vol. 1, no. 1 | december 2020 therapeutic approaches you’ve … · 2020. 12. 3. · mark...

Therapeutic approaches you’ve never heard of but will use next week

INSIDE:Integrative MedicineEvidence of effectiveness builds

Pediatric AcneNew products improve success rates

Surgical CornerCarcinoma and an orphan disease

E D U C AT I O N A L • I N T E R A C T I V E • A U T H O R I TAT I V E

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THE

Vol. 1, No. 1 | December 2020

THE D

ERMATOLOGY D

IGEST VOLUM

E 1, NUM

BER 1 D

ECEMBER 2020

PREMIERE

ISSUE

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December 2020 | 1

ContentsVolume 1, Number 1 | December 2020

22 Surgical Corner

A rare but deadly combination:

squamous cell carcinoma and

hidradenitis suppurativa

20 Literature Update

Options for stage III melanoma continue to evolve as a result

of study data


THE

26

Cover Story

2 Ted Talks

Welcome to The Dermatology Digest from the Editor-in-Chief

8 Literature Lessons

Research updates in pediatric dermatology, infectious diseases,

rheumatologic disease, psoriasis, cosmetic

dermatology, rosacea, contact dermatology,

and general dermatology

Bright ideas that will change your practice, natural treatments that patients love, and innovative

solutions for itch

continued on page 3

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2 | The Dermatology Digest

It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.

—attributed to Charles Darwin

Welcome to the premiere issue of The Dermatology Digest! I am honored to have been asked to serve as this publication’s Editor-in-Chief. Although I am certainly not a mind reader, I know what you’re thinking right now: Why, oh why, should there be yet another magazine

dedicated to the field of dermatology? Am I right? So let me answer that question up front.

The rationale for any new publication should be to fill a gap, to answer a need, for a community. In this case, The Dermatology Digest is for those who provide medical, surgical, and cosmetic care to patients with skin, hair, and nail diseases and disorders. New information on dermatological issues is constantly being generated. This includes, but is not limited to: scholarly journal articles, presentations at continuing medical education conferences, FDA bulletins, and pharmaceutical releases. It is virtually impossible for any one of us to stay abreast of this deluge of information. The Dermatology Digest will assist you, the clinician, in remaining aware of new developments in our field.

Moreover, we recognize that medical personnel all have a limited amount of time to spend on professional endeavors. All of us do deserve some personal time! The Dermatology Digest, as the name implies, is dedicated to “digesting” the most important new information and presenting it to you in a concise format that should take a small amount of your precious free time to absorb. We are also a comprehensive publication in that each offering will have something of both interest to and relevance for every reader. We are furthermore committed to providing newsworthy information in multiple channels, because all of us have our own favorite ways of learning. Ultimately, we will produce a regular print magazine (you are holding the first edition in your hands!), a website with videos, an electronic bulletin, and periodic timely podcasts. We are also planning some surprises.

Who is the “we” I keep referring to? Take a moment to check out, on the next page, the list of contributors to The Dermatology Digest. I am quite proud that so many thought leaders, innovators, and educators have agreed to help support this publication. This is not intended to be a static list. We will expand it as needed to keep fresh ideas and novel viewpoints flowing from our editorial contributors to you, our readers.

Finally, we are devoted to making The Dermatology Digest fun. Yes, we want you to look forward to receiving our messages. From an eye-catching design and world-class writing to clearly highlighted practical pearls, we want this suite of products to be the one you trust and rely on. We are neither supplanting traditional journals nor replacing essential CME meetings. Instead, our mission is to augment and enhance the dissemination of pragmatic information, ultimately benefiting the patients we all serve.

Did you enjoy our first issue? Do you have comments about our goals? Do you have suggestions? We aim to be responsive to your needs. I invite you to tell me what you think. Feel free to contact me directly at [email protected].

Ted Rosen, MD, FAADEditor-in-Chief

Ted Talks

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42 Voices & Viewpoints

Dermatology’s threats and opportunities, according to two leaders in the specialty

49 New Drugs

Clascoterone, a first-in-class hormonal-targeted therapy, shows great promise in acne treatment

C3 Diagnose this Zebra

A patient presents with unusual

symptoms. Can you make the diagnosis?

54 Pediatrics

Six new acne products add to the armamentarium in the acne treatment arsenal

Contents continued

37 Crystal Ball

Integrative medicine is gaining a foothold in the practice of dermatology

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EDITOR-IN-CHIEF

TED ROSEN, MDHouston, Texas

ASSOCIATE EDITORS

BRIAN BERMAN, MD, PHDMiami, Florida

JOEL COHEN, MDGreenwood Village, Colorado

SEEMAL DESAI, MDPlano, Texas

SHEILA FRIEDLANDER, MDSan Diego, California

DAVID OZOG, MDDetroit, Michigan

MATT ZIRWAS, MDColumbus, Ohio

EDITORIAL BOARD

HILARY BALDWIN, MDNew York, New York

VALERIE CALLENDER, MDGlenn Dale, Maryland

LARRY EICHENFIELD, MDSan Diego, California

WHITNEY HIGH, MD, JDAurora, Colorado

SUZANNE KILMER, MDSacramento, California

BRUCE STROBER, MD, PHDCromwell, Connecticut

JIM TREAT, MDPhiladelphia, Pennsylvania

CONTRIBUTING EDITORS

LUCIA DIAZ, MDAustin, Texas

HAYES GLADSTONE, MDSan Ramon, California

MICHAEL GOLD, MDNashville, Tennessee

MITCHEL GOLDMAN, MDMiami Beach, Florida

ADITYA GUPTA, MD, PHDToronto, Canada

RAJANI KATTA, MDBellaire, Texas

MARK KAUFMANN, MDNew York, New York

ARTHUR KAVANAUGH, MDSan Diego, California

ROB KIRSNER, MD, PHDMiami, Florida

HENRY LIM, MDDetroit, Michigan

NATASHA MESINKOVSKA, MDIrvine, California

DANIEL SIEGEL, MDNew York, New York

LINDA STEIN GOLD, MDDetroit, Michigan

SANDY TSAO, MD Boston, Massachusetts

STEPHEN TYRING, MD, PHDHouston, Texas

GUY WEBSTER, MD, PHDPhiladelphia, Pennsylvania

CONTRIBUTORS

NEAL BHATIA, MDSan Diego, California

CHERYL BURGESS, MDWashington, DC

SUNEEL CHILUKURI, MDHouston, Texas

RISA GOLDMAN-LUSKABurbank, California

RAEGAN HUNT, MDHouston, Texas

NEIL KORMAN, MD, PHDCleveland, Ohio

DAVID LAUB, MDMill Valley, California

GEORGE MARTIN, MDKihei, Hawaii

WENDY ROBERTS, MDRancho Mirage, California

REENA RUPANI, MDNew York, New York

JONATHAN SILVERBERG, MDWashington, DC

PUBLISHING & SALES

AMY AMMON Executive Director, Publisher [email protected]

DON BERMAN Executive Director, Digital [email protected]

GEORGE MARTIN, MDExecutive Director

EDITORIAL

TERESA MCNULTYManaging Editor

SUSAN C. OLMSTEADEditor

NANCY BITTEKERCreative Director

MICHAEL WESTFALL

Product Manager

EDITORIAL BOARD

THE


Print Circulation: 13,500 dermatologists USA 2,800 dermatological NP/PA’s

The Dermatology Digest ® is published monthly by The Dermatology Digest, LLC, 88 N Main Street, Pearl River, NY 10965.

© 2020 The Dermatology Digest, LLC. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/educational or personal use of specific clients is granted by The Dermatology Digest, LLC. For uses beyond those listed above, please direct your written request to Amy Ammon, Executive Director, Publisher at: [email protected].

POSTMASTER: Please send address changes to The Dermatology Digest LLC, 88 N Main Street, Pearl River, NY 10965. Printed in the U.S.A.

The Dermatology Digest ® does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take any responsibility for any losses or other damages incurred by readers in reliance on such content.

The Dermatology Digest ® welcomes unsolicited articles, manuscripts, photographs, illustrations and other materials, but cannot be held responsible for their safekeeping or return

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Options for regional melanomaBy Mary Beth Nierengarten Reviewed by Reinhard Dummer, MD, and Dirk Schadendorf, MD

Results from clinical trials published over the past several years are swiftly shaping what some are calling a new paradigm for the treatment of stage III melanoma.1,2

LITERATURE UPDATE MELANOMA

Evidence from surgical studies calls into question the role of complete lymph node dissection (CLND) in patients with positive sentinel lymph node biopsies, with studies showing that CLND may help refine staging and increase regional disease control but that it does not

confer a survival advantage over observation.2-4

Within this evolving surgical approach to metastatic melanoma are important adjuvant therapies that have improved relapse-free survival for the many patients at risk of relapse after surgery. Preventing relapse is also a strong factor in maintaining patients’ quality of life.5 Two classes of drugs have emerged as the current standard of care for adjuvant therapies for patients with high-risk melanoma: immune checkpoint inhibitors (nivolumab and pembrolizumab) that target programmed cell death 1 (PD-1) protein, and targeted therapy (combination dabrafenib plus trametinib) that stops or slows the growth of cancer cells by blocking proteins that help cancer cells grow.6

Data from studies published in 2017 and 2018 established the role of these 2 classes of drugs as adjuvant therapies for patients with resected, high-risk melanoma7-10 (Table 1).

The results of these studies were based on 1-year follow up for the anti-PD-1 therapies7,8, and 3-year follow-up for combination dabrafenib plus trametinib.9,10

In September 2020, longer-term follow up data became available for combination dabrafenib plus trametinib. To date, this is the longest follow-up data on these new adjuvant treatments. Published in the New England Journal of Medicine by Dummer and colleagues, the study reports the results of 5-year follow-up of the Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD) trial showing a durable, long-term, relapse-free survival in patients treated with the combination therapy.6

The COMBI-AD trialThe COMBI-AD trial is a phase III, double-blind, controlled trial in which 870 patients with resected stage III melanoma with BRAFV600E or V600K mutations were randomized to 12 months of oral dabrafenib plus trametinib (n = 438) or placebo (n = 432) to assess the primary end point of relapse-free survival.

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LITERATURE UPDATE MELANOMA

continued on page 20

All patients had the BRAF mutation (a muta-tion that can lead to growth and spread of can-cer cells) and were classified by stage based on the risk of recurrence (stage A is the lowest risk and stage C the highest risk). Patient character-istics were similar in the 2 groups.

Critical in the study was the inclusion of only patients with the BRAF mutations as the combination of dabrafenib plus trametinib is targeted to work only on patients with these mutations. “The BRAF V600E and V600K are so-called driver mutations, which are detectable in roughly 40% of cutaneous melanomas,” said senior author of the study, Dirk Schadendorf,

MD, Director and Chair, Department of Dermatology, Director, Comprehensive Cancer Center, University Hospital Essen, Essen, Germany, adding that combination adjuvant dabrafenib plus trametinib will work only in patients carrying a BRAF V600 mutation and not in other mutations. “Detection of the mutation is of critical importance in order to be able to use a targeted treatment approach,” he emphasized.

All patients underwent melanoma resection within 12 weeks prior to the start of the study and were classified by stage based on the risk of recurrence (stage A is the lowest risk and

TABLE 1. Adjuvant therapies for high-risk melanoma: key study results

Patients Relapse-free survival

PD-1 Inhibitors

Pembrolizumab (compared to placebo)7

Resected, stage III disease with or without BRAF V600 mutation

1-year results: 75.4% vs 61.0%, P<0.001

Nivolumab (compared to ipilimumab)8

Resected, stage IIIB/IIIC/IV disease 1-year results: 70.5% vs 60.8%, P<0.001

Targeted therapy

Dabrafenib plus trametinib (compared to placebo)9,10

Resected stage III melanoma with BRAF V600E or V600K mutations

3-year results: 58% vs 39%, P<0.001

TABLE 2. Patient characteristics: COMBI-AD trial

Dabrafenib plus trametinib combination therapy Placebo

Age <65 years 81% 83%

Male 56% 55%

White 99% 99%

STAGE

IIIA 19% 16%

IIIB 39% 43%

IIIC 41% 38%



Off-label PearlBy Ted Rosen, MD, FAAD, Editor-in-Chief

Literature LessonsPEDIATRIC DERMATOLOGY

Notalgia paresthetica (NP) consists of refractory itch at, medial to, or inferior to the scapula. Itch may be accompanied by pain or paresthesia. Chronic scratching or rubbing leads to prominent hyperpigmentation. NP most likely represents damage to cutaneous nerves due to impingement by bone, herniated disc, or muscle as the affected nerve exits the vertebral column. Many pharmacologic and surgical approaches to this problem exist. NP may respond to an average of 4 once-weekly treatments using a 308-nm excimer laser. Standardized fluence appears to be 300 mJ/cm2.

To read more: Fonda-Pascual P, et al. Effectiveness of 308-nm excimer lamp in the treatment of notalgia paresthetica. J Eur J Dermatol Venereol. 2020;July 24.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jdv.16836

The clinical speculation that use of hair oil may increase the rate of TINEA CAPITIS IN AFRICAN-AMERICAN CHILDREN does not seem to be valid. Moreover, use of cosmetic hair oil has minimal impact on the sensitivity of a fungal culture for tinea capitis. Therefore, diagnosis and treatment of tinea capitis may proceed along standard lines, regardless of whether or not hair oil is routinely applied to the scalp. To read more: Wichterman C, Kumar MG. Bayliss SJ. Influence of hair oil on scalp fungal cultures. Pediatr Dermatol. 2020;37(5):977-978. https://pubmed.ncbi.nlm.nih.gov/32757310/

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INFECTIOUS DISEASES

HIV-positive individuals who reliably take ANTI-RETROVIRAL THERAPY (ART) and achieve viral suppression (defined as HIV-1 RNA <200 copies per mL) do not transmit the virus to uninfected contacts, despite condomless sex. This supports the supposition that “undetectable equals untransmittable” and underscores the importance of adherence to ART regimens. To read more: Rodger AJ, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393:2428-2438. https://pubmed.ncbi.nlm.nih.gov/31056293/

Compression therapy may help reduce the likelihood of new CELLULITIS episodes in patients with leg edema and multiple prior episodes of lower extremity cellulitis. To read more: Webb E. Compression therapy to prevent recurrent cellulitis of the leg. N Engl J Med. 2020;383(7):630-63. https://pubmed.ncbi.nlm.nih.gov/32786188/

Adapalene gel 0.1% applied twice daily for 4 weeks may adequately treat TINEA VERSICOLOR. Moreover, this therapy is equipotent to ketoconazole cream 2% applied in a similar regimen. To read more: Bakr E, et al. Adapalene gel 0.1% vs ketoconazole cream 2% and their combination in treatment of pityriasis versicolor: A randomized clinical study. Dermatol Ther. 2020;33(3):e13319. https://pubmed.ncbi.nlm.nih.gov/32182387/

Based on a large-scale Danish cohort study over 10 years, exposure to ORAL TERBINAFINE during pregnancy does not lead to an increased risk of either congenital malformations or spontaneous abortion. To read more: Andersson NW, et al. Evaluation of association between oral and topical terbinafine use in pregnancy and risk of major malformations and spontaneous abortion. JAMA Dermatol. 2020;156(4):375-383. https://pubmed.ncbi.nlm.nih.gov/32129793/

Mycophenolate mofetil, at standard doses, may be beneficial for the management of MORPHEA. This is true even in cases of refractory generalized or linear morphea. To read more: Arthur M, et al. Evaluation of the effectiveness and tolerability of mycophenolate mofetil and mycophenolic acid for the treatment of morphea. JAMA Dermatol. 2020;156(5):1-8. https://pubmed.ncbi.nlm.nih.gov/32236497/

ADULT-ONSET DERMATOMYOSITIS carries some risk of associated internal neoplasia. When anti-transcriptional intermediary factor-1γ (anti-TIF-1γ) antibody is present, there is a 9 times greater risk of cancer than when this autoantibody is absent. However, some 60% of those who are positive will remain cancer-free. Dermatomyositis patients who are anti-TIF-1γ positive should undergo a thorough evaluation for cancer, even though many will not have occult neoplasia. To read more: Best M. Use of anti-transcriptional intermediary factor-1 gamma autoantibody in identifying adult dermatomyositis patients with cancer: a systematic review and meta-analysis. Acta Derm Venereol. 2019;99(3):256-262. https://pubmed.ncbi.nlm.nih.gov/30460368/

RHEUMATOLOGIC DISEASES

9X GREATER RISK OF CANCER

TNF-inhibitors and low-dose IL-17 inhibitors respond normally to killed virus influenza vaccine injection. If possible, those taking METHOTREXATE should stop the drug for 2 weeks after influenza vaccine administration to maximize seroprotective titers. About half of those on cyclosporine will not achieve protective titers. There are not enough data to comment on interaction between IL-23 inhibitors and influenza vaccination. To read more: Kim JY, Dao H. Influenza vaccination recommendations during use of select immunosuppressants for psoriasis. Cutis. 2020;106:194-195.



