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Vol. 2, No. 3 | March 2021 Hidradenitis Suppurativa FOUR CORNERS OF CARE

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The LEO Pharma logo, LEO Pharma, and Finacea are registered trademarks of LEO Pharma A/S. www.FinaceaFoam.com ©2020 LEO Pharma Inc. All rights reserved. March 2020 MAT-32481 THE Contents www.thedermdigest.com Volume 2, Number 3 | March 2021

14 Cover Article You can help hidradenitis suppurativa patients achieve long-term control and avoid flares

2 20 Ted Talks Pediatrics

Do you talk politics in your office? Combination therapy can produce good clearance of pediatric warts

6 Literature Lessons

Research updates in rheumatologic diseases, psoriasis, hair and nails, contact dermatitis, acne, rosacea, and more continued on page 3

March 2021 | 1 Ted Talks “ In politics, stupidity is not a handicap.”

—Attributed to Napoleon Bonaparte

he year was 1960, in the middle of a highly conten- T tious presidential contest between John F. Kennedy and Richard Nixon. I was only 11 years old as I sat at the kitchen table while my parents discussed the upcoming election. My father was a dedicated Democrat and my mother a devout Republican, Ted Rosen, MD, FAAD following steadfastly in the foot- Editor-in-Chief steps of their own parents. I was This is Ted's take. pretty amazed at how quietly, What's yours? calmly, and openly they expressed [email protected] their differing opinions about the candidates and their various surrogates often candidates and the two major political parties. used hyperbole about the “fate of the human While they were clearly destined to cast differ- race” hanging in the balance of this particular ing votes, they were at least trying to under- election cycle. Dueling media outlets were stand where the other one stood on critical busy casting aspersions on the other’s com- issues, and why. They even arrived at consensus mentators, while claiming that they had an on a few items, and concluded that the world actual monopoly on the truth. I saw, and I would go on regardless of who got elected. This suspect you did too, a country so hyperpolar- was democracy in action, and in fact, democra- ized that civilized, rational discussion was cy at its very best. I will never forget that night; nearly impossible. it left a lasting impression on me. All this brings me to the point of this edito- Fast-forward to the election of 2020 and rial: Does politics belong in the medical office? compare this childhood experience to today's My employer, a medical school, of course political scene, one dominated by name-call- forbids wearing campaign buttons or posting ing and mudslinging, demonization of can- campaign posters. So, there are no overt visual didates, and attempts to drown out speakers cues to suggest that the topic is welcome. with whom a crowd doesn’t agree. Violence, Nonetheless, during the recent election, many or the threat of violence, often pervaded the patients attempted to engage me in political discourse. A political situation in which both discussion. “Isn’t it disgusting that ... ” or “Can

I cherish those individuals who have entrusted me with their care for so many decades, and it would be painful to potentially “ lose them over an issue like marginal tax rates.” continued on page 4 2 | The Dermatology Digest Contents continued from page 1

Cosmetic Corner New Drugs 36 45 Rejuvenation Melasma Will regeneration replace A new agent is safe, well rejuvenation? The second tolerated, and effective of 2 articles covering regenerative aesthetic 23 medicine Pediatrics 30 It may take some Crystal Ball sleuthing to determine what's causing a child's Topical cannabinoids 49 contact dermatitis are gaining ground in Actinic Keratosis dermatology, despite 25 lingering stigma and A newly available Literature Update spotty FDA approval ointment shows promise for actinic keratosis Like it or not, you may be the only doctor many of your patients see regularly

39 High-impact innovations Two cosmetic 55 dermatologists share Diagnose this Zebra the innovations they feel The puzzling case have the most impact of the purple penis

March 2021 | 3 www.thedermdigest.com/TED_TALKS

continued from page 2 THE you believe this ... ” were heard many a time political discussion belongs inside the doctor- in the examination room. I also had scores patient relationship, so let’s get back to your of patients exclaim that they were “sure” they medical problem.” This was not always easy. knew my political leaning, and that’s why they I readily admit that, on some occasions, I had www.thedermdigest.com felt comfortable sharing their opinions with to suppress an overwhelming urge to throttle me. Of course, half of them were dead wrong a patient, while at other times I felt like giving CORPORATE in their supposition! In an environment of a “high-five.” However, I consciously chose AMY AMMON extreme partisan positioning and almost total the path of strict neutrality and attempted to Executive Director, Publisher refusal to find any common ground, I felt that completely separate the election and associ- [email protected] DON BERMAN these situations put me in an uncomfortable ated political dogma from my professional Executive Director, Digital Strategy and difficult position. No matter what I would life. Similarly, when staff—be they trusted [email protected] say, there could be negative consequences. If nurses, medical assistants, schedulers, or bill- GEORGE MARTIN, MD Executive Director the patient espoused a political preference with ing personnel—would bring up the election which I did not particularly agree, it could lead or matters surrounding it, I would stop and EDITORIAL to an unpleasant verbal altercation and even say something along these lines: “I’m not go- TERESA MCNULTY Print Editor lead to loss of the patient. Being in practice ing to tell you what you can and can’t say, but ELIZA CABANA Digital Editor NANCY BITTEKER Creative Director I chose to basically banish political discourse from the office.” MICHAEL WESTFALL Product Manager for 42 years, I cherish those individuals who political disagreements can cause permanent “have entrusted me with their care for so many negative feelings which could interfere with decades, and it would be painful to potentially our functioning as a harmonious team. Also, Print Circulation: 13,500 dermatologists USA lose them over an issue like marginal tax rates. I really would prefer if you avoiding discussing 2,800 dermatological NP/PA’s Conversely, should the patient champion a po- politics with any patients, as you notice I do The Dermatology Digest ® is published monthly by The Dermatology Digest, sition with which I did identify, and I verbally myself.” For the most part, a single admon- LLC, 88 N Main Street, Pearl River, confirmed that, I could imagine that person ishment along these lines led to peace in the NY 10965. quoting my stance to anyone and everyone as office, both before and after the election. © 2020 The Dermatology Digest, LLC. All rights reserved. No part of this pub- a sort of validation. I could just hear the pa- lication may be reproduced or trans- Was I being a coward? Should I have put my mitted in any form or by any means, tient declaring to a neighbor, friend, relative, electronic or mechanical including by vision of the “best” America front and center, photocopy, recording, or information or co-worker, “Well, my physician, Dr. Ted on full display? Should I have vociferously storage and retrieval without permis- Rosen, told me that he thinks ... ” Wouldn’t it sion in writing from the publisher. stated and then defended what I personally Authorization to photocopy items for just be my luck if the audience for that declara- internal/educational or personal use, believe in? Should I have used my special posi- or the internal/educational or personal tion might be another of my patients who use of specific clients is granted by The tion of authority as a purveyor of health care Dermatology Digest, LLC. For uses disagreed with my take on some issue? Bingo: to try to secure a few votes for one candidate beyond those listed above, please another potentially lost patient. Moreover, who direct your written request to Amy or another in local, state, or national elections? Ammon, Executive Director, Publisher knows how accurately I might be quoted? at: [email protected]. Was I shirking my moral or civic duty? What POSTMASTER: Please send address So, although I am interested in, and relatively do you think? Drop me a note and tell me changes to The Dermatology Digest LLC, 88 N Main Street, Pearl River, NY well informed about, political issues, and how you handle this issue in your professional 10965. Printed in the U.S.A. do have fairly strong convictions, I chose to environment. I will share a synopsis (“digest”) The Dermatology Digest ® does not verify any claims or other information basically banish political discourse from the of your opinions in a future issue. Maybe I can appearing in any of the advertisements  contained in the publication and cannot office. When patients raised partisan politi- also share a few useful tips or suggestions! take any responsibility for any losses cal questions or made inflammatory politi- or other damages incurred by readers in reliance on such content. cal statements, I simply said, “I don’t think The Dermatology Digest ® welcomes unsolicited articles, manuscripts, photographs, illustrations and other materials, but cannot be held respon- sible for their safekeeping or return.

4 | The Dermatology Digest THE

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EDITORIAL BOARD

EDITOR-IN-CHIEF

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

March 2021 | 5 Off-label Pearl

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

Metformin: a cheap, relatively safe medication Metformin, either as a stand-alone or as part of a regimen, is beneficial in women with polycystic ovary syndrome (PCOS) who have acne. Dosage required may vary from 500 mg QD to 500 mg TID. This recommendation is based on a meta-analysis including 51 studies and 2405 patients. TO READ MORE: Yen H, et al. Metformin therapy for acne in patients with polycystic ovary syndrome: a systematic review and meta-analysis. Am J Clin Dermatol. 2020 Oct 13. DOI: 10.1007/s40257-020-00565-5.

Metformin has also been described as beneficial for patients with hidradenitis suppurativa. This recommendation is based on a recent study of 53 patients (85% female) who took a mean dose of 1.5 g/day during a follow-up period of just under a year and showed a 68% rate of subjective response. TO READ MORE: Jennings L, et al. Metformin use in hidradenitis suppurativa. J Dermatolog Treat. 2020;31(3):261-263.

Literature Lessons RHEUMATOLOGIC DISEASES

Many inflammatory diseases are co-managed by dermatologists and rheumatologists. Beware the increasing trend toward NON-MEDICAL SWITCHING BY INSURANCE CARRIERS. For example, beginning January 1, 2021, patients who use the Express Scripts formulary will be forced to switch from secukinumab to ixekizumab, regardless of whether or not they or their doctor agree with this change.

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

HAIR AND NAILS ATOPIC PSORIASIS DERMATITIS Cases of TELOGEN EFFLUVIUM have increased since Triggers for flares ofPEDIATRIC PSORIASIS the onset of the COVID-19 pandemic. It is theorized Although much include infections, emotional stress, and cigarette that this may be associated with increased stress, more work remains smoke exposure. anxiety, and sleep disturbance. to be done to TO READ MORE: Pithadia DJ, et al. Translating the TO READ MORE: Xerfan EMS, et al. The role of sleep determine optimal 2019 AAD-NPF guidelines of care for the man- in telogen effluvium and trichodynia: a commentary formulations and agement of psoriasis in pediatric patients. Cutis. in the context of the current pandemic. J Cosmet usage patterns, a 2020;106:257-260. Dermatol. 2021;Jan 2. doi: 10.1111/jocd.13929 small observational study indicated that TOPICAL CANNABINOIDS hold promise in the management of atopic dermatitis and other A very small American prospective study indicates eczematous states. that APREMILAST THERAPY may improve signs and symptoms of nail psoriasis. TO READ MORE: 30 mg apremilast BID led to a Maghfour J, et al. An observational study of the % CONTACT DERMATITIS application of a 75 topical cannabinoid decrease in mNAPSI scores Contact dermatitis related to MINOXIDIL use for gel on sensitive androgenetic alopecia is usually due to a solvent (objective measurement of nail psoriasis severity) dry skin. constituent of the product. However, it can be due to Week 12 Week 36 Week 52 hypersensitivity to the minoxidil itself, as document- J Drugs Dermatol. ed in this report. Patch testing is accomplished with 2020;19(12): % % % pure minoxidil powder provided by the manufacturer. 1204-1208. 27.2 36.4 45.5 TO READ MORE: Nagarajan H, Rai R. Contact derma- of patients of patients of patients titis to minoxidil. Contact Dermatitis. 2021;84(1):57. Oak A. EADV Congress, Oct 2020.

EFINACONAZOLE AND LULICONAZOLE are relatively Due to exclusion of PREGNANT WOMEN and inade- recent introductions to the American anti-fungal ar- quate identification of pregnancies in registry data, mamentarium. Although considered quite rare, acute little reliable information exists to guide treatment contact dermatitis has been documented to occur of psoriasis during pregnancy. In general, limited due to hypersensitivity to both agents. non-occluded use of topical steroids, UVB photo- therapy, and administration of TNF-alfa inhibitors TO READ MORE: Fujimoto K, et al. Contact dermatitis are considered “reasonable.” caused by efinaconazole and luliconazole.J Nippon Med Sch. 2020 Aug 31. TO READ MORE: Flood KS, et al. Treatment of doi: 10.1272/jnms.JNMS.2021_88-312 psoriasis in pregnancy. Cutis. 2020;106(S2):15-20.

March 2021 | 7 PSORIASIS (CONT) GENERAL DERMATOLOGY

A prospective German study suggested that DELUSIONAL PARASITOSIS can be effectively treated with low-dose pimozide SUBCUTANEOUS METHOTREXATE has a faster (3 mg or less daily). Such a low dose may only rarely be associated with the onset and a higher PASI 90 outcome compared dreaded complication of tardive dyskinesia. After symptom resolution, the drug to oral methotrexate. can often be tapered and then stopped without recurrence. TO READ MORE: Reich K, et al. The value of subcu- TO READ MORE: Brownstone ND, Koo J. Recent developments in psychoderma- taneous vs. oral methotrexate: real-world data from tology and psychopharmacology for delusional patients. Cutis. 2021;107:5-6. the german psoriasis registry psoBest. Br J Dermatol. 2020 Nov 21. doi: 10.1111/bjd.1969

Although yearly testing for TUBERCULOSIS is a standard protocol when administering biological drugs, the actual rate of conversion is quite low, when considering some classes. For example, a recent pooled cohort study of 28 secukinumab trials disclosed latent tuberculosis appearance in 0.1% of 12,319 subjects. TO READ MORE: Elewski BE: Association of seculkinumab treatment with tuberculosis reactiva- tion in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis. JAMA Dermatol. 2021;157: 43-51

Dermatologists should be aware that chronic use or covert ABUSE OF OPIOIDS may result in generalized pruritus. Abuse of cocaine or amphetamines may result in crawling sensations under the skin, resembling delusional parasitosis. Due to overlapping pathways, both addiction and pruritus may be perpetuated in parallel. TO READ MORE: Lipman ZM, Yosipovitch G. Substance use disorders and chronic itch. J Am Acad Dermatol. 2021;84:148-55.

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

GENERAL DERMATOLOGY

Along with tattoos and body piercings, incarcerated individuals may create multi- Apparently, many college students have not gotten ple subcutaneous penile nodules called “SPEED HUMPS.” Various small objects the message about PHOTOPROTECTION. A sample are formed into a smoothed sphere, and then inserted through a self-made super- of 673 collegiates disclosed that only 9.5% used ficial incision in the penile shaft. This practice allegedly enhances sexual pleasure sunscreen and 12.6% used tanning beds, the latter for partners. being particularly common in the winter.

TO READ MORE: Chateau AV, et al. Penile nodules in prisoners. Int J Dermatol. TO READ MORE: Graham EM, Merrill KC. Sunscreen 2020;59:1520-21. and tanning bed use in high-risk college-aged students. JDNA. 2020;12(6):286-92.

Perhaps not too surprisingly, a study of 62 patients with HAND ECZEMA disclosed that almost 68% of them suffered from significant stress, suggesting that stress management should be an important part of their therapeutic regimen. Stress was assessed using the validated Perceived Stress Scale questionnaire. TO READ MORE: Janardhanan AK, et al. Therapeutic considerations related to stress levels associated with hand eczema: a clinico-etiological study. Dermatol Ther. 2020;33(6):e14508. doi: 10.1111/dth.14508

A recent online study of a nationally representative sample (N=705) of American men showed that 83% REPORTED NOT USING SUNSCREEN DAILY, and only 38% USED SUNSCREEN AT LEAST WEEKLY. FACIAL ANGIOFIBROMAS associated with tuberous sclerosis can be successfully managed by sequential surgical debulking followed by long-term application of Yearly income over $100,000 correlated with greater topical rapamycin (sirolimus). degree of sunscreen use. TO READ MORE: Patterson JL, et al. Combined treatment of disfiguring facial TO READ MORE: Roberts CA. Men’s attitudes angiofibromas in tuberous sclerosis complex with surgical debulking and topical and behaviors about skincare and sunscreen use. sirolimus. Cutis. 2020;106(6):307-308. J Drugs Dermatol. 2021;20:88-93.

