The Chronicle of Skin & Allergy - February 2022

Tr e a t m e n t u p d a t e

P RACTICAL T HERAPEUTICS and C LINICAL N EWS from the W ORLD of D ERMATOLOGY

n

F EBRUARY 2022

All rights reserved. Chronicle Information Resources Ltd. Canada Post Canadian Publications Mail Sales Product Agreement Number 40016917

2022 Pipeline:

n Enhanced understanding of immunology behind many advances

New approvals on the horizon

by LOUISE GAGNON, Correspondent, The Chronicle

D

the pediatric data shows is that [anti-IL-17 medications] have a fast onset, and tend to give higher PASIs than the other biologics that we have,” she said.

There are approximately oneyear safety data for both secukinumab and ixekDr. Cathryn izumab in this Sibbald indication in pediatric patients, Dr. Sibbald noted. That data shows the primary side effects have been in-

espite the adverse impact that the Covid-19 pandemic has had on clinical trial enrolment and the continuity of clinical trials, many new treatments are providing dermatologists with more options for a variety of diseases.

During a presentation on new and anticipated drug therapies at Derm Update, Dr. Charles Lynde noted that as a result of the pandemic, 433 trials were permanently terminated and 665 had to be reactivated.

Dr. Charles Lynde Despite the setbacks in research, many agents are being added and will continue to be added to the dermatologist’s toolbox, said Dr. Lynde, who stressed that the innovations in dermatology are driven by increased understanding of immunology. “Dermatologists are becoming immunologists,” noted Dr. Lynde. He is an associate professor, Department of Medicine

Please turn to Psoriasis page 8→

Please turn to Tx page 12→

◼ Canadian physicians discuss new treatments likely to be approved in 2022

see page 4 Pediatrics

Update: Pediatric inflammatory disease

n More approved biologics for PsO, recommendations for comorbidity screening

by JOHN EVANS, Senior Editor, The Chronicle

N

ew systemic medications for pediatric psoriasis, guidance on screening children for joint involvement, managing the side effects of biologic treatment of atopic dermatitis, and further insights on retinoid treatment for ichthyoses are some of the topics relating to inflammatory skin conditions covered by Dr. Cathryn Sibbald during a presentation on pediatric dermatology Dr. Sibbald is a dermatologist

at The Hospital for Sick Children (SickKids) in Toronto and an assistant professor at the University of Toronto in the Department of Pediatrics with a cross appointment to the Department of Medicine. She spoke at the virtual Toronto Psoriasis Seminar (ToPS) and Robert S. Lester Postgraduate Dermatology Seminar on Nov. 19, 2021.

Psoriasis treatments There are now two interleukin (IL)17 blockers approved in Canada for treating psoriasis in children, said Dr. Sibbald.

“Similar to the adult data, what

JAK inhibitors among therapies improving outcomes

Psoriasis

Canadian studies lead to improved PsO Tx

n Dr. Wayne Gulliver delivers keynote during the 2021 Stuart Maddin Lecture Series

by LOUISE GAGNON, Correspondent, The Chronicle

G

enetic research has been critical to advancing the understanding of psoriasis and the development of effective therapies, according to Dr. Wayne Gulliver, Professor of Dermatology and Medicine at Memorial University of Newfoundland in St. John’s, Newfoundland & Labrador.

Delivering the Stuart Please turn to Maddin Lecture page 18→

Connect with The Chronicle on

www.derm.city “Where Dermatology Lives”

n Share your experiences and observations with a worldwide community of practitioners and researchers.

Follow developments in skin health as they occur. Visit www.derm.city

NOW

IN MODERATE TO SEVERE ATOPIC DERMATITIS

RINVOQ is indicated for the treatment of adults and adolescents 12 years of age and older with refractory moderate to severe atopic dermatitis (AD) who are not adequately controlled with a systemic treatment (e.g., steroid or biologic) or when use of those therapies is inadvisable. RINVOQ can be used with or without topical corticosteroids.

Reach out to your AbbVie sales representative for more details Consult the Product Monograph at rinvoq.ca/pm for information about contraindications, warnings, precautions, adverse reactions, interactions, dosing, and conditions of clinical use. The Product Monograph is also available by calling us at 1-888-704-8271.

