patients with EYELID DERMATITIS, from sites all across the United States, were 86.3% of the 54 respondents would be willing to undergo future injections. analyzed. Irritant contact dermatitis was more TO READ MORE: Garelik J, et al. Efficacy of high-dose intralesional triamcinolone common if only eyelids were involved, whereas for hidradenitis supprativa. Int J Dermatol2021;60:217-21 doi: 10.1111/ijd.15124 allergic contact dermatitis was more frequent if head and neck sites were also involved. An atopic diathesis was common among those with any type The authors performed a systematic literature review and meta-analysis related to of eyelid dermatitis. the occurrence of major CARDIOVASCULAR EVENTS associated with HS. Using TO READ MORE: Warshaw E, et al. Eyelid dermatitis high-quality cohort and case-control studies, they found an increased risk of both in patients referred for patch testing: retrospective heart attack and stroke in HS patients. The clinician should be screening for such analysis of North American Contact Dermatitis events, looking for early warning signs. Group data, 1994-2016. J Am Acad Dermatol. TO READ MORE: Bailey AMJ, et al. Hidradenitis and major adverse cardiac events: 2021;84(4):953-964. A systematic review and meta-analysis. J Am Aced Dermatol 2021;84:844-846. doi: 10.1016/j.jaad.2020.07.020 doi: 10.1016/j.jaad.2020.10.005

May 2021 | 9 CUTANEOUS ONCOLOGY, SURGERY, AND LASERS

A joint group of Dutch and Australian investigators, using large TO READ MORE ABOUT THIS POWERFUL INSTRUMENT: cohorts, developed and validated nomograms to predict which El-Sharouni MA, et al. Development and validation of nomograms patients with thin MELANOMAS were at risk for local, regional, to predict local, regional, and distant recurrence in patients and distant recurrences. This was then translated into a simple, with thin (T1) melanomas. J Clin Oncol. 2021; Feb 18. free online tool: www.melanomarisk.org.au. doi:10.1200/JCO.20.02446

(Editor’s note: try the online tool; it is easy to use and quite informative.)

A single-center, retrospective analysis was conducted to assess rate was a remarkably low 1.78%, even in this very aged patient the complication rate when MOHS MICROGRAPHIC SURGERY subset. was conducted on those over age 85. Infection, wound dehiscence, TO READ MORE: Nemer KM, et al. Complications after Mohs hematoma formation, post-operative hemorrhage, flap necrosis, micrographic surgery in patients aged 85 and older. Dermatol Surg. and graft necrosis were noted in small numbers of cases among 2021;47(2): 189-193. doi: 10.1097/DSS.0000000000002452 the 949 patients (1683 lesions) studied. The overall complication

10 | The Dermatology Digest www.thedermdigest.com/LITERATURE_LESSONS

CUTANEOUS ONCOLOGY, SURGERY, AND LASERS, con’t GENERAL DERMATOLOGY

Although surgical excision remains the standard of care for While clinical benefit from a gluten-free diet is most closely associ- LENTIGO MALIGNA, topical application of 5% imiquimod (5 times ated with DERMATITIS HERPETIFORMIS, several other diseases weekly for 12 weeks) may also be effective. Analysis of a cohort may also improve. Most notably, there is significant evidence that of 103 patients followed for a median 5.1 years (mean 6.2 years) chronic, recurrent aphthous stomatitis; ; palmoplan- demonstrated 89% disease- and recurrence-free survival. tar pustulosis; and even may benefit from elimination of gluten from the diet. TO READ MORE: Chambers M, et al. Topical imiquimod for lentigo maligna: Survival analysis of 103 cases with 17 years follow-up. TO REVIEW THE EVIDENCE, READ: Muddasani S, et al. Gluten J Drugs Dermatol. 2021;20(3):346-48. doi: 10.36849/JDD.5660 and skin disease beyond dermatitis herpetiformis: a review. Int J Dermatol. 2021;60:281-88. https://doi.org/10.1111/ijd.15098

A single-center retrospective review covering a recent 7-year period disclosed that 73% of MYCOSIS FUNGOIDES patients who received topical corticosteroid monotherapy responded, with a

DECREASE IN AFFECTED % BODY SURFACE AREA. 65 Early-stage disease and female gender were more represented in the responder group. TO READ MORE: Kartan S, et al. Response to topical corticosteroid monotherapy in mycosis fungoides. J Am Acad Dermatol. 2021;84:615-25. doi: 10.1016/j.jaad.2020.05.043 LICHEN AMYLOIDOSIS may respond to topical application of fixed combination halobetasol-tazarotene lotion. Clinical benefit is In a large (N=6156) cohort study, local excision of MERKEL CELL likely due to synergistic anti-inflammatory effects and the retinoid’s CARCINOMA with margins over 1 cm was associated with higher capacity to reduce hyperkeratosis and epidermal acanthosis. overall survival compared to smaller excisional margins. Addition of TO READ MORE: Shoen E, et al. Successful treatment of lichen adjuvant radiotherapy to larger excisional margins increased overall amyloidosis using a fixed combination of halobetasol propionate survival even more. and tazarotene lotion. J Drugs Dermatol. 2021;20:336-37. TO READ MORE: Andruska N, et al. Association between surgical doi: 10.36849/JDD.5794 margins larger than 1 cm and overall survival in patients with merkel cell carcinoma. JAMA Dermatol. 2021, March 24. doi:10.1001/jamadermatol.2021.0247 Mohammad2018/ Wikimedia Commons Photo credit: Mohammad2018/

May 2021 | 11 COVID-19

Some patients may develop IPSILATERAL AXILLARY ADENOPATHY on average 2-4 days after receipt of either mRNA COVID-19 vaccine. This may resemble a pattern strongly suggestive of breast cancer. Adenopathy typically resolves in about 10 days. TO READ MORE: Mehta N, et al. Unilateral axillary adenopathy in the setting of COVID-19 vaccine. Breast Imaging. 2021;75:12-15. https://pubmed.ncbi.nlm.nih.gov/33486146 (Editor’s note: For those who want to “catch up” on the various cutaneous signs of COVID-19 infection, we recommend this mercifully concise summary: Schwartzberg L, et al. Cutaneous manifestations of COVID-19. Cutis. 2021;107:90-94.) https://pubmed.ncbi.nlm.nih.gov/33891838

A Kaiser Family Foundation/Washington Post nationally representative survey of more than 1300 HEALTH CARE WORKERS found that nearly two- thirds of those interviewed report worry or stress related to COVID. Many feel “burned out” at work and about half have experienced abnormal sleep patterns. TO READ MORE: Kirzinger A, et al. KFF/The Washington Post Frontline Health Care Workers Survey. Published online and accessible at: https://www.kff.org/coronavirus-covid-19/poll- finding/kff-washington-post-health-care-workers

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COVID-19, con’t COSMETIC RHEUMATOLOGIC DISEASES DERMATOLOGY

Using complex models, CDC investigators conclude that To effectively Literature suggests that ingestion of OF COVID TRANSMISSION manage periorbital HERBAL SUPPLEMENTS designed to be % COMES FROM ASYMPTOMATIC hyperpigmentation, immnostimulatory may lead to acute onset, 59 INDIVIDUALS it is imperative flare, or both of autoimmune cutaneous to determine the This includes 35% from those who eventually will disorders (such as lupus). These include develop symptomatic disease and 24% from those etiology: volume several forms of microalgae, echinacea, who never will develop symptomatic disease. loss or melanin or and alfalfa. It is therefore reasonable and vascular anomaly. TO READ MORE: Johansson MA, et al. SARS-CoV-2 rational to screen patients with autoimmune Transmission from people without COVID-19 symp- Appropriate skin diseases for herbal supplement use. toms. JAMA Netw Open. 2021 Jan 4;4(1):e2035057. treatments which doi: 10.1001/jamanetworkopen.2020.35057 follow from this determination might TO READ MORE: Bax CE, et al. The effects include: soft tissue of immunostimulatory herbal supplements A retrospective study done in New York state re- on autoimmune skin diseases. J Am Acad vealed that the RATE OF COVID DIAGNOSIS among filers and autologous the general population was 19.4 per 1000 persons, fat transplantation; Dermatol. 2021;84(4):1051-58. lower than the rate among those living with HIV, chemical peels, doi: 10.1016/j.jaad.2020.06.037 which was 27.7 per 1000 persons. Hospitalization hydroquinone or rate due to COVID was about 2 times greater and vitamin serums; mortality rate about 3 times higher among the HIV carboxytherapy and co-infected compared to the general population. platelet rich plasma TO READ MORE: Tesoriero JM, et al. COVID-19 injections; or laser outcomes among persons living with or without surgery. diagnosed HIV infection in New York State. JAMA Netw Open. 2021;4(2):e2037069. doi:10.1001/jamanetworkopen.2020.37069 TO READ MORE: Michelle L, et al. Treatments for periorbital hyperpigmentation: a systematic review. Dematol Surg. 2021;47(1):70-74. doi: 10.1097/ DSS.000000000000 2484

May 2021 | 13 /ECZEMA

A small Japanese cohort of moderate-to-severe atopics was treated with DUPILUMAB. Not only did clinical parameters (EASI, IGA, BSA) improve, but also serum IgE and peripheral eosinophil counts improved from pre-treatment, elevated state. TO READ MORE: Yamauchi T, et al. Dupilumab treatment ameliorates clinical and hematological symptoms, including blood eosinophilia, in patients with atopic dermatitis. Int J Dermatol. 2021;60:190- 95. https://doi.org/10.1111/ijd.15183

Investigators from India found that patients with HAND ECZEMA, regardless of basic cause, were under very high stress (16.1%) and high stress (51.6%). It was not clear if the stress contributed to the hand eczema or resulted from the hand eczema. In any event, stress management might be considered in patients with hand dermatitis. TO READ MORE: Janardhanan AK, et al. Therapeutic considerations related to stress levels associated with hand eczema: A clinic-etiological study. Dermatol Ther. 2020 Nov;33(6):e14508. doi: 10.1111/dth.14508

Based upon reports received by the FDA, the most common adverse event associated with DUPILUMAB are ocular. These include (in order of decreasing frequency): conjunctivitis, eye pruritus, ocular hyperemia, dry eye, eye “irritation,” and increased lacrimation. All adverse events occurred in less than 5% of patients. TO READ MORE: Wang Y, Jorizzo J. Retrospective analysis of adverse events with dupilumab reported to the United States Food and Drug Administration. J Am Acad Dermatol. 2021;84(4):1010-1014. doi: 10.1016/j.jaad.2020.11.042

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ACNE

The impact of on QUALITY OF LIFE is important to remember. A small case series (N=6) verified the benefit of treating the Acne has been clearly associated with increased risk of stress associated with select chemotherapeutic (with associated excoriation disorder); social phobia disorder; fear agents with either acitretin or isotretinoin, although the latter and anxiety; depression and suicidal thoughts/attempts; sexual appeared to be more effective. dysfunction; and stigmatization. Mental health intervention may TO READ MORE: Costello CM. Choosing between isotretinoin well be required. and acitretin for epidermal growth factor receptor inhibitor and TO READ MORE: Stamu-O’Brien C, et al. Psycho dermatology of small molecule tyrosine kinase inhibitor acneiform eruption. acne: psychological aspects and effects of acne vulgaris. J Cosmet J Am Acad Dermatol. 2021;84:840-41. Dermatol. 2021;20(4):1080-1083. doi: 10.1111/jocd.13765 doi: 10.1016/j.jaad.2020.09.090

May 2021 | 15 DRUGS AND DEVICES HAIR AND NAILS

A recurrent EPIDERMAL CYST was punctured by BITEMPORAL carries a broad differential diagnosis, including both ultrasound-guided large-bore needle; the cyst was scarring and non-scarring etiologies. The results of a hair pull test, the presence then subjected to repeated injections of a sclerosing (or absence) of a “fringe sign,” symptomatic pruritus, and family history can help agent (1 ml of anhydrous alcohol), followed by aspi- determine the precise diagnosis. rations, until the withdrawn fluid was clear. Pressure TO READ MORE: De Souza B, et al. Bi-temporal scalp hair loss: differential diagno- was applied. The cyst resolved without any sequela. sis of nonscarring and scarring conditions. J Clin Aesthet Dermatol. 2021;14(2): 26-33. https://jcadonline.com/hair-loss-differential-diagnosis-scarring TO READ MORE: Zhang Q, Huang Y. Ultrasound- guided sclerotherapy for recurrent : A case report. Dermatol Therapy. 2021 Jan;34(1): e14552. doi:10.1111/dth.14552

KOILONYCHIA, or “spoon-shaped” nails, is most typically associated with iron deficiency. This case reminds us that this specific nail finding can rarely also be seen in conjunction with alopecia areata. Oral corticosteroids, given for the hair loss, also led to resolution of nail findings. TO READ MORE: Litaiem N, et al. in a patient with alopecia areata. J Clin Aesthet Dermatol. 2021;14(2):42-43. https://jcadonline.com/koilonychia-alopecia-areata (Editor’s note: pitting and are the common nail findings in alopecia areata.) 