COSMETIC DERMATOLOGY

Does ingestion of ORAL COLLAGEN do anything? A meta-analysis of 11 randomized controlled studies suggests that it does. Both collagen hydrolysate (2.5-10.0g/day x 8-24 weeks) and collagen tripeptide (3g/day x 12 weeks) were benefi-cial. Both, for example, decreased xerosis and increased elasticity. Larger, longitudinal studies are needed. However, it does ap-pear that oral collagen ingestion may carry some cutaneous bene-fits. Choi FD, et al. Oral collagen supplemen-tation: a systematic review of dermato-logical applications. J Drugs Dermatol. 2019;18(1):9-16. https://pubmed.ncbi.nlm.nih.gov/30681787/

GENITAL PSORIASIS may be less scaly than disease elsewhere, but may be accompanied by pain, itching, or burning. To read more: Cather JC, et al. Patients’ perspectives on the impact of geni-tal psoriasis: a qualitative study. Dermatol Ther (Heidelb). 2017;7:447-461. https://pubmed.ncbi.nlm.nih.gov/29076000/

The only biologic drug specifically approved for GENITAL PSORIASIS is IXEKIZUMAB, although the entire gamut of topical and system drugs may be employed based upon patient preferences and prior experiences. To read more: Ryan C, et al. Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis. Br J Dermatol. 2018;179:844-852. https://pubmed.ncbi.nlm.nih.gov/29747232/

PSORIASIS

FACIAL PSORIASIS is associated with

severe overall disease and early age of onset.

Interestingly, the pinna is quite often involved

compared to other facial sites. To read more: Passos AN, et al. Facial involvement

and the severity of psoriasis. Int J Dermatol. 2019;58(11):1300-1304.

https://pubmed.ncbi.nlm.nih.gov/31347152/

63% of psoriasis patients

have genital involvement during their lifetimes

A prospective German study strongly suggests that PSORIASIS, regardless of body surface area affected, is associated with an increased risk of severe PERIODONTITIS. Patients with psoriasis should be encouraged to get regular dental examinations. To read more: Woeste S, et al. Oral health in patients with psoriasis—a prospective study. J Invest Dermatol. 2019;139(6):1237-1244. https://pubmed.ncbi.nlm.nih.gov/30610840/


December 2020 | 13


A German case-control study demonstrated that the risk of

developing RHINOPHYMA correlates with higher alcohol

intake. This association is

especially true if the patient is also diabetic or has a family history of

rhinophyma. To read more: Second J, et al. Rhinophyma is associated with alcohol intake. J

Am Acad Dermatol. 2019;81(1):249-

250. https://pubmed.ncbi.nlm.nih.gov/30630023/

ROSACEA

The COVID-19 PANDEMIC has severely disrupted the medical care system’s ability to screen for and detect cancer in the United States. Among the largest decreases in medical encounters related to the diagnosis of neoplasia during the pandemic include malignant melanoma, prostate cancer, and breast cancer. To read more: London JW, et al. Effects of the COVID-19 pandemic on cancer-related patient encounters. JCO Clin Cancer Inform. 2020;4:657-665. https://pubmed.ncbi.nlm.nih.gov/32716647/

COVID-19 CONTACT DERMATITIS

HIDRADENITIS SUPPURATIVA is associated with about a

28% A large-scale Korean study suggests that hidra-denitis suppurativa is associated with about a 28% excess risk of cancer, perhaps due to chronic inflammation and an aberrant immune response. Specifically, Hodgkin lymphoma, oral cavity cancer and pharyngeal cancer, central nervous system cancer, and prostate cancer had at least twice the incidence among those with hidradenitis when compared to a matched case-control popula-tion. To read more: Jung JM, et al. Assessment of overall and specific cancer risks in patients with hidradenitis suppurativa. JAMA Dermatol. 2020;156(8):1-10. https://pubmed.ncbi.nlm.nih.gov/32459291/

En bloc SURGICAL REMOVAL OF HIDRADENITIS SUPPURATIVA-AFFECTED AREAS is a viable option in the management of this disorder. Despite a high recurrence rate of about 35%, most patients prefer surgical management over medical man-agement, given the current methods available to accomplish the latter. To read more: Fertitta L, et al. Efficacy and satisfaction of surgical treatment for hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2020;34(4):839-845. https://pubmed.ncbi.nlm.nih.gov/31799758/

SECONDARY SQUAMOUS CELL CARCINOMA may occur in the setting of HIDRADENITIS SUPPURATIVA. Despite seemingly adequate wide local excision, cancer recurrence is common, often leading to death. To read more: Kohorst JJ, et al. Squamous cell carcinoma in perineal, perianal, and gluteal hidradenitis suppurativa: experience in 12 patients. Dermatol Surg. 2019;45(4):519-526. https://pubmed.ncbi.nlm.nih.gov/30608295/

EXCESS RISK OF CANCER

DRUGS AND DEVICES

SYSTEMIC 5-FLUOROURACIL (5-FU) is indicated for the treatment of adenocarcinoma of colon/rectum, stomach, pancreas, and breast. Systemic 5-FU can cause intense, but reversible, palmar hyperpigmentation. To read more: Schaefer JK and Ramnath N. Fluorouracil-induced hyperpigmentation. N Engl J Med. 2020;382(4):e6. https://pubmed.ncbi.nlm.nih.gov/31971682/



GENERAL DERMATOLOGY

only

12% of the American allopathic MEDICAL SCHOOLS have a dermatology-specific course in the preclinical curriculum and only 1% have a required dermatology rotation in the third or fourth year of training. Dermatologic skills are not widely taught in medical schools. To read more: Cahn BA, et al. Current status of dermatologic education in US medical schools. JAMA Dermatol. 2020;156(4):468-470. https://pubmed.ncbi.nlm.nih.gov/32101260/

A recent analysis of just over 2000 American adults demonstrated a TATTOO prevalence of 32%. About 50% of the tattoos were in normally visible sites. In this particular study, there was a statistically significant association between tattoo placement and mental health issues, sleep abnormalities, smoking, jail time, and increased number of sex partners. The presence of tattoos may alert the clinician to the possibility of problematic behavior. To read more: Mortensen K, et al. Are tattoos associated with negative health-related outcomes and risky behaviors? Int J Dermatol. 2019;58(7):816-824. https://pubmed.ncbi.nlm.nih.gov/30677140/

When prescribing TOPICAL CORTICOSTEROIDS, don’t assume the dispensing pharmacy will provide precisely the product you request, in the quantity you desire and with the instructions you prefer. Be aware that the amount of medication dispensed is often less than that prescribed, and patients may be told to discontinue treatment long before intended. Warn the patient that, should those things occur, to contact you so that you may discuss the situation with the pharmacist. To read more: Millard AN, Stratman EJ. Assessment of topical corticosteroid prescribing, counseling, and communication among derma-tologists and pharmacists. JAMA Dermatol. 2019;155(7):838-843. https://pubmed.ncbi.nlm.nih.gov/30916731/

A large-scale retrospective European study demonstrated that chronic use of TOPICAL CORTICOSTEROIDS is associated with an increased risk of developing Type 2 diabetes (T2D).

There was a dose-response relationship between new onset T2D and the potency of topical

steroids being used. Be careful with topical steroid use in those with a family history of diabetes

or existent borderline hyperglycemia. To read more: Andersen YMF, et al. Association between

topical corticosteroid use and type 2 diabetes in two European population-based adult cohorts.

Diabetes Care. 2019;42(6):1095-1103. https://pubmed.ncbi.nlm.nih.gov/30936111/


December 2020 | 15


CUTANEOUS ONCOLOGY

Patients who experience significant DISCOMFORT DURING THE INJECTION OF LOCAL ANESTHETIC may be made more comfortable via use of localized vibration delivered to the surrounding area. This strategy to mitigate pain during injection works best in the head and neck region and among individuals over the age of 65. To read more: Govas P, et al. Effect of a vibratory anesthetic device on pain anticipation and subsequent pain perception among patients undergoing cutaneous cancer removal surgery: A randomized clinical trial. JAMA Facial Plast Surg. 2019;21(6):480-486. https://pubmed.ncbi.nlm.nih.gov/31513234/

SURGICAL GLUES, based on n-butyl or 2-octyl cyanoacrylate, are durable, flexible, watertight, bactericidal, and afford excellent cosmesis. However, there is a risk of allergic contact dermatitis associated with surgical glue application. To read more: Nigro LC, et al. Should we stick with surgical glues? The incidence of dermatitis after 2-octyl cyanoacrylate exposure in 102 consecutive breast cases. Plast Reconstr Surg. 2020;145(1):32-37. https://pubmed.ncbi.nlm.nih.gov/31881600/

Intralesional injection of classic KERATOACANTHOMAS WITH METHOTREXATE leads to almost as frequent a complete remission as surgical excision. Consider intralesional methotrexate in: areas which might be difficult to close following removal, areas which may not heal readily or well, or when there is a plethora of such lesions. To read more: Moss M, et al. Management of keratoacanthoma: 157 tumors treated with surgery or intralesional methotrexate. Dermatol Surg. 2019;45(7):877-883. https://pubmed.ncbi.nlm.nih.gov/30608293/

GENERAL DERMATOLOGY (CONT)

Patients may have easy access

to low-cost, ultrapotent TOPICAL CORTICOSTEROIDS

manufactured overseas by

purchasing them at local stores and

shops specializing in “foreign products.”

To read more: Kimyon RS, et al.

Prescription-strength topical corticosteroids

available over the counter: Cross-sectional study

of 80 stores in 13 United States cities. J Am Acad Dermatol. 2020;82(2):524-525.

https://pubmed.ncbi.nlm.nih.

gov/31672686/

Patients receiving EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS for the treatment of cancer are prone to develop severe acneiform eruptions. This adverse event may be prevented or lessened in severity by prophylactic administration of oral tetracycline derivatives at typical therapeutic doses. To read more: Yu Z, et al. Evaluation of a comprehensive skin toxicity program for patients treated with epidermal growth factor receptor inhibitors at a cancer treatment center. JAMA Dermatol. 2020;e201795. https://pubmed.ncbi.nlm.nih.gov/32609305/

Studies show that VISIBLE SKIN ABNORMALITIES may evoke strong negative reactions from others. This may lead to everything from stares to verbal insults to online harassment. Males and those who have no association with healthcare are most likely to react negatively to abnormal skin. You may have to help your patients cope with this social ostracism. To read more: Pereira PA, et al. Aversion caused by skin diseases: a crowdsourcing study. Int J Dermatol. 2019;58(1):60-66. https://pubmed.ncbi.nlm.nih.gov/30229877/




Despite a black-box warning, a large-scale observational study of more than 7 years duration failed to demonstrate an increased risk of non-melanoma skin cancer among adult ATOPIC DERMATITIS patients exposed to topical calcineurin inhibitors (TCI). Control comparison group included those exposed to topical cortico-steroids (TCS) or neither TCI nor TCS. To read more: Asgari MM, et al. Association between topical calcineurin inhibitor use and keratinocyte carcinoma risk among adults with atopic dermatitis. JAMA Dermatol. 2020;Aug 12. https://pubmed.ncbi.nlm.nih.gov/32785626/

A meta-analysis of 15 studies including

more than

310,000 patients demonstrated that

patients with

ATOPIC DERMATITIS ARE AT RISK FOR

SUICIDAL IDEATION

and suicide attempts.

To read more: Sandhu JK, et al.

Association between

atopic dermatitis

and suicidality: a

systematic review

and meta-analysis.

JAMA Dermatol. 2019;155(2):178-18.

https://pubmed.

ncbi.nlm.nih.

gov/30540348/

ATOPIC DERMATITIS

61% OF US ADULTS WITH ACTIVE

ATOPIC DERMATITIS REPORT PAIN

Pain is a distinct symptom associated with atopic dermatitis. The occurrence of pain correlates, overall, with the severity of atopic dermatitis. To read more: Silverberg JI, et L. Pain is a common and burdensome symptom of atopic dermatitis in United States adults. J Allergy Clin Immunol Pract. 2019;7(8):2699-2706. https://pubmed.ncbi.nlm.nih.gov/31228619/

33%

AT LEAST WEEKLY 5%DAILY

Based upon a large US cohort study, there does not appear to be an increased risk of non-melanoma skin cancer among adults with ATOPIC DERMATITIS who utilize topical calcineurin inhibitors. This holds true regardless of which drug is employed and is not related to frequency and duration of use. To read more: Asgari MM, et al. Association between topical calcineurin inhibitor use and keratinocyte carcinoma risk among adults with atopic dermatitis. JAMA Dermatol. 2020;Aug 12. https://pubmed.ncbi.nlm.nih.gov/32785626/

Based upon-large scale European studies, there may not be an increased risk of cancer among ATOPIC DERMATITIS patients. To read more: Mansfield KE, et al. Association between atopic eczema and cancer in England and Denmark. JAMA Dermatol. 2020;Aug 12. https://pubmed.ncbi.nlm.nih.gov/32579178/

ACNE CAN LEAVE HER

FOR LIFEEpiduo® Forte (adapalene and benzoyl peroxide) Gel 0.3%/2.5% reduces acne lesions and the risk of scarring for results your patients can see.1

• Powerful Combinationto address 3 out of 4 causative factors of acne2*

• Proven Effi cacyin reducing acne lesions and acne scar risk3

• Highly Tolerablein moderate to severe acne

Please see brief summary of full Prescribing Information on next page.

IMPORTANT SAFETY INFORMATIONIndication: Epiduo® Forte (adapalene and benzoyl peroxide) Gel, 0.3%/2.5% is indicated for the topical treatment of acne vulgaris. Adverse Events: In the pivotal study, the most commonly reported adverse reactions (≥1%) in patients treated with Epiduo ForteGel were skin irritation, eczema, atopic dermatitis and skin burning sensation. Warnings/Precautions:Patients using Epiduo Forte Gel should avoid exposure to sunlight and sunlamps and wear sunscreen when sun exposure cannot be avoided. Erythema, scaling, dryness, stinging/burning, irritant and allergic contact dermatitis may occur with use of Epiduo Forte Gel and may necessitate discontinuation. When applying Epiduo Forte Gel, care should be taken to avoid the eyes, lips and mucous membranes.

You are encouraged to report negative side effectsof prescription drugs to the FDA. Visit WWW.FDA.GOV/MEDWATCH or call 1-800-FDA-1088.

www.epiduoforte.com/hcp*not including Sebum production.

A two-phase, randomized, multicenter, investigator-blinded, vehicle-controlled trial evaluating once-daily Epiduo Forte Gel compared moderate to severe acne subjects 16 to 35 years old with a clinical diagnosis of moderate to severe acne vulgaris on the face (defi ned by IGA score of 3 or 4, with the same score on both sides); a minimum of 25 infl ammatory lesions (papules and pustules) in total, with at least 10 on each side (excluding the nose); and no more than 2 acne nodules (≥1 cm); and ≥10 atrophic acne scars in total (>2 mm), excluding the nose. Phase 1 was a split-face, 24-week, investigator-blinded, vehicle-controlled evaluation (N=67) at 8 visits (baseline, weeks 1, 4, 8, 12, 16, 20, and 24). Phase 2 was a whole-face, open-label observation with 2 visits. Primary endpoint was scar count.1

JOB #: 10451 PROD. ART.: DEEJ No. of PAGES: 2

JOB TITLE: Galderma Epiduo TDD Ad ART DIR.: ME COLORS: CMYK

CLIENT: Galderma ACCT SERV.: MO TRIM: 8.375”x10.875”

DATE: 11/16/2020 BLEED: 1.25”

LIVE AREA: NA

NOTES:

CYAN

YELLOWMAGENTA

BLACK

EPIDUO FORTE - The Dermatology Digest - PRINT AD (PG.1)8.375” x 10.875”

8.375”

10.875”

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stage C the highest risk). Patient characteristics were similar in the 2 groups.

As shown in Table 1, 3-year follow-up results showed a significant benefit of this combined targeted therapy compared to placebo.

Updated study at 5 years In the updated study, investigators report on relapse-free survival in this cohort of patients after 5 years as well as survival without distant metastasis based on the intention-to-treat analysis.6

Table 2 shows the results of the 5-year analysis.

The study results indicate a 49% reduction in the risk of melanoma coming back in patients treated with combination therapy. By stage, patients with stage IIIA had a 39% reduction, those with stage IIIB had a 50% reduction, and patients with stage IIIC had a 52% reduction. When looking at distant metastasis-free sur-vival, 45% of patients treated with the combi-nation therapy had a reduced risk of melanoma coming back at a distant site.

“...the durability of relapse-free survival at 5 years suggest that a fraction of patients might be cured

and not die from melanoma any longer.”

Commenting on the study, Keith T. Flaherty, MD, Director of Clinical Research, Massachusetts General Hospital Cancer Center, Boston, said that the 5-year analysis reinforces the initial analysis that led to the April 2018 FDA approval

of combination dabrafenib plus trametinib for stage III melanoma patients with BRAF V600 mutations.

“That [initial] study was monumental for the field as it showed for the first time that oncogene-targeted therapy could prevent recurrence in high-resected melanoma,” he said. “This publication confirms and extends the findings of the initial analysis, making it very clear that relapses can be prevented with dabrafenib/trametinib.”

Saying that the combination therapy remains a “pillar of our systemic therapy options for patients with resected stage III melanoma,” Dr. Flaherty said that this therapy, along with PD-1 antibody therapy, are both adjuvant treatment options that clinicians can offer their patients.

“Patients with BRAF mutation and resected stage III disease have dabrafenib/trametinib or a PD-1 antibody to choose from,” said Dr. Flaherty. The choice of treatment, he said, may depend on factors such as convenience (dabrafenib/trametinib is given orally, whereas a PD-1 antibody is administered intravenously), cost (patients may need to pay more out-of-pocket for oral medications), and side effects (fewer potentially life-threatening toxicities are associated with dabrafenib/trametinib). This last factor, he said, “causes some patients to prefer dabrafenib/trametinib.”

continued from page 9

52% OF TREATMENT

GROUP remain relapse-free

at 5 years

Study results indicate a

49% REDUCTION IN RISK of melanoma coming

back in patients treated with

combination therapy


December 2020 | 21

www.thedermdigest.com/LITERATURE_UPDATE

“This study represents the longest follow-up for a current standard of care adjuvant thera-py for melanoma,” said lead author Reinhard Dummer, MD, Vice-Chairman, Department of Dermatology, Head of Skin Tumor Center, University Hospital Zurich, Switzerland. “It demonstrates that there is a sustained benefit of adjuvant dabrafenib plus trametinib long after the treatment period is over, suggesting an increase in the fraction of patients who may never relapse, which is the ultimate goal of treatment.”