Reference: RINVOQ Product Monograph. AbbVie Corporation. © AbbVie Corporation Printed in Canada CA-RNQD-210018A – November 2021

abbvie.ca 1-888-703-3006

Vol. 28, No. 1

THE CHRONICLE of S K IN & ALLE R GY

February 2022 • 3

A Message from the Medical Editor

T O P of the M O N T H

Vender on Psoriasis: Secukinumab dosing in psoriasis patients weighing 90 kg or more Also, researchers studied the occurrence of eczematous drug eruptions (EDE) in patients treated with anti-interleukin-17A therapy. The study included 289 patients with 2.8% experiencing an EDE . . . . .10 Skin of Colour Update Systemic sclerosis (SSC) is more common in Black children according to a study published in Frontiers in Immunology. Investigators found that Black patients produce a different SSC-specific autoantibody. Also, researchers find the U.S. patients with skin of colour have greater hidradenitis suppurativa disease severity . . 14 Chronicle Postgraduate Educational Supplement In this issue’s educational supplement, a team of investigators from the United States review real world treatment selection and outcomes for patients with locally advanced basal cell carcinoma . . . . . . . . . . 21

Image from stock.adobe.com

Canadian studies lead to advancements in PsO Tx During Derm Update's 2021 Stuart Maddin Lecture series, Dr. Wayne Gulliver delivered the keynote address discussing the role of genetic research in critical advancements in psoriasis treatment. . . . . . . 1

Research

AD symptoms appear to worsen during premenstrual period From the News Resources of The Chronicle

A research letter published in the Journal of the American Academy of Dermatology has outlined the degree to which symptoms of atopic dermatitis (AD) may be exacerbated during the premenstrual period.

The study, conducted by Dr. Giacomo Dal Bello and colleagues from the University of Verona in Italy, evaluated women of child-bearing age (18 to 45 years with AD [87 patients] or psoriasis [85 patients]). The results showed that evaluation indexes such as EASI, DLQI and itch rating scales for AD all worsened during the premenstrual time period.

After completing a questionnaire about their skin disease, gynecologic history and comorbid conditions, the study participants were evaluated for three consecutive months during the

premenstrual, menstrual and postmenstrual periods. Patients being treated for AD or who had been treated with systemic agents in the previous three months were excluded from the study.

Results showed that women with moderate-to-severe AD had significant exacerbations in disease severity, itch and deterioration in quality of life in the premenstrual versus the menstrual period. The exacerbations were much worse when compared to the postmenstrual period. The researchers reported the mean worsening of symptoms in the EASI score was 17.7%, 35.3% in the numerical scale worst itch, and 26.3% in the DLQI. They noted that AD exacerbation during the premenstrual period was associated with higher age at menarche and a longer menstrual period.

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“HS patients who failed treatments like antibiotics can be put on a biologic” Dr. Wayne Gulliver, Professor of Dermatology and Medicine at Memorial University of Newfoundland in St. John’s, Newfoundland & Labrador (Page 1)

Medical Editor

Wayne Gulliver,

I

n this issue of The Chronicle of Skin & Allergy, readers should be extremely impressed by the outstanding progress and rapid timelines we have seen in the development of dermatology therapeutics, which are not only available to our patients today but in the coming months and years.

At Derm Update in Montreal last fall, Dr. Charles Lynde—in true Stuart Maddin fashion—provided attendees with an update on what new developments we might expect in the landscape of dermatology therapeutics (see our report starting on page 1). He stated that even though Covid resulted in the termination or delay of over 1,000 clinical trials, many new agents are being approved that will be added to the dermatologist’s toolbox. These agents span a huge spectrum of conditions including atopic dermatitis, hidradenitis suppurativa, psoriasis, acne and vitiligo, to name but a few.

And molecules such as JAK inhibitors, new biologics and new retinoids are here. On page 4, Drs. Please turn to Message page 16→

MD, FRCPC

John P. Arlette, MD, FRCPC Benjamin Barankin, MD, FRCPC Marc Bourcier, MD, FRCPC Eric Goldstein, MD, FRCPC Peter Hull, MD, FRCPC Richard Langley, MD, FRCPC Danielle Marcoux, MD, FRCPC R.A.W. Miller, MD, FRCPC

Editor, Cosmetic Dermatology MD, FRCPC

Sheldon V. Pollack,

H. Eileen Murray, MD, FRCPC Kim Papp, MD, FRCPC Yves Poulin, MD, FRCPC Melanie D. Pratt, MD, FRCPC Denis Sasseville, MD, FRCPC Jerry Tan, MD, FRCPC Ronald B. Vender, MD, FRCPC

Founding Editor Colin A. Ramsay, MD, FRCPC (1936-2003) Publisher Mitchell Shannon Editorial Director R. Allan Ryan Senior Editor John Evans Lead Coordinator, Journals Kylie Rebernik

Assistant Editor Jeremy Visser Communications Coordinator Katherine Brenders Client Engagment Cristela Tello Ruiz Manager,Operations Cathy Dusome Comptroller Rose Arciero

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4

• February 2022

THE CHRONICLE of SKIN & ALLERGY

New approvals on the horizon

n New topicals and an oral Tx will offer options for patients with psoriasis

by LOUISE GAGNON, Correspondent, The Chronicle

J

anus kinase (JAK) inhibitors that offer clinical benefit in treating a variety of skin conditions, new topical therapies for psoriasis and acne, and new offerings in aesthetic medicine are all developments in 2022 that Canadian dermatologists are welcoming.