A systematic review and meta-analysis of 11 studies (including more than 410,000 treated patients) revealed an association between TOPICAL CALCINEURIN USE AND RISK OF LYMPHOMA but not any other type of cancer. However, the absolute risk of lymphoma was quite small, making the risk to any individual patient very low. TO READ MORE: Lam M, et al. Association between topical calcineurin inhibitor use and risk of cancer, including lymphoma, keratinocyte carcinoma, and melanoma. A systematic review and meta-analysis. JAMA Dermatol. 2021, March 31. doi:10.1001/jamadermatol.2021.0345 flickr.com/photos/coreyheitzmd/15023020192

16 | The Dermatology Digest THE

PRESENTS

A 3-part educational podcast series that will provide an overview of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and the dermatologist’s important role in diagnosis and referral.

Podcast 1

BPDCN Patient Demographics and Cutaneous Lesions In this first episode, dermatologist and dermatopathologist Dr. Whitney High discusses BPDCN patient demographics and the characteristics of cutaneous lesions.

Podcast 2

The BPDCN Diagnosis Process for Dermatologists In this podcast, dermatologist and dermatopathologist Dr. Whitney High details: The diagnosis process • Protein markers that may indicate a positive diagnosis • Common misdiagnoses • Tips for working with your dermatopathologist

Podcast 3

BPDCN Prognosis and Patient Referral In the final episode of our podcast series on BPDCN, dermatologist and The dermatopathologist Dr. Whitney High discusses disease prognosis and and offers patient-specific guidance for treatment, including: • Median survival • Fatality • Symptoms of bone marrow involvement BPDCN • Referring to a hematologist oncologist Podcast Series

TheDermDigest.com/podcast/the-bpdcn-diagnosis-process Sponsored by Caring for patients with delusions of parasitosis

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Artful interactions and effective medication are key

Nicholas D. Brownstone, MD with Cheryl Guttman Krader

Delusions of parasitosis (DOP), also known as delusional infestation or Morgellons disease, is a condition in which patients have a fixed false belief of having a cutaneous parasitic infestation or foreign materials extruding from their skin. Dysesthesia is common in this condition, as are excoriations from patient attempts to remove the infesting article. NICHOLAS D. BROWNSTONE, MD Encounters with patients suffering from DOP begins with a careful skin examination Fellow, Department DOP can cause unease and even resentment to exclude a true infestation or inflamma- of Dermatology, University of California for dermatologists whose expertise lies in tory disease as the cause for the reported San Francisco identifying objective evidence of skin disease symptoms. and who generally lack training in psycho- “Thoroughly inspecting the skin also dermatology and related pharmacotherapy. satisfies patients who consider the effort a Therefore, it might seem that these patients sign that their complaints are being taken would be best served by seeing a psychiatrist. seriously,” said Dr. Brownstone. However, the conviction of having a skin disease is what led them to seek dermatologic Patients determined to have DOP are c care, and upon being referred to a psychia- ategorized according to whether they have trist, patients with DOP are likely to proceed a spontaneous disorder, ie, primary DOP, on a doctor-shopping journey. Instead, by or secondary DOP consequent to condi- Hear the Dermatology learning simple strategies for fostering pos- tions that include illicit substance abuse or Digest interview with itive interactions and the basics of medical withdrawal, organic brain syndrome, schizo- Dr. Brownstone at management, dermatologists can successfully phrenia, major depression, hyperthyroidism, www.thedermdigest. treat DOP and provide an outcome that is and vitamin B12 deficiency, among others. com/podcast/delusions- gratifying for both patient and physician, “Some of these secondary reasons can of-parasitosis said Nicholas D. Brownstone, MD. be identified through targeted laboratory Dr. Brownstone, a fellow in the department testing, and the additional workup also gives of dermatology at the University of California patients confidence that they are receiving San Francisco, outlined an approach to the good care,” Dr. Brownstone said. evaluation and management of DOP that Treating DP includes attention to techniques for building Secondary DOP often resolves after the rapport and gaining patient trust and satisfac- underlying etiology is addressed, which may tion [see sidebar: Tactful tips]. require patient referral to a psychiatrist or Establishing the diagnosis another specialist, depending on the prima- The evaluation of patients with suspected ry diagnosis.

May 2021 | 19 Increase Maintenance Taper

Figure. Pimozide is initiated at 0.5 mg/day (half of a 1 mg tablet), increased by 0.5 mg/day every 2 to 4 weeks until the symptoms disappear or are nearly gone (increase phase), maintained at the effective dose (maintenance phase) for 3 months, and then tapered to discontinuation by decreasing the daily dose in 0.5 mg increments every 2 to 4 weeks (taper phase). Most patients respond to a daily dose of 3 mg/day with the maximum dose usually being no higher than 5 mg/day.

A variety of medications provide ef- terfere with pimozide metabolism by single published case of TD in a pa- fective treatment for both the ideation CYP 3A4 inhibition. “An electrocar- tient treated with pimozide for DOP and tactile sensations experienced by diogram is always done before starting was uncovered in a recent literature patients with primary DOP. Convinc- pimozide for older patients or a patient search, and it was unclear if the case ing a patient to start treatment may with suspicious history for an arrhyth- involved true TD or withdrawal be the biggest hurdle, however, since mia. Risperidone or aripiprazole are dyskinesia, which is a rare, usually these options are classified as antipsy- our second-line options if a patient self-limiting condition that develops chotic agents. With that issue in mind, has a contraindication to pimozide,” after stopping the treatment,” said pimozide is used as the treatment of Dr. Brownstone said. Dr. Brownstone. (Dr. Koo is Professor choice at the University of California Side effects of pimozide include of Dermatology at the UCSF School San Francisco psychodermatology extrapyramidal reactions (pseudo- of Medicine and Board Certified in clinic because Tourette’s disorder, parkinsonism) and an inner feeling Dermatology and Psychiatry.) a neurological condition, is its only of restlessness (akathisia). These He added, “Knowing that there are approved US FDA indication. side effects can be controlled with also approved effective medica- Pimozide is prescribed with a trap- diphenhydramine 25 mg 4 times tions for treating tardive dyskinesia ezoidal dosing scheme that aims to a day, which patients are told to keep (valbenazine and deutetrabenazine) optimize safety by using the lowest on hand while cautioned about possi- might increase dermatologists’ com- effective dose for the shortest possible ble sedation. fort prescribing pimozide.” duration and minimize relapse risk The potential for tardive dyskinesia Adjunctive treatments, including by avoiding abrupt discontinuation (TD) is the most worrisome side barrier dressings (such as Duoderm) (Figure). effect of pimozide because these in- and mupirocin ointment, are used as Pimozide is generally safe and well- voluntary movements can be irrevers- needed to protect and treat existing tolerated. However, it can prolong the ible, but the risk of TD is dose- and excoriations/ulcerations. Topical QT interval. Therefore, it is contrain- duration-related. products to relieve itching may also dicated in patients who have cardiac “During 30 years of experience using be considered, including crotamiton arrhythmias and in those on drugs pimozide, John Koo, MD, has seen cream/lotion, which has particularly that prolong the QT interval or in- no cases of TD. Furthermore, only a good patient acceptance because

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of its antiparasitic indication, Dr. Brownstone said. TACTFUL TIPS Even when given attentive care, only a Because patients with primary DOP seem to have an innate ability to recognize small proportion of patients suffering 1 when a physician fails to believe their complaints, Dr. Brownstone said that he makes from DOP will accept that they do not a concerted effort to enter the room with a smile. Labeling patients as “VIPs” makes have a parasitic condition. Moreover, them feel valued. some DOP patients are terminally “When making follow-up appointments, patients are told to let the front staff know delusional and want only validation they are considered a ‘VIP’ and should be scheduled at the end of the clinic day,” of their complaint. For all patients says Dr. Brownstone. who remain convinced they have a parasitic condition, Dr. Brownstone “The VIP label makes patients feel respected, and by seeing them last, I know that said he offers continued consultation what is often a lengthy visit will not cause delays earlier in the day.” with frequent follow-up visits and raises the idea that they can see an Specimens that patients often bring as evidence of their infestation are carefully entomologist or parasitologist while examined under the microscope before being declared to show no evidence of assuring them that they are always 2 a parasite. Skin scrapings, which may be taken to build patient trust, are handled welcome to return for future care. in the same manner. Treatment counseling conversations aim to establish Just as he takes care to sidestep implying that the patient is suffering from a psycho- a therapeutic partnership. 3 sis by choosing pimozide as first-line treatment, Dr. Brownstone also avoids using the “Patients are told, ‘We will not give up term “delusions” when discussing the diagnosis with patients and in his notes. on you if you do not give up on us,’ and that the main goals are to achieve “I talk about Morgellons disease, which is a neutral moniker, and because patients symptom relief and get their life back can access their records, I only write verbatim and in quotes what the patient says. on track rather than to figure out a I expect that any physician who reads the record will readily recognize that the patient cause. It is explained that treatment is suffering from delusions,” he said. may involve some trial and error, but generally leads to a cure even though it is not known exactly how it works,” Dr. Brownstone said. Connecting with these patients is often the biggest challenge, but with the right attitude and determination, these patients can be some of the most grateful seen in your practice. 

REFERENCES 1. Thomson AM, Wallace J, Kobylecki C. Tardive dys- kinesia after drug withdrawal in two older adults: clinical features, complications and management. Geriatr Gerontol Int. 2019;19:563-564.

DISCLOSURES Dr. Brownstone reports no relevant financial interests. For more practical information on managing patients with DP and related dermatologic conditions: Morgellons Disease: High Yield Principles for Clinical Practice. Brownstone ND, Beck KM, Sekhon S, Koo J. 2nd ed. Kindle Direct Publishing; 2020.

May 2021 | 21 GENERAL DERMATOLOGY HYPERHIDROSIS

Devices for hyperhidrosis

Michael Gold, MD, with Bob Kronemyer

espite having at our disposal highly effective old and new medications to Dtreat hyperhidrosis, ranging from topical aluminum chloride hexahydrate (Drysol, Person & Covey, Inc.) to the glycopyrronium cloth (Qbrexza, Dermira), medical devices still have a place.