March 2021 | 9 DRUGS AND HIDRADENITIS SUPPURATIVA DEVICES The perfect storm of increasingly prevalent childhood obesity, lowered pubertal Suicidal ideation, age, and better awareness of HS may lead to this diagnosis in ADOLESCENCE AND attempted suicide, CHILDHOOD. Treatments are largely extrapolated from the adult experience with several caveats. Doxycycline is the preferred tetracycline agent due to lowered risk and completed of tooth discoloration, and use of finasteride is uncertain with regard to eventual suicide are more prostate size, sexual dysfunction, and pubertal development. common among TO READ MORE: Choi E, et al. Hidradenitis suppurativa in pediatric patients. men aged 18-44 J Am Acad Dermatol. 2020 Aug 18. doi: 10.1016/j.jaad.2020.08.045 when they are tak- ing FINASTERIDE FOR ALOPECIA, If your hidradenitis patients go to an EMERGENCY DEPARTMENT, compared to a they are likely to receive prescriptions for opioid narcotics (58.3%) matched cohort not and non-tetracycline antibiotics (66.6%). This information was based taking finasteride. on a retrospective analysis of National Hospital Ambulatory Medical Care Survey data from 2006-2017. Whether this is di- rectly related to the TO READ MORE: Taylor MT, et al. Pain severity and management of drug or a manifesta- hidradenitis supprativa at US Emergency Department visits. JAMA Dermatol. 2021;157:115-117. tion of psychological abnormality due to the alopecia is CUTANEOUS ONCOLOGY, SURGERY, AND LASERS uncertain. TO READ MORE: Sophisticated population modeling done in Australia demonstrated that, for individuals 50 years of age and old- Nguyen DD, et er followed for the next 30 years, primary prevention (sunscreen and appropriate physical cover) was the most al. Investigation effective method of reducing both MELANOMA AND NON-MELANOMA SKIN CANCER. Preventative measures were more effective than utilizing early detection techniques, such as periodic skin examinations. of suicidality and psychological TO READ MORE: Gordon L. Prevention versus early detection for long-term control of melanoma and keratino- adverse events in cyte carcinomas: a cost-effectiveness modelling study. BMJ Open. 2020 Feb 26;10(2):e034388. doi: 10.1136/bmjopen-2019-034388 patients treated with finasteride.JAMA Dermatol. 2020 Nov ERYTHEMA AB IGNE, considered a pigmentary response, occurs following protracted exposure to infrared heat 11:e203385. at temperatures insufficient to cause a burn. As illustrated by this case report, erythema ab igne can progress to develop cutaneous squamous cell carcinoma. doi: 10.1001/ jamadermatol. TO READ MORE: Wilder EG, et al. Erythema ab igne and malignant transformation to squamous cell carcinoma. Cutis. 2021;107:51-53. 2020.3385

A retrospective analysis of nearly 109,000 IN SITU AND INVASIVE MELANOMAS derived from the National Cancer Database demonstrated no overall survival difference between lesions on the trunk, upper extremity, or lower extremity, regardless of treatment modality (wide local excision vs Mohs micrographic surgery). The mean age at diagnosis of individuals included in this analysis was 58.8, and 52.7% were male. TO READ MORE: Demer AM, et al. Association of mohs micrographic surgery vs wide local excision with overall survival outcomes for patients with melanoma of the trunk and extremities. JAMA Dermatol. 2021;157:84-89.

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ROSACEA ACNE

A meta-analysis of 13 studies, encompassing more than 50,000 patients, A case report described the efficacy of the recently demonstrated an association between rosacea and HYPERTENSION AND approved narrow-spectrum antibiotic sarecycline for DYSLIPIDEMIA. Conversely, rosacea was not associated with ischemic heart PERIORAL DERMATITIS. This usage is off-label. disease, stroke, or diabetes. TO READ MORE: Graber E, Kay CRS. Successful TO READ MORE: Chen Q, et al. Association between rosacea and cardiomet- treatment of periorificial dermatitis with novel narrow abolic disease: a systematic review and meta-analysis. J Am Acad Dermatol. spectrum sarecycline. J Dugs Dermatol. 2021;20: 2020;83(5):1331-1340. 98-1000.

OCULAR ROSACEA is a chronic inflammatory process which can lead to visual A large scale retrospective study spanning 10 years defect and even blindness. Chronic maintenance therapy is often indicated to (2008-2018) indicated that the proportion of derma- prevent periodic flares. Topical low-potency steroids and cyclosporine, as well as tologists who routinely performed SERUM POTASSI- oral tetracycline derivatives, are mainstays of therapy. However, there is a critical UM TESTING on young adult women being treated lack of well-done randomized, controlled studies to define optimal interventions. for acne with spironolactone was low and decreas- ing. This is consonant with increasing evidence that TO READ MORE: Redd T, Seitzman GD. Ocular rosacea. Curr Opin Ophthalmol. potassium monitoring is not needed in this situation. 2020;31(6):503-507. TO READ MORE: Barbieri JS, et al. Temporal trends and clinician variability in potassium monitoring of healthy young women treated for acne with spironolactone. JAMA Dermatol. 2021; January 27. doi:10.1001/jamadermatol.2020.5468

COSMETIC DERMATOLOGY

BLACK HENNA TATTOOS are often contaminated with para-phenylenediamine, thereby leading contact dermatitis of variable severity. Black henna tattoos and the contaminant can be easily removed in a single session consisting of repeated rinsing of the skin with polyethylene glycol 400 solution. A maximum of 6 rinse cycles was required to effect this removal.

TO READ MORE: Ferrari DM, et al. Efficient removal of black henna tattoos.Pediatr Dermatol. 2020;37:1063-67.

March 2021 | 11 INFECTIOUS DISEASES PEDIATRIC DERMATOLOGY

In a longitudinal study of 6515 HIV-positive individuals, ANAL CARCINOMA was Mothers of children with PSORIASIS more often 12.79 times more likely to occur when there was a present or past history of ano- suffer from depression (14 of 60) than mothers genital warts. Anal cancer developed in 4.4% of those with a history of anogenital of age/sex matched control children being followed warts compared to 0.3% of thse who did not have a history of anogenital warts. for multiple nevi (3/60). Mothers of children suffering from psoriasis achieved significantly higher scores TO READ MORE: Arnold JD, et al. The risk of anal carcinoma after anogenital in the Beck Depression Inventory questionnaire warts in adults living with HIV. JAMA Dermatol 2021, January 13. when compared to mothers in the control group doi: 10.1001/jamadermatol.2020.5252 (7.3 ± 6.91 points vs 2.75 ± 3.46 points, respective- ly; P = .000005). Although TOPICAL CICLOPIROX has the lowest relative cure rate, it remains the TO READ MORE: Žychowska M. Depressive symp- most commonly prescribed onychomycosis therapy among all groups of health toms among mothers of children with psoriasis— care providers, including dermatologists and podiatrists. A case-control study. Pediatr Dermatol. 2020; 37:1038-43. TO READ MORE: Yang EJ and Lipner SR. Prescribing patterns of onychomycosis therapies in the United States. Cutis. 2020;106(6):326-327.

RECALCITRANT DERMATOPHYTOSIS may be due to inherent antifungal resis- tance, skin barrier disruption, reinfection from clothes or the environment, and ambient factors (heat/humid- ity). Recalcitrant dermato- phytosis may be treated by homologous autoimplantation. The latter technique introduces tiny bits of fungal-infected skin into the patient’s subcutaneous tissue, in order to stimulate a vigorous immune response. Clearance may be expected in about 3 months. TO READ MORE: Kumar, S, et al. Autoimplantation therapy in extensive and recal- citrant dermatophytosis: a case series. J Clin Aesthet Dermatol. 2021;14:34-37.

A standardized 0.7% viscous investigational cantharadin product (VP-102) was applied to all MOLLUSCUM CONTAGIOSUM every 21 days for a maximum of 4 times. Plasma cantharidin concentrations were below the lower limits of quantifi- A small study demonstrated the feasibility and cation (2.5 ng/mL). efficacy (80% cure) of using topical encapsulated 1% terbinafine, twice daily for 4 weeks, in the treat- ANALYSIS OF 32 ITT SUBJECTS SHOWED A ment of pediatric TINEA CAPITIS. Further study is needed to verify and commercialize such a product, mean decrease in lesions by but the technology is available. % the end of the study (day 84). 90.4 TO READ MORE: Jerasutus S, et al. Treatment of tinea capitis with topical 1% encapsulated TO READ MORE: Niazi S, et al. A Phase 2 open-label study to evaluate VP-102 for terbinafine hydrochloride gel: a pilot study.Pediatr the treatment of molluscum contagiosum. J Drugs Dermatol 2021;20:70-75 Dermatol. 2020;37:1090-93. 

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Multimodal management key in easing the quality- of-life-impact of HS

Joslyn Kirby, MD, MS, MEd with Cheryl Guttman Krader

idradenitis suppurativa (HS) is a debilitating, chronic, Hinflammatory disease that follows a fluctuating course with periods of quiescence interrupted by intermittent flares. JOSLYN KIRBY, MD, MS, MED The principles for HS management can be “Therefore, dermatologists need to be knowl- Associate Professor characterized as a “four corner” scheme that edgeable about treating HS flares, but our of Dermatology combines medical and procedural modali- main aim should be to try to prevent them Penn State University ties in acute and maintenance therapy (Table from occurring.” Hershey, Pennsylvania 1). Preventing flares by achieving long-term control is the primary goal, said Joslyn Kirby, Setting the plan and expectations MD, MS, MEd. Management decisions for a patient with HS begin with a conversation to find out about the “The quality-of-life impact of HS was aptly individual’s disease history and previous treat- captured by a patient, who described it as ments. Learning whether patients recognize “the roller coaster from hell” because of the that HS is caused by an overactive immune great physical and emotional suffering from system and educating them about this fact is the chronic course along with the sudden, another critical component of the discussion, painful flares that contribute to anxiety and so that patients will understand and accept the worry,” said Dr. Kirby, Associate Professor of recommended treatments. Dermatology, Penn State University, Hershey, Pennsylvania. “HS lesions look like a skin infection, and pa-

Table 1. Four corners of care for HS

Medical Procedural

Acute Short-term antibiotic(s) Intralesional triamcinolone Short-term prednisone Incision and drainage Punch deroofing

Chronic Intermittent use of antibiotics Deroofing Spironolactone Excision Biologic

March 2021 | 15 HS lesions look like a skin infection, and patients who searched the internet will question using “immuno suppressive treatment.”

tients who searched the internet will question can be “magical” as rescue therapy for severe using immunosuppressive treatment because inflammation, but is reserved for the most they’re concerned they have a deficient im- extreme circumstances, Dr. Kirby said. mune system that is not fighting the infection,” “I use ertapenem as a bridge for patients Dr. Kirby explained. requiring a change in their biologic and/or “It is important to frame HS as a disease in extensive surgery. Relapse rates after stopping which a stimulated immune system is creating ertapenem are high, and so it is important to the lesions and that treatment aims to control have an exit plan.” THE KEY 3 the overactive immune response and target If a patient with stage I HS has scarring, bacteria that contribute secondarily by causing Dr. Kirby said she aims to achieve chronic Achieving long- more inflammation.” control sooner rather than later, because term control Acute medical treatment for flares includes scarring will accumulate and affect quality to avoid flares is short-term oral prednisone along with short- of life long-term. Therefore, patients who the primary goal term antibiotic therapy. Chronic treatment do not respond sufficiently to the oral thera- of HS management decisions follow a stage-based approach that pies are considered candidates for a biologic, weighs treatment risks against the impact of and adalimumab is Dr. Kirby’s agent of choice Spironolactone is a the disease. because it is FDA-approved for HS, which valuable alternative For a treatment-naïve patient with Hurley makes access easier. to antimicrobial stage I HS who does not have significant scar- Biologic therapy is generally indicated for all treatment for care ring, Dr. Kirby said she generally begins with patients with stage II HS, considering that they of women with HS doxycycline 100 mg once or twice daily and usually have scarring and a history of being re- might try oral clindamycin if that fails. fractory to antimicrobial therapy. At the same time, however, Dr. Kirby said she thinks about Dermatologists In the interest of avoiding long-term antimi- enrollment in a clinical trial for patients with can optimize HS crobial use (>12 weeks), however, she likes to stage II HS who are not yet on a biologic. management by switch women to oral spironolactone. Spirono- integrating surgical lactone is started at a dose of 100 mg/day and Infliximab may be used instead of adalim- and medical care increased if needed, but not to more than 100 umab for patients with stage II or III HS who mg twice daily because higher doses are more have extensive inflammation or as a next- likely to cause breast tenderness and intermen- step biologic if adalimumab is not working strual spotting. to maintain control. To get best results with Other oral antimicrobial agents, including infliximab, “go big” with the dose and infusion rifampin, moxifloxacin, and metronidazole, frequency, Dr. Kirby said, adding that she uses are used for patients with recalcitrant or lat- a dose of 10 mg/kg and repeats the infusion er-stage HS (Table 2). Intravenous ertapenem every 4 to 6 weeks.

16 | The Dermatology Digest www.thedermdigest.com/GENERAL_DERMATOLOGY

Integrating surgery Table 2. Antimicrobials for HS Procedural interventions for acute manage- ment of HS include intralesional triamcin- Doxycycline 20 mg or 100 mg QD to BID olone injection, incision and drainage, and Clindamycin 300 mg/Rifampin 300 mg BID punch deroofing. However, Dr. Kirby said that if a patient is still developing some migratory Moxifloxacin 400 mg QD/rifampin 300 mg BID/metronidazole 500 mg TID lesions after being on medical therapy for 3 to Ertapenem 1g IV QD 6 months, she will likely change medications rather than turn to surgery. “Chasing migratory lesions with surgery is re- because the disease is associated with numer- actionary and leads to scarring. It makes sense ous comorbidities, including arthropathies, to incorporate surgery for persistent tunnels or diabetes, hypertension, inflammatory bowel nodules, despite medical therapy. This has had disease, and polycystic ovary disease. a major benefit on my care for patients with During their visit, patients are screened for HS,” Dr. Kirby said. She advocated for derma- these conditions by measuring serum he- tologists to follow her practice. moglobin A1c and by performing a simple Adalimumab “Although there has not been much emphasis examination and review of systems to inves- is Dr. Kirby’s on surgery’s role in HS management, derma- tigate the presence of joint pain and swelling, tologists have the necessary skills. It seems diarrhea and bowel urgency, or signs of poly- biologic of all that is needed is to raise awareness about cystic ovary disease. Because of the psychoso- choice surgery’s utility and empower clinicians with cial sequelae of HS, patients are also given the because it is information about the techniques,” she stated. 2-item Patient Health Questionnaire-2 as an “Punch deroofing, which is useful in acute and initial screen for depression. FDA-approved chronic care and has a slightly higher chance “I let patients know that aspects of their health for HS, which than incision and drainage to permanently other than their skin disease might be affected, makes access treat lesions, is just a 4- to 6-mm punch biopsy and it would be helpful to have a primary-care easier. with some curetting the skin.” doctor or another type of specialist involved Whole-patient care in their care. I can work on their HS, but I’m not the one they want managing their blood With their medical expertise and surgical pressure!” Dr. Kirby said.  skills, dermatologists are perfectly suited to manage HS. However, collaboration with DISCLOSURES primary-care physicians and other specialists Dr. Kirby is a speaker for AbbVie and a consultant to Abb- is also part of the care for patients with HS Vie, ChemoCentryx, Incyte, Janssen, Novartis, and UCB.

FURTHER READING

 Alikhan A, Sayed C, Alavi A, et al. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part I: Diagnosis, evaluation, and the use of complementary and procedural management. J Am Acad Dermatol. 2019;81(1):76-90.

 Garg A, Malviya N, Strunk A, et al. Comorbidity screening in Hidradenitis Suppurativa: evidence-based recommendations from the US and Canadian Hidradenitis Suppurativa Foundations. J Am Acad Dermatol. 2021;Jan 22:S0190-9622(21)00213-9.

March 2021 | 17 www.thedermdigest.com/GENERAL_DERMATOLOGY

COMMENTARY Optimizing management for patients with HS

Iltefat H. Hamzavi, MD, with Cheryl Guttman Krader

r. Kirby’s article on the management of patients who require referral to a plastic hidradenitis suppurativa (HS) provides surgeon for HS surgery. Second, be aware that D an excellent review of general principles under-resourced patients can face a huge and practical pearls along with some important challenge accessing dressings, which are often messages to practitioners. not covered by insurance. We have addressed I echo Dr. Kirby in encouraging dermatologists this latter hurdle by collaboration with our pharmacy. After providing the pharmacist with to apply both their medical knowledge and ILTEFAT H. information about the type and anticipated surgical skills to the care of patients with HS. HAMZAVI, MD Following are a few tips for optimizing surgical volume of dressings needed, our patients are Senior Staff Physician able to acquire the materials at a reasonably outcomes. Department of Dermatology low cost. Our experience highlights the value of incor- Henry Ford Hospital Detroit, Michigan porating preoperative ultrasound for lesion I also reiterate Dr. Kirby’s point that HS is asso- mapping.1 Ultrasound can aid in limiting both ciated with a number of comorbidities, so that recurrences and morbidity through its ability to patients are best served by a holistic approach to care. Diabetes and metabolic syndrome identify subclinical lesions and precisely charac- Ultrasound can terize lesion depth, which often turns out to be affect approximately 55% of our HS patients, shallower than believed. aid in limiting compared with about one-third of the general both recurrences population, and the prevalence of these con- Our experience also indicates that concern ditions is even higher within the skin-of-color about keloid formation should not affect the “and morbidity subgroup of our HS cohort. decision to perform surgery for HS in patients through its ability with skin of color. In an internal review of Referral to a nutritionist for counseling about patients in our institutional database, we to identify sub- dietary management has the potential to benefit found no cases of keloid formation among clinical lesions the skin disease and the whole health of HS more than 1000 patients of African-American patients. Patients are grateful for the care, or Hispanic descent. and precisely and their appreciation and well-being makes characterize practicing dermatology more enjoyable and Based on limited clinical studies, it appears that highly fulfilling.  it may be best to allow wounds from HS wide lesion depth, excision to heal by secondary intention in most which often REFERENCES instances involving larger lesions in the axillae/ 1. Lyons AB, Zubair R, Kohli I, Hamzavi IH. Preoperative ultrasound 2 inguinal/buttock locations. Excellent wound turns out to be for evaluation of hidradenitis suppurativa. Dermatol Surg. care is critical when following this modality, shallower than 2019;45(2):294-296. and that raises 2 points. First, because derma- 2. Balik E, Eren T, Bulut T, et al. Surgical approach to extensive believed.” hidradenitis suppurativa in the perineal/perianal and gluteal tologists are experts in wound care, we have an regions. World J Surg. 2009;33(3):481-487. important role as comanaging partners for

18 | The Dermatology Digest THE

PRESENTS

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

Podcast 1 BPDCN Patient Demographics and Cutaneous Lesions In this first episode, dermatologist and dermatopathologist Dr. Whitney High discusses BPDCN patient demographics and the characteristics of cutaneous lesions.