Long-term results provide clarificationDr. Dummer noted 2 key questions concerning adjuvant therapy for melanoma: Can 1 year of adjuvant therapy increase the fraction of patients who may never relapse? and Which patients should be receiving adjuvant therapy?

The updated 5-year results of the COMBI-AD trial answer both. “These long-term follow-up data suggest that the combination of dabrafenib plus trametinib can achieve this outcome for some patients,” he said. “The results [also] show that a benefit with adjuvant dabrafenib plus tra-metinib is apparent across all stage III substages included in the study, so clinicians can feel confident in recommending adjuvant therapy to all of these subpopulations.”

Dr. Schadendorf underscored that the durabil-ity of relapse-free survival at 5 years suggests that a fraction of patients may be cured.

Noting evidence from previous studies of stage III melanoma patients in whom loco-regional involvement is controlled surgically, he said the studies show that about one-third of patients will not develop a relapse over the next 5 years

and that relapses peak within the first 24- 30 months.

The 5-year outcome on relapse-free survival from the COMBI-AD shows that 52% of the treatment group remain relapse-free at 5 years. “The long-lasting effects of treatment are clearly visible,” Dr. Schadendorf said.

REFERENCES 1. Rudchadkar RR, Michielin O, Van Akkooi ACJ. Practice-changing

developments in stage III melanoma: surgery, adjuvant targeted therapy, and immunotherapy. 2018 ASCO Educational Book. American Society of Clinical Oncology. 2018.

2. Ascierto PA, Borgognoni L, Botti G, et al. New paradigm for stage III melanoma: from surgery to adjuvant treatment. J Transl Med. 2019;17:266.

3. Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT):a multi-centre, randomized, phase 3 trial. Lancet Oncol. 2016;17(6):757e67.

4. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissec-tion or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;377(19):1824-35.

5. Schadendodrf D, Hauschild A, Santinami M, et al. Patient- reported outcomes in patients with resected high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomized, placebo- controlled, phase 3 trial. Lancet Oncol. 2019;20(5):701-710.

6. Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Eng J Med. 2020;383:1139-1148.

7. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembroli-zumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789-1801.

8. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-1835.

9. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Eng J Med. 2017;377:1813-1823.

10. Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600-mutant stage III melanoma. J Clin Oncol. 2018;36:3441-3449.

“This publication confirms and extends the

findings of the initial analysis making it very

clear that relapses can be prevented

with dabrafenib/trametinib.”



Uncommon but deadly development demands vigilanceBy John Jesitus Reviewed by Reinhard Dummer, MD, and Dirk Schadendorf, MD

Identifying the development of aggressive squamous cell carcinoma (SCC) after en bloc excision of hidradenitis suppurativa (HS) requires more careful monitoring and a high index of suspicion, experts tell The Dermatology Digest.

SURGICAL CORNER SCC AFTER HS EXCISION

Over the past decade, said Afsaneh Alavi, MD, new biologic therapies for HS have shed light on this orphan disease, resulting

in more papers and meeting sessions on HS. Dr. Alavi is a dermatologist at the Mayo Clinic in Rochester, Minnesota.

The biologic-driven narrative highlights improvements in patients’ health and quality of life, said Neal Bhatia, MD. “But there’s little discussion of other hidden issues like squamous cell existing in patients with hidradenitis suppurativa.” He is Director of Clinical Dermatology at Therapeutics Clinical Research in San Diego, California.

In a case series published in Dermatologic Surgery in April 2019, researchers led by John J. Kohorst, MD, searched Mayo Clinic Rochester records from 1976 through 2013 and found 12 cases in which SCC arose after HS resection.1 Nine patients were male; the cancers affected the gluteal (n = 8), perianal (n = 6), perineal (n = 4), and/or vaginal (n = 1) areas. At a mean follow-up of 4.3 years after wide excision, SCC recurred in 7 patients— all of whom ultimately died.

SCC arising in the setting of HS is very uncom-mon, said lead author John J. Kohorst, MD, a Mohs surgeon at the Mayo Clinic Health System in La Crosse, Wisconsin. “But when it does occur, the mortality is very high. It’s something we’re always on the lookout for because when it does happen, it can be deadly.”

Often, he added, certain subtypes of SCC can be very aggressive. “And in the setting of a chronic inflammatory disease like hidradenitis, all of us as clinicians need to be thinking about the possibility of squamous cell carcinoma because it can go undetected and evolve into a high-grade skin cancer.”

The presence of numerous inflammatory papules and nodules in the area increases the difficulty of distinguishing whether a painful inflammatory papule is secondary to HS or may represent an SCC, said Dr. Kohorst. “So these squamous cell carcinomas can go undetected, grow, and then spread prior to being recog-nized, biopsied, and treated.”

Dr. Bhatia said, “Compared to basal cell carcinoma, with squamous cell carcinoma you

JOHN J. KOHORST, MDMohs Surgeon

Mayo Clinic Health SystemLa Crosse, Wisconsin

AFSANEH ALAVI, MDDermatologist Mayo Clinic

Rochester, Minnesota

NEAL BHATIA, MDDirector of Clinical

Dermatology atTherapeutics Clinical

Research San Diego, California

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December 2020 | 23

www.thedermdigest.com/SURGICAL_CORNER

SURGICAL CORNER SCC AFTER HS EXCISION

get a lot of lateral spread under the microscope. It’s a much more aggressive tumor once it hits the dermis.” The poorly differentiated subtype found in many of Dr. Kohorst et al.’s patients can be even more difficult to capture with a clean margin, Dr. Bhatia added.

The predominance of male patients in the series slightly surprised Dr. Kohorst. In a 2016 review of surgical outcomes in 590 patients, Dr. Kohorst and his colleagues found that 60% of patients were male.2 “So it’s not entirely shocking that those who develop squamous cell carcinoma were mostly males,” he said. “Why the percentage was that high, I can’t say.”

Dr. Alavi added that even though the Dr. Kohorst’s studies and a 2015 review on which she was senior author3 showed a predominance of cases in men, she has also seen cases of HS with SCC in females.

It is also unclear why SCC so often strikes the perianal/perineal area. In the 2016 report, the most common HS site was perianal/perineal (49.8%), followed by the axilla (21%). Dr. Kohorst said, “It’s possible that SCC could arise in any area affected by hidradenitis. Common things being common, the 2019 study supports our surgical data showing that areas commonly affected by severe hidradenitis are most commonly the groin and the axilla, with a slight predominance toward male patients.”

Although experts previously believed that human papilloma virus (HPV) contributed to SCC development in HS, said Dr. Alavi, Dr. Kohorst et al.’s 12-patient series showed no evidence of HPV. “This shows that a chronic, long-standing ulcer is enough to cause these aggressive cancers,” Dr. Alavi said. This study also showed that even at one of the best treatment centers, many patients experience postsurgical HS recurrence, added Dr. Alavi.

When viewed by surgery type, Dr. Alavi’s 2015 review revealed HS recurrence rates for wide excision, local incision, and de-roofing of 12%,

22%, and 27%, respectively.3 A single-center study involving 75 patients (most with Hurley stage III disease) showed an overall postsurgical HS recurrence rate of 35%.4 The only risk factor significantly linked with recurrence was 1-stage surgical closure.

Early detectionBecause HS cannot be prevented or cured, early detection and management of both HS and subsequent SCC are paramount. However, diagnostic difficulties abound.

Dr. Alavi said, “It’s not easy because we see patients in the dermatology clinic who have lots of draining lesions and usually are obese or large patients.” Adequately illuminating these patients’ perianal, perineal, and genital areas is challenging, she said. “That’s why many of these cancers are diagnosed when they are too advanced to do anything.” In Dr. Kohorst’s 2019 case series, mean HS duration before SCC diagnosis was 28.5 years.

Dr. Bhatia added that patients with HS are often first diagnosed as having acne, cysts, and abscesses. “Given the area—the axillary distribution or the perineum—the index of suspicion for hidradenitis should be pretty high,” he said. Instead of just getting antibiotics from their primary care doctors, said Dr. Bhatia, these patients should be evaluated by dermatologists quickly, and probably prescribed biologics more quickly than in the past.

Ongoing follow-up is equally critical. “If someone has had long-standing, difficult- to-medically-control hidradenitis,” said Dr. Kohorst, “it’s important for us as clinicians to be seeing them regularly. More frequent follow-up is a good thing for these patients.” He leaves the follow-up interval to the discre-tion of individual dermatologists. Dr. Bhatia suggests a frequency of at least every 6 months.

Patients should examine themselves often, added Drs. Alavi and Bhatia. However, noted

“It’s something we’re always on the lookout for because when it does

happen, it can be deadly.”



www.thedermdigest.com/SURGICAL_CORNER

Dr. Alavi, the perianal area is difficult for patients to see, and they cannot differentiate between HS ulceration and SCC formation. “I encourage patients to seek advice and ask for an exam if they have any concern.”

Dr. Bhatia said, “The American Academy of Dermatology does a good job with the SPOT Skin Cancer [public awareness] program. I would probably tell these patients, ‘Your risk might not be as high as someone with more sun damage, but the types of cancer you could get would be more aggressive. That should raise your concern for looking more often.’”

HS detected in early stages can be managed medically, said Dr. Alavi. With antibiotics (first-line) and biologics (second-line), she said, some patients require anti-androgens. But eventually, she said, most patients—she estimates 70%, based on current patient patterns—require surgery combined with medical therapy.

To shrink tumors before excision, Dr. Bhatia said that dermatologists now can use cemiplimab (Libtayo, Regeneron and Sanofi). “Many dermatologists aren’t familiar with cemiplimab’s use. It is the newest therapy we have for this type of squamous cell carcinoma— invasive and advanced.”

Interdisciplinary teamworkTo manage these complex cases, Drs. Kohorst, Alavi, and Bhatia recommend interdisciplinary care. “As dermatologists,” said Dr. Kohorst, “we can do a lot. But there are other specialties that have expertise in this area.”

In his 2016 case review, HS resections were performed by general surgeons (51.4%), plastic surgeons (35.8%), dermatologists (10.3%), and

other specialties (2.5%), including gynecologic surgeons. “And still, many of these patients, depending on their access to dermatologists, are going to be seeing their primary care physicians a lot. Having them on board is also very important in managing these patients, who are very difficult to manage and treat,” Dr. Kohorst said.

At the University of Toronto, where Dr. Alavi formerly worked, surgery, dermatology, and nursing make up the core of the multidisci-plinary care program. Providers in these specialties seek assistance from other disci-plines including psychiatry, gastroenterology, and nutrition as needed. “Surgery and derma-tology should work together hand-in-hand to manage patients with HS from the beginning,” said Dr. Alavi.

Dr. Bhatia added, “The dermatologists should be the quarterback for these patients. They should be directing the traffic. And then the rest of the team—the oncologists and radiation oncologists—would pass the patient back.”

Dr. Alavi said she hopes that using more multidisciplinary care for patients with HS will reduce the number of long-standing ulcers that dermatologists see. Over time, she added, diagnosing and treating HS earlier will result in less tissue damage, better out-comes, and fewer surgeries.

To refine care algorithms for these patients, Dr. Kohorst recommends additional research. To date, most studies have been small case reports and series.

“With chronic wounds like hidradenitis suppurativa,” said Dr. Alavi, “we are hoping that clinicians are cognizant of the presence of malignancy that may be under diagnosed because it’s in a difficult location—the perianal area. A good exam with proper light helps early detection, and we need to have a low threshold for biopsy when the patient has a lesion in this area.”

“Over time, diagnosing and treating HS earlier will result in less

tissue damage, better outcomes, and fewer surgeries.”

REFERENCES

1. Kohorst JJ, Shah KK, Hallemeier CL, et al. Squamous cell carcinoma in perineal, perianal, and gluteal hidradenitis suppurativa: experience in 12 patients. Dermatol Surg. 2019;45(4):519-526.

2. Kohorst JJ, Baum CL, Otley CC, et al. Surgical management of hidradenitis suppurativa: outcomes of 590 consecutive patients. Dermatol Surg. 2016;42(9):1030-40.

3. Mehdizadeh A, Hazen PG, Bechara FG, et al. Recurrence of hidradenitis suppurativa after surgical management: a systematic review and meta-analysis. J Am Acad Dermatol. 2015;73(5 Suppl 1):S70-7.

4. Fertitta L, Hotz C, Wolkenstein P, et al. Efficacy and satisfaction of surgical treatment for hidradenitis suppurativa. J Eur Acad Dermatol Venereol. 2020;34(4):839-845.

DISCLOSURES: Drs. Kohorst and Alavi report no relevant financial interests. Dr. Bhatia has been an advisor for Regeneron and Sanofi.



The treatments are so cheap that they don’t need prior authorizations and patients can

afford them. They’re safe, with no significant risks. And they make sense, meaning there is either a good study showing they work or there is a good rationale behind them, according to Dr. Zirwas’s presentation “Therapeutic Approaches You Probably Haven’t Heard of but May Actually Use,” which he gave at the 2020 Congress of Clinical Dermatology in Miramar Beach, Florida, in August.

Yet most dermatologists don’t know

the options exist.

Dr. Zirwas, director of the Ohio Contact Dermatitis Center in Columbus, said he has been using these therapeutic approaches for years or sometimes decades. They are his go-to treatments when better options don’t exist.

“I probably read a few hundred articles in the literature each week. Based on those, I make hypotheses and try them in practice,” he said. “I’m constantly trying new things for conditions when there are no good treatment options. If I already have good treatments for something that are supported by data

and evidence in trials, I’m going to use those. I’m not trying to reinvent the wheel.”

Minoxidil for chronic telogen effluviumChronic telogen effluvium is among the more challenging conditions that dermatologists treat. It’s distressing for patients, but oral minoxidil has helped to change that, according to Dr. Zirwas.

“Patients are very excited about minoxidil because normally we talk about taking biotin, nutritional supplements, or special shampoos. Patients already know about all of those things and have probably tried them and none worked,” Dr. Zirwas said.

Instead, Dr. Zirwas recommends 0.625 mg a day of minoxidil, which is one-quarter of the smallest available 2.5 mg tablet. Patients generally see results in about 6 months. Oral minoxidil reduces shedding by 50% at 12 months and seems to help with trichodynia, too.

“The only side effects I’ve seen at the dose of 0.625 mg a day is an increase in resting heart rate. Maybe 10% will get hypertrichosis. At this dose it does

Matthew J. Zirwas, MDDirector, Ohio Contact Dermatitis Center Columbus, Ohio

Member, North American Contact Dermatitis Group

Presented at

Georgia Society of Dermatology and Dermatologic Surgery2020 Congress of Clinical Dermatology

[email protected]

Therapeutic approaches you’ve never heard of but will use next weekBy Lisette Hilton | Reviewed by Matthew J. Zirwas, MD

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www.thedermdigest.com/THERAPEUTIC_APPROACHES

Dermatologist Matthew J. Zirwas, MD, says he’d be shocked

if a day went by when he didn’t use one

of these therapeutic approaches in practice. After all, each meets his criteria for being cheap

and safe as well as making sense.

December 2020 | 27



not affect blood pressure,” Dr. Zirwas said. “In some cases, I will go down to the smaller dose. Rather than a quarter tablet at 0.625 mg a day, I get it compounded to be 0.25 mg a day, which is the smallest dose that has been shown to be effective.”

Minoxidil for brittle, slow- growing nailsOral minoxidil, at the same dose as used for the hair, also stimulates nail growth, in Dr. Zirwas’ experience.

“Initially I was using minoxidil topical-

ly on the cuticles, based on a well-done study that showed a slight increase in growth rates, and maybe it helped a

little. When the oral regimens for telogen effluvium and androgenic alopecia started coming out, I switched to using oral minoxidil for patients who complained about nail ridging, slow growth, and fragility, and it definitely helped. Again, it takes from 6 months to a year to work,” Dr. Zirwas said. “When I lecture about this, concerns of drug-induced lupus have been raised. I’ve never seen a case of that. It’s a very rare side effect.”

Frontal fibrosing alopecia Environmental exposures cause frontal fibrosing alopecia, according to Dr. Zirwas. “Thirty years ago this entity did not exist or was quite rare if it did. Now it is incredibly common. The data have been fairly clear that sunscreen is the trigger,” he said. “The best information out there is that it’s probably the benzophe-nones in sunscreen.”

So Dr. Zirwas first tells patients to switch from chemical sunscreens to physical blockers. Titanium and zinc sunscreens are not completely in the clear when it comes to causing frontal fibrosing alopecia, but Dr. Zirwas said his personal belief is that they don’t.

Patients should also avoid the benzophenones in products marketed for color-treated hair, he said.

“In early cases or new-onset frontal fibrosing alopecia, making those changes typically stops the progression and may lead to regrowth,” he said. “In cases that have been going on for years, at best this is going to stop progression but it is not going to trigger regrowth.”

Acne, keratosis pilaris, rosacea, and sebaceous hyperplasia

Loratadine with isotretinoin: It’s worth reducing isotretinoin side effects because the drug works and is safe, according to Dr. Zirwas.

Researchers conducting randomized controlled trials (https://pubmed.ncbi.nlm.nih.gov/25081735/, https://pubmed.ncbi.nlm.nih.gov/30745963/ 1,2) found that treating patients on isotretinoin with 5 mg a day of desloratadine decreases cutaneous side effects.

“I find desloratadine is hard to get covered [by insurance]. So, instead I have patients use loratadine, which is generic Claritin (Bayer), one pill [10 mg] twice a day,” Dr. Zirwas said. “I do think it makes a difference and makes isotretinoin more tolerable. You’re still going to get the dryness, but it’s not going to be as bad.”