MICHAEL GOLD, MD Medical Director, Gold Skin However, there is currently only one FDA- sweat glands. In addition, the handpiece pro- Care Center and Tennessee cleared device for axillary hyperhidrosis: vides cooling to lessen patient discomfort. Clinical Research Center, miraDry (Sientra). This noninvasive treat- There is no question that miraDry provides per- Nashville, Tennessee ment, which uses microwave technology to manent sweat reduction in nearly all patients. eliminate sweat and odor glands from the armpits, was approved in 2015. Performing a miraDry procedure The in-office therapy uses a handheld appli- To prepare the patient, a grid pattern is placed cator to deliver electromagnetic energy below on the underarms (see Figure). A local anes- the skin, where it targets and destroys the thetic is also applied to the area, using tumes-

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cent anesthesia for the whole axillary region, so it is fairly simple to administer. Microwave energy is absorbed by molecules that are electric dipoles, which rotate as they try to align themselves with the alternating field of microwaves. Rapid molecular rotation generates frictional heat. Microwaves are preferentially absorbed by high water-content tissue, such as sweat glands, leading to localized heating. And when temperatures in the target tissue reach critical levels, cellular thermolysis occurs. The system has a tap-and-release button on the handpiece that initiates treatment and min- imizes user fatigue. There are also indicator lights when energy is activated. Safe use of higher energy produces greater efficacy and high patient satisfaction in as little as one treatment. The procedure takes approximately 30 minutes to 1 hour to perform. Once the numbing wears Figure: Temporary tattoo marking for miraDry. Image courtesy of miraDry off, there is a slight soreness to the area. The free-standing miraDry is an appealing a second treatment. For those people, miraDry option for those patients who do not want to is a good option. take a pill or do not want to use a topical every Besides the need for anesthesia in all patients, single day. there are rare cases of burning and blister The biggest hurdle, however, is that the formation. However, I have never seen any procedure is not covered by insurance, which scarring from the device, although I am sure can cost the patient several thousand dollars it has been reported. With the right skill set for one treatment, depending on where the to perform the procedure, it should be a truly patient lives. simple procedure and user-friendly. Once the area is anesthetized, you just follow the grid MiraDry is always given as an option for pattern that is provided with the system. hyperhidrosis at my office. Almost all patients require only one treatment session, with a few It costs about $80,000 for a practice to acquire patients choosing a second treatment 3 to 6 miraDry, for which I charge $2,500 for the months later. It is patient preference whether first treatment and about $1,500 for a second they want a second treatment. Most opt not to. treatment. When the device first came out many years I delegate the procedure to one of my staff, ago, we recommended one treatment only. under my supervision. In today’s world, it is But then we realized there is a small group important to have physician supervision for of patients, probably less than 10%, that need these kinds of procedures.

23 | The Dermatology Digest May 2021 | 23 Men & women ARE AFFECTED EQUALLY BY HYPERHIDROSIS

10 million 2% NUMBER OF PEOPLE OF SWEAT GLANDS WHO HAVE EXCESSIVE ARE LOCATED IN UNDERARM SWEATING THE UNDERARMS IN THE US

14 to 25 2 to 4 years AGE AT WHICH MOST PEOPLE FIRST NOTICE million EXCESSIVE SWEATING NUMBER OF SWEAT GLANDS IN THE HUMAN BODY

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Other options Other devices have been used for many years The biggest hurdle, however, is that the procedure to treat people with sweating, primarily radiof- is not covered by insurance, which can cost the requency (RF) systems that we also use for skin patient several thousand dollars for one treatment, tightening. These companies claim that their RF systems have sufficient RF energy to pene- “depending on where the patient lives.” trate the sweat glands and destroy sweat. But in my experience, I have never found any of these devices to be that effective at this process.

In the United States, it is not very common hyperhidrosis, I go through the treatment for RF systems to be promoted to treat hyper- algorithm with him or her. For a patient with hidrosis. An example is the SweatX system medical insurance, the insurance company (Alma Lasers) from several years ago, which usually requires that treatment begin with never came to America. But some people topical aluminum chloride hexahydrate in thought that it worked really well because it a prescription strength. However, most was RF-based heating. patients fail this treatment, even though One topical medication for hyperhidrosis that it has been around for a long time. has been used for a long time is gycopyrrolate Our back-up treatment is a glycopyrronium (Robinul, Casper Pharma). However, usually cloth or Botox. But we always bring miraDry The free-stand- patients who have successful therapy with gy- into the equation from day one. Some patients ing miraDry is copyrrolate also experience excessive dryness have already tried everything else, so they an appealing in every part of their body, which becomes an want miraDry immediately. issue for many patients. Therefore, I recom- “option for those mend this drug in extreme cases only. For chosen treatment, results may last for patients who a really long time, while others may obtain The botulinum toxin Botox (Allergan) also results that last only a few months. But for do not want to has an FDA indication to treat hyperhidrosis those who sweat profusely and achieve a few take a pill or do of the axilla. But a practice can choose what- months of relief, it is well worth it. not want to use ever toxin it prefers because they all possibly a topical every work similarly, although Botox is the only To market miraDry at our practice, we have toxin that has had clinical work and several offered a promotion called “miraDry Mon- single day.” large clinical studies. Also, occasionally Botox days” for several years now. We like to treat is covered by insurance, even though at times one or two patients every Monday. Patients reimbursement is less than the cost of the Bo- who commit to a single treatment are given tox itself. So you need to be aware of the costs a discount on a second treatment, if needed. and reimbursements in the insurance world. Overall, between 10% and 15% of my hyper- By filing for insurance, you are sometimes hidrosis patients choose miraDry. Some contractually obligated to accept what the patients even request it by name because insurance pays. of the company’s selective advertising. Furthermore, a Botox injection lasts roughly For the right patient, who is miserable with 6 months, give or take 1 month, in most pa- primary axillary hyperhidrosis, miraDry is tients, before a repeat injection is needed. definitely a game changer. 

Patient procedures DISCLOSURES When a patient comes into my office with Dr. Gold reports no relevant financial interests.

May 2021 | 25 PEDIATRICS HYPERHIDROSIS

Pediatric hyperhidrosis

Adelaide A. Hebert, MD, with Lisette Hilton

find that young children who experience excess sweating are most I hampered by the excess moisture on their hands. A telling example is that no one in preschool or kindergarten wants to hold these children’s hands when they are crossing the street or playing Ring Around the Rosie. ADELAIDE HEBERT, MD This rejection really hurts their feelings. Professor of Dermatology and Pediatrics and Chief of Pediatric Dermatology at Their artwork and paperwork get wet, and They feel they cannot do what other children UTHealth McGovern Medical teachers often berate them, not realizing with normal, not excessively sweating skin School; Chief of Pediatric that they suffer from a causative medical can do. Dermatology at Children’s condition. Children who use a computer Memorial Hermann Hospital, These children get teased and bullied about at an early age find that challenging because Houston, Texas hyperhidrosis. They may also have axillary of the wetness of their hands. hyperhidrosis, which limits the clothing choices Older children become more self-conscious they have. The axillary sweating renders them as they realize they are different from other reluctant to raise their hands in the classroom. children. Their paperwork, musical instru- Parents often feel guilty, particularly if they ments, and sports equipment often get wet. had hyperhidrosis themselves in that they

These children get teased and bullied about “hyperhidrosis.”

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could potentially have passed this condition on to their offspring. POSSIBLE CAUSES OF As you can see, this patient population faces a whole host of challenges. GENERALIZED HYPERHIDROSIS What we can do to help When to start therapy is not so much about IN CHILDREN a child’s age in terms of numbers. Instead,  Infections  Congestive heart failure consider the impact on the patient’s life.1  Hyperthyroidism  Other hormonal and metabolic I will start treatment in a child as young as  Diabetes disorders 5 years of age if I really feel it is indicated and  Hypertension  Some prescription drugs is in the child’s best interests. The decision to initiate therapy really depends on the individ­ ual patient; the overall impact on the patient’s life; what the parents want; how the patient Robinul on the weekends when they are at tolerates therapy if it is initiated; where they home and not sweating that much, that is fine. live; whether they participate in sports or play I also tell them in summer months, when we musical instruments. All these factors come have a considerable amount of heat, they may into play. need to take an extra pill. These patients can learn over time to self­titrate. We have a host of therapeutic options that include glycopyrrolate (Robinul). This anti­ If a patient grows taller and gains weight, cholinergic agent is probably my number­one we will need to increase the dose. recommended treatment. This drug is gen­ Oxybutynin is another treatment that is widely erally well­tolerated by children. But we used in pediatric patients to treat bed­wetting must guide patients in the safest use of this and can be used to treat hyperhidrosis. medication for their child’s hyperhidrosis. For example, if patients on Robinul are running If a patient is 9 years of age or older and has for gym class or soccer or a cross­country axillary hyperhidrosis, we can use a new team and they get overheated, they may have anticholinergic formulation called glycopyr­ great challenges. We warn them about the risk ronium tosylate (QBREXZA, Dermira). This of overheating. We also encourage them to dis­ is a towelette that patients apply once daily. cuss potential medication side effects with their Patients should carefully wash their hands PE teachers and coaches so they, too, are fully after use, so they do not inadvertently transfer apprised that children on this medicine may not residual medication to the eyes. If they do, the sweat enough, and these children should cool medication can dilate their pupils, which can themselves down if they are doing extensive make it difficult to see and make physicians or outside exercise. other health care providers believe they have more serious challenges going on than just In general, I begin a slow titration of Robinul hyperhidrosis and a side effect from a medica­ over a few weeks, starting as low as 1 mg in tion to treat hyperhidrosis. the morning and 1 mg at night. The patient might increase the dosage by 1 mg each I occasionally combine oral treatment with evening until they feel they have good control extra­strength antiperspirants, but I acknowl­ and, hopefully, not too many side effects. I do edge that many of my colleagues feel that tell my patients that if they do not wish to take might result in too much anticholinergic

May 2021 | 27 www.thedermdigest.com/PEDIATRICS

Fast PATIENTS’ 2 MOST OFTEN CITED REASONS FOR NOT SEEKING TREATMENT Facts 1. Belief that hyperhidrosis is not a medical condition 2. Belief that there is nothing that can be done to treat their excessive sweating

Children with hyperhidrosis AGE OF ONSET MISSING THE DX sweat as much as Excessive sweating of the hands Of pediatric patients who do see an (palmar hyperhidrosis) usually HCP about their excessive sweating, 5 times begins in childhood, only 73% more before the are diagnosed than other children age of 12

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impact. We want patients to be able to sweat to cool their core body temperature when necessary but not sweat excessively. Every patient is a little different, and fine- tuning the therapeutic strategy can be very help- ful and result in few side effects. That has to be done with forethought and a compliant patient. Listen, learn, and do not dismiss Many physicians either do not recognize hy- perhidrosis or dismiss the condition as being “normal,” which causes more emotional harm for the patient. These patients might be reluc- tant to approach another health care provider with the problem because of their disease state being downplayed. tional product looks exciting, but I do not yet We also have any data to share because we are still in We recommend that patients and physicians the preliminary stages of the research. encourage go the International Hyperhidrosis Society them to discuss website, SweatHelp.org. (I am on the Board Hyperhidrosis is coming of age. People are beginning to realize that this is a condition “potential of Directors of that organization and have served in that capacity for more than 15 years.) that warrants therapy, many suffer from it, medi cation side This website offers a tremendous amount of and drug development to treat it has value. effects with their information for patients, as well as products We are learning more about the condition in PE teachers and that can help patients sleep, function, and children. We have done recent research with coaches.” wear clothing and socks without worrying the International Hyperhidrosis Society and about resultant staining from hyperhidrosis. are beginning to realize that the impact on We also have a school nurse outreach pro- small children is substantial. In fact, small gram within the International Hyperhidrosis children may not fit the mold that we have Society, through which we have sent samples typically identified for adolescents, young of extra-strength antiperspirants, which can adults, and adults. Young children seem to be very helpful for children suffering with sweat during sleep, which was probably under- excessive axillary sweating. The school nurse appreciated previously. outreach program helps educate nurses about the condition. We also were classically taught that hyperhi- drosis in small children was primarily palmar, Early recognition and early intervention can but now we are finding that these children help these patients with hyperhidrosis. These have sweating on the palms, soles, and some- patients are grateful when we acknowledge times in the axilla.  their hyperhidrosis as a medical condition and initiate a beneficial therapeutic option. REFERENCE On the horizon 1. Remington C, Ruth J, Hebert AA. Primary hyperhidrosis in children: A review of therapeutics. Pediatr Dermatol. 2021 Mar 4. Emerging treatments include one that we are doi: 10.1111/pde.14551. Epub ahead of print. PMID: 33660889. studying in an ongoing clinical trial. This med- ication is yet another topical agent that is an DISCLOSURES anticholinergic gel formulation. The investiga- Dr. Hebert reports no relevant financial interests.