JAK inhibitors for various conditions The JAK inhibitor upadacitinib is a new addition to the Canadian atopic dermatitis (AD) armamentarium.

“I have just started my first patient on upadacitinib,” said Dr. Kyle Cullingham, a dermatologist and Medical Director of Saskatoon Dermatology Centre in Saskatoon, who welcomes the therapy because of its form of delivery. “Patients tend to prefer oral therapies to injections most of the time.”

Halifax dermatologist Dr. Kerri Purdy agreed upadacitinib offers another effective treatment choice for

patients with AD. “It is an option for patients with AD who don’t do well with dupilumab for whatever reason,” said Dr. Purdy, Division Head and AsDr. Kyle Cullingham sistant Professor in the Division of Clinical Dermatology & Cutaneous Science, Department of Medicine, Dalhousie University.

Deucravacitinib, a tyrosine kiDr. Kerri nase (TYK)-2 Purdy inhibitor that is sometimes described as a selective JAK inhibitor, is likely to represent another management option for psoriasis. “Having Dr. Ben an oral JAK inhibitor Barankin [for psoriasis] is going to be an exciting option,” said Dr. Purdy.

The data for this TYK-2 inhibitor are impressive, said dermatologist

Image from stock.adobe.com

2022 Pipeline:

Dr. Ben Barankin, Medical Director and founder of the Toronto Dermatology Centre in Toronto.

The versatility of JAK inhibitors is Dr. Jaggi Rao impressive, and some are being explored for conditions such as alopecia areata and vitiligo, noted Dr. Purdy.

Dr. Jaggi Rao, a dermatologist in Dr. Catherine Edmonton and Zip Clinical Professor of Medicine at the University of Alberta, agreed that JAK inhibitors will be valuable additions to the dermatology toolbox.

“JAK inhibitors target a very important and specific pathway in the molecular development and sustainment of atopic dermatitis and other diseases,” said Dr. Rao. “As such, their efficacy and safety are remarkable.”

Dr. Barankin pointed out topical Please turn to 2022 page 6→

In the treatment of moderate-to-severe plaque psoriasis in adult patients

Is now available

ILUMYA™ (tildrakizumab injection) is indicated for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Pr

For more information: Please consult the Product Monograph at: https://sunpharma.com/wp-content/uploads/0056-ca-m131-enpm-non-annotated-level-III-change-importer.pdf for important information relating to contraindications, warnings, precautions, adverse reactions, interactions, dosing and conditions of clinical use. The Product Monograph is also available by calling our medical information department at: 1-844-924-0656.

Enrol your patients in the Sun Patient Support Program for ILUMYA™ (1-844-561-1259 or ilumya@bayshore.ca)–designed to help you and your patients throughout the treatment journey

Current ILUMYA™ Product Monograph, Sun Pharma Canada Inc. © 2021 Sun Pharma Canada Inc. All rights reserved.

ILUMYA™ is a trademark of Sun Pharma Global FZE. Used under license.

PM-CA-ILY-0019

6 • February 2022

THE CHRONICLE of SKIN & ALLERGY

2022: New non-invasive techniques for lesion removal Continued from page 4 therapies like tapinarof, an aryl hydrocarbon receptor modulating molecule, are appealing as a psoriasis therapy because it is a non-steroidal treatment.

“It’s a topical, it is for all severities of psoriasis, and it is not a steroid,” said Dr. Barankin. “It’s something that you are potentially going to be recommending to keep things simple for patients. Because it is not a steroid, patients do not have to worry about things like thinning of the skin.”

Patients often have to be cautious about applying topical steroids to areas such as the face, groin, and armpits, explained Dr. Barankin.

Still another topical agent for psoriasis is roflumilast cream, a PDE4 inhibitor that offers several advantages, according to Dr. Barankin. “As a cream, it is more elegant to use,” he said. “We have had [calcipotriol/betamethasone] as the gold standard for years which some find a bit greasy regardless of formulation. [Roflumilast] will likely be more elegant to use, and more elegance means greater compliance, which leads to better outcomes. The lack of elegance of some of our topicals for psoriasis has been an issue. Elegance matters to patients. Gels and foams can still be greasy.”