Why bother? Because isotretinoin is much safer than the oral antibiotic minocycline and is at least as safe as doxycycline.

“Since there is only a single reported case of a fatal adverse event from isotretinoin (fatal rhabdomyolysis), I will only prescribe oral antibiotics for acne if the patient absolutely demands them and absolutely refuses isotreti-noin,” Dr. Zirwas said. “I also use isotretinoin for mild acne. I rarely treat anybody with topicals. If somebody comes in with any acne at all, I tell

Oral minoxidil reduces shedding

50%

AT 12 MONTHS

Treat sebaceous hyperplasia with isotretinoin

40mg ONCE DAILY FOR 2 MONTHS

One in 10 people are allergic to

nickle 1% will get systemic nickle dermatitis


December 2020 | 29


them that I recommend isotretinoin. If they don’t want the isotretinoin, I’m happy to put them on topicals. But I’ve never had a patient with a significant side effect from isotretinoin, and they are so much happier with the thera-peutic outcome. My patients don’t want their acne to be 75% better, they want it gone, and isotretinoin is the only option that reliably cures acne in most patients.”

The other big update about isotretinoin is that monthly lab testing is no longer necessary; instead, a set of baseline labs is required and then sometimes another set of labs after 2 months of therapy. No more labs are necessary if those labs are normal. The recommendation removes a stumbling block for teenagers who didn’t want to take isotretinoin because of the perceived need for monthly labs, he said.

“Many dermatologists are not aware that there is significant risk with phlebotomy. In about 1 in 5000 blood draws, there will be a significant complication, such as persistent pain or nerve damage,” Dr. Zirwas said. “Telling somebody to have labs done 6 times, there’s a 1 in 1000 chance that they’re going to have a significant complication as a result. I really try to minimize how much blood work I order to minimize that risk for my patients.”

Chlorine dioxide for keratosis pilaris: Chlorine dioxide (Aseptic MD cleanser, Aseptic Health) is a shock-ingly effective therapy for keratosis pilaris, a condition without good treatment options, according to Dr. Zirwas, who has ownership in the company that makes Aseptic MD and has authored a study on chlorine dioxide’s effects on keratosis pilaris published in the Journal of Drugs in

“Today, it is my first-line agent with keratosis pilaris. I find that it is dramatically effective in about 2 out of 3 patients. And in about 1 in 3 it doesn’t do much.”

Attack rosacea with this oral regimen: Dr. Zirwas often sees rosacea patients who have been referred for patch testing to rule out contact dermatitis because they haven’t responded to traditional therapies. Many, if not most, of these rosacea cases are driven primarily by demodex. Clues are tiny pustules, itching, and a poor response to standard therapies, according to Dr. Zirwas.

Dr. Zirwas uses what he said is an almost universally effective regimen to treat these patients. It combines oral ivermectin and metronidazole (https://pubmed.ncbi.nlm.nih.gov/23294870/4).

The treatment: Ivermectin 1 mg per

“...my patients don’t want their acne to be 75% better – they want it gone and isotretinoin is the only option that reliably cures acne in most patients.”

Dermatology (https://jddonline.com/articles/dermatology/S1545961618P0554X).3

“I thought this was going to be an acne product because it’s the most effective antiseptic in existence. It has been tested head to head against bleach, chlorhexidine … and it is faster and more effective than any of them,” Dr. Zirwas said. “When I started develop-ing it and using it in practice, while it worked better than other cleansers for acne, it wasn’t as dramatically effective as I expected it would be But some of my acne patients also had keratosis pilaris, and that went away.”

Studies dating as far back as the 1950s have shown that chlorine dioxide breaks keratin’s intramolecular disulfide bond and destabilizes it.

“It’s a direct exfoliator that doesn’t damage keratinocytes,” he said.



10 pounds of body weight, repeat in a week; metronidazole 250 mg 3 times daily for 14 days. The first dose of metronidazole should be taken at same time as first dose of ivermectin. Then, he maintains the effect with topical metronidazole and ivermectin.

Treating sebaceous hyperplasia: Another almost universally effective treatment is using isotretinoin 40 mg once daily for 2 months to treat sebaceous hyperplasia.

“The sebaceous hyperplasia is com-pletely gone,” he said. “My experience is that in about 50% of patients it will come back. If it comes back, I will keep them on low-dose isotretinoin.

Typically for me, that’s 40 mg 2 days a week as long-term therapy.”

Sebaceous hyperplasia patients tend to be older and no longer of childbearing age, so iPledge is less of a burden. Dr. Zirwas doesn’t usually check patients’ labs but asks about their baseline tri gly cerides. If triglycerides are 400 mg/dL or higher, Dr. Zirwas doesn’t prescribe isotretinoin.

Systemic nickel dermatitis is a real thing“When I talk about this, most derma-tologists have either never heard of it or don’t think it’s real. To say this is not real is the equivalent of saying poison ivy isn’t real. There is an enormous amount of evidence on systemic nickel dermatitis,” Dr. Zirwas said.

About 1 in 10 people are allergic to nickel and about 1% of them will develop systemic nickel dermatitis from the amount of nickel in a normal American diet, which means that about 1 out of 1000 people in the general population have systemic nickel dermatitis. It usually presents as itchy papules on extensor elbows or vesicular hand dermatitis, according to Dr. Zirwas.

Dr. Zirwas previously recommended that patients adhere to a low-nickel diet and the nickel content of foods is easy to find on the internet, including at sites such as the “Rebelytics Low Nickel Diet Scoring System,” (http://rebelytics.ca/lownickeldiet.html). However, he is now much more likely to recommend patients take calcium disodium EDTA, 600 mg capsules, as he has seen it to be much more effective than the low-nickel diet.

“It was shown years ago that EDTA prevents the nickel in food from

“Patients empty a 600 mg

capsule into 16 oz of

water and take several sips at the beginning, middle, and end of each

meal.”

getting absorbed. People buy this online. It’s cheap. Patients empty a 600 mg capsule into 16 oz of water and take several sips at the beginning, middle, and end of each meal,” he said, so they end up drinking the bottle over 2 to 3 days.

Rutin and vitamin C for pigmented purpuric dermatosisDr. Zirwas recommends pigmented purpuric dermatosis patients take a combination of Rutin (rutoside) 500 mg and vitamin C 500 mg, twice daily. Treatment works in 95% of patients, generally in 2 weeks to 2 months, and half of people eventually relapse but can simply take another course or just stay on the regimen indefinitely.

“It’s stunningly effective and widely available in 500 mg pills,” he said. “This also works in senile or solar purpura. It doesn’t prevent the bruises, but they’ll go away much faster.”

REFERENCES

1. Lee HE, Chang IK, Lee Y, et al. Effect of antihistamine as an adjuvant treatment of isotretinoin in acne: a randomized, controlled comparative study. J Eur Acad Dermatol Venereol. 2014;28(12):1654-60.

2. Van TN, Thi LD, Trong HN, et al. Efficacy of oral isotretinoin in combination with desloratadine in the treatment of common vulgaris acne in Vietnamese patients. Open Access Maced J Med Sci. 2019;7(2):217-220.

3. Zirwas MJ, Fichtel J. Chlorine dioxide complex cleanser: a new agent with rapid efficacy for kerato-sis pilaris. J Drugs Dermatol. 2018;17(5):554-556.

4. Salem DA, El-Shazly A, Nabih N, et al. Evaluation of the efficacy of oral ivermectin in comparison with ivermectin-metronidazole combined therapy in the treatment of ocular and skin lesions of demodex folliculorum. Int J Infect Dis. 2013;17(5):e343-7.

DISCLOSURES Dr. Zirwas has ties with Abbvie, Arcutis, Asana, Aseptic MD, Avillion, Dermavant, Edessa Biotech, FitBit, Foamix, Galderma, Genentech/Novartis, Incyte, Janssen, Leo, Lilly, L’Oréal, Menlo, Ortho Derm, Pfizer, Regeneron/Sanofi, Sol-Gel, and UCB.


December 2020 | 31

“The skin is supposed to be at a pH of 5 to 6. Inflamed skin has a higher pH, so restoring that natural acidity makes sense.”

Natural treatments that patients loveBy Lisette Hilton | Reviewed by Matthew J. Zirwas, MD

Inexpensive, safe, and available over the counter, these remedies appeal to patients on many levels. When

dermatologists recommend natural, easy-to-obtain solutions to skin prob-lems, it helps to build the therapeutic alliance, according to dermatologist Matthew J. Zirwas, MD, director of the Ohio Contact Dermatitis Center in Columbus. Even if they’re not efficacious, patients may at least experience a placebo effect, he said.

Apple cider vinegarThe jury is still out on apple cider vine-gar’s true value for skin, but Dr. Zirwas

said patients love it and that recommending it

helps build therapeu-tic alliance.

“It’s dirt cheap, completely safe, and there’s good rationale. The skin is sup-posed to be at a pH of 5 to 6. Inflamed skin has a higher pH, so restoring that natural acidity makes sense,” he said.

Dr. Zirwas typically recommends that patients mix a tablespoon of apple cider vinegar into a 16-oz jar of moisturizer. That’s enough to bring the moisturizer to a pH of about 5.5.

Dr. Zirwas no longer recommends bleach baths for atopic dermatitis (“Parents don’t want to put bleach on their kids and adults tend not to want to get in the bathtub,” he said), but he does sometimes recommend apple cider vinegar.

A systematic review and meta-analy-sis published in the Annals of Allergy, Asthma and Immunology (https://www.ncbi.nlm.nih.gov/pmc/articles/

PMC5726436/) found water baths were about as effective for relieving atopic dermatitis as bleach baths.1

“If I’m going to add anything to bath water, I tell people to add a cup of apple cider vinegar. It probably doesn’t do much but people love it and I’m building therapeutic alliance,” Dr. Zirwas said.

Powdered milkDr. Zirwas, a nationally known allergy patch testing expert, said he usually makes one recommendation before patch testing patients with widespread dermatitis.

“I have them start adding a half cup of nonfat powdered milk in with the clothes when they do laundry. Lots of patients swear by it. At a minimum, it has a good placebo effect and again is building therapeutic alliance,” he said.




“However, we know surfactants in detergents do cause dermatitis. We also know that on average about 2.5% of the detergent is retained in clothes. If retained, detergent gets released by warm, acidic sweat from skin and causes dermatitis.”

The thinking is the casein in the milk binds to and removes formaldehyde in clothing, researchers reported in a study published in 1974 in the Archives of Dermatology (https://jamanetwork.com/journals/jamadermatology/ful-larticle/534309).2 But formaldehyde slowly reaccumulates, so patients need to add powdered milk with each laundry load.

One in 20 cotton items releases detect-able formaldehyde, including sheets and

pillowcases, according to Dr. Zirwas. The problem is there is no way to know which items contain formaldehyde, so replacing the potentially irritating items isn’t an option, while washing clothes in powdered milk is.

Most dermatologists are surprised to learn that people don’t get contact dermatitis from fragrance or dyes in laundry detergent. In fact, for a man-ufacturer to claim its product is gentle because it doesn’t have fragrance or dyes is “insane,” according to Dr. Zirwas, since it is known that neither of these causes contact dermatitis from laundry detergent.

“However,” he said, “we know surfactants in de-tergents do cause derma-titis. We also know that on average about 2.5% of the detergent is retained in clothes. If retained, detergent gets released by warm, acidic sweat from skin and causes dermatitis.”

All Free Clear (Henkel Corporation) is the only detergent that has been shown in studies to have lower poten-

tial for irritant dermatitis than other detergents, according to Dr. Zirwas.

“It has a different mix of sur-factants, a milder mix, so the residual detergent left in the clothes does not cause irritant dermatitis,” Dr. Zirwas said. “Other ‘sensitive skin’ deter-gents use the same surfactants

as that brand’s regular detergent, so they aren’t really any better for sensi-tive skin than regular detergent.”

The downside is that the milder sur factant mix in All Free Clear may not get clothes as clean as other detergents, he said.

Heliocare Heliocare (Heliocare) is an effective topical sunscreen adjunct, according to Dr. Zirwas. It prevents sunburn in places people may miss when applying topical sunscreens and offers some sunburn protection for those who skip sunscreen altogether.

“You have to take a pretty big dose—about 1 pill of Heliocare per 25 pounds of body weight,” he said. “And it has to be Heliocare. I’ve tried generic polypo-dim leucotomos and burned to a crisp. With regular Heliocare, I’ve never gotten sunburned.”

Taking Heliocare is safe. Animal studies have shown no ill effects with taking the equivalent of 500 pills a day, according to Dr. Zirwas.

He doubts taking Heliocare prevents skin cancer and said it doesn’t work as a melasma treatment; he recommends it mostly as an “insurance policy” in case patients miss spots when applying sunscreen or forget to reapply.

REFERENCES1. Chopra R, Vakharia PP, Sacotte R, et al. Efficacy of

bleach baths in reducing severity of atopic dermatitis: A systematic review and meta-analysis. Ann Allergy Asthma Immunol. 2017;119(5):435-440.

2. Stubbart FJ. Nonfat dry milk helps prevent formaldehyde dermatitis. Arch Derma-tol. 1974;110(2):299.

DISCLOSURES: Dr. Zirwas has ties with Abbvie, Arcutis, Asana, Aseptic MD, Avillion, Dermavant, Edessa Biotech, FitBit, Foamix, Galderma, Genentech/Novartis, Incyte, Janssen, Leo, Lilly, L’Oréal, Menlo, Ortho Derm, Pfizer, Regeneron/Sanofi, Sol-Gel, and UCB.

1in 20 cotton items releases detectable formaldehyde, including sheets

and pillowcases


December 2020 | 33


Solutions for itchBy Lisette Hilton | Reviewed by Matthew J. Zirwas, MD

Clobetasol and CeraVe to reduce steroid’s effectsDermatologist Matthew J. Zirwas, MD, director of the Ohio Contact Derma-titis Center in Columbus, combines 50 ml clobetasol solution into a 16-oz jar of CeraVe. The combination makes a 0.005% clobetasol cream, with no significant allergens in the vehicle. It’s a medium-to-high potency, or class 3, steroid that overcomes barrier impairment associated with short-term steroid use.

Dr. Zirwas started using the combina-tion about 15 years ago after reading studies that included one published in 2003 in the Journal of Investigative Dermatology (https://pubmed.ncbi.nlm.nih.gov/12603860/) in which researchers concluded: “… even short-term exposure to potent glucocortico-steroids can exert profound negative effects on cutaneous structure and function […] topical replenishment with epidermal physiologic lipids could represent a potential method to reduce the adverse cutaneous effects of both topical glucocorticoid treatment and Cushing’s syndrome.”1

What most dermatologists do not know about steroids is the most important clinically relevant side effect

These little-known itch solutions will be inexpensive and simple additions to your treatment arsenal.

is not skin thinning; rather, it’s a dramatic reduction in intercellular lipid production in the epidermis, according to Dr. Zirwas.

“The only thing that has ever been shown to reverse that effect is cera-mides,” he said.

The other benefit of Dr. Zirwas’ clobetasol/CeraVe combination is it avoids propylene glycol and other common allergens that cause allergy to topical steroids.

“The combination is about as close as

one can get to the perfect topical steroid because it doesn’t have any of the common allergens, it’s medium- potency with a wide range of utility, and it prevents barrier impairment. The only thing that might be even better—and this is not something I do regularly because of cost—is using desoximetasone topical spray, 0.25%, instead of the clobetasol,” he said.

The only time Dr. Zirwas doesn’t use the clobetasol/CeraVe combination is when patients need a class 1 steroid for a localized area of severe disease.



“In that situation, I typically use clobetasol scalp solution alone. That’s because it’s the only inexpensive class 1 steroid formulation that does not have propylene glycol,” he said.

L-histidine for atopic dermatitisPatients love using l-histidine, a component of natural moisturizing factor, because it’s dietary and natural, according to Dr. Zirwas.

“It has been shown that 4 g a day of l-histidine pretty dramatically increases your body’s filaggrin and natural moisturizing factor production. In mild-to-moderate atopic dermatitis, people get about 30% better. That was in a randomized, double-blind,

placebo-controlled trial (https://www.

dovepress.com/feeding-filaggrin-

effects-of-l-histidine- supplementation-in-atopic-

der-peer-reviewed-article-CCID), so we have great data. And it’s cheap—about $20 a month on Amazon,” he said.2

Be sure to tell patients to buy l-histi-dine HCL and not histidine base. The recommended dose is an eighth of a teaspoon daily, which is 500 mg. But patients with atopic dermatitis need 4 g, or 1 teaspoon, daily, he said.

“The biggest problem with it is it tastes terrible. Probably the best feedback I’ve had from patients is to dissolve it in apple juice,” Dr. Zirwas said.

Peppermint extract: tried and trueResearchers reported in a study published in 2016 in Clinical, Cosmetic and Investigational Dermatology (https://www.dovepress.com/effectiveness-of-topical-pep-permint-oil-on-symptomat-ic-treatment-of-ch-peer-re-viewed-article-CCID) that peppermint extract reduces itch by about 50%.3

Dr. Zirwas recommends that patients order a 1-oz bottle of peppermint oil and mix it into 16 oz of moisturizer,

which makes close to the 5% strength that was shown to be effective. Or patients can buy peppermint extract in the spice section at the grocery store. The extract is one-quarter the strength of the oil. Dr. Zirwas recommends patients mix in 2 oz of peppermint ex-tract into 16 oz of moisturizer because 4 oz makes the moisturizer too runny. Patients still get results from the ex-tract-moisturizer combination, he said.

Intramuscular Kenalog Consider that 40 mg intramuscular Kenalog (Bristol-Myers Squibb) equals 50 mg prednisone, based on potency, but only 70% of prednisone is absorbed. So, 40 mg intramuscular Kenalog prob-ably equals 60 mg prednisone.