May 2021 | 29 COSMETIC CORNER VASCULAR OCCLUSION

Needle vs cannula: vascular occlusion risk when injecting fillers

Murad Alam, MD, with Eliza Cabana

hen injecting fillers, what is the risk of vascular occlusion with needles “ Wvs cannulas?” It’s the question Murad Alam, MD, and coauthors asked in a retrospective cohort study recently published in JAMA Dermatology.1

MURAD ALAM, MD “We asked several hundred dermatologists of Medicine, Northwestern University, who routinely inject fillers to pull up their Chicago, Illinois. “In addition, we asked Vice Chair, Chief of Cutaneous and Aesthetic records and report how often and exactly in them to also let us know how much filler Surgery, and Professor which circumstances they have experienced of various types they’ve injected over the of Dermatology at Feinberg filler occlusion in the past—when, at which preceding 10 years.” School of Medicine, anatomic location, of what level of severity, Northwestern University, In the context of skin fillers, Dr. Alam says Chicago, Illinois with which type of filler, and how often,” vascular occlusion happens in one of 2 ways: said Dr. Alam, who is Vice Chair, Chief filler either enters a blood vessel through a nick of Cutaneous and Aesthetic Surgery, and or perforation, or it surrounds and compresses Professor of Dermatology at Feinberg School

Watch! Murad Alam, MD, with more on recognizing and managing vascular occlusions from dermal filler injections at www.thedermdigest.com/ cosmeticcorner/ the-vascular-occlusion

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a vessel, thereby preventing blood flow. are better or worse, so I don’t want to pretend to have any special knowledge on this. There Based on data collected, “We were able to get are certain situations—for instance, when I’m both a numerator and a denominator: How injecting very superficially, or when I want to many occlusions divided by how many injec- know exactly where the filler is going—when tions of 1 cc volumes of filler. So, we were able it is sometimes easier to be very precise with to determine rates of occlusion in different a needle,” he said. circumstances,” said Dr. Alam. Another question the researchers did not Overall, they found both needles and cannu- address was the risk of blindness specifically. las to be exceedingly safe. “Even if you use a Instead, they measured severity by grade: Vascular needle in a relatively ‘higher risk’ area, the grade 1 (no sequelae), grade 2 (scar), and occlusion likelihood of getting a vascular occlusion is grade 3 (ocular injury or blindness). no more than 1 in 6000,” said Dr. Alam. “We happens in one found that cannulas can be even less likely to “We didn’t really focus on the most severe “of 2 ways: filler cause occlusions, maybe 1 in 40,000—6 times complication of vascular occlusion, which is either enters less likely.” blindness, because this wasn’t the primary aim of our study, and because we were worried a blood vessel And though it wasn’t part of this study, that if we asked for much greater detail about Dr. Alam points out that when vascular occlu- through a nick filler-associated vision problems, people sions occur, the vast majority are harmless and or perforation, might not be so forthcoming with their data,” resolve without long-term sequelae. explained Dr. Alam. or it surrounds So, needle or cannula? and compresses A learning curve Although the study shows the risk for vas- According to the study, there is a slight learn- a vessel, thereby cular occlusion is significantly lower when ing curve for less-experienced injectors. preventing injecting with cannulas, needles are very Those with more than 5 years of experience safe and still have a place in the injectable blood flow.” had 70.7% lower odds of having an occlusion filler armamentarium. than less-experienced injectors, with a 1% de- “We’re certainly not saying ‘don’t use a needle’ crease in odds for every additional injection/ or ‘needles are dangerous,’” said Dr. Alam. week. While it was more likely for occlusions “What we are saying is, in some instances— to take place in the nasolabial fold and lip when it’s appropriate given the anatomic site, areas, the most severe occlusions took place the kind of filler, the patient requirements—it in the glabella. may be helpful to consider a cannula. But it’s a Nevertheless, Dr. Alam pointed out that the complex decision made on a variety of factors, learning curve for dermatologist injectors is and only the patient and the physician collabo- relatively short and serious occlusions happen ratively can decide if it’s appropriate or not.” very infrequently—85% were reported Although the study provides no insight into to resolve without long-term sequelae. the exact set of circumstances in which to “We found a couple of reassuring things. First choose a cannula rather than a needle, certain of all, it didn’t require an enormous amount of factors could make a needle the better choice. experience for board-certified dermatologists But, said Dr. Alam, there are so many that it’s to perform filler injections very proficiently. difficult to generalize. But as with most things that require some “No one has studied the dozens of possible hand-eye coordination, there is a learning permutations of factors to see which ones curve. We know there are some areas where,

May 2021 | 31 www.thedermdigest.com/COSMETIC_CORNER

Another factor is the fact that people have different pain thresholds. “So, it’s very important to make sure your r eceptionists, your nurses, and your medical assistants know that, after filler injection, if someone calls the next morning and they’re having discomfort, they shouldn’t just be reas- sured. If the degree of discomfort seems exces- sive, you want to advise them that their coming in and being seen would be a good idea.” Study limitations Dr. Alam acknowledged that the actual rates of vascular occlusion could be slightly different than those reported due to memory and/or documentation inaccuracies. “This is based on retrospective data,” said regardless of the instrument used, there is Dr. Alam. “So, we did ask people to look a greater risk of vascular occlusion. These through their medical records. In some cases, include the glabella, around the nose, [and] respondents may have supplemented their % some other watershed areas where there are medical records with their memories of past lot of vessels in a small space.” 85 events, and we do believe that a vascular occlu- Thus, while it may be prudent for the less- sion—even a relatively benign one—is some- OF OCCLUSIONS experienced dermatologist injector to avoid thing that people generally remember well.” were reported to the higher anatomic risk zones for filler in- resolve without Overall, Dr. Alam said that the researchers jection, this does not change the fundamental were not surprised to find that cannulas have long-term sequelae truth that minimally invasive filler injections a lower occlusion rate. “But it’s nice to know are highly effective and exceedingly safe. there’s some data behind that now,” he said. Vascular occlusion happens That being said, Dr. Alam noted that their Redness, blanching, and pain are all associated study shows the safety of filler injections only with occlusion, but these tell-tale signs are all when performed by board-certified derma- also often part of the normal injection process, tologists. He added, “Our study does not say which can complicate identifying anything about the safety of filler injections an occlusion. performed by less-well-trained injectors, non-dermatologists, or non-physicians.”  “Even if you don’t have a vascular occlusion, a little bit of redness, a little bit of a blanch REFERENCE [from lidocaine], and a little bit of pain do 1. Alam M, Kakar R, Dover JS, et al. Rates of vascular occlusion occur when filler is injected,” said Dr. Alam. associated with using needles vs cannulas for filler injection. “It can be extremely difficult to differentiate JAMA Dermatol. 2021 Feb 1;157(2):174-180. at the time of injection if the redness, the doi: 10.1001/jamadermatol.2020.5102. whiteness, and the pain are normal, or if they’re elevated enough to increase suspicion DISCLOSURES for vascular occlusion.” Dr. Alam reports no relevant financial interests.

32 | The Dermatology Digest The Broadmoor Hotel Colorado Springs July 21-24, 2021

There are 2 ways to attend ADM 2021! Visit AmericanDermoscopy.com for registration and information.

On-Site at the Broadmoor Hotel “Live-Stream” Virtual Meeting Colorado Springs, Colorado Broadcast from the Broadmoor Hotel JULY 21-24, 2021 JULY 21-24, 2021

• ADM On-Site is our in-person meeting being held at • ADM Virtual is a virtual platform bringing our world- the Broadmoor in Colorado Springs, Colorado from class CME conferences direct to you. July 21-24, 2021. • Our ADM Virtual 2021 meeting from July 21-24, 2021 • The on-site meeting provides unlimited opportunities is being broadcast via live-stream for those unable to for networking and includes all social functions, join us in Colorado. exhibits, and product theater luncheons. • CME credits are earned for attending each session • On-demand video viewing of all recorded lectures will during the live meeting – July 21-24, 2021. be available for 30 days after the meeting. (Non-CME) • On-demand video viewing of all recorded lectures will • Registration is now open. be available for 30 days after the meeting. (Non-CME) • Registration is now open. COSMETIC CORNER EYELASHES

All about eyelashes

Caroline A. Chang, MD, with Lisette Hilton

air is an important identifying feature. When we lose hair, or lashes, Hor brows, it can be distressing. Dermatologists should keep this in mind and not only address eyelash concerns, but also reassure patients that losing eyelash hair can be normal and that the hair will likely grow back.

CAROLINE A. Eyelash shedding 101 gland could cause the lashes to temporarily CHANG, MD Eyelashes shed. People normally lose 1 to 5 fall out around the gland. lashes a day. Regrowth of eyelashes and eye- Dermatologist and Founder Importantly, skin cancer can cause patients brows follows the same life cycle as other hairs and CEO of Rhode Island to lose eyelashes. Patients have come in notic- Dermatology Institute, Inc. on the body. But the growth phase is shorter ing that they have lost eyelashes and point to East Greenwich, than scalp hairs (the shorter the hairs, the Rhode Island a spot on their lid. A closer dermoscopic exam quicker the growth cycle).1 can help to confirm something like a basal cell Common conditions that cause patients to carcinoma at the edge of the eye. lose eyelash hair include clogged oil glands Patients who have hair loss not only on their and blepharitis. The in the lashes but also on the scalp and brows could

34 | The Dermatology Digest www.thedermdigest.com/COSMETIC_CORNER

Many OTC lash serums have one brush, which can increase infection risk because patients use the brush “and put it back in the tube.”

have alopecia areata. These patients get because of picking or pulling, the lashes will patches, usually circular, of hair loss. On the grow back over time. eyelashes it would be seen as a contiguous I tell patients to wash their eyes and lashes patch of hair loss. nightly. Always make sure to take off eye Other causes include trichotillomania, a condi- makeup before bed, so the oil glands don’t tion usually related to some type of emotional get clogged. Keep everything clean. Use a THE KEY 3 or psychological stressor. Underlying health gentle soap and don’t scrub. issues could cause rapid or global loss of eye- Check thyroid A healthy, well-rounded diet helps skin, hair, lashes. Dermatologists should check thyroid function because and nails. Foods with iron may be important function because both hyperthyroidism and both hyperthyroidism because of the link between anemia and hair hypothyroidism can cause hair loss. Also check and hypothyroidism loss. Some people like to take biotin supple- the patient’s ferritin levels to rule out anemia. can cause hair loss ments, which have been shown to help hair Anemia can cause general hair loss. For global and nails grow more quickly. I recommend hair loss, one can consider , biotin as long as it does not interact with any Inform patients with which results in patients losing all the hair on other medications that a patient takes. While general eyelash their scalp, eyelashes, and eyebrows. biotin will not help a balding man grow back concerns (without Of course, patients undergoing chemotherapy hair, it does encourage faster hair growth a medical cause) or radiation therapy can experience global hair in someone with hair loss from an injury, about what’s normal loss, including eyelashes. for example. Lifestyle tips for healthier lashes If someone wants to grow their lashes more Foods with iron may be important I first inform patients with general eyelash quickly or longer, I recommend prescription because of the link concerns (without a medical cause) about Latisse (bimatoprost ophthalmic solution, between anemia what’s normal. Some people have short Allergan) because it is studied, and we know and hair loss eyelashes; some have long eyelashes. Do not about its proper use and potential side effects. pull them out, but if you do have eyelash loss Use caution when recommending over-the-