Another new topical therapy is tazarotene lotion 0.045% for the treatment of acne. “It is a topical retinoid,” said Dr. Purdy. “It’s a more tolerable

therapy [compared to other retinoids].”

Dr. Catherine Zip, Clinical Associate Professor, Division of Dermatology, University of Calgary, agreed that this particular preparation of tazarotene causes less cutaneous irritation to patients compared to other retinoids. “This new formulation was developed using polymeric emulsion technology to improve tolerability,” she said.

Two 12-week, phase III clinical trials demonstrated that individuals who received tazarotene 0.045% lotion had higher rates of treatment success than individuals who received vehicle, and the therapy was also well-tolerated (Ann Pharmacother 2022 Feb 3; 10600280211072155).

Other new dermatology agents on the horizon Omalizumab, a recombinant, humanized, monoclonal antibody against human immunoglobulin E, has been of benefit for managing urticaria, and some dermatologists are eager to see other management options come to market, such as ligelizumab.

“It would be great to have another option for urticaria,” said Dr. Purdy, noting she is early awaiting the arrival of ligelizumab. “Some of our patients maximize the use of [omalizumab], and they still have issues with their condition.”

A meta-analysis suggested that the biologic agents ligelizumab (72 or 240 mg), and omalizumab [300 or 600 mg], can be recommended as effective treatments for patients with chronic

spontaneous urticaria who have an inadequate response to treatment with H1 antihistamines [JAMA Dermatol 2021 Nov 1; 157(11):1316-1327].

Cosmetic dermatology advances in 2022 Dr. Cullingham noted that a new device in cosmetic medicine is Cell FX, a technology that treats skin spots and benign lesions.

“It uses nano-pulse stimulation to destroy benign lesions, including warts and sebaceous hyperplasia, as well as dermatofibromas,” he said.

“It’s a novel treatment for some of these benign presentations that we do not have a lot of treatments for.”

Dr. Rao echoed interest in using Cell FX, highlighting that it offers a non-invasive approach to removing benign lesions. “It is nano-pulse technology for the non-surgical treatment of benign cutaneous tumors,” he said.

Another exciting development in aesthetic medicine is the availability of topical, injectable, and oral tranexamic acid to treat hyperpigmentation of the skin, added Dr. Rao. Non-proprietary and brand names of therapies: upadacitinib (Rinvoq, AbbVie); deucravacitinib (not approved in Canada); tapinarof (not approved in Canada); roflumilast cream (not approved in Canada); calcipotriol/betamethasone (Dovobet, LEO); tazarotene lotion 0.045% (Arazlo, Bausch Health); omalizumab (Xolair, Novartis); ligelizumab (not approved in Canada).

Don't let their acne be the focus Over 50% of patients with facial acne also have truncal acne, but they may feel too self-conscious to discuss it with their physician.1 Help your patients to treat acne beyond their face.

AKLIEF® is the first topical treatment specifically studied to treat both facial and truncal acne.* AKLIEF (Trifarotene 50 mcg/g) cream is indicated for the topical treatment of acne vulgaris of the face and/or trunk in patients 12 years of age or older.2 Consult the AKLIEF ® Product Monograph at http://ncs.galderma.acsitefactory.com/sites/g/files/jcdfhc196/files/inline-files/Aklief%20PM-E-Nov-25.pdf for important information about: • Contraindications in eczema or seborrheic dermatitis; and in pregnancy or women planning a pregnancy.

• The most serious warnings and precautions regarding external use only, not for ophthalmic use; and use in pregnancy or women planning a pregnancy.

• Other relevant warnings and precautions regarding use if allergic/hypersensitivity reactions occur; contact with eyes, lips, angles of the nose, mucous membranes, abraded skin, open wounds, cuts, and eczematous and sunburned skin; use of other dermatologic medications and potentially irritating topical products that have a strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes; use of noncomedogenic cosmetics; treatment areas with dressing or bandages; weather extremes, such as wind or cold; exposure to excessive sunlight, including sunlamps, and recommended use of sunscreen and protective clothing; certain cutaneous signs and symptoms; use of electrolysis, “waxing”, and chemical depilatories for hair removal; taking drugs with known photosensitizers; use on chest during breastfeeding.

• Conditions of clinical use, adverse reactions, interactions, and dosing instructions.

The Product Monograph is also available by calling us at 1-800-467-2081.

References: 1. Del Rosso JQ, et al. A closer look at truncal acne vulgaris: Prevalence, severity, and clinical significance. J Drugs Dermatol. 2007;6(6):597-600. 2. AKLIEF ® Product Monograph. Galderma Canada Inc. November 25, 2019. * Comparative clinical significance is unknown.