The BPDCN Podcast Series

TheDermDigest.com Sponsored by PEDIATRICS WARTS

MAUI DERM 2021 PEDS STYLE Pearls to manage tough warts

Sheila Fallon Friedlander, MD with Bob Kronemyer

Sheila Friedlander, MD Staff Dermatologist Scripps Clinic, San Diego

Professor Emeritus in Dermatology University of California San Diego School of Medicine

Presented at Maui Derm Connect 2021

or difficult pediatric warts, there are viable treatments other than Fcryotherapy and salicylic acid.

Several newer breakthroughs are combination therapies that offer new options, such as com- bining cryotherapy with immunization or combining different intralesional (IL) treatments like tuberculin purified protein derivative (PPD) and Candida. Another therapy is the human papillomavirus (HPV) vaccine. I have been discussing IL Candida for years now, and I use it all the time in kids who have warts. The beauty of IL Candida is that you can treat 1 or 2 lesions, often achieving a systemic immunologic effect with all the warts resolving. A study published last year in the Journal of the American Academy of Dermatology (JAAD) alternated IL agents for warts.1 The study divided patients into 4 groups, all of whom were injected with 0.1 mL into the larg- est wart every 2 weeks for up to 6 treatment sessions as needed: IL PPD; IL Candida 1/1000; alternating PPD and Candida; or saline. Among the 143 patients who completed the study, complete clearance occurred in 61% of pa- tients administered PPD; 36.8% of patients given Candida; 70.6% of patients with the alternat-

20 | The Dermatology Digest www.thedermdigest.com/PEDIATRICS

ing therapy (P < 0.0001); and 8.6% of patients with saline. I think these outcomes are exciting for recalcitrant disease. Why not alternate PPD with Candida? A second study from last year’s JAAD com- pared IL to intramuscular (IM) bivalent HPV vaccine for recalcitrant warts.2 For the study, 22 patients were given an IM injection at 0, 1, and 6 months. Another 22 patients were given an IL injection into The beauty of their largest wart every 2 weeks until clear, IL Candida is or 6 injections total. we know that the risk of exposure to HPV that you can Overall, 82% of patients in the IL group increases with age. We also know that the treat 1 or 2 attained complete clearance compared to “ vaccine is not as effective after your patient has 63% in the IM group. lesions, often been infected. achieving a We know that warts can sometimes respond The Advisory Committee on Immunization to anything, even saline. But this is another systemic Practices and the American Cancer Soci- option to consider—injecting a vaccine right immunologic ety recommend that everyone between the into the wart. ages of 9 and 12 be vaccinated. A catch-up effect and all A 9-valent HPV vaccine is available as well. So vaccination can be administered up to age the warts instead of being limited to 2 HPV subtypes, 26. Thus, if you have a patient who comes resolving.” we now have an additional 7: 16, 18, 31, 33, 45, in who is older, you want that person to get 52, and 48. Might this vaccine do a better job vaccinated. But the vaccine is not necessarily with warts? I think this is definitely the way beneficial for older people. to go and hopefully we will have more studies looking at the use of a 9-valent HPV vaccine. When I see a patient in the office with bad Among the 143 patients who completed the study, warts, the first question I ask is if the patient complete clearance occurred in has had an HPV vaccine. If the patient has not, and is aged 7, 8 or 9, I will encourage the patient to get the vaccine. I also want to make % sure there is no sign of immunosuppression. 61 Occasionally, children may suffer from OF PATIENTS ADMINISTERED PPD. conditions such as dedicator of cytokinesis 8 (DOCK8) deficiency, which may present % % % with severe warts or molluscum. It is im- 36.8 8.6 70.6 portant to ask if the patient has had recurrent OF PATIENTS OF PATIENTS OF PATIENTS WITH pneumonia or otitis. When in doubt, refer to GIVEN CANDIDA WITH SALINE THE ALTERNATING an immunologist. THERAPY (P < 0.0001) As far as the guidelines for HPV vaccination,

March 2021 | 21 www.thedermdigest.com/PEDIATRICS

Still, the vaccination is recommended for peo- releases this agent. Patients apply the cream at ple between the ages of 27 and 45 who have night, then remove it in the morning and clean multiple sexual partners or are at high risk for the wart. HPV for other reasons. One cream kit costs $80 and is generally not There was a time when I was very excited covered by insurance. about oral zinc sulfate to treat warts. I tried A 2020 literature review of viral warts in children in Dermatologic Therapy reveals WITHOUT TREATMENT that without treatment, 63.6% of kids will be 4 FOR VIRAL WARTS clear in 2 years, but only 5.8% by 6 weeks. The review also found that cryotherapy in the % of kids will be clear canister is equivalent to cotton wool (Q-tip) 63.6 in 2 years, but only application, which is against my own experi- ence. But the authors say if you apply liquid % by 6 weeks. cotton wool to the tip of a cotton swab and 5.8 place it on the wart, it will be as effective as a cryotherapy spray gun. it on a number of patients, but many react- In addition, the literature review conclud- We know that ed with stomachaches. I also cannot recall a ed that immunotherapy topical clearance warts can patient who got better. rates were 88% for diphenylcyclopropenone (DPCP), 60% for bacillus Calmette-Guerin sometimes A double-blind study published in 2018 in the (BGC) and 71% to 87% for Candida. “respond to International Journal of Women’s Dermatology anything, even compared cryotherapy plus oral zinc sulfate The authors also said it is not unreasonable to cryotherapy plus placebo for warts.3 The to follow non-palmoplantar warts; however, saline. But bottom line is that the zinc did not make much palmoplantar warts are unlikely to go away on this is another of a difference. their own.  option you can Although controversial, some believe that if REFERENCES consider— a patient actually has a low serum zinc level, 1. Nofal A, Yehia E, Khater E, Bessar H. Alternating intralesional purified injecting a zinc therapy for warts may be more efficacious. protein derivative and Candida antigen versus either agent alone in vaccine right There are no large controlled studies to sup- the treatment of multiple common warts. J Am Acad Dermatol. 2020 Jul;83(1):208-210. doi:10.1016/j.jaad.2020.01.054 into the wart.” port this, but occasionally practitioners will check zinc levels and use zinc if the level 2. Nofal A, Marei A, Ibrahim ASM, et al. Intralesional versus intramuscu- lar bivalent human papillomavirus vaccine in the treatment of recal- is below normal. citrant common warts. J Am Acad Dermatol. 2020 Jan;82(1):94-100. doi:10.1016/j.jaad.2019.07.070 WartPEEL cream (NuCara Pharmacy) is a non- 3. Mahmoudi H, Ghodsi SZ, Tavakolpour S, Daneshpazhooh M. FDA-approved product that people are very ex- Cryotherapy plus oral zinc sulfate versus cryotherapy plus placebo cited about. Despite the lack of much literature, to treat common warts: a double blind, randomized, placebo- many patients are now using it and coming controlled trial. Int. J Womens Dermatol. 2018 Jun;4(2): 87–90. doi:10.1016/j.ijwd.2017.09.004 back to the office saying it is very helpful. 4. Soenjovo KR, Chua BWB, Wee LWY, et al. Treatment of cutaneous The cream is a combination of 17% salicylic viral warts in children: a review. Dermatol Ther. 2020;33:e14034. acid and 2% 5-fluorouracil in an adhesive vehicle that leads to sustained release. It is not DISCLOSURES duct tape, but a plastic tape that very slowly Dr. Friedlander reports no relevant financial interests.

22 | The Dermatology Digest PEDIATRICS CONTACT DERMATITIS

Sources of pediatric allergic contact dermatitis

Nanette Silverberg, MD with Bob Kronemyer

hen it comes to detecting pediatric contact dermatitis, clinicians often Woverlook potential sources of irritation, tending to focus on toys. But other items, such as jewelry, electronics, and crafts, may be culprits as well.

“It is not just little toys that kids react to,” has most recently been reported in electronic said Nanette Silverberg, MD, a clinical toys, according to Dr. Silverberg, including professor of dermatology and pediatrics at cell phones with metal casings, laptops, tablets, the Icahn School of Medicine at Mount Sinai and video-game controllers. in New York City. “There is costume jewelry “We know that the number-one aller gen world- that might be sold in a toy store or in a wide is nickel,” Dr. Silverberg said. “In Europe, NANETTE dress-up kit. Children can also react to toy legislation limits the release of nickel from metal SILVERBERG, MD watches with lovely characters shining coming in contact with the skin, such as jewelry. Clinical Professor of in pretty colors.” Unfortunately, here in America, we lack that Dermatology and Pediatrics Icahn School of Medicine, Similarly, a bicycle handle might contain legislation.” certain kinds of plastics that cause reactions. Mount Sinai Copper, gold, black rubber, and homemade New York City But the leading source of contact dermatitis “slime” have also been reported as sources of in children is nickel. This ubiquitous metal

The leading source of contact dermatitis in children is nickel.

March 2021 | 23 www.thedermdigest.com/PEDIATRICS

contact dermatitis. “Slime is like Likewise, costume jewelry may contain wood, Play-Doh, but slightly moister, and latex, rubber, plastics, and dyes that can cause contains harsh ingredients such as contact dermatitis. Moreover, ceramic- or pot- detergents and glue,” Dr. Silver- tery-containing jewelry might contain allergenic berg said. Slime may also contain chromates, turpentine, and other metals. the high-level allergen methyl- Temporary tattoos were another source of toy chloroisothiazolinone (MCI). “These dermatitis identified in the review. ingredients can be rather irritating to the hands or allergenic,” she said. Recommendations Recent review findings “Based on our review, there is still an unmet need for observation of this segment of Dr. Silverberg, chief of pediatric dermatology industry for labeling of contents and ongoing for Mount Sinai Health Systems in New York surveillance,” Dr. Silverberg said. Among the City, was the senior author of a systematic review of pediatric toy contact dermatitis Because contact dermatitis can mimic eczema, toys in the published last year in the journal Contact it is crucial that relevant allergens be identified review found to Dermatitis.1 “We identified only 25 good to distinguish the 2 conditions, according to Dr. be associated original reports of contact dermatitis to toys,” Silverberg. “Kids will not improve, unfortunate- with contact she said. “Therefore, it behooves physicians ly, without elimination of the allergens,” she said. to report and be on top of thinking about toys Children who have extensive dermatitis dermatitis were at home as a potential relevant allergen.” electronics, toy poorly responsive to medications or limited Among the toys in the review found to be to specific locations, such as hands or eyelids, cars, costume associated with contact dermatitis were elec- should be patch tested to screen them for dif- jewelry, bicycles, tronics, toy cars, costume jewelry, bicycles, ferent types of allergens. “Also, when counsel- “sqwish” balls, “sqwish” balls, slime, Play-Doh and plasticine. ling patients and families, we need to not only elicit from them the history of allergens like slime, Play-Doh Implicated electronics included video-game slime, but also to teach them to avoid toys that controllers, cellphones, iPads, and computers. and plasticine. have the relevant allergens identified on patch The most commonly reported electronic testing,” Dr. Silverberg said. product causing contact dermatitis was the cell Although metal-embedded products prevent phone. Besides nickel, chromate was suspected radiation exposure, Dr. Silverberg encourages to play a role in some cases. people who are allergic to place covers on their Cell phone dermatitis ranged from facial derma- devices. “It is also helpful to have legislation titis (cheek and periauricular) to hand dermati- that protects children,” she said. “For instance, tis. One patient even developed breast dermatitis items that are in close contact with the skin, by keeping her cell phone in her brassiere. such as jewelry and watches, could be required to have reduced nickel release, as is mandated Discontinuation of the cell phone or use of in Europe.”  protective barriers resulted in resolution of the rash in all cases. REFERENCES Allergenic metals are also found in die-cast 1. Fenner J, Hadi A, Yeh L, Silverberg N. Hidden risks in toys: A system- model cars made of zinc, aluminum, mag- atic review of pediatric toy contact dermatitis. Contact Dermatitis. 2020 May;82(5):265-271. doi:10.1111/cod.13500 nesium, and copper alloy, which can cause

recurrent finger dermatitis. DISCLOSURES Dr. Silverberg reports no relevant financial interests.

24 | The Dermatology Digest LITERATURE UPDATE DERMATOLOGISTS

The dermatologist as PCP

John S. Barbieri, MD, MBA with Lisette Hilton

ermatologists may be the only health care providers caring for a Dsubstantial proportion of patients with common chronic inflammatory and autoimmune skin diseases. So, what roles do dermatologists play in screening for and managing known comorbidities of chronic skin disease, including cardiovascular disease and mental heath disorders?

“As dermatologists, it is important not just American Academy of Dermatology International to think about caring for the skin disease (JAAD International).1 that we see on our patients, but also to think Skin diseases can have diverse mental and phys- John S. Barbieri, more broadly about the other ways these ical effects on patients. MD, MBA conditions can manifest and can impact our Postdoctoral Research Fellow patients’ lives,” said dermatologist John S. “For instance, psoriasis, which is a common University of Pennsylvania, Barbieri, MD, MBA, author of the study “Use inflammatory skin disease, is associated with Philadelphia of primary care services among patients with increased risk of mortality and cardiovascular chronic skin disease seen by dermatologists,” disease, as well as with depression. … 85% of published March 1, 2021 in the Journal of the adolescents will experience acne at some point.

Hear the full interview at www.thedermdigest. com/Literature Up- date-The-dermatologist as-PCP_podcast

March 2021 | 25 www.thedermdigest.com/LITERATURE_UPDATE

It can be associated with profound mental a primary-care doctor that they see regular- health impacts, including depression and ly,” Dr. Barbieri said. “If they are only seeing suicidality,” said Dr. Barbieri, a Postdoctoral their dermatologist, the assumption that their Research Fellow at University of Pennsylvania, primary-care doctor may take care of some of Philadelphia. these other issues might be a false premise. It suggests the need for a dermatologist to play a Dr. Barbieri and coauthors retrospectively larger role, either helping to connect patients analyzed US claims data among patients seeing with associated clinicians who could help dermatologists for psoriasis, hidradenitis manage these comorbidities, or even to take a suppurativa, acne, and alopecia areata. They role themselves, at least initially screening for focused on those 4 diseases because they are some of these conditions.” common dermatologic conditions and are as- sociated with important systemic and mental The investigators found that among patients health comorbidities, according to the paper. seeing a dermatologist for psoriasis, hidrad- enitis suppurativa, acne, and alopecia areata, In their research, Dr. Barbieri and colleagues from nearly 17% to more than 31% did not see asked how many patients seeing dermatolo- a primary-care clinician in the year after their gists for chronic inflammatory skin diseases initial dermatology visit. had seen primary-care providers, including pediatricians, internal medicine doctors, and More specifically, of the 71,857 psoriasis family medicine specialists, in the year after patients identified in the study, 21.6% of men establishing care with their dermatologists. and 16.9% of women had no primary-care en- counters. Among 5407 hidradenitis suppurati- “We know from other research that about half va patients, 28.1% of men and 22% of women of commercially insured patients do not have had no primary-care visits in the following Psoriasis, which is a common inflammatory “skin disease, is associated with increased risk of mortality and cardiovascular disease, as well as with depression.”

continued on page 28

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

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

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

JUNE 24-26, 2021 Live-Stream Virtual Meeting Broadcast from Colorado Springs, CO Main Conference Program for only $199!