May 2021 | 35 www.thedermdigest.com/COSMETIC_CORNER

Many OTC lash serums have one brush, which can increase infection risk because patients use the brush and put it back in the tube. Other types of treatments for longer lashes include strip lashes that glue onto the eyelash- es. Magnetic eyelashes attach to eyelids with magnetic lash liner. Lash extensions involve a technician gluing lashes onto individual natural lashes. In all cases, I recommend patients see a techni- cian who is trained and uses sterile technique. With at-home methods, patients run the risk It is not counter (OTC) lash serums because addi- of applying too much glue and then pulling out or damaging lashes in the process. recommended tives in those products can potentially cause unwanted side effects. If a patient wants to that people Overall, the caution for all those methods is use an OTC lash serum, advise him or her to the adhesive, which could be irritating to the “apply it to the stop using the products if they result in a rash, skin. Some people develop an allergy to it. If lower eyelid sensitivity, or an infection. they have an issue, I recommend that they because Tips for using Latisse have the lashes removed and do not use the treatment again. it can cause Latisse is an eye drop for glaucoma. When treating eyelashes, we instruct patients to use the fat in the When removing lashes after any of these it nightly until they get to a lash length that techniques, people should take them off gently lower eyelid to makes them happy; then cut back and use the or have a technician remove them to avoid atrophy, causing product once a week to maintain the length. pulling off natural lashes. a sunken eye The most common side effect from Latisse Off-label uses and cautions appearance.” in studies is irritation at the eyelid where Some of my colleagues are using Latisse off- patients apply the product. Very rarely, label for eyebrow hair growth and are getting patients get pigmentation of the iris. Patients good results. might also get a little bit of skin pigmentation at the lash line where they apply it. To help Latisse has been shown to cause fat atrophy. It avoid these problems, instruct patients to use is not recommended that people apply it to the a very small amount—half a drop—and apply lower eyelid because it can cause the fat in the it to the lash line. lower eyelid to atrophy, causing a sunken eye appearance. Some people are using it off-label The packaging for Latisse, which now also use to treat excess fat under the eye, but I do comes in a generic version, comes with many not have experience with that.  little brushes. The idea is that patients should use a new brush for each application for REFERENCE sanitary reasons. If they do not want to use the 1. Aumond S, Bitton E. The eyelash follicle features and little brushes, I recommend they get a separate anomalies: A review. J Optom. 2018;11(4):211-222. eyeliner brush to apply Latisse to lashes. They doi:10.1016/j.optom.2018.05.003 should then wash the brush with soap and wa- DISCLOSURES ter after each use and leave it for the next day. Dr. Chang reports no relevant financial interests. They should not use that brush for makeup.

36 | The Dermatology Digest NEW DRUGS CAVROTOLIMOD

Cavrotolimod targets PD-1 inhibitor resistance

Douglas Laux, MD, with John Jesitus

atients with Merkel cell carcinoma (MCC) and cutaneous squamous cell Pcarcinoma (cSCC) refractory to programmed cell death protein 1 (PD-1) inhibition may one day have a silver bullet that renders these cancers DOUGLAS LAUX, MD Medical Co-director of susceptible to PD-1 checkpoint inhibitors. This is one of the goals for the clinical Clinical Research Services development of cavrotolimod (also called AST-008, Exicure), a novel toll-like at Holden Comprehensive Cancer Center and Clinical receptor 9 (TLR9) agonist that is currently the focus of an ongoing phase 2 Associate Professor of Hematology, Oncology, clinical trial for these indications. Blood, and Marrow Transplantation at the University of Iowa Patients with MCC or cSCC who have never effects. “Cavrotolimod helps to recruit these Hospitals & Clinics, Iowa City, Iowa. responded to or who have lost response to cells into the tumor microenvironment and PD-1 inhibition have limited subsequent to activate them, harnessing the power of both options, said Douglas Laux, MD. “So we’re the innate and adaptive immune responses looking for a way to sensitize or in some cases against the cancer,” said Dr. Laux. re-sensitize this disease to immune checkpoint Compared to linear oligonucleotide TLR9 inhibitor therapy.” agonists, cavrotolimod leverages Exicure’s pro- TLR9 agonists, which naturally include bac- prietary spherical nucleic acid (SNA) technol- terial and viral DNA oligonucleotides that are ogy, Dr. Laux said. SNAs have a strong affinity rich in unmethylated CpG repeats, can shift for scavenger receptors on the surfaces of cells, the immune environment to a pro-inflamma- which leads to high cellular uptake in the com- tory interferon-1-like milieu. Such an environ- partment containing TLR9. Targeting TLR9, ment attracts and activates T cells and natural which is expressed mainly on dendritic cells killer (NK) cells, both of which offer antitumor and B-cells, leads to a cascade of innate and

May 2021 | 37 Figure. Response in refractory melanoma patient with progression on anti-PD-1 at enrollment

Response to cavrotolimod + pembrolizumab Prior to cavrotolimod, progression on pembrolizumab at 12 Weeks

Before After 3 cycles PR ongoing pembrolizumab of pembrolizumab through 36 weeks

76-year-old man with melanoma

adaptive immune responses against the tumor. tions once weekly for 8 weeks, then once every SNAs consist of a benign lipid nanoparticle 3 weeks; pembrolizumab dosing occurred We’re looking core, from which strand-like oligonucleotides every 3 weeks, starting at week 3. radiate.1 The dense spherical arrangement of for a way to As of November 2020, interim results of the these oligonucleotides and high cellular uptake sensitize or phase 1b stage demonstrated a confirmed ultimately lead to enhanced stimulation of overall response rate (ORR) of 21%.1,2 This “in some cases TLR9, resulting in more efficient and potent figure includes one complete response and 3 re-sensitize activation of this receptor. this disease to partial responses, which investigators defined Trial observations as at least 30% tumor shrinkage from base- immune check- In the phase 1b dose-escalation portion of the line. Among the 4 responders, 3 had actively point inhibitor ongoing phase 1b/2 trial, investigators treated progressing disease on PD-1 blockade at study therapy.” 20 patients with inoperable advanced or met- enrollment. “This helps to support the concept astatic solid tumors—mostly melanoma and that by giving cavrotolimod with a PD-1 MCC—using cavrotolimod combined with inhibitor, we can help to re-induce tumor intravenous pembrolizumab. Patients under- response to immune checkpoint inhibitor went intratumoral (IT) cavrotolimod injec- therapy,” said Dr. Laux.

38 | The Dermatology Digest www.thedermdigest.com/NEW_DRUGS

Response to cavrotolimod + pembrolizumab NK cells Cytotoxic cells at 12 Weeks IP-10 (pg/mL) (% activated) (% activated)

Effects on both 2399 Lesions at baseline lesions 86

63

Non-injected 26 25

Injected 132

Predose Postdose Predose Postdose Predose Postdose

Postdose: 24 hours post cavrotolimod 32 mg + pembrolizumab

FIGURE: Melanoma from 76-year-old male before study At the highest dose, 32 mg, ORR was 33%. Of the immune environment to a pro-inflamma- enrollment, after 3 cycles of pembrolizumab, and with 6 patients given this dose, 2, both with mel- tory phenotype in and around that lesion, but partial response ongoing anoma, responded. Two patients with MCC we’re also stimulating antigen presenting cells through 36 weeks responded to doses of 2 mg and 4 mg, respec- and B cells to activate effector NK cells and tively. As of November 2020, progression-free CD8+ cytotoxic killer T cells to recognize and survival exceeded 6 months in all 4 respond- kill tumor cells at other sites,” said Dr. Laux. ers, and 16 months in 2 of them. Increased serum interferon gamma-induced protein (IP)-10 levels observed in responders Additionally, investigators observed shrinkage attest to this systemic effect. Likewise, pre- of noninjected tumors distant from the injec- liminary immunohistochemistry data from tion site, demonstrating an abscopal response. the injected tumor of one responder reflect For example, one patient with cSCC experi- increased levels of infiltrating CD45RO+ enced not only 33% reduction of an injected memory T cells.1 facial tumor, but also reductions in neck and lung tumors of 33% and 20%, respectively. Flu-like side effects, which investigators expected, also support the presence of a “The idea is that by injecting cavrotolimod systemic immune response, he said. Low- directly into a tumor, we’re not only changing grade flu-like symptoms and injection-site

May 2021 | 39 Investigators observed shrinkage of noninjected tumors distant “from the injection site, demonstrating an abscopal response.” reactions were the most common adverse advanced or metastatic PD-1 refractory solid events (AEs), occurring in all patients at tumors without superficial lesions.4 the highest dose; 98% of treatment-related In January, the FDA granted fast-track AEs were grade 1 or 2. In the phase 1b stage, designation to cavrotolimod for PD-1 2 patients reported treatment-related grade 3 refractory MCC and cSCC. Regarding how AEs, which were injection-site reactions and soon cavrotolimod could become available psychological agitation. if the clinical development and approval The phase 1b trial demonstrated promising process goes well, Dr. Laux said it is too soon pharmacodynamic potential for combination to speculate. “At this time, we are focused on treatment with cavrotolimod, as well as strong enrollment on the phase 2 portion of the trial safety data and evidence of systemic, abscopal and are looking forward to evaluating the data responses. Said Dr. Laux, “We now have early from this study.”  evidence that this is a worthwhile strategy to pursue for patients who have PD-1 refractory REFERENCES disease. We’re excited to be able to move on to 1. O’Day SJ, Perez CA, Wise-Draper T, et al. Safety and preliminary phase 2 (NCT03684785) in patients with PD-1 efficacy of intratumoral cavrotolimod (AST-008), a spherical nucleic acid TLR9 agonist, in combination with pembrolizumab in patients refractory Merkel cell carcinoma and cutane- with advanced solid tumors. Abstract 423. Society for Immunothera- ous squamous cell carcinoma.” py of Cancer Annual Meeting. November 9-14, 2020. 2. Milhem MM, Perez CA, Hanna GJ, et al. Phase 1b/2 studying of an Ongoing research intratumoral TLR9 agonist spherical nucleic acid (AST-008) and Including Dr. Laux’s site at the University of pembrolizumab: evidence of immune activation. Abstract LB-140. Iowa, researchers at 16 sites have begun enroll- American Association for Cancer Research Virtual Annual Meeting. June 22-24, 2020. ing patients with such cancers. Each cohort of 3. Milhem MM, Perez CA, Hanna GJ, et al. AST-008: a novel approach up to 29 patients will receive the 32 mg dose to TLR9 agonism with PD-1 blockade for anti-PD-1 refractory Merkel of cavrotolimod, combined with the PD-1 in- cell carcinoma (MCC) and cutaneous squamous cell carcinoma hibitor pembrolizumab (MCC) or cemiplimab (cSCC). J Clin Oncol. 2020 May; 38(15_suppl):TPS3164. (cSCC).3 The first patient in the MCC cohort 4. Intratumoral cavrotolimod combined with pembrolizumab or cemiplimab in patients with Merkel cell carcinoma, cutaneous was dosed in June 2020. squamous cell carcinoma, or other advanced solid tumors. Clini- calTrials.gov identifier: NCT03684785. Updated January 12, 2021. The trial also will include exploratory cohorts Accessed March 5, 2021. https://www.clinicaltrials.gov/ct2/show/ to evaluate cavrotolimod administered in a NCT03684785 subcutaneous fashion, as well as given as an injection into liver metastases in combination DISCLOSURES with pembrolizumab in patients with locally Dr. Laux reports no relevant financial interests.

40 | The Dermatology Digest INTEGRATIVE MEDICINE AESTHETIC IV THERAPY

aesthetic iv: Bypassing the gut to get glowing

Deepa Verma, MD, with Eliza Cabana

Deepa Verma, MD Founder of Synergistiq Integrative Health, Clearwater, Florida

How to Increase Longevity with IV, Gut Health and Diet Based on her presentation at the American Academy of Anti-Aging Medicine Conference June 4-5, 2020, Dubai, UAE

ntegrative medicine specialist Deepa Verma, MD, demystifies IIV therapy and offers practical advice for adding it as an aesthetic treatment to the dermatology practice.