“So, 40 mg of Kenalog a month is roughly equivalent to about 2 mg a day of prednisone. The ratio of itch relief to systemic steroid exposure is higher for Kenalog than for prednisone.

The literature says that 2 mg a day of prednisone is incredibly safe. Do we really know that 40 mg of Kenalog is equivalent to 2 mg a day of prednisone in terms of side effects? No, we don’t. But that should be the case,” Dr. Zirwas said. “Clinicians have reported treat-ing many patients with Kenalog given monthly or every 2 months. I’ve done that in patients for years. I have not seen steroid side effects except for solar purpura.” The cost for Kenalog is only slightly higher than the already low cost of prednisone, he pointed out.

l-histadine

4mg PER DAY

dramatically increases the body’s filaggrin and natural moisturizing

factor production.

40mg KENALOG A MONTH

2mg PREDISONE A DAY

is roughly equivalent to about

Peppermint extract reduces itch by about

50%


December 2020 | 35


Tanning beds aren’t all badTanning beds aren’t all bad, according to Dr. Zirwas. For example, not all patients can make it to dermatology practices for in-office phototherapy, and tanning beds may be an alterna-tive. Tanning salons tend to have more flexible hours for patients who work, and are less expensive than photo-therapy in a dermatologist’s office, Dr. Zirwas said.

Dr. Zirwas uses this tanning salon regimen for some patients with atopic dermatitis or itch. He hasn’t had as good outcomes with psoriasis patients. He recommends patients go to tanning beds 3 to 5 times a week, for a total of 20 sessions during a course of 4 to 6 weeks. If they get dramatically better, he’ll have them cut down to once a week, initially. If they’re still improv-ing, he’ll go down to once every 2 weeks.

The UV exposure from using a tanning bed 2 to 4 times a month is low and offsets risks associated with metho-trexate or cyclosporine, or repeated use of steroids.

“If somebody needed to go twice a week to maintain the effect, that’s too much. I start to get nervous having anybody go twice a week, long term. If once a week gives them excellent control over their dermatitis, it’s a very reasonable thing to do,” he said.

Dr. Zirwas talks with patients about the increased risk of skin cancer with phototherapy versus risks associated with systemic medication. Dermatolo-gists who recommend tanning bed use should do their homework by calling local chains and asking which beds have the most UVB.

“If [the chain] knows, recommend that one to your patients. If they don’t know, find another chain,” he said.

Getting beyond the tacrolimus burnTacrolimus is a good medication for itch that patients often don’t take because it can cause burning. This therapeutic alternative has more to do with how dermatologists prepare patients for what’s to come, so they don’t stop taking the drug. A signifi-cant part of the drug’s efficacy for itch is that it causes substance P release, just like capsaicin, but this means it also causes burning just like capsaicin.

“I tell patients that tacrolimus is not a steroid and is totally safe to use every day indefinitely (there’s tons of data to show that it doesn’t cause cancer). Then I tell them that if we’re really lucky, when they put it on the first time it’s going to burn horribly. If it burns, it means it’s going to work really well. The burning will last about 15 minutes, and each time you put it on it will be a little less intense and end a little faster. Typically, within 1 to 2 weeks, it won’t

burn at all when you put it on,” Dr. Zirwas said. “I tell them to have an ice pack ready the first time they use tacrolimus, just in case we get really lucky and the burning is horrendous.”

Use this approach, said Dr. Zirwas, and it’s rare that patients will say they can’t use tacrolimus.

The UV exposure from using a tanning bed 2 to 4 times a month is low and offsets risks associated with methotrexate or cyclosporine, or repeated use of steroids.

REFERENCES1. Kao JS, Fluhr JW, Man MQ, et al. Short-term gluco-

corticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol. 2003;120(3):456-64.

2. Tan SP, Brown SB, Griffiths CEM, et al. Feeding filaggrin: effects of L-histidine supplementation in atopic dermatitis. Clin Cosmet Investig Dermatol. 2017;10:403-411.

3. Elsaie LT, El Mohsen AM, Ibrahim IM, et al. Effec-tiveness of topical peppermint oil on symptomatic treatment of chronic pruritus. Clin Cosmet Investig Dermatol. 2016;9:333-338.

DISCLOSURES: Dr. Zirwas has ties with Abbvie, Arcutis, Asana, Aseptic MD, Avillion, Dermavant, Edessa Biotech, Fit-Bit, Foamix, Galderma, Genentech/Novartis, Incyte, Janssen, Leo, Lilly, L’Oréal, Menlo, Ortho Derm, Pfizer, Regeneron/Sanofi, Sol-Gel, and UCB.


forecast: Integrative medicine is here to stayBy Cheryl Guttman Krader Reviewed by Reena N. Rupani, MD, and Peter A. Lio, MD

Integrative medicine has gained a foothold in dermatology care. Fueled by growing patient and provider interest and supported by accumulating evidence, it is expected to have a greater role in the future, according to Reena N. Rupani, MD, and Peter A. Lio, MD.

CRYSTAL BALL INTEGRATIVE MEDICINE

Dr. Rupani and Dr. Lio are co-chairs of the American Academy of Dermatology’s Expert Resource Group (AAD ERG) on integrative medicine.

“There is an undeniable interest among patients in the type of holistic, human-encompassing care that defines integrative medicine, and it has also garnered the attention of clinicians. Although the AAD Integrative Medicine ERG was formally organized in 2018, it had already been in existence for about a decade through various shapes and forms, first as a task force and then as a work group,” said Dr. Rupani, who is Clinical Assistant Professor of Dermatology at ICAHN School of Medicine, Mount Sinai Hospital, New York, and a graduate of the Arizona Center for Integrative Medicine fellowship program.

“In 2020, the Integrative Medicine ERG has a solid and growing membership, and I believe that strongly demonstrates the demand for and interest in continued education on integrative medicine and dermatology among practitioners.”

PETER A. LIO, MDClinical Assistant

Professor, Departments of Dermatology and Pediatrics,

Northwestern University Feinberg School of Medicine,

Chicago, Illinois

REENA N. RUPANI, MDClinical Assistant Professor

of Dermatology at ICAHN School of Medicine,

Mount Sinai Hospital, New York


TDD_Dec20_Crystal Ball.indd 36TDD_Dec20_Crystal Ball.indd 36 11/23/20 2:47 PM11/23/20 2:47 PM

December 2020 | 37

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The literature shows that integrative medicine has a burgeoning role in dermatology. Dr. Rupani noted that a recent query in Google Scholar using the term “integrative dermatology” yielded more than 30,000 hits. The results include thousands of journal articles along with dedicated textbooks or textbook chapters, including several written by Dr. Rupani and Dr. Lio.

Most recently, Dr. Rupani and Dr. Lio, along with a number of colleagues, have written a textbook titled Integrative Dermatology: Practical Applications in Acne and Rosacea. The book is being published by Springer with a planned release date in December 2020, and is expected to be the first in a series.

Dr. Lio is Clinical Assistant Professor, Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Founding Director, Chicago Integrative Eczema Center, and in private practice at Medical Dermatology Associates of Chicago. He noted that several years ago he was invited to co-author the chapter “Complementary and Alternative Medicine” in the current edition of Dermatology, a textbook edited by Jean Bolognia, MD, and colleagues, and he is currently updating the chapter for the forthcoming edition.

“Dr. Bolognia’s Dermatology is considered a definitive textbook in our specialty that is widely used in teaching and as a reference by practitioners. The inclusion of a chapter on complementary and alternative medicine within this comprehensive tome points to at least some degree of acceptance of integrative medicine,” Dr. Lio said.

Complementing, not replacingIntegrative medicine interventions are gen-erally used in conjunction with conventional modalities, and they are comprised of a broad spectrum of methods. Use of the term “integrative” to describe this area of medicine

obviates the need for the term “alternative,” said Dr. Rupani.

“Clinicians who practice integrative medicine do not reject, or seek to replace, what traditional allopathic medicine has already achieved,” she explained.

“By striving to incorporate guidance on nutri-tion, stress reduction, botanical supplements that may augment therapy or mitigate side effects, and successful aspects of other world traditions, such as Ayurveda and traditional Chinese medicine, we fully inhabit our roles as physicians and healers.”

Facing the skepticsCritics who question the validity of integra-tive medicine approaches often raise concerns about the quantity and quality of the evidence, including lack of data from large-scale studies that incorporate blinding, randomization, and controls.

“These design features are the hallmark of our current body of accepted scientific evidence. However, it has become increasingly important to note that the approaches taken in integrative care are more personalized and perhaps not amenable to the double-blind, randomized, controlled trial model,” Dr. Rupani said.

Yet she acknowledged a need for more informa-tion on safety. “Safety studies, particularly with supplements, are what I feel are strongly needed before more physicians can feel comfortable adopting an integrative model,” she said.

Finding new venuesDr. Lio said that physicians considering integrative medicine approaches should take into account the evidence pointing to efficacy and safety. Accessibility/practicality is another factor to consider.

“Although there may be some data supporting an approach from traditional Chinese medi-cine, it may not be a practical option because of time or cost issues,” he explained.

“Clinicians who practice integrative medicine

do not reject, or seek to

replace, what traditional allopathic medicine

has already achieved.”

THE KEY 3

Integrative medicine is gaining a role in dermatology

Patient interest in this type of care is high

Opportunities for learning about

integrative medicine approaches are

increasing



According to Dr. Rupani, the greatest amount of research on benefits of integrative medicine approaches exists for conditions stemming from inflammation, including acne, rosa-cea, atopic dermatitis, and psoriasis. Dr. Lio said that it seems rational to add integrative therapies for the management of these dis-eases, which can have many pathogeneses or triggers. He suggested that integrative medicine approaches can be particularly helpful when patients do not respond adequately to conven-tional therapies.

“In trying to find new venues of therapy rather than just giving up, it is natural and reasonable to gravitate toward alternative and complemen-tary approaches,” he said.

Integrative medicine can also be particularly helpful when patients experience side effects from conventional therapies or are concerned about potential risks.

For example, Dr. Lio recommends topical coconut oil and oral vitamin D supplementa-tion to some patients with atopic dermatitis. He explained that coconut oil has been shown

to have antibacterial activity, appears to have some anti-inflammatory properties, and im-proves the skin barrier. Vitamin D may provide benefits based on its positive effects on skin immunity, barrier function, and inflammation, he said, adding that a number of studies have reported that it is not universally helpful for patients with atopic dermatitis.

Dr. Rupani mentioned that dietary modifi-cations, such as reducing calorie intake for psoriasis and reducing dairy and carbohydrate intake for acne, can often make a real difference in clinical outcomes. In addition, she said that patients suffering from hair loss often benefit from the use of mindfulness-based practices or adaptogenic herbal supplements to address the “stress” component of their conditions.

“More broadly, any patient who needs a greater sense of agency in their own health and healing can benefit from simple guidance on diet, exercise, and stress reduction. These lifestyle and behavioral interventions are unlikely to do harm and more likely to show benefit, both

Coconut oil has been

shown to have antibacterial

activity, appears to

have some anti- inflammatory

properties, and improves the skin barrier.

“Any patient who needs a greater sense of agency in their own health and healing can benefit from simple guidance on diet, exercise, and stress reduction.”


December 2020 | 39

www.thedermdigest.com/CRYSTAL_BALL

“You may think that your

patients are not interested in integrative medicine, but they probably

are, even if they are not asking about these

options.”

from the individual power that comes from ‘controlling’ one’s own health and from the general improvement in whole- body wellness that comes from taking better care of oneself,” she said.

Learning opportunitiesData show that dermatology patients have a high interest in alternative and complementary therapies. For example, a survey of patients with atopic dermatitis found that 50% of respondents said they had used some form of complementary and alternative medicine to manage their disease.1

“You may think that your patients are not interested in integrative medicine, but they probably are, even if they are not asking about these options,” said Dr. Lio. “Dermatologists who are not convinced that integrative medi-cine has a role may still benefit by being famil-iar with the information and being able to discuss it, because it is something that patients may want to explore.”

Dr. Rupani concurred, stating that having some degree of interest in and openness toward inte-grative medicine goes a long way with patients. “Our patients are asking questions and will continue to do so in greater numbers,” she said.

Several fellowships are available to physicians in practice who are looking to expand their knowledge. Dr. Lio, in collaboration with Apple Bodemer, MD, and Raja Sivamani, MD, MS, AP, founded one such program in 2020. Known as the Integrative Dermatology Certificate Program (get.learnskin.com/fellowship-certif-icate-program/), it is a 9-month program for board-certified dermatologists that includes nearly 100 lectures and provides more than 50 hours of continuing medical education (CME) credit.

“We expected that a handful of dermatologists would sign up, but have over 20 participants so far,” Dr. Lio said. The next fellowship program is in May 2021.

REFERENCE

1. Simpson EL, Basco M, Hanifin J. A cross-sectional survey of complementary and alternative medicine use in patients with atopic dermatitis. Am J Contact Dermat. 2003;14(3):144-7.

DISCLOSURES: Dr. Rupani receives royalties for the books Clinical Cases in Integrative Dermatology (Springer), Integrative Dermatology 1st Ed (Oxford University Press), and Integrative Dermatology: Practical Applications in Acne and Rosacea (Springer). Dr. Lio is a shareholder at LearnSkin and receives royalties for the books Handbook of Integrative Dermatology: An Evidence-Based Approach (Springer) and Integrative Dermatology: Practical Applications in Acne and Rosacea (Springer).

A survey of patients with atopic dermatitis found that

50% OF RESPONDENTS said they had used or

explored alternative and complementary therapies.


I don’t understand the attraction of alternative or complementary medicine, nor do I believe that renaming it “integrative medicine” makes

it any more palatable. But that’s just me.

I am a protein chemist by training and got into medicine because I do very well on standard-ized tests, not because I have warm, fuzzy re-lationships with other people. In fact, I almost failed Pediatrics in medical school because of my abrasively cynical, questioning nature. To me, the concept of integrative medicine just seems lacking. If integrative medicine claims to be distinctive by caring for patients in a more holistic way, I believe this insults standard med-icine, which, by its nature, is already supposed to address all the relevant areas of human care.

There is no doubt that many patients are inter-ested in the approaches of integrative medicine; their interest can be objectively measured. But if the integrative approaches can’t be objectively measured in double-blind randomized trials, to my perspective, it is no more than nonsense, albeit attractive nonsense.

I could be wrong. Since we cannot scientifically assess integrative medicine, there is no way to know. Maybe traditional Chinese medicines truly work (and maybe they contain cortico-steroids). Surely I am guilty of more than a little hypocrisy and could find hundreds of treat-ments that I prescribe to patients for various skin diseases that are not fully supported by clinical evidence of today’s standard.

My guess is that many patients are happy to see documentation that their dermatologist has pursued education in integrative medicine. If that gives them more faith in their doctor, they may even take their prescribed medications

better and have better outcomes.

Although I do not have a crystal ball for pre-dicting the future, I believe there will be very rapid growth in the adoption of integrative medicine. Maybe it will grow 10- or 20-fold in the next few years. But 10 or 20 times almost zero doesn’t amount to much.

DR. FELDMAN has received research, speaking, and/or con-sulting support from a variety of companies including Abbvie, Advance Medical, Almirall, Alvotech, BMS, Boehringer Ingelheim, Caremark, Celgene, Galderma, GSK/Stiefel, Informa, Janssen, Lilly, Leo Pharma, Menlo, Merck, Mylan, National Biological Corporation, the National Psoriasis Foundation, Novan, Novartis, Ortho Dermatology, Pfizer, Qurient, Regeneron, Samsung, Sanofi, Sun Pharma, Suncare Research, and UpToDate.

STEVEN R. FELDMAN, MD, PhD

Professor of Dermatology, Pathology, and Social

Sciences & Health Policy, Wake Forest University Health

Sciences, Winston-Salem, North Carolina

To whatever extent integrative medicine claims to be distinctive by caring

for patients in a more holistic way, I believe this insults standard medicine

which, by its nature, is already supposed to address

all the relevant areas of human care.

COMMENTARY

I’m not convinced



December 2020 | 43

Today’s biggest threat

American Academy of Dermatology (AAD) President Bruce H. Thiers, MD, FAAD, and President-elect Kenneth J. Tomecki, MD, FAAD, have their fingers on the specialty’s pulse as leaders of the world’s largest dermatology society and long-time practicing dermatologists.

The Dermatology Digest asked each dermatologist to share what he thinks are the specialty’s single biggest threat and opportunity.

Here is what they had to say.

DERMATOLOGY’S THREATS AND

OPPORTUNITIESBy Lisette Hilton

ACCORDING TO DR. THIERS

LOSS OF CONTROL“The greatest challenge facing dermatology, and indeed all of medicine, is the loss of control, specifically in how we run our practices and how we treat our patients,” said Dr. Thiers, Distinguished University Professor of Dermatology and Dermatologic Surgery at the Medical University of South Carolina, Charleston. “Many of us went into medicine because we expected to make a difference and have the liberty to treat patients in the manner we deemed best. That is no longer the case.”

Many patients still believe their doctors control their treatment or make the decisions about optimal care. That might have been true 20 years ago, but now doctors really just make “suggestions” to outside decision makers, according to Dr. Thiers.

Nowadays, a dermatologist suggests the best course of treatment to the insurance company or the best drug

Bruce H. Thiers, MD, FAAD

President, AAD

Kenneth J. Tomecki, MD, FAAD

President-elect, AAD

VOICES & VIEWPOINTS

TDD_Dec20_DermsTalk.indd 43TDD_Dec20_DermsTalk.indd 43 11/23/20 2:38 PM11/23/20 2:38 PM


to the pharmacy benefits manager. They are the true decision makers, he said.