Join us at one of our upcoming meetings in Asheville, North Carolina and Maui, Hawaii. OCTOBER 1-3, 2021 Omni Grove Park Inn • Asheville, NC Plus Special Pre-Conference Day on September 29, 2021

JANUARY 24-28, 2022 Maui Derm for Dermatologists Grand Wailea • Maui, Hawaii

For meeting information and registration, please visit THE ACKNOWLEDGED LEADER IN DERMATOLOGY CME FOR OVER 18 YEARS. MauiDerm.com continued from page 26 year; among 238,647 acne patients, 27.1% of men and 26.2% of women; and among 10,904 DATAPOINTS alopecia areata patients, 31.2% of men and 19.2% of women. According to the paper: “About 20% to 25% [of dermatology patients]  Studies have shown that screening for common health problems in overall did not have a visit with a primary-care settings outside of primary care, including dental clinics and barber doctor in 12 months of their initial dermatol- shops, can improve outcomes. ogy encounter for these conditions. So, it does support that many of our patients who we are

 Given that nearly one-third of all dermatology patients experience seeing may not have a primary-care doctor some form of mental health disorder, an opportunity exists for whom they are seeing regularly or may not dermatologists to incorporate routine screening into clinical practice. have a primary-care doctor at all,” he said. However, depression screening is infrequently performed during visits for skin diseases. In terms of subgroups, men, as well as younger patients (particularly those between 20 and

 Dermatologists check routine blood work before starting systemic 40 years old) were less likely to have visited medications for psoriasis. By adding a lipid panel, they could also primary-care providers in the year after their screen for additional cardiovascular risk factors and even prescribe dermatologic appointments. statins when recommended to reduce cardiovascular events and mortality. Only 24% of psoriasis patients who are eligible for statins The investigators did sensitivity analyses are taking them. revealing that between 15.2% and 21.9% of men and 11.4% to 18.9% of women did not see  While primary-care providers are among those who often manage primary-care providers 6 months prior to the cardiovascular, mental health, and other comorbidities, visits to initial dermatology visit, or index date. And primary-care providers are trending downward. 12.3% to 18.7% of men and 8.7% to 14.3%  Between 2008 and 2016, visits to primary-care providers among of women did not have any primary-care commercially insured patients declined by 24%, with only 54% of encounters 2 years after the index date. adults seeing a primary-care provider in 2016. “I think those findings largely reflect that the underlying demographics of use of prima- ry-care services in the United States,” Dr. Barbieri said. Dermatology visits were the only health care encounters, including with other specialists, for 9.4% to 15.8% of men and 4.1% to 5.8%

If patients are only seeing their dermatologist, the assumption that their primary-care doctor may take care of some of these “other issues might be a false premise.”

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

of women who sought treatment for the 4 skin the Patient-Reported Outcomes Measurement conditions studied. Information System (PROMIS) depression measure, both of which have been used “We don’t know about other skin diseases, but successfully in routine dermatology clini- I suspect that we might find similar results if cal practice, according to Dr. Barbieri. And we looked at other diseases, such as eczema,” dermatologists suggesting that patients go to he said. a primary-care doctor or another clinician Another study published October 2 in JAMA should help pave the way for those visits, Network Open reported that COVID-19 fueled including making referrals and helping to the downward trend.2 Primary-care visits eliminate barriers to care, he said. decreased by 21.4% during the second quarter “Dermatologists should consider offering ser- of 2020 compared with the average quarterly vices in the office that are simple and require visit volume of the second quarters of 2018 little infrastructure, like vaccinations,” he said. and 2019. Offering flu and other recommended vaccines “Evaluations of blood pressure and cholesterol in the dermatology practice makes sense levels decreased owing to fewer total visits and when one considers that many of the medi- less frequent assessment during telemedicine cations that dermatologists prescribe to treat encounters,” authors of the study wrote. inflammatory skin diseases may suppress the Implications for dermatologists immune system and put patients at increased Dermatologists should address important co- risk for infection. morbidities when patients may not be seeking “Certainly, I don’t think it would make sense care outside the dermatology practice, Dr. for dermatologists to do things they don’t Barbieri said. know how to do or don’t feel comfortable “From an ethical standpoint … we want doing. We want to make sure that in those to make sure that we are doing the best for scenarios we refer patients to other clinicians our patients. And that may involve expand- who can help.... We want to make sure that ing some of the scope of practice that we as we’re building collaborative health care net- dermatologists do when it comes to managing works with groups of clinicians who can work these conditions,” he said. together to manage the spectrum of impact from skin diseases,” he said.  First, dermatologists need to be aware that inflammatory skin diseases and many of the DISCLOSURES skin conditions that dermatologists manage Dr. Barbieri reports no relevant financial interests. can have associated comorbidities, such as increased risk for cardiovascular disease and REFERENCES impact on patients’ mental health. The next 1. Barbieri JS, Mostaghimi A, Noe MH, et al. Use of primary care ser- step is for dermatologists to screen for some of vices among patients with chronic skin disease seen by dermatolo- these conditions or to have a plan for patients gists. 2021; JAAD International. 2:31-36. https://doi.org/10.1016/j. jdin.2020.10.010 to see primary-care or other providers. 2. Alexander GC, Tajanlangit M, Heyward J, et al. Use and content Dermatologists can use simple patient- of primary care office-based vs telemedicine care visits during the COVID-19 pandemic in the US. JAMA Netw Open. 2020;Oct reported outcome measures, such as the 1;3(10):e2021476. doi: 10.1001/jamanetworkopen.2020.21476. Patient Health Questionnaire-2 (PHQ-2) or

March 2021 | 29 CRYSTAL BALL TOPICAL CANNABINOIDS

from bud to breakthrough The therapeutic potential and current landscape of cannabinoids in dermatology

Adam Friedman, MD, with John Jesitus

Adam Friedman, MD Professor and Interim Chair of Dermatology George Washington School of Medicine and Health Sciences Washington, DC

Presented at Montréal Dermatological Society, February 11, 2021, Montréal, Canada

opical cannabinoids including cannabidiol (CBD) show promise for Ttargeting many inflammatory dermatologic conditions. Although a few such products have begun the path toward FDA approval, much work Don’t miss Dr. Friedman on Cannabinoids Part 1: remains with regard to optimizing formulas, vehicles, and regimens, and The Future in overcoming lingering cannabis-associated stigma. There is tremendous Dermatology at www.thedermdigest. potential for CBD if the amount and delivery are optimized. com/cannabinoids_ part1_podcast. Targeting inflammation What’s unique about manipulation of the CBD is one of approximately 120 cannabinoids endocannabinoid system (ECS) is that the im- found in cannabis, and many skin-cell types pact can be multifaceted; for example, resolv- express cannabinoid receptor 2 (CB2R). Pres- ing, not just inhibiting, inflammation.2 ently, CBD’s primary and best-understood role Ligand binding to CB2R and other G-protein is as an anti-inflammatory agent.1 coupled receptors (eg, GPR18) creates an

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anti-inflammatory effect beyond that of evidence of efficacy—multitudinous canna- blocking a single pathway, signal, or receptor. binoid-containing over-the-counter (OTC) CBD binding can block immune cells from products birthed by the Farm Bill. As a result, infiltrating the skin as well as inhibit their convincing the pharmaceutical industry to ability to secrete inflammation-perpetuating invest in CBD products is tough. Why spend cytokines. Ligand binding moreover switches $20 million for an FDA pipeline when you can certain immune cells such as macrophages sell something OTC and people will buy it? from a pro-inflammatory (M1) to an inflam- A handful of ongoing or recently published mation-resolving subtype (M2).3 clinical trials target inflammatory skin CBD also can bind to many other receptors conditions with topical CBD. BTX 1503 gel outside the ECS. While we generally don’t think (Botanix) has recently completed phase 2 in about CBD as an agent that can affect sensa- acne and is in phase 1 for rosacea.7 In AD, a tion, like tetrahydrocannabinol (THC), CBD CBD gel achieved significant reductions in can influence pain and itch through its impact Patient-Oriented Eczema Measure (POEM) on various other receptors and channels like and other scores.8 Canno Cream (Greenway serotonin and opioid receptors and transient Therapeutix) is also under development receptor potential channels. So CBD has a lot for AD (see page 34). In psoriasis, a topical of potential to treat, manage, and maybe even ointment containing 3% CBD (One World CBD binding can prevent many inflammatory skin diseases. Cannabis) has completed phase 1 testing (NCT02976779). Additionally, early-stage block immune Supporting data for cannabinoids in acne, research is exploring potential indications atopic dermatitis, and psoriasis are mostly cells from including wound healing and cutaneous preclinical.4-6 Such research helps scientists un- infiltrating the lupus erythematosus. “ derstand how CBD works in these indications. skin as well But it all comes down to meaningful develop- Mellowing out stigma as inhibit their ment—coming up with the formulation that Meanwhile, some patients and dermatol- ability to secrete can get the CBD where it needs to be. ogists remain hesitant to embrace CBD. inflammation- Being highly lipophilic, CBD has challenges When queried in 2017, 10% of dermatolo- permeating through the skin and must be gists reported being asked by at least 10 pa- perpetuating 9 incorporated into a lipid-rich vehicle. What tients yearly about medical cannabis. That cytokines. delivery vehicle for cannabinoid makes a huge difference in terms of whether it gets through. The challenge includes not only delivering the CBD, but also determining how much is needed and how frequently. Many more ques- tions than answers exist at this point. Answering these questions will take time. The 2018 Farm Bill passed by the US Senate legalized CBD containing less than 0.3% THC obtained from hemp. Because cannabinoids previously were a Schedule 1 controlled sub- stance in the US, drug developers have only recently begun CBD development efforts. This whole field is fledgling because it was very difficult to study these plant-based derivatives. Consumers have now embraced—without

March 2021 | 31 of Health websites, Health Canada, and online toolkits from organizations such as the University of Washington’s Alcohol and Drug Abuse Institute. Dermatologists also may consider the nation’s first medical-can- nabis graduate certification programs, offered through Thomas Jefferson University. Additionally, professional societies should create multidisciplinary task forces to help address the dearth of CBD-related medical literature and CME. We’re so early in our figure is probably much higher today. Why spend understanding of CBD—what’s the best way to The same survey showed that 64% of derma- the deliver it that has an impact on a particular $20 million for tologists did not know if CBD has psycho- disease? We need clinical-trial programs. We an FDA pipeline active effects. need dose-escalation phase 2 studies. “when you can There still is to some degree a stigma. Some The future for cannabinoid-based drugs, sell something patients say other physicians have chastised as well as OTC products, is bright. We just them for mentioning cannabinoids. There is OTC and people need to prove what works best and how to concern even though the regulatory landscape best use it.  will buy it?” has changed dramatically. More than 2/3 of the states allow medical REFERENCES cannabis, and 14, plus the District of 1. Marks DH, Friedman A. The therapeutic potential of cannabinoids in dermatology. Skin Therapy Lett. 2018;23(6):1-5. Columbia, permit medical and recreational 2. Friedman AJ. From bud to breakthrough: the therapeutic potential use. A few states allow dermatologic indica- and current landscape of cannabinoids in dermatology. Montreal tions including psoriasis (Connecticut and Dermatological Society; February 11, 2021; Montréal. New Mexico), lupus (Hawaii, Illinois, and 3. Serhan CN, Chiang N, Dalli J. The resolution code of acute inflam- mation: Novel pro-resolving lipid mediators in resolution. Semin New Hampshire), and genetic syndromes Immunol. 2015;27(3):200-215. (Illinois, Maine, and Michigan) as the basis 4. Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic for medical-marijuana use. and antiinflammatory effects on human sebocytes.J Clin Invest. Be sure to hear Dr. 2014;124(9):3713-3724. Friedman on Cannabi- Most states don’t have a true dermatologic 5. Kim HJ, Kim B, Park BM, et al. Topical cannabinoid receptor 1 indication. However, every state with medical agonist attenuates the cutaneous inflammatory responses in noids Part 2: The Legal oxazolone-induced atopic dermatitis model. Int J Dermatol. Framework at marijuana considers chronic pain a legitimate 2015;54(10):e401-e408. www.thedermdigest. indication. Accordingly, I typically list pain as 6. Friedman AJ, Momeni K, Kogan M. Topical cannabinoids for the com/cannabinoids_ the qualifying diagnosis when recommending management of psoriasis vulgaris: report of a case and review of the literature. J Drugs Dermatol. 2020;19(8):795. doi:10.36849/ part2_podcast. medical cannabis, which I commonly do for JDD.2020.5229. local patients with hidradenitis suppurativa, 7. Botanix Pharmaceuticals. Product pipeline. https://botanixpharma. AD, or chronic itch. com/pipeline/. Accessed February 11, 2021. 8. Maghfour J, Rietcheck HR, Rundle CW, et al. An observational study Around 30% of patients reject cannabinoids, of the application of a topical cannabinoid gel on sensitive dry skin. but most patients are very amenable, especially J Drugs Dermatol. 2020;19(12):1204-1208. 9. Robinson E, Murphy E, Friedman A. Knowledge, attitudes, and if I talk to them about why I’m recommending perceptions of cannabinoids in the dermatology community. J Drugs it. That’s why education is so important in the Dermatol. 2018;17(12):1273-1278. dermatology community. We know there’s an interest among consumers and patients. DISCLOSURES Dr. Friedman is a consultant and/or advisory board member for Dermatologists interested in educating Corbus Pharmaceuticals Holdings, Greenway Therapeutix, Hoth themselves should consult State Department Therapeutics, TruPotency, and Zylo Therapeutics.

32 | The Dermatology Digest www.thedermdigest.com/CRYSTAL_BALL

COMMENTARY Lack of topical cannabinoid research warrants caution

Shawn Kwatra, MD, with John Jesitus

he dearth of data regarding topical cannabi- no other approved therapies available, it Tnoids in dermatology leads to a lack of may make sense to try experimental or com- confidence for prescribers. In this climate, pounded therapies.” experts recommend using FDA-approved Patients are increasingly interested in topical treatments when possible, and, when needed, cannabinoids, he added. “But if we don’t have sticking to cannabinoids that have the most great studies showing what is the right patient data behind them. population, what is the right dosing, and how SHAWN KWATRA, MD “Topical cannabinoids are an exciting new to monitor for side effects, it’s very difficult for potential therapeutic option for dermatology Assistant Professor clinicians to give their full approval.” of Dermatology, patients,” said Shawn Kwatra, MD. “Studies Johns Hopkins University Accordingly, Dr. Kwatra said that for conditions have shown tremendous anti-inflammatory Director of the with on-label, FDA-approved treatments, “it properties of cannabinoids, particularly in itch, Johns Hopkins Itch Center makes sense to try those agents first. But if atopic dermatitis, and other inflammatory skin a patient is uncontrolled and the disease is conditions.” Dr. Kwatra is Assistant Professor of Dermatology at Johns Hopkins University, Baltimore, Maryland, and Director of the Johns Hopkins Itch Center. If a patient fails classic first-line But with no drugs specifically FDA-approved for itch, he said, treating this symptom can be dermatological extremely difficult. “We are forced to manage “therapies like top- patients primarily with off-label therapies. If ical steroids and a patient fails classic first-line dermatological there are no other therapies like topical steroids and there are approved therapies available, it may impacting their quality of life, as an off-label make sense to therapy, I would try to pick products that have a little more data on them.” Among topical try experimental cannabinoids, he said, palmitoylethanolamide Don’t miss Shawn Kwatra, MD, on or compounded (PEA) compounds rank among the most Cannabinoids Part 3: Proceed with Caution at therapies.” thoroughly studied.1,2 www.thedermdigest.com/cannabinoids_ part3_podcast Some researchers have expressed concern that the use of unregulated topical cannabinoids continued on page 35

March 2021 | 33 COMMENTARY CBD Cream for Inflammatory Conditions

Michael Milane, MD, MBA, MPH with John Jesitus

annabinoids (CBDs) have potential as Mechanistically, topical CBD works on the Canti-inflammatory products. Chief among CB2 receptor directly, causing reductions in topical CBD’s therapeutic advantages is safety. IL-6 and TNF-α concentrations and inflamma- The size of the market for topical cannabinoids tory pathways in the skin, providing a poten- is potentially massive. An Allied Market Re- tial alternative to steroids. Because topical search report projects that by 2026, the global CBD does not cause side effects, patients can CBD skincare market will reach $3.48 billion.1 use it longer than they can use steroids, or MICHAEL MILANE, as a steroid-sparing agent for maintenance A pharmaceutical-grade CBD product is now MD, MBA, MPH therapy. In a Greenway case report, a patient in clinical trials. In Greenway’s preclinical test- with recalcitrant rosacea who used Canno ing and ongoing Canno Cream trials involving President and CEO, Greenway Therapeutix, Cream monotherapy for 4 consecutive months more than 100 patients thus far, no serious Torrance, CA achieved and maintained 90% clearance.2 adverse events (AEs) have been reported. Similarly, a patient with treatment-resistant Greenway’s observations in pediatric patients eczema cleared in 5 days and subsequently show similar safety. Based on the available data flared when she ran out of the product, then and our own data and experience, we’re find- quickly cleared again when she resumed using ing that it’s very safe for use on the skin. the CBD cream. Because CBD affects mainly the peripheral ClinicalClinical Case Report: case report (Eczema) (Eczema) nervous system, it produces no “high.” That’s

FacialFacial Eczema more from tetrahydrocannabinol (THC), another molecule that is in the plant. Tar- geting the peripheral nervous system also allows greater therapeutic impact on the body, including pain, erythema, and itching. Study of the endocannabinoid system (ECS) shows that humans already have the receptors in our bodies. And we produce a molecule that is similar to CBD or THC, which is called BASELINE 5 DAYS AFTER NANO-CBD BID Tx Study and pictures courtesyBASELINE of Apple A. Bodemer, MD, Dermatologist and Faculty5 DAYS member, AFTER University NANO -ofCBD Wisconsin BID Tx anandamide, discovered only recently (in School of Medicine and Public Health, Madison, WI, October 2019. 1992). The ECS uses these endogenous mole- Study & pictures courtesy of Dr. Apple Bodemer. Board Certified Dermatologist. October 2019. Madison, WI. cules to direct the body toward equilibrium.3 Female patient before and five days after using Canno Cream BID. So if the body is inflamed, it helps reduce that.