“We always think of beauty as things we do on the outside. But what we have to under- stand is it starts from within. I always address gut health. Doing IV therapy is a great way to give the skin a nice glow and to boost collagen and the growth of new cells,” said Deepa Verma, MD, founder of Synergistiq Integrative Health, Clearwater, Florida. Dr. Verma is board-certified in family and integrative medicine and has been using IV therapy in practice for 7 years. She presented “How to Increase Longevity with IV, Gut Health and Diet,” at A4M (American Academy of Anti-Aging Medicine) Dubai Watch! Dr. Verma talks add- UAE, June 4-5, 2020. ing IV therapy to your practice at www.thedermdigest.com/ More than mere aesthetics, IV therapy is used to address many health issues, from energy video_verma_IVaesthetics levels and immunity to cancer, skin conditions, and autoimmune disease, she said. Helping skin from within Probably the most well-known is the Myers’ Cocktail, a mix of IV vitamins and minerals initiated by John Myers, MD, in 1960s. The IV-infused cocktail includes magnesium,

May 2021 | 41 to feel the effects right away: energy, clarity. Your immunity is going to be boosted. That’s why IV therapy is so great.” Ingredients for aesthetic IV therapy It’s well known that inflammation is the root cause of many skin and dermatologic conditions. “We often label things as dermatitis. We have hyperpigmentation disorders. We have skin issues that are associated with certain disease processes—melasma, lupus, or an autoimmune condition, and general aging issues: crepiness of the skin, the fine lines, the wrinkles, the loss of collagen,” said Dr. Verma. “When I concoct these IVs I’m looking at the building blocks that we need to regain youthfulness and get elasticity back in the skin.” calcium, B12, B6, B5, B complex, and vitamin C. IV infusion allows for a higher concentra- Her most-used ingredients include vitamin C, tion of nutrients to directly enter and circulate glutathione, and alpha lipoic acid (ALA). throughout the body. “I always start with vitamin C. Vitamin C is “Let’s just think about it,” said Dr. Deepa. really my go-to for everything. Ascorbic acid “IV therapy is intravenous therapy. So we’re is very essential in boosting immunity and With IV therapy, bypassing the gut. This is the key. This is 100% also helps with your skin in terms of colla- we’re giving efficacy in terms of the availability of what gen. Zinc is also something that’s very, very anywhere from you’re administering. Whereas if you do some- important for the foundation of your skin,” 10 to 50 times the thing orally, you’re lucky if you get even 35% she said. “So ascorbic acid is always the base. “ to 50% because it has to go through your gut Glutathione is another one. Glutathione is a amount that we and everybody has gut issues. master antioxidant, and its precursor is NAC, can take orally. N-acetyl cysteine.” Bioavailability is “I use IV Myers’ for a lot of different things: large enough to migraines, alcohol hangovers, fibromyalgia, NAC, often associated with liver detox, is low energy, infections, colds, and more. used to treat acetaminophen poisoning. But get used properly So people recover more quickly than with it also replenishes glutathione. “As we age that and you’re going oral treatment. declines,” said Dr. Verma. “Also associated to feel the effects with aging are a decline in immunity, more They get a lot of energy. They feel good right right away.” propensity for chronic conditions, signs of away is because it’s going right into the veins, aging skin—it starts getting dull, crepey, thin. and it’s circulating throughout the body. To We can start seeing vessels depending on your put it in perspective, if someone’s feeling sick skin type.” and takes extra vitamin C orally, anything higher than 1 g to 3 g will affect the gut, lead- In many ethnic cultures, glutathione is often ing to diarrhea. With IV therapy, we’re giving used also for “lightening” the complexion. It anywhere from 10 to 50 times the amount won’t actually make the skin lighter, but it can that we can take orally. Bioavailability is large help to create a more even complexion and enough to get used properly and you’re going make skin glow. continued on page 44

42 | The Dermatology Digest COULD THE SKIN ACTUALLY BE LESION A DEADLY BLOOD YOU’RE SEEING... CANCER?

LOOK FOR SKIN LESIONS

BPDCN lesions can vary in size, shape, and color.1,2*

YOU PLAY A CRITICAL ROLE IN EARLY AND ACCURATE DIAGNOSIS OF BPDCN

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is Plasmacytoid dendritic cells an aggressive and deadly hematologic cancer with skin invade the dermis where they lesions that may be mistaken for other skin disorders.1,2 proliferate, resulting in skin lesions that take the form of 1-3,6: WHO ARE PATIENTS WITH BPDCN? • Nodular lesions • ~85% to 90% present with skin lesions 2-4 • Diffuse bruise-like macules • ~75% are men 2,5 • Typically between 60 to 70 years of age, but all ages can be affected 2,5

Research has uncovered key markers, including CD123, For more information, that allow for the proper diagnosis of BPDCN.6† visit BPDCNinfo.com.

WHEN BIOPSYING APPROPRIATE SKIN LESIONS, ASK YOUR PATHOLOGIST TO CONSIDER CD123.‡

*Left image republished with permission from Blood; right image reprinted by permission from Springer Nature: Modern Pathology, Neoplasms derived from plasmacytoid dendritic cells. Facchetti F. © 2016. †BPDCN diagnosis can include other markers, such as CD4, CD56, TCL1, and CD303 (BDCA2).7 ‡Skin lesions associated with BPDCN may include violaceous nodules, bruise-like patches, or disseminated and mixed lesions (macules and nodules).1,2 References: 1. Julia F, Petrella T, Beylot-Barry M, et al. Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients. Br J Dermatol. 2013;169(3):579-586. 2. Riaz W, Zhang L, Horna P, Sokol L. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control. 2014;21(4):279-289. 3. Sullivan JM, Rizzieri DA. Treatment of blastic plasmacytoid dendritic cell neoplasm. Hematology Am Soc Hematol Educ Program. 2016;2016(1):16-23. 4. Laribi K, Denizon N, Besançon A, et al. Blastic plasmacytoid dendritic cell neoplasm: from origin of the cell to targeted therapies. Biol Blood Marrow Transplant. 2016;22(8):1357-1367. 5. Pagano L, Valentini CG, Pulsoni A, et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica. 2013;98(2):239-246. 6. Facchetti F, Cigognetti M, Fisogni S, Rossi G, Lonardi S, Vermi W. Neoplasms derived from plasmacytoid dendritic cells. Mod Pathol. 2016;29(2):98-111. 7. Reichard KK. Blastic plasmacytoid dendritic cell neoplasm: how do you distinguish it from acute myeloid leukemia? Surg Pathol Clin. 2013;6(4):743-765.

Copyright 2019 - Stemline Therapeutics, Inc. All rights reserved. 1/2019 US-NON-1800016 continued from page 42 IV ELEMENTS

 Vitamin C

 Zinc

 Iron

 Glutathione

 Alpha lipoic acid (ALA)

 N-acetyl cysteine (NAC)

 Magnesium

 Calcium

 B12, B6, B5, B complex

 Nicotinamide adenine dinucleotide (NAD)

THE KEY 3 ALA helps to reduce inflammation. “So if I like to use,” she said. someone is suffering from rosacea or eczema In terms of chair time, the more common IV IV therapy or psoriasis, I like to use ALA,” said Dr. Verma. therapies, including Myers’ cocktail, vitamin addresses energy “I also use amino acids. As we know those C, iron, and ALA, generally take from 45 to and other health are the building blocks—the protein building 60 minutes. issues as well as blocks. And that’s very important as well in skin aesthetics the foundation of skin integrity.” IV therapies with NAD (nicotinamide adenine dinucleotide), used for anti-aging, addiction, IV therapy treatment protocols and depression, can take up to 90 minutes. This alternative “There are no cookie-cutter protocols. Those for chelation or heart health can take to the oral route Everyone’s going to be different. I really have 2 to 3 hours.  delivers vitamins to assess them: look at where they are in their and minerals life, what medical conditions they may have, immediately and REFERENCES and what their lifestyle is,” said Dr. Verma. Gaby AR. Intravenous nutrient therapy: the “Myers’ cocktail”. effectively Altern For aesthetic treatment, if someone is looking Med Rev. 2002 Oct;7(5):389-403. PMID: 12410623. Ogston-Tuck S. Intravenous therapy: guidance on devices, manage- for fresher skin with a nice glow, Dr. Verma In certain patients ment and care. Br J Community Nurs. 2012 Oct;17(10):474, 476-9, may recommend laser and/or RF micro- 482-4. doi: 10.12968/bjcn.2012.17.10.474. PMID: 23124374. it may be prudent needling treatment followed by IV therapy Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley to consider a to help with healing. RA, Levine M. Vitamin C pharmacokinetics: implications for oral and suitable treatment intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. doi: alternative, such as In general, the protocol would be a 1-2 IV 10.7326/0003-4819-140-7-200404060-00010. PMID: 15068981. a systemic therapy sessions per week of 10 g to 15 g vitamin C Jamali M, Majid A. Intravenous glutathione for fair skin; to give or not to give? J Pak Med Assoc. 2017 Jul;67(7):1127. PMID: 28770905. or a steroid-sparing plus 2 g to 4 g glutathione for at least 6 weeks. topical drug “I customize it. It depends on their avail- DISCLOSURES ability, but that’s the typical protocol that Dr. Verma reports no relevant financial interests.

44 | The Dermatology Digest LITERATURE UPDATE TOPICAL CORTICOSTEROIDS

Topical corticosteroids and the risk of osteoporosis, fractures

Alexander Egeberg, MD, PhD, with Bob Kronemyer

opical corticosteroids (TCSs) are some of the most frequently used drugs Tfor skin diseases worldwide. While these agents are generally considered ALEXANDER safe, they are often prescribed with little thought about the dosage or duration. EGEBERG, MD, PhD Dermato-epidemiologist, Department of Dermatology Systemic and inhaled corticosteroids From clinical experience, my colleagues and Allergy, Herlev and negatively impact bone remodeling and and I have observed patients who develop Gentofte Hospital cause osteoporosis and bone fracture when a cushingoid appearance or individuals University of Copenhagen prescribed continuously or in high doses. with diabetes who end up with dysregulated Hellerup, Denmark However, risk of osteoporosis and a major blood sugar following use of potent TCSs osteoporotic fracture after application of on large body surface areas. TCSs is largely unexplored.

May 2021 | 45 www.thedermdigest.com/LITERATURE_UPDATE

Upon scrutinizing the published literature, we During this span of 15 years, 25.8% of patients observed a noticeable data gap about the safety were categorized as exposed to 500 g to 999 g of these therapies. Also, when we contacted of mometasone or equivalent; 15.4% to 1000 g the manufacturers of the drugs, we were sur- to 1999 g; 13.0% to 2000 g to 9999 g; and 1.9% prised to learn that most of them had no data to at least 10,000 g. on the systemic effects of these medications. The study found dose-response associations Because these drugs are used by millions between increased use of a potent or a very of people, even a small risk is important from potent TCS and the risk of osteoporosis and a public health perspective. We therefore a major osteoporotic fracture. decided to undertake a study to assess the For example, each time the amount of TCSs potential for systemic effects of TCSs. doubles—for example, from 100 g to 200 g The Danish study or from 400 g to 800 g—the relative risk of The nationwide retrospective Danish study osteoporosis increases by 3%. gleaned data from the Danish National Patient The study concluded that the hazard ratios Registry, which contains patient information (HRs) of a major osteoporotic fracture from all inpatient and outpatient visits at all were 1.01 for exposure to 500 g to 999 g of 1 Danish hospitals and a number of private clinics. mometasone or equivalent; 1.05 for exposure The study analyzed a total of 723,251 adults, to 1000 g to 1999 g; 1.10 for exposure to 2000 g 52.8% women and 47.2% men, all aged 18 and to 9999 g; and 1.27 for exposure to at least older, who were alive and residents of Den- 10,000 g (see Figure). The study found mark from 2003 to 2017. During the study Moreover, our results showed that 4.3% of all period, they all filled prescriptions of at least dose-response cases of osteoporosis are due to TCSs. Howev- 200 g of mometasone furoate (1 mg/g) or the er, it is very important to emphasize that the associations equivalent amount in equipotent doses of absolute risk to the individual patient (in other “between other potent or very potent TCSs. increased use of a potent or a very potent TCS and the risk of osteoporosis and a major osteoporotic fracture.”