“They are the ones who are controlling treatment. In my opinion, insurance companies and pharmacy benefit managers are practicing medicine without a license. To me, this is totally unethical,” Dr. Thiers said.

These companies are motivated by profit, and their goal is to make shareholders happy. One could make the argument that physicians have an incentive to make a profit as well, but they also are bound by the Hippocratic Oath and have a moral obligation to do what is best for their patients. Doctors ultimately have their patients’ best interests in mind and should be in control of decisions about treatment, Dr. Thiers said.

An example of how the decision-making process has gone awry is the oppressive, inefficient process of prior authorization for procedures and drugs. Companies claim prior authorizations control spending on patient medications. For physician practices, this policy increases costs in time and paperwork, with many practices employing people to solely handle prior authorizations. In the meantime, patients wait for care or completely forgo treatment.

Dr. Thiers shared his experience as a patient with prior authorization.

“Maybe a few times a month, I will take the generic version of Ambien if I’m working late and feel a bit too wound up

to fall asleep,” he said. “To get the prescription filled, we had to get a prior authorization. The cost of the prescription was $1.13. Think about it: we probably expended $50 to $100 of human capital to get authorization for a prescription that costs $1.13. That is how the system works and how we, as physicians, have lost control.”

Other things erode dermatologists’ control of their practices and patient care. According to Dr. Thiers, electronic health record (EHR) burdens and government programs such as the Merit-based Incentive Payment System (MIPS) top the list.

“With MIPS, we basically have to prove to the government that we are doing a good job treating patients,” he said.

Dr. Thiers argued that a scoring system that impacts physician reimbursement based on areas of care that Medicare deems important suggests there is a cookbook approach to treating patients. There is not, he said. But the MIPS process is yet another hoop the physician must jump through—another obstacle to providing individualized dermatologic care.

Maintenance of Certification (MOC) is another example of a program that many dermatologists believe has little correlation with their ability to practice good medicine. Constant scope-of-practice and truth-in-advertising battles

round out a list of distractions that dermatologists face daily and that interfere with their primary purpose: to give patients the best care possible, said Dr. Thiers.

“We have often stood by paralyzed by an inability to act and defend the stature and the independence of the physician. I am not so naïve to think we can reverse this ourselves, but by working with like-minded physicians … from other specialties and concerned legislators I am confident we can begin to turn the tide,” Dr. Thiers said. “Advocacy is the key on both the federal and state levels. Strong state dermatology societies are critical. Get involved!”

“In my opinion, insurance companies and pharmacy benefit managers are practicing medicine without a license. To me, this is totally unethical.” Bruce H. Thiers, MD, FAAD

“Advocacy is the key on both the federal and state levels. Strong state dermatology societies are critical.” Bruce H. Thiers, MD, FAAD


December 2020 | 45

www.thedermdigest.com/VOICES_&_VIEWPOINTS

ACCORDING TO DR. TOMECKI

REIMBURSEMENT“The working premise for most physicians, dermatologists specifically, is that all of us assume that we individually and collectively as a group will receive fair compensation for services rendered, be they surgical, be they pathologic, be they cognitive services,” said Dr. Tomecki, Vice Chairman of Dermatology at the Cleveland Clinic, who will become AAD President for one year beginning in March 2021.

Instead, declining reimbursement is a daily concern for dermatologists and other physicians. And the pandemic has made things much worse.

Physicians in general have taken a financial hit in the last 6 to 8 months because of COVID-19.

“Probably 75% or 80% of dermatologists have been impacted by the pandemic, and patient care has suffered and been compromised because patients cannot make it to office, clinics, etc.,” he said.

Many doctors did not work at all for 3 or 4 months. Income was slashed by more than 70%, according to Dr. Tomecki.

To compound the acute problem of the pandemic and threat of declining reimbursement, the Centers for Medicare & Medicaid Services (CMS) final Medicare Physician Fee Schedule (MPFS) rule for 2020 will go into effect January 2021. Broad changes are proposed, especially with regard to evaluation and management (E/M) services.

“To meet the budget neutrality requirements that are required under the MPFS, the expected increased payments for E/M visits in 2021 will be offset by a decrease in the conversion factor of more than 10%. This decrease will translate into drastic cuts in Medicare reimbursement for dermatology practices and could undermine the financial stability of practices and their ability to serve their patients,” according to AAD (https://www.aad.org/member/advocacy/leg-conference/policy-medicare-physician-payment).

The conversion factor helps determine how much physicians get paid for what they do. The proposed conversion factor will reduce total reimbursement to dermatology by about 2% or 3%. It will hit dermatologic surgeons and dermatopathologists more because of the procedural work they do. Their income reduction would be between 6% and 8%, according to AAD.

“Those folks who do contemplative or cognitive work—they see something, they make a diagnosis, make a recommendation, and write a prescription—they may actually benefit somewhat because there’s going to be an adjustment in payment for the E/M codes. Still, in general,

2% or 3% AMOUNT THE PROPOSED

CONVERSION FACTOR WILL REDUCE REIMBURSEMENT

TO DERMATOLOGY

6% & 8% AMOUNT INCOME FOR

DERMATOLOGIC SURGEONS AND DERMATO-PATHOLOGISTS

WOULD BE REDUCED

75% –80% OF DERMATOLOGISTS HAVE BEEN IMPACTED

BY THE PANDEMIC

Approximately About Between

Today’s biggest threat



ACCORDING TO DR. THIERS

DERMATOLOGY’S GROWING STATUREMajor therapeutic advances have elevated dermatology’s stature in the house of medicine since the turn of the century.

These game-changing therapies initially found application in the treatment of inflammatory skin diseases, including biologics for psoriasis and Janus kinase (JAK) inhibitors for atopic dermatitis, as well as treatments for cutaneous malignancies, such as targeted therapies and immune checkpoint inhibitors for melanoma.

“Dermatology was at the forefront of these advances, and since then the same or similar treatments have been shown to help more effectively treat a multitude of other systemic

diseases, including rheumatoid arthritis, inflammatory bowel disease, and solid organ tumors, to name a few,” Dr. Thiers said.

Dermatologists also have learned a great deal about the systemic comorbidities that accompany many dermatologic conditions. From a procedural standpoint, dermatologic surgeons display skills in treating skin cancers that are unmatched by any other specialty, according to Dr. Thiers.

“Dermatologists should leverage their well-deserved increased level of respect among our non-dermatologist colleagues to emphasize their importance not only in treating diseases of the skin, hair, and nails, but also in advancing the well-being of the patient as a whole,” he said.

Taking that lead means addressing scope-of-practice issues that affect not only dermatology but also other specialties, according to Dr. Thiers.

”Providers such as nurse practitioners and physician assistants are not the ones who should lead the healthcare team,” he said. “We are physicians, not providers, and we are leaders, not followers. Being at the cutting edge of breakthrough therapies obligates us to work with the house of medicine to ensure that patients understand that their physicians work for them and are ultimately responsible for the decisions that affect their well-being.”

“We are physicians, not providers, and we are leaders, not followers.” Bruce H. Thiers, MD, FAAD

The biggest opportunity

dermatologists will take a hit, some more than others,” Dr. Tomecki said.

Leaders in dermatology and other specialties are asking Congress and the CMS to provide relief from the pending payment cuts as dermatologists and other physicians are just getting back up and running.

Dermatologists took part in the AAD’s annual legislative conference in mid-September making a strong pitch to legislators in Washington D.C. to offset the conversion factor and support legislation that would waive the budget neutrality requirements, according to Dr. Tomecki.

“There’s a fixed amount of money that the government has to move from one pot to another. That is the way it works,” he said. “The AAD favors a waiving of budget neutrality requirements, as planned for January 2021. In same vein, during the 2020 AAD Legislative Conference dermatologist-advocates supported a bipartisan Marshall-Rush letter which asked CMS to delay suggested Medicare cuts. The AAD continues to support efforts to allow Congress more time to consider alternatives.”

“There’s still time to make a correction,” he added.

The major threat now, however, remains the double whammy from the pandemic and potential reduction in reimbursement from the government, he said.


December 2020 | 47

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“It has really taken on a life of its own during the last 3 to 6 months,” said Dr. Tomecki. “In dermatology, it probably works best for things like lesions and growths. At least the patient can get a sense of what he or she has on the skin, and the doctor can say, yes, it needs an in-person look and may-be a biopsy, or if it’s a wart or harmless-looking mole maybe the patient can be simply reassured.”

While teledermatology is not expected to take the place of in-person care, Dr. Tomecki said it will likely have a bigger role in practice even after the approval and widespread use of a vaccine.

“It allows us to provide some dermatologic care for patients who cannot make it to a clinic or a physician’s office. Hospi-tals and clinics like it. The government likes it,” he said.

Is it perfect? Far from it, according to Dr. Tomecki.

“For the dermatologist, a live, inpatient visit is always preferable,” he said.

“Teledermatology ... fills a niche. And it’s here to stay.” Kenneth J. Tomecki, MD, FAAD

ACCORDING TO DR. TOMECKI

TELEDERMATOLOGY “According to a recent Academy poll,10% of dermatologists regularly used telemedicine and that number sky-rocketed to 91% during the PHE.”

Kenneth J. Tomecki, MD, FAAD

Telemedicine went from a blip on doctors’ radars before the pandemic to a practice and patient life-line post-COVID-19. While dermatologists have pioneered the technique for decades, its use has been adopted slowly.

“I only started to use teledermatology in the last 3 or 4 months. It fills a niche; it fills a void,” Dr. Tomecki said. “And it’s here to stay.”

Telemedicine’s role had been to provide access to rural and other outlying clinics. NASA has long used telemedicine for medical care on its International Space Station.

In early March Congress passed a law (HR 6074) com-monly referred to as COVID Phase One, which allowed for CMS waiver of telehealth restrictions on sites of service, devices, HIPAA compliance, and reimbursement, effectively allowing for telehealth to be used in lieu of in-person care. These waivers hurled telemedicine into the mainstream, with dermatologists and other medical specialties turning to it to care for patients when practices were shut down and later to maintain care but limit person-to-person contact. According to a recent AAD poll, 10% of dermatologists regularly used telemedicine and that number skyrocketed to 91% during the COVID-19 public health emergency.

The biggest opportunity



First-in-class clascoterone opens a new door for acne careBy Cheryl Guttman Krader Reviewed by Linda Stein Gold, MD, and Adelaide Hebert, MD

The FDA approval of clascoterone 1% cream (Winlevi, Cassiopea) for the topical treatment of acne vulgaris in patients 12 years of age and older gives clinicians a novel tool for managing the large and diverse population of patients who could benefit from hormonal-targeted therapy.

NEW DRUGS CLASCOTERONE

Evidence supporting the regulatory agency’s decision included data from 2

identically designed, phase 3 clinical trials that enrolled patients ages 9 years and older with moderate-to-severe acne (grade 3 or 4 on the 5-point Investigator Global Assessment [IGA] scale). As reported in an article published in JAMA Dermatology1, the trials met all their primary and secondary efficacy end points by demonstrated superiority of clascoterone 1% cream for getting patients to clear or almost-clear status and reducing the numbers of noninflammatory and inflammatory lesions. In addition, the data from the 12-week studies showed that the new product was safe and well-tolerated across the entire patient population.

“Clascoterone offers us an additional option for treating acne that has a unique mechanism of action in that it is a topical androgen receptor, competing with androgens for binding to the androgen receptor in sebocytes,” said Linda Stein Gold, MD, Director of Dermatology Clinical Research, Henry Ford Health System, Detroit, and Head, Division of Dermatology, Henry Ford Health System, West Bloomfield, Michigan.

“In vitro studies have shown that clascoterone reduces transcription of androgen-responsive genes that drive sebum production and activate inflammatory pathways, including those involved in

LINDA STEIN GOLD, MDDirector of Dermatology

Clinical Research, Henry Ford Health System,

Detroit, and Head, Division of Dermatology,

Henry Ford Health System, West Bloomfield, Michigan

ADELAIDE HEBERT, MDProfessor and Director of Pediatric Dermatology,

McGovern Medical School, UTHealth, Houston, Texas

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December 2020 | 49

www.thedermdigest.com/NEW_DRUGS

THE KEY 3

Clascoterone 1% cream (Winlevi, Cassiopea) is a

first-in-class topical androgen receptor

Its efficacy and safety for treating

moderate-to-severe acne and reducing

noninflammatory and inflammatory lesions was demonstrated in 2 pivotal trials including 1440 patients ages

9 years and older

Studies of clascoterone 1%

cream investigated its use as

monotherapy, but experts expect

it will be used in combination

regimens

proinflammatory cytokine synthesis. Through its actions, clascoterone targets more than one acnegenic pathway,” she said.

Dr. Stein Gold was an investigator in the clascoterone pivotal trials and a co-author of the JAMA Dermatology study, as was Adelaide Hebert, MD, Professor and Director of Pediatric Dermatology, McGovern Medical School, UTHealth, Houston. As a board-certified pediatric dermatologist, Dr. Hebert said she is excited that the FDA approved clascoterone cream for pediatric patient use.

She explained, “Lack of approval for use in the pediatric age group is often an obstacle in our ability to treat younger patients most effectively because insurers deny coverage for off-label medications. It is important to note that the pivotal trials included patients as young as 9 years of age and that the reason clascoterone was approved for use in patients ages 12 years and older was the limited number of younger participants, and not because of any evidence of differences in efficacy or safety in the preteen patients.”.

She added that she considers topical clascoterone an advance for other reasons as well.

“As a topical androgen receptor inhibitor, clascoterone is truly a first-in-class drug,” she said. “This new topical medication was used safely in non-pregnant females of childbearing age in the clinical trials, and it was very effective in males as well as females. Although we have systemic medications, including spironolactone and oral contraceptives, that could be used as hormonal treatment for acne in females, these agents have not been an option for males. Clascoterone opens up a new pharmacologic arena for younger patients, females, and males with moderate- to-severe acne.”

Pivotal trial summaryThe 2 pivotal trials included 1440 patients who were treated at 99 sites in the United States and several Eastern European

countries. Eligible patients had to have 30 to 75 inflammatory lesions, 30 to 100 noninflammatory lesions, and to have been on a consistent skin care regimen for at least 1 month that they agreed to continue for the duration of the 12-week study. Patients with nodulocystic acne were excluded.

The total population was comprised of 540 males and 900 females. The vast majority of the study participants (90%) were white, although approximately 30% of patients in 1 study were Fitzpatrick skin type IV-VI; 46% were in the pediatric age range (9 years to 17 years), and the adult subgroup included patients up to 58 years of age. The baseline IGA ratings showed the majority of patients in all 4 treatment groups (82% to 86%) had moderate acne with a mean of approximately 60 noninflammatory lesions and 42 inflam-matory lesions.

Patients were instructed to apply 1 g of their assigned study medication to the face twice daily, and they returned for scheduled follow-up visits at 4-week intervals. The protocols followed the FDA’s industry guidelines for establishing effectiveness of drugs intended to treat acne vulgaris and assessed 3 coprimary efficacy endpoints: 1) proportion of patients achieving treatment success at week 12, defined as an IGA rating of clear to almost-clear (score of 0 or 1) and a ≥2-point reduction from baseline; 2) absolute change from baseline in noninflammatory lesion count at week 12; and 3) inflammatory lesion count at week 12.

“We are in a new era of clinical trials in dermatology when medication safety during extended periods of use is being examined up front.”



The treatment success rates in the 2 studies were 18.4% and 20.3% for the clascoterone groups and 9.0% and 6.5% for the vehicle-treated patients. Clascoterone reduced noninflammatory and inflammatory lesion counts by approximately 30% and 45%, respectively, compared with reductions of approximately 16%-22% and 30%-36.5%, respectively, in the control groups.

Treatment compliance was also assessed by weighing the returned study product tubes. The data showed that the majority of patients

in both the clascoterone and control groups (almost 90%) were compliant with using their assigned treatment as defined by achieving ≥80% of expected application at each follow- up visit.

No safety issues occurred with the use of clascoterone cream during the 12-week treatment period of the pivotal trials. Local skin reactions, including erythema, scaling, dryness, and pruritus, occurred at similar rates in the clascoterone and vehicle treatment groups. Across the 2 studies, only 13 adverse

30% –36.5%

2 PIVOTAL TRIALS

FEMALES MALES

900 5409–17 YEARS OLD UP TO 58 YEARS

46% 54%

Treatment success rates in two 12-week studies

18.4% CLASCOTERONE GROUP 1

CLASCOTERONE GROUP 2

Reduced noninflammatory and inflammatory lesion counts

(approximate)

30%

45%

CONTROL GROUP 1

CONTROL GROUP 2

9.0%

6.5%16% –22%

20.3%

Study participants


December 2020 | 51

www.thedermdigest.com/NEW_DRUGS

Dr. Hebert also believes that clascoterone cream will be used in combination with other acne therapies.

“With the exception of oral isotretinoin, the standard of care for managing acne involves a multimodal approach, and that is especially true in the population with moderate-to-severe disease that was the focus of the clascoterone trials. Success in clearing acne in these patients almost always requires use of more than one medication,” she said.

REFERENCES

1. Hebert A, Thiboutot D, Stein Gold L, et al. Efficacy and safety of topical clascoterone Cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials. JAMA Dermatol. 2020;156(6):1-10.

2. Eichenfield L, Hebert A, Gold LS, et al. Open-label, long-term extension study to evaluate the safety of clascoterone (CB-03-01) cream, 1% twice daily, in patients with acne vulgaris. J Am Acad Dermatol. 2020;83(2):477-485.