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continued from page 33 To increase penetration, Greenway uses before or after dermatologic procedures could DISCLOSURES: ultrasound technology to pulverize CBD into increase the risk for infection and possibly lead Dr. Kwatra reports no relevant nano-sized (≤ 50 nm) particles. Cannabinoids to systemic absorption and/or wound-healing financial interests. are large molecules. Over-the-counter topical difficulties.3 However, Dr. Kwatra said this is a Dr. Friedman is a consultant formulations currently being advertised typi- hypothetical concern. and/or advisory board member for Corbus Pharmaceuticals cally include emulsions, oils, or substrates such Marketplace concerns include misrepresenta- Holdings, Greenway Therapeu- as coconut oil. These substances clump CBD tix, Hoth Therapeutics, TruPo- tion of what topical cannabinoids can do. tency, and Zylo Therapeutics. molecules together, allowing, at best, only 15% Adam Friedman, MD, said, “Cannabinoids to 20% of the active ingredient to penetrate the offer a fleet of possible new therapeutics. But skin. you have to be science-driven. I worry that peo- ple will make outrageous and erroneous claims Mechanistically, topical CBD that can lead people down a dangerous path of works on the CB2 receptor directly, not seeking proper medical care and relying on causing reductions in IL-6 and TNF-α a ‘natural’ product that has no evidence sup- concentrations and inflammatory porting its use.” Dr. Friedman is Professor and Interim Chairman of Dermatology at George pathways in the skin, providing a Washington School of Medicine and Health potential alternative to steroids. Sciences in Washington, DC. Just because a product is natural, he added, Conversely, Canno Cream’s smaller particles, does not necessarily mean it is safe or effective. medical-grade penetration enhancers, and Allergic reactions to excipients used in cannabi- concentration up to 300 mg per ounce allow diol (CBD) oils and creams have been reported. up to 80% CBD absorption, resulting in sig- CBD is essentially safe, said Dr. Friedman, but nificantly higher intended effect. To date, the one must ask, “What else is in the product?” product has shown the best results in atopic Small manufacturers that have sprung up dermatitis. Although the COVID-19 pandem- virtually overnight typically lack the capital ic has slowed clinical trial efforts, Greenway and expertise to ensure that their products is very optimistic and plans to submit trial do not contain irritants or allergens, he said. results to the FDA as soon as possible. Allergic reactions to topical cannabinoids In the future, multiple topical CBD products, and vehicle ingredients may occur, Dr. Kwatra even prescription products, which we also are concurred. The most common side effects are working on, may be big in dermatology.  redness and stinging, which is why, he said, it’s always a good idea to do a test spot before REFERENCES applying to a larger body surface area. Weighing 1. Allied Market Research. CBD skin care market by product type (oils, lotion & creams, masks & serums, bath & soaps, and others), source the risks and benefits, he added, this may be a (hemp and marijuana), and distribution channel (departmental small price to pay compared to topical cannabi- stores, e-commerce, hypermarkets/supermarkets, retail pharmacies,  and others): global opportunity analysis and industry forecast, noids’ potential benefits. 2019–2026. https://www.alliedmarketresearch.com/cbd-skin-care- market. Published January 2020. Accessed February 9, 2021. REFERENCES 2. Milane M. Cannabinoids and dermatology. SUNY Downstate Autumn 1. Avila C, Massick S, Kaffenberger BH, Kwatra SG, Bechtel M. Dermatology Conference; November 4, 2019; New York. Cannabinoids for the treatment of chronic pruritus: a review. 3. Milane M. Potential for cannabinoid therapeutics in dermatology. J Am Acad Dermatol. 2020;82(5):1205-1212. Music City SCALE Symposium for Cosmetic Advances and Laser 2. Khanna R, Khanna R, Denny G, Kwatra SG. Cannabinoids for Education; July 24, 2020; Nashville. the treatment of chronic refractory pruritus. J Dermatolog Treat. 2021;32(2):266-267.

DISCLOSURES 3. Hashim PW, Cohen JL, Pompei DT, Goldenberg G. Topical cannabinoids in dermatology. Cutis. 2017;100(1):50-52. Dr. Milane is president and CEO of Greenway Therapeutix.

March 2021 | 35 COSMETIC CORNER REGENERATIVE MEDICINE

WILL REGENERATION REPLACE REJUVENATION? The science behind regeneration

Wm Philip Werschler, MD, FAAD, FAACS with Lisette Hilton

Wm. Philip Werschler, MD, FAAD, FAACS Founding member of Spokane Dermatology Clinic and Premier Clinical Research The second of 2 articles covering regenerative aesthetic medicine.

Presented at Maui Derm Connect 2021

he two gateway procedures that most dermatologists use Tto get into aesthetic regenerative medicine are platelet-rich plasma (PRP) and fat transfer.

Suneva has FDA clearance on a fat transfer in the office. Dermapose, for example, uses system. This is really stem cells. The procedure a relatively small-volume aspirate. It involves involves taking out fat and processing it. Stem sucking some fat out of the belly or hip, taking cells are what is being processed. So, fat trans- that fat and, within the closed multi-chamber Be sure to watch fer is, in fact, adipose-derived stem cells. system, washing the fat to get rid of the red blood cells, then processing it. The goal is to Regenerative Aesthet- Suneva’s syringe device, Dermapose, is an tease out those stem cells and the associated ics in Dermatology all-in-one system to harvest, wash, and inject with Dr. Werschler at supportive cells and to inject them so that sized fat. The company also has Amplifine, www.thedermdigest. they live and induce more growth of the a system for obtaining high-density PRP. com/regeneration_ requisite tissues. video Suneva’s regenerative devices are marketed to Dermatologists can size the fat, starting with a dermatologists because they can be easily used

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2.4-mm screen, then push it through again with a screen half the filter size, at 1.2 mm. Process- ing the fat more, to stromal vascular fractions, or what plastic surgeons call “nanofat,” puts providers in the gray zone with the FDA. Nanofat offers the highest concentrations of the stem cells, stromal vascular cells, immune cells, endothelial cells, and smooth muscle cells, which gives you the most bang for your buck. But the FDA has ruled that dermatolo- gists can no longer do stromal vascular frac- tion. In the approval of the Dermapose, they stopped at 1.2 mm because that falls within the guidelines. The situation is similar with PRP, but PRP is simpler than adipose-derived stem cell procedures. It involves drawing some blood, spinning it down and sucking off the plate- wounding cascade without creating scarring. Regenerative let-rich and platelet-poor plasma. Then it is Stem cells not only grow collagen, but these aesthetic used for micro needling or radiofrequency adipose-derived stem cells upregulate the medicine comes micro needling. The PRP has platelets and healing cascade and bring in all these sig- down to three growth factors. The growth factors coming nals, or growth factors. The alpha granules, things: out of the platelets are the exosomes. the exosomes, send out signals and release Regenerative aesthetic medicine, or RAM, these proteins that stimulate a controlled wound-healing cascade. 1 is pretty simple, really. It comes down to THE CELL TYPE 3 things: the cell type; the growth factors, Up-and-coming regenerative treatments whether from platelet rich plasma (platelets) So far, plant stem cells have no effect on or fat (stem cells); and the matrix, or the scaf- humans. They do not have the right coding 2 folding that holds everything together. sequence. THE GROWTH FACTORS That’s why wounding with PRP in micro Embryonic stem cells have been on the market Whether from platelet needling, PRP in RF stamping, and probably for a long time with placenta and amnion. rich plasma (platelets) PRP in injections with fillers, creates channels These are registered biomaterials that do not or fat (stem cells) of wounds. It activates the fibrous matrix. We have much of a presence in dermatology. But have gotten much better at amplifying the they are approved and are being picked up and used more and more in dermatology by Mohs 3 surgeons, who use pellets, powders, or sheets THE MATRIX in wounds. The scaffolding that Embryonic stem cells holds everything Embryonic stem cell types are placenta- have been on the market together derived mesenchymal stem/stromal cells for a long time with (PMSCs), amnion-derived MSCs (AMSCs), placenta and amnion. blood vessel-derived MSCs (BV-MSCs) and Wharton’s jelly-derived MSCs (WJ-MSCs) from the umbilical cord.

March 2021 | 37 www.thedermdigest.com/COSMETIC_CORNER

Does it matter where these different embryon- a multitude of growth factors that can ic stem cells come from? The beauty of embry- enhance the coordinated cascade of cellular onic stem cells is they are privileged cells. The and biochemical events involved in natural embryonic stem cell types act the same, with wound healing and skin rejuvenation. similar beneficial effects of wound closure and XoGlo has the potential to improve skin vascularization. texture, reduce scarring, stimulate hair growth, and shorten recovery time. Why haven’t we picked up on the use of these as part of regenerative aesthetic medicine as The company Kimera has taken this product we have with PRP? The answer is we have, but through the robust FDA new-drug application quietly. But I think the bigger answer is be- and their anticipated FDA conformance is in If companies cause they are really expensive and insurance May 2021. We are now seeing the beginning come out does not pay for this. of commercialization of regenerative aesthetic products under the moniker of FDA approval. This is the challenge of making these cheaper. with those It is getting more mainstream. When XoGlo “products and However, if companies come out with those is approved, it will explode in the marketplace really target products and really target the aesthetic mar- for microneedling or injecting. I predict that ketplace, my educated guess is these products Medicare is going to refuse to pay for it, and the aesthetic will work as well and be much easier. This the company will target aesthetics. would be very much like having a prepackaged marketplace, The impact on dermatologists filler in the practice. my educated Until now, smaller companies have devel- guess is these XoGlo is a purified mesenchymal stem cell oped these therapies. Now we’re going to see (MSC)-derived exosome product that contains consolidation. My guess is that big pharma products will will buy up all the little startups. Will regen- work as well eration replace rejuvenation? Probably not and be much completely in most of our practice lifetimes, but I believe it will significantly affect what easier.” we do, how we do it, and our concept of com- bination therapy. 

DISCLOSURES Dr. Werschler is a consultant or independent contractor for Abbvie, Suneva, and Ulthera. He receives grants or research support from Allergan, Amgen, Boehringer Ingelheim, Dermavance, Galderma, Genentech, Janssen, Kythera, Pfizer, Suneva, and Ulthera. He has received honoraria from Abbvie, Allergan, Cellgene, Continued Med, Leo, Merz, Prescriber’s Choice, and Sunev. He is a speaker for Abbvie, Allergan, Cellgene, Eskata, Leo, Merz, Prescriber’s Choice, Pfizer, Ulthera, and Xoft.

38 | The Dermatology Digest COSMETIC CORNER INNOVATIONS

The 3 most high-impact cosmetic innovations

Glynis Ablon, MD and Seth Matarraso, MD with Eliza Cabana

nnovation is a process of change or transformation. It can be subtle, obvious, Ior disruptive, or all 3 in the ever-evolving field of cosmetic dermatology.

The Dermatology Digest asked 2 recognized But supplements may offer only delayed experts in cosmetic dermatology to share what gratification, at best, and aren’t always an easy GLYNIS ABLON, they believe the most innovative aesthetic sell—to the patient or the dermatologist. MD, FAAD treatments are today, how they’ve affected “I think we’re getting more and more informa- their treatment approaches, and what advice Ablon Skin Institute and tion about supplements in general, and there Research Center, they have for others interested in adding such are many different ones out there,” said Dr. Manhattan Beach, treatment options to their practice. California Ablon. “There are more studies coming and we Hair supplements: subtle yet effective really are seeing that they can change people’s For Glynis Ablon, MD, FAAD, of Ablon Skin lives with hair, skin, and nails.” Institute and Research Center, Manhattan Dr. Ablon has conducted and published stud- Beach, California, hair supplements top the list ies on supplements for hair loss in men and of innovations in cosmetic dermatology. women, the latest of which appeared in 2018 1 “Diet and nutrition are key to everything that in the Journal of Drugs in Dermatology. has to do with hair, skin, and nails. And as The 6-month, randomized, double-blind, place- SETH L. MATARASSO, dermatologists that’s what we do. That’s our bo-controlled study assessed the safety and effi- MD specialty. So, an extension of that really is supplements,” she said. Clinical Professor of Dermatology at the University of California School of Medicine in Supplements can change people’s San Francisco “lives with hair, skin, and nails.”

Be sure to watch High-Impact Cosmetic Innovations with Drs. Ablon and Matarraso at www.thedermdigest.com/ cosmetic_innovations_video

March 2021 | 39 www.thedermdigest.com/COSMETIC_CORNER

cacy of an oral supplement (Nutrafol Women’s Dr. Matarasso, who recalls the days of yore Balance Capsules) to promote hair growth in when the glabella was the sole indication for 70 perimenopausal, post-menopausal, or meno- neurotoxin injections. “Now [we use it for] the pausal women with perceived hair thinning. forehead, crow’s feet, masseter and platysma muscles, and sometimes in the perioral area.” “We saw an increase in terminal and vellus But even more notable, he said, “We’ve refined hairs throughout the 6-month study,” said and finessed the technique so that we’re able to Dr. Ablon. “It was really exciting because I soften lines, as opposed to paralyze muscles.” see a lot of hair loss in my practice, and having something that I can offer my patients that is Neurotoxins have been remarkably effective natural, a nutraceutical … that they can take in cosmetic dermatology, but, said Dr. at home I think is a really big deal.” Matarasso, they also have extraordinary therapeutic benefits. Neurotoxins (and fillers), obviously Seth L. Matarasso, MD, Clinical Professor of “For patients with hyperhidrosis … for pa- tients with migraine headaches, for patients For patients Dermatology at the University of California School of Medicine in San Francisco, said the with temporal mandibular joint syndrome— with single most innovative aesthetic dermatology it is a game-changer.” hyperhidrosis treatment is “unequivocally, neurotoxins.” It can also be a game-changer for derma- “… for patients Although there are multiple FDA-approved tologists who decide to foray into aesthetics. neurotoxins available to dermatologists (with with migraine In this case, Dr. Matarasso called neurotoxins more on the horizon), the innovative aspect the “gateway drug.” headaches, isn’t so much in the neurotoxins themselves— for patients it’s in the plethora of ways and areas in which “For someone who really wants to add this they’re used, he said. to their practice, I think this is a great way to with temporal start because it’s not too terribly expensive. mandibular joint “I think of it more … in terms of how we’ve The procedure is quick, the results are predict- approached people with neurotoxins,” said syndrome— able, and it is safe,” he said. “So, for a young dermatologist coming out of their training, neurotoxins or a physician who has been in practice for are a game- a few years and wants to add some aesthetic changer.” procedures, to me this is really an ideal way to break that ice.” Like neurotoxins, many FDA-approved dermal fillers are now available, with many more to come. The innovation here, said Dr. Matarasso, is how they help to refine overall aesthetic results. “In addition to the patient’s face, their hands and their neck really can unmask what their chronologic age can be. [A dermal filler] really gives them a more homogenous unified appearance,” he explained. For dermatologists who plan to add neuro- toxins, fillers, or both to their practice, Dr. continued on page 44

40 | The Dermatology Digest Most commercially insured patients pay as little as $20*

An experience worth noticing. With clinical effi cacy and safety profi le in a once-daily spray foam, choose the Enstilar® Foam experience for your patients with plaque psoriasis.1

In adults, patients achieved "Clear" or "Almost Clear" skin as measured by IGA1,2†: • 53.3% vs 4.8% for vehicle at Week 4 (P<0.001) • 26.4% vs 1.9% for vehicle at Week 2

*Valid for up to 12 prescription fi lls per calendar year. Patients are not eligible if they are enrolled in or eligible for any state or federally funded health care program (eg, Medicare, Medicaid). Additional restrictions and limitations apply; see www.leopharmaconnect.com. † A randomized clinical trial with 426 patients, ≥18 years of age, that investigated the eff ectiveness of Enstilar® or the vehicle alone for the treatment of psoriasis vulgaris on the trunk and/or limbs. Effi cacy was assessed using a 5-point IGA at Week 4, with treatment success defi ned as the percentage of patients who achieved at least a 2-step improvement to reach "Clear" or "Almost Clear" disease severity. Patients with "Mild" disease were required to be "Clear" to be considered a treatment success.1,2 IGA=Investigator’s Global Assessment. Not an actual patient. Image is a representation of plaque psoriasis. Individual results may vary. References: 1. Enstilar® [prescribing information]. LEO Pharma Inc. 2. Leonardi C, Bagel J, Yamauchi P, et al. Effi cacy and safety of calcipotriene plus betamethasone dipropionate aerosol foam in patients with psoriasis vulgaris — a randomized phase III study (PSO-FAST). J Drugs Dermatol. 2015;14(12):1468-1477. INDICATION AND USAGE Enstilar® (calcipotriene and betamethasone dipropionate) Foam is indicated for the topical treatment of plaque psoriasis in patients 12 years and older. Apply Enstilar Foam to aff ected areas once daily for up to 4 weeks. Discontinue use when control is achieved. Instruct patients not to use more than 60 grams every 4 days. IMPORTANT SAFETY INFORMATION For topical use only. Enstilar Foam is not for oral, ophthalmic or intravaginal use and should not be applied on the face, groin or axillae or if skin atrophy is present at the treatment site. Do not use with occlusive dressings. Patients should wash hands after application. Please see Brief Summary of Prescribing Information on following page.