46 | The Dermatology Digest www.thedermdigest.com/LITERATURE_UPDATE

Figure courtesy of Alexander Egeberg, MD, PhD words, the average topical corticosteroid user) son-years for 500 g to 999 g; 100.6 cases per is still very low. 10,000 person-years for 1000 g to 1999 g; 113.1 cases per 10,000 person-years for 2000 g For a major osteoporotic fracture, 2.7% of all to 9999 g; and 122.2 cases per 10,000 per- fractures were attributable to TCS use. son-years for at least 10,000 g. The lowest exposure needed for one additional The incidence rate of osteoporosis among patient to develop a major osteoporotic frac- patients treated with the equivalent of 200 g ture in 454 person-years was an exposure of to 499 g of mometasone was 36.7 new cases at least 10,000 g of mometasone or equivalent, per 10,000 person-years; 43.1 cases per 10,000 which is 2 to 3 times higher than what is seen person-years for 500 g to 999 g; 50.2 cases per with oral corticosteroids. 10,000 person-years for 1000 g to 1999 g; 55.2 The specific incidence rates for a major cases per 10,000 person-years for 2000 g to osteoporotic fracture were 81.6 new cases 9999 g; and 58.7 cases per 10,000 person-years per 10,000 person-years for 200 g to 499 g for at least 10,000 g. of mometasone; 88.7 cases per 10,000 per-

May 2021 | 47 www.thedermdigest.com/LITERATURE_UPDATE

Our results confirm what we have treatment alternative, such as probably long suspected, but never THE KEY 3 a systemic therapy or a steroid- had any data on: that there may be sparing topical drug. Because these clinically relevant systemic effects drugs are used by In some cases, alternative pharma- of TCSs in large quantities. millions of people, ceutical therapies exist. If not, it The most The outcomes also remained even a small risk might be worth recommending important consistent across a wide range is important from oral prophylaxis with calcium takeaway from of sensitivity analyses and after a public health and vitamin D for these patients, “the study is adjusting for potential confound- perspective. and considering a DXA scan in that the risk ing factors. Women younger than some instances. 50, though, had slightly higher The study found One limitation of the study is that to the average risk estimates linked to TCS than dose-response we lacked weight and smoking sta- user of TCSs did older women. associations between tus for patients, yet we found com- is extremely increased use of Study takeaways a potent or a very parable estimates among patients low.” The most important takeaway potent TCS and the with and without psoriasis, which from the study is that the risk risk of osteoporosis is a condition strongly linked to to the average user of TCSs is and a major obesity and smoking. extremely low. However, our osteoporotic fracture. Surveillance bias is also a concern study demonstrates that there with observational register-based There may be are indeed systemic effects when studies, but when analyzing our clinically relevant using these drugs. We used a very data we did not find evidence systemic effects hard-to-achieve endpoint in our of surveillance bias. Furthermore, of TCSs in large study, but other effects, such as our endpoint of major osteoporotic quantities. the potential for dysregulated fracture is unlikely to be affected by diabetes, is something that we surveillance because it is consid- may need to be aware of when ered a very “hard endpoint.” prescribing these therapies. TCSs are rightfully here to stay; however, In some cases, the risk of bone disease for a as more and more novel treatment alternatives specific total cumulative topical steroid dose become available, it will be interesting may be greater than the benefit of continuing to see data on whether use of these novel topical therapy. treatment options can lead to a more modest As dermatologists, we do not prescribe these use of TCSs, such as in patients with severe drugs for fun, but rather we prescribe them atopic dermatitis.  to patients who need an effective therapy. As such, there is no specific threshold for “too REFERENCE much TCS use,” and TCSs remain a valuable 1. Egeberg A, Schwarz P, Harslof T, e al. Association of potent and tool for all dermatologists. However, in patients very potent topical corticosteroids and the risk of osteoporosis and major osteoporotic fractures. JAMA Dermatol. 2021;157(3):275-282. who have used vast amounts of potent TCSs doi:10.1001/jamadermatol.2020.4968 on large body surface areas or for prolonged

periods, such as for skin diseases including DISCLOSURES atopic dermatitis and psoriasis, it may be Dr. Egeberg reports no relevant financial interests. prudent to consider whether there is a suitable

48 | The Dermatology Digest MAUI DERM IS THE NAME IN DERMATOLOGY CME The world is changing and so are we! Maui Derm meetings are evolving to provide exciting options for both virtual and on-site learning.

Whether you prefer to earn your CME Credits remotely or at an inspiring location, we will continue to bring you our cutting-edge, dermatology-focused curriculum combining a great blend of science and clinical medicine taught by our world-class faculty. Visit MauiDerm.com for more information about upcoming events.

2 ways to attend Maui Derm NP+PA Summer 2021! Registration is now open. JUNE 23-26, 2021 Live In-Person at Broadmoor Hotel Colorado Springs, CO Includes Pre-Conferene Day on June 23, 2021

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For meeting information and registration, please visit THE ACKNOWLEDGED LEADER IN DERMATOLOGY CME FOR OVER 18 YEARS. MauiDerm.com DIAGNOSE THIS ZEBRA A DIFFERENTIAL DIAGNOSIS CASE A bullous eruption in a middle-aged man

Matthew J. Zirwas, MD, with Cheryl Guttman Krader

Matthew J. Zirwas, MD Director, Ohio Contact Dermatitis Center Columbus, Ohio Member, North American Contact Dermatitis Group

Presented at Maui Derm Connect 2021

CASE HISTORY A 40-year-old white man presented with a 2-week history of widespread blisters. Clinical examination showed tense, subepidermal-appearing bullae on mildly erythematous bases (Figure 1). Palms, soles, scalp, and mucous membranes were all spared. On history, the patient reported having ulcerative colitis for which he had been taking a 5-aminosalicylic acid (5-ASA) medication, mesalamine, for at least 5 years. He was not on any other medications and reported that he felt generally well. A biopsy was taken for evaluation with hematoxylin and eosin (H&E) staining and direct immunofluorescence (DIF). Pending the histopathology results, treatment was initiated with oral prednisone. After the patient had been on prednisone at 40 mg/day for 14 days his eruption was unchanged. The pathology report was received and showed eosinophils, subepidermal blistering, and lymphocytes on H&E. The DIF revealed dense granular and linear C3 and IgG deposition along the basement membrane (Figure 2) and faint deposits of C3 in the basal cell cytoplasm. The pathologist’s interpretation was “pemphigoid-like pattern, suggestive of drug-related etiology.”

50 | The Dermatology Digest www.thedermdigest.com/DIAGNOSE_THIS_ZEBRA

Figure 1. Widespread, tense bullae on mildly erythematous bases.

How would you approach further investigation in this case, considering that the patient reported being on a single medication for the last 5 years?

Figure 2. Direct immunofluorescence shows strong basement membrane and weak cytoplasmic IgG deposition. (Images courtesy of Matthew J. Zirwas, MD)

For more on this case, turn to page 55 

May 2021 | 51 Updating dermatologists on treatments, vaccine COVID CONCERNS developments, and the outlook for the next 6 months

Immunosuppression does not hinder COVID-19 outcomes

Kayte Andersen, MSc, and G. Caleb Alexander, MD, MS, with John Jesitus

ccording to a recent study, clinical outcomes for chronically Aimmunosuppressed patients hospitalized with COVID-19 mirror those of non-immunosuppressed peers. The analysis included immunosuppressive medications commonly used in dermatology.

KAYTE ANDERSEN, MSC When the COVID-19 pandemic began, said Conversely, some observers theorized that Doctoral candidate, first author Kayte Andersen, MSc, it was immunosuppressed people might experience Johns Hopkins Bloomberg uncertain whether infected people who were better outcomes because immunosuppressive School of Public Health, chronically immunosuppressed would fare medications would prevent their immune Baltimore, Maryland worse because immunosuppressed people systems from going into overdrive, which can are more likely to contract viral infections in complicate COVID-19. “There were arguments general. Ms. Andersen is a doctoral candi- in either direction,” said Andersen, “and given date in the Johns Hopkins Bloomberg School how many people need a chronic immuno- of Public Health in Baltimore, Maryland. suppressive medicine to manage an important

52 | The Dermatology Digest www.thedermdigest.com/COVID_CONCERNS

health condition, we thought it was a good Unadjusted regression analyses and inverse question to follow up.” probability of treatment weighting (IPTW) showed no significant differences in use of Study findings mechanical ventilation, likelihood of in-hospi- To that end, Andersen and colleagues retro- tal death, and length of stay by immune status. spectively analyzed medical records of 2121 Restricting the analysis to patients with at least consecutively treated adults hospitalized with one health-system encounter before COVID-19 confirmed or suspected COVID-19 who were hospitalization (to eliminate possible misclassi- admitted to one of 5 hospitals contributing to fication of patients without pre-hospitalization the Johns Hopkins COVID Precision Medicine data) showed similar results. Analytics Platform Registry (JH-CROWN) Once these 1 “These findings are important because of the registry through August 2020. Using a World people are Health Organization definition, researchers magnitude of continuing morbidity and mortal- hospitalized, categorized patients as immunosuppressed ity attributable to the pandemic,” investigators if they had current prescriptions for im- write, “as well as the frequent use of immuno- “do they need munosuppressive drugs—namely, selective suppressive medications for the management to go on to a immunosuppressants, antineoplastic agents, of a range of chronic conditions.” ventilator, stay or prednisone greater than 7.5 mg daily or When investigators limited their analysis to in the hospital equivalent—on the date of COVID-19 hospi- patients on more than 10 mg prednisone daily, longer, or are talization. Altogether, 108 patients (5% of the the only difference between the 2 groups was they more likely sample) met immunosuppression criteria. that immunosuppressed patients were dis- to die? We After controlling for a host of potential con- charged sooner (HR 0.72, 95% CI 0.60-0.85). found none Additionally, immunosuppressed patients had founders reflecting patients’ baseline health and of those.” sociodemographic status, investigators found a significantly shorter length of stay (HR 0.75, no significant differences between immuno- 95% CI 0.66-0.86) in analyses that defined compromised and immunocompetent patients immunosuppression in terms of diagnoses and/ in terms of survival (88% vs 91%, respectively, or medication use. It is unclear whether this P = 0.28), length of hospital stay (6.9 vs 5.1 difference was clinically significant, Andersen days, P = 0.09), or need for mechanical ventila- said, because the study was not designed to tion (16% vs 15%, P = 0.75). explore the impact of diagnoses. “Adding diagnoses added a lot more people into our “There’s no indication that people who need ‘immunosuppression’ definition (n = 232 or an immunosuppressive medication for another 11% of the sample),” she added, “so this may diagnosed condition should stop the medicine be a reflection of increased sample size.” because they’re worried about severe COVID,” Andersen said. “Once these people are hospi- Further applications talized, do they need to go on to a ventilator, The study included immunosuppressants stay in the hospital longer, or are they more frequently used in dermatology, including likely to die? We found none of those.” biologics, methotrexate, and cyclosporine, Andersen said. “We also considered chemo- Median time to ventilation was slightly longer therapy and medicines for solid organ trans- for immunocompromised patients (3.0 days plantation.” However, she said that because of vs 2.6 days, P = 0.02). But with a small, the study’s limited sample size, investigators immunosuppressed cohort and a between- were unable to separate out medicines specific group difference of around 10 hours, she said, to dermatology or any other specialties. “But investigators did not consider this difference that’s something we’re doing now, using a na- clinically meaningful.

May 2021 | 53 www.thedermdigest.com/COVID_CONCERNS

tional data set with hundreds of thousands of authors are unaware of whether such protocols hospitalized COVID patients.” This study will were differentially applied to immunosup- include Johns Hopkins among a total pressed patients. of approximately 40 healthcare systems. Other groups worldwide have investigated “It’s a very diverse, rich sample, with people the relationship between immunosuppression of different ages, geographic regions, races, and COVID-19 outcomes and found similar and ethnicities.” Investigators were completing results.2-4 “It’s reassuring that we’re all seeming data analysis in early April, and she said that to find that immunosuppression doesn’t neces- the team hopes this study will be published sarily make people do any worse once they are It’s reassuring this spring or summer. hospitalized,” Andersen said. that we’re all Strengths of the present study include its Senior author G. Caleb Alexander, MD, MS, seeming to find examination of real-world experience in a added that the study was not designed to that immuno­ large cohort of patients hospitalized with examine whether chronic immunosuppression “ COVID-19 in the geographic region served by facilitates SARS-CoV-2 infection in the first suppression Johns Hopkins hospitals. Additional strengths place. “Further work is needed to examine doesn’t necessarily include the comprehensiveness of the JH- this important scientific and clinical question.” make people CROWN registry and the electronic medical Dr. Alexander is a founding co-director of the do any worse records stored therein. Johns Hopkins Center for Drug Safety and Effectiveness and professor in the Department once they are Investigators moreover used a variety of of Epidemiology at Johns Hopkins Bloomberg hospitalized.” methods to maximize causal inference by School of Public Health. The study appeared eliminating patients who were not at risk of online January 7 in Clinical Infectious Diseases. the primary outcome—mechanical ventilation.