DISCLOSURES: Dr. Stein Gold was a study investigator and a compensated (ie, honoraria, personal fees) advisor to Cassiopea. She has also received personal fees for advisory, speaking, consulting, research, and/or other ties with Almirall, Foamix, Galderma Laboratories, Novartis, Sol-Gel, and Sun Pharmaceuticals. Dr. Hebert was a study investigator and serves as a consultant to Cassiopea and has received honoraria and fees. She is an advisor or consultant for Allergan, Almirall, Galderma, and Ortho Dermatologics.

“Success in clearing acne in these patients almost always requires use of more than one medication.”

events were considered related to use of clascoterone cream, and application site dryness was the only 1 of the 13 that occurred in more than a single patient (n = 2).

None of the 13 adverse events considered related to topical clascoterone was judged to be severe, but 5 patients withdrew from the study because of an adverse event (all rated mild) as did 13 patients using vehicle cream. There were no systemic adverse events.

Experience with clascoterone in an open-label, long-term extension study enrolling patients who had completed a pivotal trial reaffirmed the safety and tolerability of the topical agent2. A total of 347 patients completed the 9-month extension trial, of whom 179 had used clascoterone for 12 weeks in a pivotal trial. No new safety signals emerged with ongoing use of clascoterone, and the overall frequency of treatment-related adverse events remained low. A total of 19 adverse events occurred that were considered related to clascoterone, but none was serious and most were mild.

“We are in a new era of clinical trials in dermatology when medication safety during extended periods of use is being examined up front. This is important for drugs used to treat acne and other conditions that require ongoing management,” said Dr. Hebert.

“The fact that there was a lack of any new or serious adverse events that would deter longer-term use of topical clascoterone further establishes that this new drug provides an opportunity for treating acne in a way we have not had available before.”

Adoption into clinical careClascoterone was studied only as monotherapy in the premarketing clinical trials and in a predominantly white patient population. Therefore, data from further studies and outcomes from clinical experience are needed to determine its best use in clinical practice. Dr. Stein Gold said she suspects that it may complement other treatment modalities.


Topical clascoterone is the first approved molecule for acne therapy that has a primary effect on sebaceous gland

function due to its anti-androgen effect on androgen receptors. Researchers have been attempting to develop this type of topical drug as long as I have been involved in acne research. Numerous other compounds failed, mainly because they could not deliver sufficient drug to the sebaceous glands or because they caused systemic adverse hormonal effects. Clasco-terone is metabolized to cortexolone, a mole-cule naturally found in human cells, and thus is free of systemic side effects.

No studies have been done to determine the magnitude of sebum suppression achieved with

COMMENTARY

JAMES J. LEYDEN, MD

Emeritus Professor CE of Dermatology,

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

A new treatment with great promise

clascoterone. Nor have been studies been done to determine if greater efficacy can be achieved at a higher concentration.

Importantly, in clinical trials for the FDA, clascoterone agent was evaluated as a mono-therapy. Acne is a multifactorial disease, and this new agent will and should be used in combination with other classes of drugs that counteract the other pathways in its pathophysiology.

DISCLOSURES: Dr. Leyden initially advised Medicis (now Valeant) to make an arrangement with Cosmo Pharmaceuticals, the Italian company that was developing clascoterone. He has served as an advisor to Cassiopea but has no ongoing relationships.

Acne is a multifactorial disease,

and this new agent will and should be

used in combination with other classes

of drugs that counteract the

other pathways in its pathophysiology.



December 2020 | 53

Acne vulgaris is the most common skin condition that dermatologists see, and thanks to the breadth of available therapeutic options, they have successfully treated patients with acne across the spectrum of disease severity.

Adding to this success, the FDA approval in the past 2 years (between August 2018 and August 2020) of 6 new products with indications for treating acne vulgaris is a key advance in patient care, considering that each product offers a distinct benefit, said Hilary Baldwin, MD.

The 6 new products include a novel oral antibiotic—sarecycline (Seysara, Almirall)—and 5 topical agents comprising 3 retinoids: trifarotene 0.005% cream (Aklief, Galderma), tretinoin 0.05% lotion (Altreno, Ortho Dermatologics), and tazarotene 0.045% lotion (Arazlo, Ortho Dermatologics); a topical tetracycline: minocycline 4.0% foam (Amzeeq, Foamix); and a first-in-class topical androgen receptor inhibitor: clascoterone 1.0% cream (Winlevi, Cassiopea) (Table).

“Our toolbox for treating patients with acne has not just gotten a lot bigger. It is a lot better,” said Dr. Baldwin, who is the Medical Director of the Acne Treatment and Research Center, Brooklyn, New York, and Clinical Associate Professor at Rutgers Robert Wood Johnson Medical Center, New Brunswick, New Jersey.

New products enrich acne treatment armamentariumBy Cheryl Guttman Krader | Reviewed by Hilary Baldwin, MD

PEDIATRICS ACNE

Hilary Baldwin, MDMedical Director Acne Treatment and Research Center Brooklyn, New York

Clinical Associate Professor Rutgers Robert Wood Johnson Medical Center New Brunswick, New Jersey

Hear Pediatric Derma-tologist Dr. Bernard Cohen from Johns Hopkins discuss these new acne agents at www.thedermdigest.com/cohen_podcast.

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“These new products represent true innova-tions, including advanced formulations that can improve drug delivery, tolerability, and patient acceptance, as well as novel agents that can change the way we treat acne. With these options, I believe that the future is extremely bright for clinicians and our patients with acne.”

ClascoteroneDr. Baldwin said that clascoterone 1.0% cream grants her wish for a topical acne medication that acts to inhibit sebum production. More-over, it brings an alternative to isotretinoin for controlling sebum production in men. “Our topical options for acne have allowed us to address 3 of the 4 factors that are involved in acne pathogenesis—hyperkeratinzation, inflammation, and inhibition of C. acnes. As a topical sebum inhibitor, clascoterone closes the tetrad so that we no longer have to prescribe an oral agent for patients who require sebum

inhibition to have maximum control of their disease,” said Dr. Baldwin.

“If topical clascoterone works as well in the real world as it did in the clinical trials, it will certainly be an important option.”

Topical retinoids Trifarotene 0.005% cream is a novel topical retinoid with data on its efficacy for treating truncal acne. Dr. Baldwin explained that trifar-otene is the first retinoid that has high selectivi-ty for the γ subtype of the retinoic acid receptor (RAR). Adapalene, tazarotene, and tretinoin all

TABLE. Acne products approved by the FDA since August 2018

Product (trade name) Indication Dosing Pivotal trial treatment success rates (%)*

Trifarotene 0.005% cream (Aklief)

Acne vulgaris in patients ≥9 years

QD Active: 29.4/42.3 (face)Placebo: 19.5/25.7 (face)Active: 35.7/42.6 (trunk)Placebo: 25.0/29.9 (trunk)

Tretinoin 0.05% lotion (Altreno)


QD Active: 16.5/19.9Placebo: 6.9/12.5

Tazarotene 0.045% lotion (Arazlo)


QD Active: 25.5/29.6Placebo: 13.0/17.3

Clascoterone 1.0% cream (Winlevi)


BID Active: 16.1/18.7Placebo: 7.0/4.7

Minocycline 4.0% foam (Amzeeq)

Inflammatory lesions of non-nodular moderate-to- severe acne vulgaris

QD Active: 8.1/15.8/30.8Placebo: 4.8/8.4/19.6

Sarecycline (Seysara)

Inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients ≥9 years

Weight-based

60 mg, 100 mg, or 150 mg QD with or without food

Active: 21.9/22.6Placebo: 10.5/15.3

*Success defined as % clear or almost clear with a ≥2 grade improvement from baseline Investigator Global Assessment Score at week 12. Data are from 3 clinical trials for minocycline and from 2 pivotal trials for all other products.

Tretinoin 0.05% lotionbecame the first available topical retinoid formulated in a lotion vehicle


December 2020 | 55

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bind to both RAR subtypes found in the skin, RARγ and RARβ. RARγ is the more prevalent.

“It is not clear that there is a clinical benefit of the selectivity of trifarotene for RARγ in terms of improving efficacy or reducing side effects relative to other retinoid molecules. It may explain, however, why trifarotene could be formulated topically in such a low concentra-tion, just 0.005%,” she said.

“This may translate into less systemic retinoid exposure, and that could have relevance in women who might get pregnant while using the medication as well as patients utilizing it on face, chest, and back.”

Discussing truncal acne, Dr. Baldwin com-mented, “We have always assumed that acne is acne and that lesions would respond similarly to treatment no matter the anatomic location. However, we have been lacking confirmatory evidence. The design of the phase 3 trials for trifarotene addressed that gap by analyzing lesion counts on the shoulders, upper back and anterior chest as well as the face.”

With their novel formulations, both tretinoin 0.05% lotion and tazarotene 0.045% address the tolerability issue that historically plagues topical retinoid treatment. Approved in August 2018, tretinoin 0.05% lotion became the first available topical retinoid formulated in a lotion vehicle.

Both formulations utilize a unique polymeric emulsion technology engineered to deliver the active ingredient and moisturizing agents evenly on the skin. The tazarotene formulation consists of a 3-dimensional mesh matrix that holds water and water-soluble hydrating agents along with droplets of tazarotene and oil-soluble moisturizing agents. The mesh dissolves upon contact with salts that are present on the skin surface, releasing the tretinoin or tazarotene and moisturizing/hydrating ingredients uniformly.

“In clinical use, the end result of the novel formulation is that the irritation profile of

topical tretinoin or tazarotene is dramatically reduced. It is not known which of the formu-lation’s features—the inclusion of moisturizing ingredients, the micronization of the active ingredient, or the polymeric technology that prevents larger ‘clumps’ of irritating tazaro-tene coming in contact with the skin—is most important for contributing to this benefit,” Dr. Baldwin said.

“Speaking from personal experience, however, I was able to use tazarotene 0.045% lotion on my skin for 7 consecutive days without having to take a break. That was never possible when I tried using any of the previously available tazarotene products because they were so drying.”

New tetracycline treatmentsMinocycline 4.0% foam brings a topical acne treatment in a patient-preferred vehicle and overcomes issues accompanying existing antibiotic options.

“Minocycline foam fills an important gap in our antibiotic therapies. As a topical product it minimizes concerns about systemic side effects, and unlike topical benzoyl peroxide, it does not bleach fabric,” Dr. Baldwin said.

THE KEY 3

Six new products for treating acne

vulgaris were approved by

the FDA since August 2018

The approvals include new

molecules, novel formulations, and

a first-in-class topical androgen receptor inhibitor

Adopting these new modalities

is warranted considering their unique features

and benefits

“Minocycline foam fills an important gap in our antibiotic therapies. As a topical product it minimizes concerns about systemic side effects, and unlike topical benzoyl peroxide, it does not bleach fabric.”


She also pointed out that pharmacokinetics data for minocycline foam show that its use results in very low or no systemic exposure to minocycline despite achieving very high levels in the skin.

“The cutaneous levels of minocycline are so high that we may not have to worry about the development of C. acnes resistance and therefore would not have to use benzoyl peroxide in combination to limit the emergence of resistance. Simplifying the treatment regimen by reducing the number of medications a patient needs to use has advantages for convenience, cost, and compliance,” Dr. Baldwin said.

Sarecycline is a new tetracycline- derived antibiotic with several distinguishing features, including approval for use in patients as young as 9 years of age, narrower antimicrobial

spectrum, and lower propensity to induce bacterial resistance.

“Sarecycline has minimal activity against gram-negative enteric bacteria. Theoretically therefore it is less likely than doxycycline or minocycline to alter the gastrointestinal (GI) tract flora, and in fact it had very good GI tolerability in the clinical trials,” Dr. Baldwin said. “In vitro testing also shows that sarecycline has a low

potential for inducing C. acnes resistance as it had a spontaneous mutation frequency on the order of 10-10. The clinical relevance of these laboratory data, however, remains to be seen.”

Dr. Baldwin also noted that the sarecycline pivotal trials captured changes in lesion counts for back and chest acne.

“With these data, we now have good evidence documenting that 2 of our therapeutic options for acne work well for truncal acne,” she said.

Implementing the new optionsDr. Baldwin said that although she was satisfied with her ability to effectively treat acne prior to the spate of FDA approvals (assuming patients had access to brand-name medications), she promptly adopted the new options as they became available.

“I strongly believe in embracing new tech-nologies and new therapies that represent improvements in our clinical options. I see no reason to reserve them for situations involving patients who are not responding to older agents,” she said.

“If I were the patient, I would not want to be treated with medications that may be less effective or that could irritate my skin if better alternatives are available.”

DISCLOSURES: Dr. Baldwin has ties with Almirall, Cassiopeia, Foamix, Galderma, and Ortho Dermatologics.

“I strongly believe in embracing new technologies and new therapies that represent improvements in our clinical options.”

“With these data, we now have good evidence documenting that 2 of our therapeutic options for acne work well for truncal acne.”


The recent approvals of numerous medications for acne greatly expand our therapeutic “toolkit,” proving that

pharmaceutical companies are listening to our demands, derived from patient feedback, to develop medications that overcome the efficacy-tolerability tradeoff.

As Dr. Baldwin explains, research and devel-opment in acne treatment has not waned or faltered. This is evidenced by:

• Foamix converting minocycline into a stable topical medication delivered at such a high concentration that it may even make the development of antibiotic resistance nearly impossible,

• Galderma developing a novel retinoid molecule, trifarotene, that follows the trend in our specialty toward precisely target-ed treatments, in this case the ubiquitous RAR-γ receptor,

• Ortho Dermatologics’ innovative approach to vehicles, that in the case of its new tazarotene 0.045% lotion, delivers similar efficacy as generic tazarotene 0.1% cream at less than half the concentration and with better tolerability,

• Cassiopeia’s achievement of bringing to market a new molecule in clascoterone 1.0% cream that uses a new mechanism of action for a topical product, ie, reducing sebum production, and

• Almirall improving our systemic antibiotic options with sarecycline, a novel tetracycline-class antibiotic with a narrow spectrum that effectively bypasses the enteric microbiome, and has very low propensity to cause C. acnes resistance.

I am as enthusiastic as Dr. Baldwin about not only all these new medications, but also the trend toward continued innovation in acne treatment. By enhancing compliance through improved tolerability of topical medications, developing medications with totally new mechanisms of action, and either avoiding systemic antibiotics by delivering the mol-ecule topically or improving our systemic antibiotic options with a molecule having greater selectivity for C. acnes, pharmaceutical companies are providing us with options to better help our patients.

DISCLOSURES: Dr. Lain has been an investigator, consultant, and/or speaker for Almirall, Cassiopeia, Foamix, Galderma, and Ortho Dermatologic.

Ted Lain, MD, MBA Chief Medical Officer Sanova Dermatology

Austin, Texas

I am as enthusiastic

as Dr. Baldwin about not only all these new medications, but also the trend toward

continued innovation in

acne treatment.

COMMENTARY

Derm asked, pharm acted

December 2020 | 57

www.thedermdigest.com/PEDIATRICS_ACNE



Oral zinc supplementation

200 mg BIDIS INDICATED REGARDLESS OF

THE PATIENT’S ZINC LEVEL

NAE is highly linked to HCV infection and may develop as an early sign preceding onset of viremia

DISCUSSION

Localization to the acral areas and a presen-tation that could resemble a variety of papu-losquamous disorders led us to formulate a broad differential diagnosis.

Conditions such as psoriasis in skin of color, necrolytic acral erythema (NAE), nutritional deficiency, acrokeratosis paraneoplastica (Bazex syndrome), and others could be considered. Many of these manifest as a psoriasiform dermatitis. Therefore, additional work-up should be considered. Some can be associated with underlying health conditions such as malignancy and infections.

Epidemiology of NAENAE is a rare condition that was first described only approximately 25 years ago in a patient in Egypt.1 As of 2019, 145 cases of NAE were reported in the literature, 119 from Egypt.2 Its true prevalence is unknown, but reports have been increasing, perhaps because growing awareness is leading to increased recognition.

Most cases of NAE have been in adults who are middle aged (35 to 55 years), but affected patients have ranged in age from 9 to 76 years.2,3 Males and females appear to be equally affected; most patients have had darker skin types.2,3

Clinical and histopathological findingsNAE tends to affect the lower limbs. However, there may be lesional involvement of the knees, thighs, genitalia,

abdomen, buttocks, hands, and elbows, as well as the nails.3 Palms, soles, nails, and mucous membranes are generally spared. Patients typi-cally report pruritus and may also complain of burning.

The manifestations have been divided into initial, well-developed, and late stages.4 Initially, scaly erythematous papules or plaques appear with a dark red-violet or eroded central region. Subsequently the lesions coalesce and become scaly with lichenification. Hyperpigmentation increases, and pustules may appear. In the late stage, hyperpigmentation remains, there may be superficial epidermal necrosis, and the lesions become thinner with possible crusting and erosions.

The histopathological features of NAE also vary by stage (Table).4 NAE lesions may under-go spontaneous remission and relapse.5

Etiology and pathophysiologyNAE is highly linked to hepatitis C virus (HCV) infection and may develop preceding onset of viremia. The population rate of HCV is relatively high in Egypt. Interestingly, no cases have been reported in Japan, where there is also a high prevalence of HCV, and NAE has been reported in the absence of HCV.3 It has also developed following vaccination for hepatitis B infection and after treatment with rivaroxaban.6,7

The pathophysiology of NAE is yet to be fully elucidated. It may involve hepatic dysfunction leading to metabolic abnormalities, particularly zinc deficiency, but also including hypoalbu-minemia, hypoaminoacidemia, and hyper-glucagon emia. Zinc deficiency has been reported in lesional and perilesional skin in patients with a normal serum zinc level.8

Differential diagnosis and work-upConditions to consider in the differential diag-

Eruption on the bilateral lower extremities continued from C3

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and should be referred to a gastroenterologist, hepatologist, or infectious disease specialist. Oral zinc supplementation (200 mg BID) is also indicated regardless of the patient’s zinc level. Zinc may provide therapeutic benefit as a treatment for NAE through multimodal mechanisms that relate to its reported anti-

inflammatory, immunomodulatory, antiviral, and antioxidant properties.3 Consistent with published reports, the only patient I have seen with NAE achieved complete resolution when treated with oral zinc supplementation.