The LEO Pharma logo, LEO Pharma, and Enstilar are registered trademarks of LEO Pharma A/S. ©2020 LEO Pharma Inc. All rights reserved. March 2020 MAT-29982 ENSTILAR® (calcipotriene and betamethasone dipropionate) foam, for topical use Clinical Trials Conducted in Subjects 18 years and older with Psoriasis Rx Only The rates of adverse reactions described below were from three randomized, BRIEF SUMMARY OF PRESCRIBING INFORMATION. multicenter, vehicle and/or active-controlled clinical trials in adult subjects with plaque psoriasis. Subjects applied study product once daily for 4 weeks, and the INDICATIONS AND USAGE ® median weekly dose of Enstilar Foam was 25 grams. Adverse reactions reported in Enstilar (calcipotriene and betamethasone dipropionate) Foam is indicated for the <1% of adult subjects treated with Enstilar Foam included: application site irritation, topical treatment of plaque psoriasis in patients 12 years and older. application site pruritus, folliculitis, skin hypopigmentation, hypercalcemia, urticaria, DOSAGE AND ADMINISTRATION and exacerbation of psoriasis. Instruct patients to shake can prior to using Enstilar Foam and to wash their hands Clinical Trials Conducted in Subjects 12 to 17 years with Psoriasis after applying the product. Apply Enstilar Foam to affected areas once daily for up to In one uncontrolled clinical trial, 106 subjects aged 12 to 17 years with plaque 4 weeks. Rub in Enstilar Foam gently. Discontinue Enstilar Foam when control is psoriasis of the scalp and body applied Enstilar Foam once daily for up to 4 weeks. achieved. The median weekly dose was 40 grams. Adverse reactions reported in <1% of Patients should not use more than 60 grams every 4 days. pediatric subjects treated were acne, erythema, application site pain, and skin Enstilar Foam should not be: reactions. • Used with occlusive dressings unless directed by a healthcare provider. Postmarketing Experience • Used on the face, groin, or axillae, or if skin atrophy is present at the treatment Because adverse reactions are reported voluntarily from a population of uncertain site. size, it is not always possible to reliably estimate their frequency or establish a Enstilar Foam is not for oral, ophthalmic, or intravaginal use. causal relationship to drug exposure. DOSAGE FORMS AND STRENGTHS Postmarketing reports for local adverse reactions to topical corticosteroids included Enstilar Foam: 0.005%/0.064% - each gram contains 50 mcg calcipotriene and atrophy, striae, telangiectasia, dryness, perioral dermatitis, secondary infection, and 0.643 mg of betamethasone dipropionate in a white to off-white opalescent liquid in miliaria. a pressurized aluminum spray can with a continuous valve and actuator. At Ophthalmic adverse reactions of cataracts, glaucoma, increased intraocular pressure, administration the product is a white to off-white foam after evaporation of the and central serous chorioretinopathy have been reported with the use of topical propellants. corticosteroids, including topical betamethasone products. CONTRAINDICATIONS USE IN SPECIFIC POPULATIONS None. Pregnancy WARNINGS AND PRECAUTIONS Risk Summary Flammability Available data with Enstilar Foam are not sufficient to evaluate a drug-associated The propellants in Enstilar Foam are flammable. Instruct the patient to avoid fire, risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. flame, and smoking during and immediately following application. Although there are no available data on use of the calcipotriene component in Hypercalcemia and Hypercalciuria pregnant women, systemic exposure to calcipotriene after topical administration of Hypercalcemia and hypercalciuria have been observed with use of Enstilar Foam. Enstilar Foam is likely to be low. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters Observational studies suggest an increased risk of having low birth weight infants of calcium metabolism have normalized. The incidence of hypercalcemia and with the maternal use of potent or super potent topical corticosteroids. Advise hypercalciuria following Enstilar Foam treatment of more than 4 weeks has not been pregnant women that Enstilar Foam may increase the potential risk of having a low evaluated. birth weight infant and to use Enstilar Foam on the smallest area of skin and for the Effects on Endocrine System shortest duration possible. Hypothalamic-Pituitary-Adrenal Axis Suppression In animal reproduction studies, oral administration of calcipotriene to pregnant rats Systemic absorption of topical corticosteroids can cause reversible hypothalamic- during the period of organogenesis resulted in an increased incidence of minor pituitary-adrenal (HPA) axis suppression with the potential for clinical skeletal abnormalities, including enlarged fontanelles and extra ribs. Oral administration glucocorticosteroid insufficiency. This may occur during treatment or upon of calcipotriene to pregnant rabbits during the period of organogenesis had no withdrawal of treatment. Factors that predispose a patient to HPA axis suppression apparent effects on embryo-fetal development. Subcutaneous administration of include the use of high-potency steroids, large treatment surface areas, prolonged betamethasone dipropionate to pregnant rats and rabbits during the period of use, use of occlusive dressings, altered skin barrier, liver failure, and young age. organogenesis resulted in fetal toxicity, including fetal deaths, reduced fetal weight, Evaluation for HPA axis suppression may be done by using the adrenocorticotropic and fetal malformations (cleft palate and crooked or short tail). The available data hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually do not allow the calculation of relevant comparisons between the systemic withdraw Enstilar Foam, reduce the frequency of application, or substitute with a exposures of calcipotriene and betamethasone dipropionate observed in animal less potent corticosteroid. studies to the systemic exposures that would be expected in humans after topical use of Enstilar® Foam. The following trials evaluated the effects of Enstilar Foam on HPA axis suppression: The estimated background risk of major birth defects and miscarriage of the • In a trial evaluating the effects of Enstilar Foam on the HPA axis, 35 adult indicated population is unknown. All pregnancies have a background risk of birth subjects applied Enstilar Foam on the body and scalp. Adrenal suppression defect, loss, or other adverse outcomes. In the U.S. general population, the was not observed in any subjects after 4 weeks of treatment. In another trial, estimated background risk of major birth defects and miscarriage in clinically 33 pediatric subjects age 12 to 17 years applied Enstilar Foam on the body and recognized pregnancies is 2% to 4% and 15% to 20%, respectively. scalp. Adrenal suppression occurred in 3 (9%) of the subjects. Data Cushing’s Syndrome and Hyperglycemia Human Data Systemic effects of topical corticosteroids may also include Cushing’s syndrome, Available observational studies in pregnant women did not identify a drug- hyperglycemia, and glucosuria. associated risk of major birth defects, preterm delivery, or fetal mortality with Additional Considerations for Endocrine Adverse Reactions the use of topical corticosteroids of any potency. However, when the dispensed Pediatric patients may be more susceptible to systemic toxicity due to their larger amount of potent or super potent topical corticosteroids exceeded 300 grams skin surface to body mass ratios. during the entire pregnancy, maternal use was associated with an increased risk of Use of more than one corticosteroid-containing product at the same time may low birth weight in infants. increase the total systemic corticosteroid exposure. Animal Data Allergic Contact Dermatitis Embryo-fetal development studies with calcipotriene were performed by the oral Allergic contact dermatitis has been observed with topical calcipotriene and topical route in rats and rabbits. Pregnant rats received dosages of 0, 6, 18, or 54 mcg/kg/day corticosteroids. Allergic contact dermatitis to a topical corticosteroid is usually (0, 36, 108, and 324 mcg/m2/day, respectively) on days 6-15 of gestation (the diagnosed by observing a failure to heal rather than a clinical exacerbation. period of organogenesis). There were no apparent effects on maternal survival, Corroborate such an observation with appropriate diagnostic patch testing. behavior, or body weight gain, no effects on litter parameters, and no effects on Ophthalmic Adverse Reactions the incidence of major malformations in fetuses. Fetuses from dams dosed at Use of topical corticosteroids, including Enstilar® Foam, may increase the risk 54 mcg/kg/day exhibited a significantly increased incidence of minor skeletal of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have abnormalities, including enlarged fontanelles and extra ribs. been reported with the postmarketing use of topical corticosteroid products. Avoid Pregnant rabbits were dosed daily with calcipotriene at exposures of 0, 4, 12, or contact with Enstilar Foam with eyes. Enstilar Foam may cause eye irritation. Advise 36 mcg/kg/day (0, 48, 144, and 432 mcg/m2/day, respectively) on days 6-18 of patients to report any visual symptoms and consider referral to an ophthalmologist gestation (the period of organogenesis). Mean maternal body weight gain was for evaluation. reduced in animals dosed at 12 or 36 mcg/kg/day. The incidence of fetal deaths was ADVERSE REACTIONS increased in the group dosed at 36 mcg/kg/day; reduced fetal weight was also Clinical Trials Experience observed in this group. The incidence of major malformations among fetuses was Because clinical trials are conducted under widely varying conditions, adverse not affected. An increase in the incidence of minor skeletal abnormalities, including reaction rates observed in the clinical trials of a drug cannot be directly compared to incomplete ossification of sternebrae, pubic bones, and forelimb phalanges, was rates in the clinical trials of another drug and may not reflect the rates observed in observed in the group dosed at 36 mcg/kg/day. practice.

/day, /day, 2 /day, /day, 2 /day), and 2 /day), of /day) of 2 2

/day and 39 mcg/m 2 /day, respectively), no significant respectively), no /day, 2 /day, respectively), no significant /day, 2 . /day). A treatment-related increase in /day). A treatment-related increase 2 Foam may increase the potential risk of . ®

except horizontally. except horizontally. healthcare provider. medicine gets on face or in mouth or eyes, wash area right away. Instruct the patients not to use other directed by the healthcare provider. Foam without products containing calcipotriene or a corticosteroid with Enstilar first talking to the healthcare provider. areola to avoid direct infant exposure having a low birth weight infant and to use Enstilar Foam on the smallest area of skin and for the shortest duration possible • Shake before use and spray the foam by holding the can in any orientation • Shake before use and spray the foam by holding the can in • Do not use more than 60 grams every 4 days. otherwise • Discontinue therapy when control is achieved unless directed by the use of Enstilar Foam on the face, underarms, groin or eyes. If this • Avoid covering unless • Do not occlude the treatment area with a bandage or other hands after application. • Wash Advise patients to avoid contact of Enstilar Foam with eyes and to report any visual symptoms. Advise patients that Enstilar Foam can cause HPA axis suppression, Cushing’s axis suppression, Cushing’s Advise patients that Enstilar Foam can cause HPA syndrome, and/or hyperglycemia. Ophthalmic Adverse Reactions in female rats at oral doses of up to 1000 mcg/kg/day (6000 mcg/m in females and males, respectively), no significant changes in tumor incidence were in females and males, respectively), observed when compared to control. was administered via oral gavage to male and When betamethasone dipropionate up to 24 months at dosages of 20, 60, and female Sprague Dawley rats for 1200 mcg/m 200 mcg/kg/day (120, 360, and Instruct patients that Enstilar Foam is flammable; avoid heat, flame, or smoking Instruct patients that Enstilar Foam is flammable; avoid heat, flame, when applying this medication. Administration Instructions respectively). Beginning week 71, the dosage for high-dose animals of both genders respectively). Beginning week 71, (60 mcg/m was reduced to 10 mcg/kg/day changes in tumor incidence were observedchanges in tumor to control. when compared was conducted with calcipotriene in male study A 104-week oral carcinogenicity and 15 mcg/kg/day (6, 30, and 90 mcg/m and female rats at doses of 1, 5, benign C-cell adenomas was observed thyroid of females that received in the in benign pheochromocytomas was A treatment-related increase 15 mcg/kg/day. No other observed received 15 mcg/kg/day. in the adrenal glands of males that in tumor incidence were observedstatistically significant differences when compared findings to patients is unknown. to control. The relevance of these was applied topically to CD-1 mice for up to When betamethasone dipropionate 1.3, 4.2, and 8.5 mcg/kg/day in females, and 24 months at dosages approximating males (up to 26 mcg/m 1.3, 4.2, and 12.9 mcg/kg/day in Local Reactions and Skin Atrophy Carcinogenesis, Mutagenesis, Impairment of Fertility Mutagenesis, Impairment of Carcinogenesis, of for up to 24 months at dosages was applied topically to mice When calcipotriene (9, 30, and 90 mcg/m 3, 10, and 30 mcg/kg/day • Advise pregnant women that Enstilar HPA Axis Suppression, Cushing’s Syndrome, and Hyperglycemia Axis Suppression, Cushing’s HPA Pregnancy and Lactation • Advise breastfeeding women not to apply Enstilar Foam directly to the nipple and Advise patients that hypercalcemia and hypercalciuria have been observed with the and hypercalciuria Advise patients that hypercalcemia use of Enstilar Foam. calcipotriene indicated no impairment of fertility or general reproductive performance.calcipotriene indicated no impairment of fertility or general reproductive mcg/m Studies in male rats at oral doses of up to 200 mcg/kg/day (1200 betamethasone dipropionate indicated no impairment of fertility. betamethasone dipropionate indicated no impairment of fertility. Flammability changes in tumor incidence were observed when compared to control. the assay, Calcipotriene did not elicit any genotoxic effects in the Ames mutagenicity the human lymphocyte chromosome aberration mouse lymphoma TK locus assay, did not elicit any test, or the mouse micronucleus test. Betamethasone dipropionate the mouse lymphoma TK locus genotoxic effects in the Ames mutagenicity assay, or in the rat micronucleus test. assay, Studies in rats with oral doses of up to 54 mcg/kg/day (324 mcg/m Advise patients that local reactions and skin atrophy are more likely to occur with Advise patients that local reactions and skin atrophy are more occlusive use, prolonged use or use of higher potency corticosteroids. and Hypercalciuria Hypercalcemia NONCLINICAL TOXICOLOGY NONCLINICAL PATIENT COUNSELING INFORMATION INFORMATION COUNSELING PATIENT Manufactured by: LEO Laboratories Ltd., 285 Cashel Road, Dublin 12, Ireland or Colep Laupheim GmbH & Co. KG, Fockestraße 12, 88471 Laupheim, Germany (DE) Distributed by: LEO Pharma Inc., Madison, NJ 07940, USA 2020 March MAT-32588 /day, respectively) from respectively) /day, 2

/day, respectively) on days 6 through 18 respectively) on days 6 through /day, 2

/day, respectively) from gestation day 15 through day 20 respectively) from gestation day /day, 2