The study protocol excluded patients who were REFERENCES ventilated on admission or had advance direc- 1. Andersen KM, Mehta HB, Palamuttam N, et al. Association between tives placed within 24 hours of admission. chronic use of immunosuppresive drugs and clinical outcomes from coronavirus disease 2019 (COVID-19) hospitalization: a retrospective Furthermore, investigators used stabilized cohort study in a large US health system [published online ahead of IPTW with doubly robust adjustment and ac- print, 2021 Jan 7]. Clin Infect Dis. 2021;ciaa1488. doi:10.1093/cid/ ciaa1488 counted for the competing risk of death where 2. Colmenero J, Rodríguez-Perálvarez M, Salcedo M, et al. death was not the primary outcome, Andersen Epidemiological pattern, incidence, and outcomes of COVID-19 said. “Once we applied state-of-the-art statis- in liver transplant patients. J Hepatol. 2021;74(1):148-155. tical and epidemiological principles, we didn’t 3. Sanchez-Piedra C, Diaz-Torne C, Manero J, et al. Clinical features find any difference. We believe that we did the and outcomes of COVID-19 in patients with rheumatic diseases treated with biological and synthetic targeted therapies. Ann Rheum best job we possibly could to provide appro- Dis. 2020;79(7):988-990. priate analysis.” 4. Cavagna L, Bruno R, Zanframundo G, et al. Clinical presentation and evolution of COVID-19 in immunosuppressed patients: preliminary Study limitations include the fact that investi- evaluation in a North Italian cohort on calcineurin-inhibitors based gators characterized a limited set of short-term therapy. medRxiv. Posted online 2020 May 1 (preprint) https://www. outcomes. Andersen and colleagues therefore medrxiv.org/content/10.1101/2020.04.26.20080663v1. recommend further research into the associ- DISCLOSURES ation between chronic immunosuppression Ms. Andersen reports no relevant financial interests. and longer-term COVID-19 morbidity and Dr. Alexander has been a paid advisor to IQVIA and is a consultant mortality. Additionally, performing the study and equity holder in Monument Analytics, a consultancy whose during a period of rapidly changing clinical clients include the life sciences industry and plaintiffs in opioid protocols may have impacted results, although litigation. He is also a member of the OptumRx National Pharmacy & Therapeutics Committee.

54 | The Dermatology Digest www.thedermdigest.com/DIAGNOSE_THIS_ZEBRA

continued from page 51 A BULLOUS ERUPTION IN A MIDDLE-AGED MAN

DISCUSSION

As reviewed in a published article presenting of his eruption, considering that he had been this case, the clinical appearance of the on the medication for several years. patient’s skin eruption raised suspicion of Because patients may fail to mention OTC bullous pemphigoid (BP).1 Idiopathic BP products, herbal supplements, or illicit drugs typically develops in older adults (aged > 70 when queried about medication use, a more years).2 However, an independent association detailed history was pursued with the patient, between ulcerative colitis and BP has been asking specifically about oral or topical use of reported, and in one study, the association was nonprescription agents and about any recent seen especially in patients aged < 50 years.2-4 dietary changes that might suggest potential As noted by the pathologist’s report, a subepi- exposure to a new preservative. The patient dermal blistering eruption can also develop as denied using any other drugs or making an adverse reaction to a prescription or OTC changes in his diet. medication. Lesions of drug-related BP appear Upon further questioning about his use of clinically similar or identical to those seen in mesalamine, the patient revealed that he had idiopathic BP, and the 2 disorders also have overlapping histological features.5 Authors of a recent systematic review of drug-associated BP identified 89 drugs that had been implicated in The patient said that for his most drug-related BP. Mesalamine was included in recent refill, he switched from the list, although its association with BP was using a brand-name product to a categorized as “uncertain,” and its use by this patient was not initially suspected as the cause less expensive generic mesalamine.

May 2021 | 55 www.thedermdigest.com/DIAGNOSE_THIS_ZEBRA

been ordering the medication online from a Medications that are approved by regulatory Canadian pharmacy as a cost-saving measure. agencies in other countries can differ in their Then he mentioned that for his most recent refill, he switched from using a brand-name formulation characteristics with consequences product (Asacol), which is approved by both for efficacy and/or safety. the FDA and Health Canada, to a less expensive generic mesalamine. The patient reported that he had begun taking the generic medication As illustrated by this case, however, ordering just a few weeks before he developed the through legitimate pharmacies also poses blistering eruption. potential risks. The manufacturers of the generic and brand Medications that are approved by regulatory name products were contacted to obtain details agencies in other countries can differ in their about the formulations. Upon reviewing the formulation characteristics, with consequenc- information, it was hypothesized that the es for efficacy and/or safety. Even in the US, generic product, which had a different release changing from a brand-name product to a profile, triggered the patient’s skin reaction. generic version of the same medication or Oral mesalamine products are formulated between generic versions can result in adverse with the aim of delivering the active drug reactions because generic products can be man- to the colon while minimizing systemic ufactured with different inactive ingredients. absorption. The brand-name product is Therefore, a thorough medication history that formulated with an enteric coating that is probes for a possible product switch is always designed to dissolve at a pH of ≥ 7 so that important when puzzled by a case involving a the active ingredient is not released before suspected drug-induced skin reaction.  the tablet reaches the terminal ileum.6 The generic tablet, which was not approved by REFERENCES the US Food and Drug Administration and 1. Ferris LK, Jukic D, English JC III, Zirwas MJ. Drug-induced bullous pemphigoid caused by a generic Canadian medication obtained over not available in the United States, releases the internet. Arch Dermatol. 2005;141(11):1474-1476. 80% of the active ingredient at a pH of 2. Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepidermal auto- ≤ 6, thereby allowing systemic absorption immune blistering dermatoses: Clinical features and diagnosis. J Am of mesalamine through the stomach and Acad Dermatol. 2021; Mar 5:S0190-9622(21)00475-8. doi:10.1016/j. jaad.2020.11.076. Epub ahead of print. small intestine.7 3. Chen YJ, Juan CK, Chang YT, et al. Association between inflammatory bowel disease and bullous pemphigoid: a population-based case-con- The patient was told to stop the generic 5-ASA. trol study. Sci Rep. 2020;10(1):12727. He restarted the brand-name 5-ASA product, 4. Narla S, Silverberg JI. Associations of pemphigus or pemphigoid with and began a rapid taper to discontinue the autoimmune disorders in US adult inpatients. J Am Acad Dermatol. prednisone. His bullous eruption resolved 2020;82(3):586-595. spontaneously within a few weeks and he had 5. Verheyden MJ, Bilgic A, Murrell DF. A systematic review of drug-induced pemphigoid. Acta Derm Venereol. 2020 Aug no recurrences during 8 months of available 17;100(15):adv00224. follow-up. 6. Asacol. Package insert. Allergan; 2020. This case serves as a reminder about the 7. Sauriol C, Comtois F. Relative in vitro dissolution profiles of Salofalk, Asacol, and Pentasa 5-ASA tablets: proceedings of the 5th Falk potential risks associated with obtaining Symposium. In: Williams CN, ed. Trends in Inflammatory Bowel Disease medications online from unverified sources Therapy. Dordrecht. The Netherlands: Kluwer Academic Publishers; or foreign pharmacies. Much of the concern 1991;441-442. relates to dealings with fake pharmacies DISCLOSURES distributing “medications” that are counterfeit, Dr. Zirwas reports no relevant financial interests. expired, or substandard in some other way.

56 | The Dermatology Digest GRAND HYATT • NASHVILLE, TN AUGUST 18 -22, 2021

Michael H. Gold, MD MuPresentedsic by TSLMS City

Symposium for CosmeticAdvances & Laser Education

16TH ANNUAL MEETING Brian S. Biesman, MD DR. BIESMAN AND DR. GOLD WELCOME YOU BACK TO LIVE SCALE MEETINGS IN NASHVILLE IN AUGUST!! Music City SCALE, the Premier Meeting in Cosmetic and Medical Dermatology, is ready to welcome everyone back for its 16th Annual Meeting, from August 18-22, 2021 in Nashville, Tennessee. It has surely been a most challenging past year and we hope that everyone is safe, healthy, and either vaccinated or close to being vaccinated. The SCALE team has been busy planning for the 2021 edition of SCALE and we welcome everyone to our new home, the brand new Grand Hyatt Hotel, perfectly located in the heart of Downtown Nashville. The Grand Hyatt is one of the newest, most sophisticated hotels in Music City, with a prime location within walking distance of the Lower Broadway entertainment district, the newly developed Upper Broadway entertainment district, as well as the Gulch and our Midtown areas. The Music City SCALE meeting brings some of the finest faculty to the meeting and vendors from all walks of both medical and cosmetic dermatology to the meeting. Our attendees are physicians, clinicians, and staff interested in learning the latest trends in Aesthetic Medicine as well as the most up-to-date information on medical dermatology diseases, diagnoses, and therapeutics. We offer wonderful product theaters compliments of our industry sponsors and special workshops designed to enhance your learning experiences. At SCALE wE wiLL AddrESS topiCS thAt ArE bESt for you And your prACtiCE. SCALE 2021 WILL BE LIVE AND PRESENTED VIRTUALLY FOR THOSE WHO CHOOSE NOT TO OR WHO ARE UNABLE TO TRAVEL

The Music City SCALE meeting brings some of the finest faculty to the meeting and vendors from all walks of both medical and cosmetic dermatology to the meeting. Our attendees are physicians, clinicians, and staff interested in learning the latest trends in Aesthetic Medicine as well as the most up-to-date information on medical dermatology diseases, diagnoses, and therapeutics. We offer wonderful product theaters compliments of our industry sponsors and special workshops designed to enhance your learning experiences. CME CREDITS WILL BE AVAILABLE TO MEDICAL PRACTITIONERS! Music City SCALE LASERS 101 with Cadaver Workshop Pre-registration is required. Patrick Clark, PhD, CMLSO Pre-registration is required. August 18, 2021 August 18, 2021 REGISTER AT WWW.SCALEMUSICCITY.COM! EARLY BIRD SPECIAL IF SIGNED UP BEFORE JUNE 30,2021

SCALE we are live 2021 DIGEST.indd 2 3/31/21 10:07 AM Understanding of a key pathway in AD is emerging1,2 AD is a chronic inflammatory skin disease caused by the dysregulation of cytokines and other immune mediators. However, there is more to understand when it comes to a pathway key to mediating this response—the JAK-STAT pathway. Gain insight into why the JAK-STAT pathway is a critical target in the pathogenesis of AD, including1,2 • How the dysregulation of the JAK-STAT pathway helps perpetuate AD • Which key JAK-mediated cytokines depend on this pathway to promote itch, inflammation, and skin barrier dysfunction in AD

Learn why the JAK-STAT pathway is critical to our understanding of AD1

JAK=Janus kinase; JAK-STAT=Janus kinase-signal transducer and activator of transcription. References: 1. Bao L, Zhang H, Chan LS. JAK-STAT. 2013;2(3):e24137. doi:10.4161/jkst.24137. 2. Howell MD, Kuo FI, Smith PA. Front Immunol. 2019;10:2342. doi:10.3389/fimmu.2019.02342.

Learn more at ThinkYouKnowJAK.com

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