Other treatments for NAE reported in the literature include topical tacrolimus, vitamin B1 and vitamin B6, and phototherapy.3,9 Topical, intralesional, and systemic cortico steroid treatment has also been described, but without consistent benefit.2,3 Tinea pedis should be identified and treated in any patient with a dermatitis involving the feet.

Patients with this rare condition should be counseled that while the condition may clear, there can be residual scarring and pigmentary changes, and the lesions may recur.²

nosis of NAE include chronic eczema, psoriasis, necrolytic migratory erythema, lichen simplex chronicus, acrodermatitis enteropathica, and pellagra, although these alternative diagnoses can often be ruled out based on the absence of their hallmark clinical and laboratory features.

Necrolytic migratory erythema, a condition related to glucagonoma, tends to develop in intertriginous areas. In addition, affected patients will have elevated blood glucose and glucagon levels and likely will present with unintentional weight loss. Cutaneous lesions associated with pellagra usually develop on sun-exposed skin, and the patient’s history may include gastro intestinal symptoms. Laboratory testing should include serology for HCV infection, liver function tests, and zinc. Other tests to consider include serum glucagon, biotin, free fatty acids, and vitamin B3.

ManagementPatients with NAE who test positive for HCV infection should receive antiviral treatment with interferon alpha-2b and/or ribavirin

TABLE. Histopathological features of NAE according to stage

Initial Well-developed Late

Epidermal acanthosis and spongiosis

Superficial dermal inflammatory infiltrate

Pigment incontinence

Parakeratosis

Prominent papillomatosis

Subcorneal pustules

Epidermal pallor

Necrotic keratinocytes with epidermal cleft formation

Focal hypergranulosis


Vascular ectaisa

Papillary dermal inflammatory infiltrate

Minimal-to-moderate inflammatory cell infiltrate


Consistent with published reports, the only patient I had seen previously with NAE achieved complete resolution

when treated with oral zinc supplementation.

REFERENCES

1. el Darouti M, Abu el Ela M. Necrolytic acral erythema: a cutaneous marker of viral hepatitis C. Int J Dermatol. 1996;35(4):252-256.

2. Nutan F. Necrolytic acral ery-thema. June 25, 2020. https://emedicine.medscape.com/article/1098243-overview#a4. Accessed October 14, 2020.

3. Inamadar AC, Shivanna R, Ankad BS. Necrolytic acral erythema: current insights. Clin Cosmet Investig Dermatol. 2020;13:275-281.

4. Abdallah MA, Ghozzi MY, Monib HA, et al. Histological study of necrolytic acral erythema. J Ark Med Soc. 2004;100(10):354-355.

5. Bentley D, Andea A, Holzer A, Elewski B. Lack of classic histology should not prevent diagnosis of necrolytic acral erythema. J Am Acad Dermatol. 2009;60(3):504–507.

6. Pernet C, Guillot B, Araka O, Dereure O, Bessis D. Necrolytic acral erythema following hepatitis B vaccination. Br J Dermatol. 2014;171(5):1255–1256.

7. Pathania YS, Budania A. Rivaroxaban induced necrolytic acral erythema. Postgrad Med J. 2019;1.

8. Najarian DJ, Lefkowitz I, Balfour E, Pappert AS, Rao BK. Zinc deficiency associated with necrolytic acral erythema. J Am Acad Dermatol. 2006;55 (5 Suppl):S108–S110.

9. Manzur A, Siddiqui AH. Necro-lytic acral erythema: successful treatment with topical tacroli-mus ointment. Int J Dermatol. 2008;47(10):1073-1075.

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COVID-19: An Update for the DermatologistBy George Martin, MD

Will there be a standout treatment and vaccine to fight COVID-19 in the coming months? And will vaccine candidates that emerge winners in this race allow us to go on with our practices and our lives?

COVID CONCERNS

Monoclonal antibody against SARS-CoV-2 update

REGN-COV2: Monoclonal antibody cocktail against SARS-CoV-2 I interviewed Christos Kyratsous, PhD, Vice President of Research of Infectious Diseases and Viral Vector Technologies at Regeneron, about the development of Regeneron’s REGN-COV2.trial to observe the effects of two doses of their vaccine, instead of just one. The vaccine requires no refrigeration which is important for global distribution.

We discussed Regeneron’s strategy for the clinical trials program. Neutralizing antibodies against SARS-CoV-2 started with successful antibody treatments developed for Ebola. Two approach-es have been used for neutralizing antibodies against SARS-CoV-2. One is from genetically humanized mice, the other from convalescent patients’ B cells. This strategy yielded a sizeable antibody collection with diverse sequences, 3-dimensional structure, binding properties, neutralization, and antiviral activity against the SARS-CoV-2 spike protein.

Pairs of highly potent antibodies that bind to the receptor-binding domain of the spike protein were selected to minimize risk of “viral escape.” Dr. Kyratsous explained that a mutated virus has been observed in response to selective pressure from a single antibody treatment. Science mag-

azine published those results at https://science.sciencemag.org/content/sci/early/2020/06/15/science.abd0831.full.pdf.

In a study in animals infected with the virus posted August 20 on the site bioRxiv, researchers reported that REGN-COV-2 notably reduced virus load in the lower and upper airway and decreased virus-induced pathological sequelae (https://www.biorxiv.org/content/10.1101/2020.08.02.233320v1).

A seamless phase 1/2/3 trial in more than 900 non-hospitalized COVID-19 patients has results from a cohort of 275 patients, showing the REGN-COV2 antibody cocktail reduces viral loads and symptoms versus placebo in non- hospitalized COVID-19 patients. The great-est improvements were in those patients who had not mounted their own effective immune response prior to treatment and had a high viral load. The company also has about 2000 hospital-ized patients enrolled in a seamless phase 1/2/3 trial, according to Regeneron (https://investor.regeneron.com/static-files/a596a85e-e72d-4529-8eb5-d52d87a99070).

Other studies are under way or recruiting for REGN-COV2, including a prophylaxis study of household contacts using a subcutaneous formu-lation and a study of normal human volunteers receiving multi-dose injections using a subcuta-neous formulation.

George Martin, MD

Updating dermatologists on treatments, vaccine developments, and the outlook for the next 6 months

Read more on COVID considerations in treating patients with psoriasis at www.thedermdigest.com/psoriasis_in_ pandemic.

continued on page 63

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The phase 3 RECOVERY study arm in the sickest hospitalized patients (those receiving high-flow oxygen or mechanical ventilation) was suspended after an independent monitoring committee observed a potential safety signal and an unfavorable risk/benefit profile.

Eli Lilly’s bamlanivimab: A monoclonal antibody against SARS-CoV-2 Eli Lilly and Company’s investigational neu-tralizing antibody bamlanivimab (LY-CoV555) received an Emergency Use Authorization (EUA) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients 12 years and older with a positive COVID-19 test, who are at high risk for progressing to severe COVID-19 and/or hospitalization. LY-CoV555 is a potent anti-spike neutralizing monoclonal antibody that binds with high affinity to the receptor-binding domain of SARS-CoV-2, and was derived from convalescent plasma obtained from a patient with COVID-19. Bamlanivimab should be administered via a single 700-mg IV infusion as soon as possible after a positive COVID-19 test and within 10 days of symptom onset. The EUA is based on data from BLAZE-1, a randomized, double-blind, placebo-con-trolled phase 2 study in patients with recently diagnosed mild-to-moderate COVID-19 in the outpatient setting. Patients treated with bam-lanivimab showed reduced viral load and rates of symptoms and hospitalization. On day 29, the percentage of patients who were hospitalized was 1.6% in the LY-CoV555 group and 6.3% in the placebo group. In a post-hoc analysis that was focused on high-risk subgroups (an age of ≥65 years or a BMI of ≥35), the percentage of hospi-talization was 4.2% in the LY-CoV555 group and 14.6% in the placebo group.

In summary, the use of monoclonal antibodies appears to have the most beneficial outcomes early in the course of the disease, ie, pre-hospi-talization and before “cytokine storm” sets in.

Vaccine updateAs we go to press, the New York Times’ vaccine

tracker reports that there are 54 vaccines in clin-ical trials on humans, and at least 87 preclinical vaccines under active investigation in animals.

Newer RNA and DNA vaccine platforms have been developed over the past decade to provide a more rapid vaccine development pathway. Paul A. Offit, MD, Director of the Vaccine Education Center and an attending physician in the divi-sion of infectious diseases at Children’s Hospital of Philadelphia, stated in an interview in Genetic Engineering and Biotechnology News (GEN): “What makes RNA technology attractive is that it’s easy to make. The minute that you knew the sequence of this virus in January, then you knew the genetic sequence of the spike protein, so it was plug and play…”

MRNA Vaccines from Pfizer/BioNTech interim and final analysis and Moderna interim data analysis from vaccine trialsFrontrunners in the COVID-19 vaccine develop-ment race Pfizer/BioNTech and Moderna recently released their vaccine trial data. As we go to press, the results are from press releases and have not been peer-reviewed by outside scientists or pub-lished in a medical journal. Of interest is that both platforms are mRNA vaccines that use a propri-etary lipid capsules to deliver the mRNA vaccine. The fact that both trials had similar efficacy and safety profiles involving a combined total of more than 70,000 patients is very encouraging.

On November 9, Pfizer and BioNTech released its first interim analysis of its BNT162b2 vaccine, which proved to be more than 90% effective in preventing COVID-19 in participants without prior SARS-CoV-2 infection. This first interim analysis was to occur after 32 volunteers, both those who received the vaccine and those on placebo, had contracted COVID-19. Following vaccination on day 1 and 22, at day 29 if fewer than 6 volunteers in the group who received the vaccine had developed COVID-19, the com-panies would make an announcement that the vaccine appeared to be effective. When samples were recently tested, there were 94 cases of

8.375”

10.875”

ORACEA - The Dermatology Digest - PRINT AD (PG.2) 8.375” x 10.875”

©2020 Galderma Laboratories, L.P. All rights reserved.All trademarks are the property of their respective owners. Galderma Laboratories, L.P., 14501 N. Freeway Fort Worth, TX 76177 USMP/ORA/0011/0220 02/20

www.oracea.com

REFERENCES

1. ORACEA [package insert]. Fort Worth, TX: Galderma Laboratories, L.P.;2013. 2. Del Rosso JQ, et al. Two randomized phase Ill clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791–802. 3. Del Rosso JQ, et al. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7(8):573-576. 4. Bhatia N. ORACEA 40 mg capsules for papulopustular rosacea. The Dermatologist. 2013;6(21s):1-4. Available at: https://pdfs.semantic scholar.org/363e/66311811307ccfdc9e9d8bd8b594bdaf4254.pdf. Accessed: October 2019. 5. Theobald K, et al. Anti-inflammatory dose doxycycline ( 40 mg controlled-release) confers maximum anti-inflammatory efficacy in rosacea. Skinmed. 2007;6(5):221-226. 6. Wise RD. Sub microbial doxycycline and rosacea. Compr Ther. 2007;33(2):78-81. 7. Etchegaray JP, Wagner N, Shah MS, Difalco RJ, inventors; Galderma S.A., Cerovene, Inc. assignees. Doxycycline formulations, and methods of treating rosacea. US Patent 8,652,516 Bl. February 18, 2014. 8. Preshaw PM, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planning in subjects with periodontal disease. J Periodontal. 2008;79(3):440-452.

ORACEA®

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“Monoclonal antibodies

appear to have the most beneficial

outcomes early in the course

of the disease, i.e. pre-hospital

and before ‘cytokine storm’

sets in.”

continued from page 60

Moderna’s

mRNA-1273

vaccine

Frontrunner

Pfizer’s BNT162

(a collaboration

with BioNTech)

The viral vector

vaccine CanSino

Ad5-nCoV

Adenovirus 26

(Ad26) by Johnson

& Johnson

1

2

3

4

Leaders of the pack



COVID-19. The clinical trial will continue to final analysis at 164 confirmed COVID-19 cases to collect data and characterize the vaccine’s per-formance against additional study endpoints.

According to the company, the study has enrolled 43,538 volunteers and 38,955 have received their second dose. About 42% of global participants and 30% of US participants are racial and ethnic minorities. The FDA is requiring half of those receiving the vaccine to be monitored for safety issues for 2 months.

On November 17, the data from the primary efficacy analysis were released. They demon-strated BNT162b2 to be 95% effective against COVID-19 beginning 28 days after the first dose. There were 170 confirmed cases of COVID-19, with 162 observed in the placebo group versus 8 in the vaccine group. Vaccine efficacy was consistent across age, gender, race and ethnicity demographics; observed efficacy in adults over 65 years of age was more than 94%. The vaccine was well-tolerated across all populations with no serious safety concerns observed. The only grade 3 adverse event greater than 2% in frequency were fatigue at 3.8% and headache at 2.0%.

Details from the independent monitors have not been released. Of particular interest is whether the vaccine has the ability to prevent vaccinated patients from spreading COVID-19 and to maintain efficacy over time. In early clinical human testing, the vaccine produced a robust T-cell response. Most importantly, there were no serious safety concerns reported in the trial. According to Pfizer, vaccinations could begin sometime in December. Logistical concerns remain because the vaccine requires specialized ultracold freezers capable of cooling below -700C (-940 F) to maintain a shelf life of 6 months. At 250 F the shelf life is 5 days.

Moderna’s vaccine, mRNA-1273On November 15, the trial oversight group shared its interim analysis of the trial data of Moderna’s phase 3 trial of the investigational COVID-19 vaccine known as mRNA-1273. The

Moderna vaccine reduced the risk of COVID-19 infection by 94.5%. There were 95 cases of infec-tion assessed 14 days post second vaccination: 5 among patients who received the vaccine at day 1 and 29, and 90 among patients who received placebo. Of importance, all 11 severe COVID-19 infections occurred in the placebo group. Mod-erna reports that of its 30,000 enrollees, 6000 identified as Hispanic or Latinx and more than 3000 participants identified as Black or African American, as well as 7000 people older than 65, and 5000 with high-risk chronic diseases. No serious safety concerns were reported. Ques-tions remain whether vaccinated patients are capable of spreading the virus and to what extent the vaccine’s efficacy is maintained over time. Despite these unanswered questions, early clin-ical testing in humans revealed a robust T-cell response. “Cold chain” delivery is also an issue because the vaccine needs to be stored at -200 C but has a shelf life of 1 month at 250 F (modified refrigeration temperatures).

Other playersJohnson & Johnson’s Adenovirus 26 (Ad26) platform began a phase 3 trial with as many as 60,000 subjects in September. On October 12, Johnson & Johnson announced it put its trial on pause to investigate an adverse reaction in a volunteer but resumed the trial 11 days later. On November 16, J&J launched a second phase 3 trial to observe the effects of 2 doses of their vaccine, instead of just one. The vaccine requires no refrigeration, which is important for global distribution.

AstraZeneca’s vaccine (AZD122) employs a vec-tored platform that employs a chimpanzee ade-novirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein. On September 6, AstraZeneca halted its phase 2/3 global trials of the vaccine to investigate a single volunteer who developed transverse myelitis. Within a week, the trials began in all countries except the US. On October 23, the FDA autho-rized the restart of the trial with results expected by the end of December.

“

www.thedermdigest.com/COVID_CONCERNS

Logistical concerns

remain as the Pfizer vaccine

requires specialized ultracold freezers

capable of cooling below -70˚ C (-94˚ F)

to maintain a shelf life

of 6 months. At 25˚ F

the shelf life is 5 days.”


December 2020 | C3

Eruption on the bilateral lower extremities is rare conditionBy Cheryl Guttman Krader | Reviewed by Seemal R. Desai, MD

DIAGNOSE THIS ZEBRA

CASE HISTORY

A 58-year-old woman of Indian origin presented with a chronic, hyperkeratotic, verrucous eruption on the bilateral lower extremities (Figure 1). The lesions covered the dorsal aspect

of the feet and toes and extended to just above the ankles. Erosions and flaccid bullae were also seen along with areas of erythema, scarring, and hypopigmentation. Toenail dystrophy was present as well.

The patient reported that the condition was pruritic and developed with an acute onset approximately 6 to 8 months earlier. There were no other remarkable findings on skin examination or medical history.

The patient was prescribed topical triamcinolone acetonide 0.1% oint-ment twice daily along with emollients and was scheduled for a follow- up visit in 1 month. On return, the lesions were only mildly improved.

What is your suspected diagnosis?

Seemal R. Desai, MD, FAADClinical Assistant Professor of DermatologyUniversity of Texas Southwestern Medical CenterDallas, Texas

Founder & Medical Director Innovative Dermatology, PAPlano, Texas

Presented at

Maui Derm 2020

FIGURE 1.

Image courtesy of Seemal R. Desai, MD (all rights reserved)

A DIFFERENTIAL DIAGNOSIS CASE

For more on this case, turn to page 33

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INNOVATIVEtopical skin medications across a diverse pipeline

IMPROVEMENTS in the tolerability of topical dermatological drug products

NOVEL FIXED-DOSEcombinations of 2 otherwise incompatible drug substances to be delivered in the same formulation

DELIVERY TECHNOLOGY DESIGNED TO CONTROL TOPICAL DRUG RELEASE

Sol-Gel, a pharmaceutical company on the cutting edge of dermatological solutions, is currently developing…

Research using the proprietary delivery technology is also ongoing to determine the potential for:

See how Sol-Gel is transforming topical treatmentwww.Sol-Gel.com/technology

@SolGelDerm

Advanced Topical Therapy

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