/day, respectively) on days 7 through 13 of gestation (the period of days 7 through 13 of gestation respectively) on /day, 2 It is not known whether topical administration of large amounts of It is not known whether topical administration of large amounts . Foam and any potential adverse effects on the breastfed child from Foam and any potential adverse effects on the breastfed child ® betamethasone dipropionate could result in sufficient systemic absorption to betamethasone dipropionate could result in sufficient systemic and health benefits produce detectable quantities in human milk. The developmental clinical need for of breastfeeding should be considered along with the mother’s Enstilar To minimize potential exposure to the breastfed infant via breast milk, use Enstilar To possible while Foam on the smallest area of skin and for the shortest duration Foam directly to breastfeeding. Advise breastfeeding women not to apply Enstilar the nipple and areola to avoid direct infant exposure. gestation day 6 through day 20 postpartum. Mean maternal body weight was gestation day 6 through day 20 postpartum. Mean maternal body and 1000 mcg/kg/day. significantly reduced on gestation day 20 in animals dosed at 300 increased but statistically significantly, The mean duration of gestation was slightly, of pups that survived to The mean percentage at 100, 300, and 1000 mcg/kg/day. of pups percentage day 4 was reduced in relation to dosage. On lactation day 5, the significantly reduced with a reflex to right themselves when placed on their back was No effects on the ability of pups to learn were observed, and at 1000 mcg/kg/day. affected. the ability of the offspring of treated rats to reproduce was not Lactation Risk Summary Because of a higher ratio of skin surface area to body mass, children under the age of 12 years are at particular risk of systemic adverse effects when they are treated with topical corticosteroids. Pediatric patients are, therefore, also at greater risk of and adrenal insufficiency with the use of topical corticosteroids axis suppression HPA including Enstilar Foam. Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial Cushing’s hypertension have been reported in pediatric patients treated with topical corticosteroids. Local adverse reactions including striae have been reported with use of topical corticosteroids in pediatric patients. The safety and effectiveness of Enstilar Foam in pediatric patients less than 12 years of age have not been established. Geriatric Use Of the total number of subjects in the controlled clinical studies of Enstilar Foam, and 21 were 75 and over. 97 subjects were 65 years and over, No overall differences in safety or effectiveness of Enstilar Foam were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pediatric Use of mild to severe The safety and effectiveness of Enstilar Foam for the treatment 12 to 17 years. The plaque psoriasis have been established in pediatric patients age from adequate and use of Enstilar Foam for this indication is supported by evidence 106 adolescents well-controlled trials in adults and from one uncontrolled trial in metabolism was age 12 to 17 years with psoriasis of the body and scalp. Calcium or clinically evaluated in all pediatric subjects and no cases of hypercalcemia relevant changes in urinary calcium were reported. Hypothalamic pituitary adrenal was evaluated in a subset of 33 pediatric subjects with axis suppression (HPA) moderate plaque psoriasis of the body and scalp (mean body surface area involvement of 16% and mean scalp area involvement of 56%). After 4 weeks of axis suppression once daily treatment with a mean weekly dose of 47 grams, HPA was observed in 3 of 33 subjects (9%). Embryo-fetal were studies with betamethasone dipropionate development performed and rabbits. Pregnant mice were subcutaneous injection in mice via (0, 468, 1875, and of 0, 156, 625, or 2500 mcg/kg/day administered doses 7500 mcg/m of gestation (the period of organogenesis). Betamethasone dipropionate induced of gestation (the period of organogenesis). fetal weight, external malformations including fetal deaths, reduced fetal toxicity, palate, umbilical hernia, kinked tail, club foot, and (including malformed ears, cleft (including absence of phalanges of the first club hand), and skeletal malformations of 2.5 mcg/kg/day and above. digit and cranial dysplasia) at dosages effects on peri- and post-natal development when Calcipotriene was evaluated for rats at dosages of 0, 6, 18 or 54 mcg/kg/day orally administered to pregnant (0, 36, 108, and 324 mcg/m postpartum. No remarkable effects were observed on any parameter, including including were observedpostpartum. No remarkable effects on any parameter, rear pups. body weight, litter parameters, or the ability to nurse or survival, behavior, evaluated for effects on peri- and post-natal Betamethasone dipropionate was of 0, 100, 300, development when orally administered to pregnant rats at dosages and 1000 mcg/kg/day (0, 600, 1800, and 6000 mcg/m Enstilar Foam or from the underlying maternal condition. Clinical Considerations organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal fetal toxicity, Betamethasone dipropionate induced organogenesis). (increased incidence of the cleft palate deaths, reduced fetal weight, malformations skeletal abnormalities (delayed ossification of and crooked or short tail), and minor toxicity was observedvertebra and sternebrae). Fetal at the lowest exposure that was evaluated (156 mcg/kg/day). at dosages of 0, 0.625, 2.5, and Pregnant rabbits were injected subcutaneously 120 mcg/m 10 mcg/kg/day (0, 7.5, 30, and There is no information regarding the presence of topically administered calcipotriene There is no information regarding the presence of topically administered the breastfed infant, and betamethasone dipropionate in human milk, the effects on in plasma are low or the effects on milk production. Concentrations of calcipotriene milk are likely after topical administration, and therefore, concentrations in human to be low

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continued from page 40 Matarasso offered this advice: “Go slow. Start antees with PRP, but there’s not much in REFERENCES with FDA-approved products and indications.” dermatology that comes with them. But, 1. Ablon G, Kogan S. A she said, in her experience, using a micro- randomized, double-blind, He also recommended looking to professional needling device to get PRP into the skin placebo-controlled study societies and manufacturers for injectable prod- returns great results. evaluating the ability and uct and technique education and guidance. safety of a nutraceutical “It doesn’t work 100%, but I think if you’re supplement with “For those who are just starting, the manufac- standardized botanicals using the right devices and getting good PRP, turers are more than happy to help you edu- to promote hair growth you can see some really nice results with scars, in perimenopausal, cate yourself on the injectable. And equally as hair loss, and other conditions.” menopausal, and post- important, the AAD and the ASDS have many menopausal women with courses with hands-on training, so that you Another plus? Microneedling is colorblind. self-perceived thinning hair. J Drugs Dermatol. 2018 can learn the anatomy and learn the proper “You’re dealing with a device that can be used May 1;17(5):558-565. technique, so that you can learn to recognize on all skin types,” she said. “It has a very, very a complication, and most importantly, how to rare risk of post inflammatory hyperpigmenta- DISCLOSURES: treat a complication,” he said. tion and patients do really well.” Dr. Matarraso has been a con- sultant to Allergan, Galderma Microneedling (and PRP: the disruptor) But not all microneedling devices are alike, and Revance. It’s not a new technology, but combining mi- cautioned Dr. Ablon. “I think it’s important to Dr. Ablon is a research croneedling with other treatments makes it a know that whatever device you do choose is investigator for Nutrafol and tool ripe for disruptive innovation. Ameinmed and serves on the one that has been tested, [and] there are stud- advisory board for Omnilux. “I use my microneedling device for many ies that have been performed on that specific different things. I don’t just use it for wrinkles device, because they do work slightly different- and I don’t just use it for acne scars,” said Dr. ly from one another.”  Ablon, who combines it with platelet-rich plasma (PRP) for hair loss and other topical actives for specific skin conditions. “It’s really nice for resistant melasma. I’ll use transdermal drug delivery systems, using the microneedling device to get that medicine into the skin,” she said. While Dr. Ablon admitted that the clinical benefits of PRP may not yet be fully realized in medicine, she believes it’s worth serious consideration by the dermatologist. “[PRP] acts like a fertilizer. You’re getting The Broadmoor growth factors and when the platelets are ac- Colorado Springs, CO tivated, we can see some dramatic results,” she July 21-24, 2021 said. “I think that it’s important to understand that it can be used for many dermatologic conditions.” REGISTER NOW AT She especially likes the benefits it offers to acci- AMERICANDERMOSCOPY.COM dent patients who have facial wounds or scars. Dr. Ablon acknowledged that there are no guar-

44 | The Dermatology Digest NEW DRUGS MELASMA

Study finds cysteamine safe and effective in treating melasma

Helio Miot, MD, PhD with Bob Kronemyer

he first head-to-head comparison study of cysteamine cream to Thydroquinone for the treatment of recalcitrant melasma has found the relatively new topical agent to be safe, well-tolerated and effective, despite its inferior performance to hydroquinone.

HELIO MIOT, MD, PhD The study, which was published last year in “The incidence of melasma is increasing among Professor of Dermatology, the International Journal of Dermatology, adult women all around the world,” said princi- Unesp, Botucatu Campus, compared topical 5% cysteamine to 4% State of São Paulo, pal investigator Helio Miot, MD, PhD, a Brazil hydroquinone in treating facial melasma Professor of Dermatology at Unesp, Botucatu 1 in 40 women. Campus, State of São Paulo, Brazil, who noted

Watch Cysteamine for Pigmentation Disorders with Jeanine Downie, MD at www.thedermdigest. com/downie_video

March 2021 | 45 The sulfur odor from the cysteamine was judged by the participants to be mild and completely“ subsided after facial washing,” Dr. Miot said. “But one patient reported headache because of the odor.”

that researchers have hypothesized that con- Cysteamine is an aminothiol compound natu- traceptive pills, air pollution, and visible light rally produced in the human body during the exposure may be causing this increase. coenzyme A metabolism cycle and is a degrada- tion product of the amino acid L-cysteine. “The Melasma also has a high rate of recurrence, agent’s mechanisms of action are not fully un- despite effective therapies like hydroquinone The photographic derstood, though,” Dr. Miot said. “It is postulat- or triple combination cream (hydroquinone evaluation ed that the skin lightening effect by cysteamine 5%, hydrocortisone 1%, and tretinoin 0.1%). concluded that is due to its inherent antioxidant properties.” there was up to “The majority of the effective depigmenting agents are tyrosinase inhibitors, of which The antioxidant also inhibits the melanin hydroquinone is the most studied drug,” Dr. synthesis by decreasing the formation of dopa- % Miot said. “But new treatments are welcome, chrome (the immediate precursor of eumela- especially because melasma is relapsing.” nin) and increasing intracellular glutathione, 74 which shifts the eumelanin to pheomelanin Melasma is a common chronic hypermelanosis IMPROVEMENT synthesis, as well as to chelating copper ions that affects photoexposed areas, especially in in both groups required in melanogenesis. women, and may have a negative effect on the patient’s quality of life. “Despite having been discovered decades ago, the strong odor of cysteamine prohibited However, because of the risk of exogenous its use,” Dr. Miot said. “Fortunately, a recent ochronosis and “confetti” depigmentation as a change in the formulation has reduced the result of the hydroquinone-induced melanocyte sulfur odor and skin irritability, allowing its toxicity, “other potent depigmenting agents are use as a cream.” frequently researched for the treatment of me- lasma,” Dr. Miot said. “Cysteamine is a potent Trial details bleaching agent with a different mode of action The quasi-randomized, multicenter, evalua- than other tyrosinase inhibitors.” tor-blinded clinical trial from Brazil was con-

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

ducted between October 2019 and February Melasma Area and Severity Index (mMASI) 2020, involving 40 women representative of and the Melasma Quality of Life Scale a Brazilian sample of melasma patients, all of (MELASQoL). Also assessed was the dif- whom had facial melasma with skin phototype ference in colorimetric luminosity between II to V, and aged 30 to 55. melasma and the adjacent unaffected skin. Patients were divided into 2 groups of nightly The Global Aesthetic Improvement Scale drug application on hyperpigmented areas for (GAIS) assessed the difference in the ap- 120 days: 5% cysteamine gel-cream (n = 20) pearance of the skin through standardized and 4% hydroquinone (n = 20). photographs. Both groups of women were also required to “Both groups exhibited a reduction in mMASI use tinted sunscreen with a sun protection after 120 days of treatment,” Dr. Miot said factor (SPF) of 50 and a persistent pigment (see Graph below). However, the improve- darkening (PPD) of 9. ment was greater in the group that received hydroquinone treatment: 41% vs 24% at 60 Patients in the cysteamine group were in- days, respectively, and 53% vs 38% at 120 days, structed to maintain the cream on their skin respectively. for 15 minutes on the first night, followed by facial washing. Application time progressively “The results of other trials reveal a mean increased up to 2 hours, if there was no skin 38% to 58% decrease in mMASI with topical irritation during the previous nights, again cysteamine after 120 days, which is consistent followed by facial washing. with our outcomes,” Dr. Miot said. The hydroquinone group was instructed to The photographic evaluation concluded that keep the cream on the face overnight. there was up to 74% improvement in both groups, without a statistically significant differ- Subjects were assessed at baseline and after ence between them (P = 0.087). 60 days and 120 days of treatment via the

0

−10

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−50 Percentile mMASI reduction Percentile

−60 T0 T60 T120

CYS HQ

Graph courtesy of Helio Miot, MD, PhD

Percentile mMASI reduction by Cysteamine and hydroquinone.

March 2021 | 47 www.thedermdigest.com/NEW_DRUGS

But MELASQoL favored hydroquinone: 20% Using them in combination also has yet to be vs 19% at 60 days, and 41% vs 27% at 120 defined. “There is still no clinical trial evaluat- days, respectively. ing the sequential or alternate use of these 2 drugs in melasma treatment,” he said. Colorimetric assessment revealed progressive depigmenting in both groups, again without The disadvantage of cysteamine, however, is a statistically significant difference between the need to wash the applied area after 2 hours them (P > 0.160). of treatment because there is a risk of itching and burning after long maintenance, according “The sulfur odor from the cysteamine was to Dr. Miot. “Most of our participants toler- judged by the participants to be mild and ated more than 1 hour of treatment, therefore completely subsided after facial washing,” the effect of overnight application should be Our trial Dr. Miot said. “But one patient reported assessed further,” he said. confirms the headache because of the odor.” Case reports indicate that cysteamine cream efficacy and There were no severe adverse effects related is effective for treating refractory post-inflam- “acceptability of either to treatment or deviances in protocol matory hyperpigmentation resistant to triple a novel topical as a result of skin intolerance. Erythema and combination cream. cysteamine burning sensation were the 2 most reported formulation for local adverse events in both groups. However, The next steps are to evaluate the long-term their frequency of up to 20% did not differ efficacy and tolerability of cysteamine, or the treatment between the 2 groups. perhaps to test the benefit of its association of facial with other bleaching strategies, according Tolerability of erythema, desquamation, to Dr. Miot. melasma.” and burning also did not differ between the 2 groups (P > 0.17). Because melasma has a complex pathogene- sis that surpasses melanocyte hypertrophy, a “Our trial confirms the efficacy and accept- combination of strategies could lead to more ability of a novel topical cysteamine formula- effective outcomes. “For example, cysteamine tion for the treatment of facial melasma, with might be positioned as a maintenance treat- the advantages of being safe, well-tolerated, ment after prescribing other potent depig- and an option to patients that are intolerant menting agents, microneedling, laser, or oral or allergic to hydroquinone,” said Dr. Miot, tranexamic acid,” Dr. Miot said.  who is not surprised by any of the study’s results. “Cysteamine has a different mode of REFERENCES action than hydroquinone 4% that has been 1. Lima PB, Dias JAF, Cassiano D, et al. A comparative study of proven to be effective.” topical 5% cysteamine versus 4% hydroquinone in the treatment of facial melasma in women. Int J Dermatol. 2020;August 31. Limitations and possibilities doi:org/10.1111/ijd.15146 Three potential limitations of the study are that

it was open, was performed in the summer, DISCLOSURES and had a relatively short follow-up period. Dr. Miot reports no relevant financial interests. Dr. Miot said there are no reasons why hydro- quinone or cysteamine should be used first.

48 | The Dermatology Digest NEW DRUGS ACTINIC KERATOSIS

Tirbanibulin topical therapy for actinic keratosis

George Martin, MD with Bob Kronemyer

he molecule contained in tirbanibulin 1% ointment (Klisyri; Almirall SA) Tfor treating actinic keratosis of the face and scalp is clearly a game changer, according to George Martin, MD, Medical Director at Dr. George Martin Dermatology Associates in Kihei, Hawaii.

George Martin, MD “In a pooled analysis of results from phase truly remarkable,” Dr. Martin said. 3 trials, this molecule resulted in 50% of The molecule was developed by Athenex, patients clearing their actinic keratosis “which creates truly unique oncologic mole- completely on the face and scalp, whereas cules,” he said. 75% of patients cleared 75% of their disease,” Dr. Martin said. These results were twice as The topical therapy is applied once daily for likely on the face as compared to the scalp. 5 days, usually at nighttime for best compli - “This 75% success rate is more in alignment ance. “This translates into great compliance, with real-world practice,” he said. not only because of its efficacy and short dura- tion, but also because of the minimal irritation,” The trials also achieved an individual lesion Dr. Martin said. The composite irritation score clearance rate of more than 87%. “This is

Essential viewing! Dr. Martin on Tirbanibulin for Topical AK Treatment at www.thedermdigest. com/tirbanibulin_video

March 2021 | 49 Alpha tubulin, though, is not limited to cell replication, but makes up the cytoskeleton and facilitates transport of molecules within the cell as well.” Therefore, a woman of childbearing age should be treated with tirbanibulin with the same consideration as when treating with fluoroura- cil—only if she has a reliable form of contra- ception. “A lot of our actinic keratosis patients are over the age of 60, but I am treating young ladies who are 32 or 33 with the disease,” Dr. Martin said. “Certainly, age 30 to 50 is the space where we are noticing an increased inci- dence of actinic keratosis.” The treatment field is also limited to 25 2cm , which is modeled after the ingenol mebutate gel studies of 25 cm2. “Of course, when we talk (0 to 18) was, on average, 3, and severe local about a field therapy, we think about a full face % skin reaction occurred in less than 10% of or a full scalp,” Dr. Martin said. “Although patients. “This finding is also extraordinary,” tirbanibulin is approved for the treatment of he said. face and scalp, the treatment parameters are 75 2 25 cm , which is about the size of an individu- OF PATIENTS In addition, application-site pruritus was 9% al’s palm.” CLEARED vs 6% for placebo. For pain, it was 10%, vs 3% for placebo. Hence, clinicians accustomed to 5% imiquimod sachets will need to spread % Treatment will allow patients to maintain their tirbanibulin over a wider surface area. “There work schedules and continue their normal will be enough in the sachet to potentially 75 lives, “without the long, protracted, cosmet- treat the entire field surface, as we often do ically awful look they have with a 2-week with 5% imiquimod sachets,” Dr. Martin said. OF THEIR DISEASE on-off-on regimen of imiquimod cream or “But does that mean that the tirbanibulin between 1 and 4 weeks of treatment with molecule will be somewhat diluted and fluorouracil cream,” said Dr. Martin. “Similar- potentially less efficacious than what we ly, photodynamic therapy (PDT), which is an have seen in the original studies? That is excellent treatment, makes patients photosen- unknown. Meanwhile, I encourage those who sitive and swollen for a few days and crusty for will be using tirbanibulin to start applying by days. My patients usually take at least 1 week spreading the ointment over the more severe off work.” actinically damaged areas.” However, there are some caveats to the medi- Because of the drug’s ease of use, Dr. Martin cation. “This molecule is absorbed at very low said that, if clinically indicated, it is appro- levels into the bloodstream in some patients,” priate to retreat a few months after the first Dr. Martin said. “The mechanism of action is application. “Clearance rates were measured inhibiting alpha tubulin or breaking up the at day 57 in the phase 3 trials, so I would spindle apparatus of rapidly dividing cells probably consider retreatment if an incomplete and inhibiting cells that are rapidly growing. response occurs after assessing the patient at

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3 months,” he said. “Remember, actinic kerato- patients. Already, many of my patients with ses is a chronic disease. My patients have 1 or actinic keratosis who have been previously 2 cycles of field therapy each year, depending treated with these other therapies are ready on their risk for nonmelanoma skin cancer.” to sign up.” Dr. Martin believes tirbanibulin is probably Dr. Martin is eager to observe 3-month the easiest drug to use for the treatment of follow-up results with tirbanibulin. “It should field cancerization. “The strategies we use for also be well covered by commercial insuranc- fluorouracil cream can be applied to tirbanibu- es,” he said. “Medicare patients always present Roughly 50% lin,” he said. a challenge with brand-name medications. of patients This will be no different. However, I know that A 1-year longitudinal followup study of tirban- who cleared Almirall, the company marketing this mole- ibulin enrolled patients who had cleared 100% cule, is making great strides to ensure that our “their treatment of their field at day 57, for which the number Medicare patients have access to the drug.” area by initial of baseline lesions was typically 5 to 8. “The Food and Drug Administration defines recur- A safety study of a large field therapy area in day 57 remained rences as any actinic keratosis that emerges in excess of 100 cm2 to treat difficult areas such clear for an the treatment field within 1 year,” Dr. Martin as the extremities or décolleté of the chest is additional year.” said. “However, the study investigators were currently under way. very specific in their mapping. They showed Furthermore, Almirall is also in discussions that, while 73% of individuals developed an to use tirbanibulin to treat squamous cell actinic keratosis in the treatment field during carcinoma in situ, “which is basically an ex- the 1-year followup, many of the recurrences panded actinic keratosis, and secondarily the that were noted were actually new lesions, not treatment of superficial basal cell carcinomas,” initially treated lesions.” Dr. Martin said. “I think this molecule would After stratification, roughly 50% of patients be a great fit for both indications.” who cleared their treatment area by initial day Other disease states in cutaneous oncology 57 remained clear for an additional year. And might also benefit from tirbanibulin, accord- for patients who developed new lesions during ing to Dr. Martin. “So this drug holds great the 1-year follow-up, at least two-thirds were promise for not only cutaneous skin cancers, limited to 1 or 2 new lesions. but also potentially for other non-malignant A drug with promise growths such as warts,” he said. “We are eager “The cosmetic impact on individuals who are to see the complete spectrum of what this treated with tirbanibulin should be pretty min- molecule is capable of doing.”  imal,” he said. “I do not think we are going to have many callbacks, like we do with imiqui- DISCLOSURES mod, fluorouracil, and PDT. I look forward Dr. Martin serves on the scientific advisory board and/or is a paid consultant to Almirall, Bausch/Ortho, Biofrontera, LEO Pharma, and to using this molecule in my practice on my SUN/DUSA.

March 2021 | 51 COMMENTARY Tirbanibulin ointment for actinic keratosis

Drs. Tyring, Schlesinger, and Lain, with Bob Kronemyer STEPHEN TYRING, MD, PhD irbanibulin 1% ointment (Klisyri; Almirall Mechanism of action TSA) for treating actinic keratosis of the face “Actinic keratosis is associated with proliferat- Clinical Professor of Dermatology and scalp is now commercially available in the ing atypical keratinocytes and p53 mutations University of Texas Health United States. that render them resistant to apoptosis,” said Science Center co-author Todd Schlesinger, MD, the Founder Houston, Texas Results of 2 identically designed phase 3 trials and Director of the Clinical Research Center of the drug, which was FDA-approved in of the Carolinas in Charleston, South Caroli- December 2020, were recently published in na. “Alpha and beta tubulin come together to The New England Journal of Medicine.1 form dimers, or pairs that become part of the The 2 studies totaled 702 adult patients with growing microtubule.” (See Figure.) actinic keratoses, who were randomly as- Tubulin helps form the cytoskeleton and signed, in a 1:1 ratio, to receive either topical maintain the structure of the cell, according tirbanibulin or vehicle (placebo) ointment to Dr. Schlesinger. “Tubulin functions in cell to the face or scalp. TODD SCHLESINGER, transport by allowing proteins to move along MD The ointment was applied by the patients to the surface of the formed microtubule,” he 2 Founder and Director, a 25 cm contiguous area containing 4 to 8 said. “It also plays a major role in cell division Clinical Research Center lesions, once daily for 5 consecutive days. by pulling the 2 chromosomes apart during of the Carolinas cell division, creating 2 cells each with a copy Charleston, South Carolina Complete clearance in trial 1 occurred in 44% of the genetic material.” of the patients in the tirbanibulin group, com- pared to only 5% of those in the vehicle group. Tirbanibulin exerts its effect by binding tubulin and preventing dimerization, thus In trial 2, the percentages were 54% and inhibiting its polymerization. “It also inhibits 13%, respectively. Src kinase signaling, which results in increased The percentage of patients with partial p53 expression and the arrest of cell division at clearance was also significantly higher in interphase Gap 2 and mitosis in fast-proliferat- the tirbanibulin groups: 72% vs 18% for ing cells,” Dr. Schlesinger said. placebo. EDWARD LAIN, MD Dr. Schlesinger is pleasantly surprised by the Chief Medical Officer At 1 year, the recurrent lesion rate was 47% study results. “Because of the drug’s unique Sanova Dermatology Austin, Texas among patients who attained a complete mechanism of action, there is little or no in- response to the medication. flammation as opposed to necrosis, and hence there were reduced side effects compared to

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other treatments,” he said. “The good tolerability therefore, because the actinic damage persists, profile, along with a shorter treatment regimen, we will continue to see actinic keratosis arising means greater patient acceptance and improved in the treatment area.” compliance. Research shows that compliance Dr. Lain predicts that tirbanibulin “will leap to increases with shorter treatment durations.” the top” of the armamentarium for treating ac- Promising results tinic keratosis. “Compliance should not be an Co-author Edward Lain, MD, Chief Medical issue,” he said. “Over 99% of patients complet- Officer at Sanova Dermatology in Austin, ed the 5-day course of treatment. That is such Texas, noted that none of the study outcomes a short course and it is only once a day.” are unexpected to him. “During my experience In the phase 3 trials, the peak local skin as an investigator for the clinical trials, reaction (LSR) score occurred at day 8, which I noticed very good efficacy, as well as very is 3 days after completing treatment. “Hence, good tolerability,” he said. LSRs should not mitigate the treatment course Recurrent actinic keratosis was strictly defined at all,” Dr. Lain said. “In fact, many of my as those lesions that were present in the treat- patients felt they were not receiving active ment field at baseline and appeared again by medication because the LSRs were so minimal, the 1-year follow-up. “The incidence was 47%, like redness, scaling and crusting, which is which compares favorably to data we have common with available field therapy agents.” on other topical therapies for actinic kera- Despite tirbanibulin having a limited treat- tosis, although no head-to-head studies are ment area, Dr. Lain believes the medication available,” Dr. Lain said. “Hence, this finding will be popular, due to its excellent tolerability. is not unexpected at all. Actinic keratosis is “A traditional therapy on the entire face, such the symptom of the disease actinic damage; as fluorouracil cream or imiquimod cream,

Alpha - tubulin Tubulin dimers Beta - tubulin X Inhibition of tubulin polymerization

Disruption of spindle – + microtubule formation Growing microtubule in proliferating cells

Cell death by apoptosis

Source: Almirall Figure. Tirbanibulin mechanism of action.

March 2021 | 53 www.thedermdigest.com/NEW_DRUGS

has both a longer treatment course and much Investigating a larger area “would be a higher rates of LSRs,” he said. prudent move, especially given the favorable adverse event profile with the small field,” Dr. Overall, Dr. Lain is highly excited for tirbani- Schlesinger said. “Meanwhile, the small field bulin to launch. “It will be a game changer for allows us to treat the affected areas in many both dermatologists and their patients,” he said. patients, such as the forehead, the two cheeks, Co-author Stephen Tyring, MD, PhD, a Clini- or the central part of the scalp.” cal Professor of Dermatology at the University Tirbanibulin might also play a role in treating of Texas Health Science Center in Houston, is nonmelanoma skin cancer. “The medication Compliance also not surprised by study results, “consider- has been looked at to inhibit keratinocyte ing both the mechanism of action of tirbani- should not be proliferation in-vitro, and even had effect in bulin and data from previous clinical obser- an issue,” he some melanoma cell lines and in a number of vations,” he said. “The mechanism of action said. “Over other tumors such as breast, stomach, prostate, “ of the medication is via inhibition of tubulin bone, ovarian, and others for which it is under 99% of patients polymerization and Src kinase signaling.” development,” Dr. Schlesinger said. completed the Dr. Tyring said tirbanibulin represents an Dr. Schlesinger believes the dermatologic 5-day course of advancement in therapy, “due both to its short community will benefit from longer trials duration of application and its well-tolerated treatment. That of tirbanibulin for actinic keratosis to further adverse events. Other therapies either produce is such a short delineate the benefits and risks. “Actinic more pain, such as cryotherapy, or require course and it is keratosis is a chronic recurring disease,” he longer durations of therapy, like imiquimod.” only once a day.” said. “I think that dermatologists will try The most common local reaction to tirbanibu- to combine the new medication with other lin was erythema in 91% of patients, followed currently used modalities for actinic keratosis by flaking or scaling in 82%. to see if patients can achieve an even better response and reduce recurrence over time.”  The 2 most prevalent adverse events were application pain (in 10% of patients) and pruritus, which both resolved. DISCLOSURES Dr. Lain has served as an investigator, consultant, speaker, and Further studies are required to show efficacy advisor to Almirall. and safety for areas of the skin greater than Dr. Tyring reports no relevant financial interests. 25 cm and in combination with cryotherapy, Dr. Schlesinger serves as an investigator, speaker and ongoing for example, according to Dr. Tyring. consultant for Almirall and was an investigator for Athenex (formerly Kinex), the developer of tirbanibulin. He also conducts research Dr. Schlesinger acknowledged that treating a for other dermatologic companies such as Galderma and receives consulting and speaking fees from Sun Pharmaceutical Industries. smaller area is a limitation of the study, but is in line with prior studies and drug approvals. “It would be nice to have a larger area in the REFERENCE 1. Blauvelt A, Kempers S, Lain E, et al. Phase 3 trials of tirbanibulin future,” he said. “As with current treatments ointment for actinic keratosis. N Engl J Med. 2021;384:512-520. for actinic keratosis, physicians may find a way doi:10.1056/NEJMoa2024040 to treat larger areas with the dose provided as an off-label extension.”

54 | The Dermatology Digest DIAGNOSE THIS ZEBRA A DIFFERENTIAL DIAGNOSIS CASE The puzzling case of the purple penis

Ted Rosen, MD, with Cheryl Guttman Krader

From the files of: CASE HISTORY A 48-year-old white man was admitted to the hospital for diagnosis of penile tenderness accompanied by blue-black skin discoloration (Figure). He reported experiencing the same problem in the past episodically. He was otherwise asymptomatic and denied having TED ROSEN, MD, FAAD any epistaxis, bloody stools, or other bleeding Editor-in-Chief diathesis. The patient was married and ostensibly in good health. He was not taking any prescription or over-the-counter medications or nutritional supplements, and both family and social history were entirely noncon- tributory. The patient had already been seen by an internist, infectious disease specialist, urologist, hematologist, oncologist, and vascular surgeon before a dermatology consultation was ordered. Over the course of his evaluation, the diagnostic work-up included extensive laboratory testing and imaging (Table). No abnormalities were identified.

FIGURE. Image courtesy of Ted Rosen, MD, FAAD (all rights reserved) Table. Diagnostic testing

LABORATORY TESTS IMAGING Complete blood count with platelet count Abdominopelvic X-ray and CT scan Blood smear including bone marrow Digital subtraction angiography of What other evaluation aspirate internal and external iliac vessels Platelet function analyzer Doppler ultrasound of penile blood flow would you consider? Prothrombin time and partial thromboplastin time Clotting factors (VIII, IX, and fibrinogen) Lupus anticoagulant, D-dimers Liver function tests and albumin For more on this case, Cryoglobulins turn to page 56 

March 2021 | 55 www.thedermdigest.com/DIAGNOSE_THIS_ZEBRA

continued from page 55 THE PUZZLING CASE OF THE PURPLE PENIS

Following local buffered xylocaine with epinephrine anesthesia, a 3-mm punch biopsy was taken from dorsal penile skin; the wound was closed with a single suture. The histology report showed non-inflammatory upper dermal hemorrhage with extensive red blood cells and hemosiderin-laden macrophages. Thus, the tender, blue-black penile discoloration of the penis was diagnosed as simple ecchymosis (a bruise!). I asked the patient’s wife to excuse herself from the room for a few minutes so that I could share the diagnosis with the patient in private and try to elicit the etiology. He was informed that the discol- oration was traumatic bruising and, in a straightforward manner, I inquired what he did to cause it. After a pause, the patient finally described taking a tourniquet from his primary care doctor’s office, wrapping it around the base of his penis so that it became engorged with blood, and then hitting himself to induce bruising. He stated he was doing this intermittently because he wanted to avoid having sex with his wife, who refused to deal with “a purple penis.” The patient was diagnosed with dermatitis artefacta related to a primary psychiatric disorder. He was given a referral to a psychiatrist and asked if he might want to see a marriage counselor.

DISCUSSION avoidance strategy. Dermatologists should The diagnosis in this case depended on the maintain suspicion for dermatitis artefacta in findings of a penile biopsy, especially consid- cases in which the lesions seem clinically atyp- ering negative/normal results from an exten- ical, morphologically bizarre, or disfiguring, or sive investigation for clotting and structural when a targeted work-up fails to identify any vascular abnormalities. Guidelines for the use organic reason for the findings. A recurrent of local anesthesia in office-based dermato- course and sudden onset of lesions are other logic surgery from the American Academy clues. Sensing that the patient’s affect is not of Dermatology state that the addition of consonant with the problem is also a red flag. epinephrine to local infiltration anesthesia Patients may be too calm because they know may be considered for use during penile their problem is self-inflicted, or behave in a procedures, although the panel noted that hyperbolic and aggressive manner as they try studies are limited and additional data would to evade responsibility for their own actions. help to strengthen the recommendation.1 A Confrontation of the patient in cases of der- subsequently published survey of dermatolo- matitis artefacta is controversial. On the one gists and venereologists in the UK showed that hand, it may not be productive because the epinephrine-containing local anesthesia for patient may not admit to the self-injurious penile biopsy was common and identified no behavior. In some cases, however, direct con- cases of consequent necrosis.2 Because the tis- frontation may lead to a confession, especially sue is well-vascularized, there is an increased REFERENCES if the patient is not expecting to be questioned. risk for bleeding after penile biopsy, and the 1. Kouba DJ, LoPiccolo MC, Clinicians should remain empathetic and Alam M, et al. Guidelines for biopsy site should be closed with a suture. The non-judgmental when talking to patients with the use of local anesthesia good vascular supply, however, also enables in office-based dermatologic dermatitis artefacta. Psychiatric evaluation to surgery. J Am Acad Dermatol. rapid healing with minimal risk of scarring. 2016;74(6):1201-1219. identify and treat an underlying mental health 2. Wernham A, Shim TN. Dermatitis artefacta, also known as factitious disorder is warranted, although patients may Survey of dermatologists and dermatitis, is a psychocutaneous disorder in resist the referral. One way to help patients venereologists shows varying which a patient purposely creates lesions to accept psychological assistance is to point out approach to penile biopsies. J Clin Aesthet Dermatol. satisfy a psychological need, to attract atten- that this intervention would at least mitigate 2017;19(10):26-27 tion, or, as was the situation in this case, as an against the stress they are experiencing. 

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