AKLIEF ® is a registered trademark of Galderma Canada Inc. Galderma Canada Inc. Thornhill, Ontario

8 • February 2022

THE CHRONICLE of SKIN & ALLERGY

Psoriasis: New screening protocol for joint involvement Continued from page 1 fections or injection site reactions.

The data on irritable bowel disease (IBD) as a side effect is not as strong, and it is important to recognize this population is generally at elevated risk of IBD. Some case reports of children treated with secukinumab suggest there may be some benefit for pustular psoriasis, she said. A post hoc analysis of a pediatric trial of ixekizumab examined changes in nail psoriasis. “The numbers are not amazing [for nail improvement with ixekizumab], but this is such a difficult subset of psoriasis to treat, that this might be something to look for in the future,” Dr. Sibbald said. “And I think we need head-to-head trials to sort out how it compares to some of the other medications [for nail psoriasis].”

Joint disease screening Psoriasis also has the potential for joint involvement, even in children, and joint problems can be associated with other dermatologic conditions or medications, Dr. Sibbald said. She noted that a paper that came out early last year detailed a simple, quick screening protocol for joint involvement that could be added to a pediatric dermatology examination (Pediatric Dermatology Jan. 2021; 38(1):92-97).

The screening detailed in the paper involves a one-minute clinical examination involving looking for swelling and palpating for tenderness along the wrists, the hands, the knees, the ankles, and asking the patient to move their body into four specific poses to illustrate the patient's range of motion or pain on range of motion. Parents are also asked to answer four questions about the presence and location of pain, how long the pain has been occurring, the impact of time of day or activity on the pain, and if the child has been limping at all.

“This [screening] has yet to be validated, but I think it gives us the language that rheumatologists would like to see on referrals to help them triage. If a diagnosis of psoriatic arthritis is identified, this would also inform treatment decisions,” said Dr. Sibbald.

Atopic dermatitis Dr. Sibbald mentioned some of the recent research related to emollients in the prevention and treat-

ment of pediatric atopic dermatitis (AD). She described a Cochrane systematic review, published in Feb. 2021, that examined the findings of several randomized controlled trials of emollients as a means to prevent the development of AD in at-risk children.

“Overall, this systematic review came to the conclusion that moisturizers likely do not decrease the risk of eczema at one to two years.

These are patients who may have a high risk of eczema, but do not have a current diagnosis of eczema at presentation,” said Dr. Sibbald.

The paper also reported that early moisturization may be associated with a higher rate of infections, but a mechanism for this has not been confirmed.

For children who already have AD, the evidence remains strong that moisturizing can decrease the number of flares experienced by a child and can reduce the amount of topical corticosteroids used, she said. There is also no strong evidence that one moisturizer is better than another for this purpose, Dr. Sibbald said.

With dupilumab approved in Canada for moderate-to-severe AD in children, and with her practice using more dupilumab, Dr. Sibbald said it is important to recognize some of the potential side effects of this therapy and how to manage them.

She described a case series of seven children, aged four to 18 years, who developed psoriasiform reactions while being treated with dupilumab. “Five of these children had a good response to their [atopic] dermatitis—IGA of four going to one—but developed new areas with psoriasis. The time to onset was roughly eight months which is a bit longer than you see in adults. All of these children resolved with mid-potency topical steroids while continuing the dupilumab.”

Two other patients in that case series had both baseline atopic dermatitis and concurrent psoriasis that did not respond to the dupilumab.

Of those, one patient remained on dupilumab which was effective for their atopic dermatitis and their psoriasis was treated topically. The other patient required tofacitinib and intravenous immunoglobulin for their atopic dermatitis and was prescribed ustekinumab for their

psoriasis, she said.

“The take-home message from this data suggests that if a patient is developing these new psoriasiform lesions, you might be able to treat them with topical steroids,” Dr. Sibbald said.

In another case series Dr. Sibbald mentioned, two children had been treated with dupilumab for four months and developed folliculitis on their faces. Scrapings were positive for Demodex, and both children resolved with topical ivermectin treatment twice a day, she said. “Sparing of the neck in a new pustular eruption can be a nice clue to demodicosis as it was in these patients,” Dr. Sibbald said.

Ichthyosis and retinoids Topical and systemic retinoids are beneficial in the treatment of ichthyosis, decreasing scaling and erythema and reversing ectropion and contractures, Dr. Sibbald said.

She noted that a consensus recommendation document on retinoids and pediatric ichthyoses was published in Pediatric Dermatology (Jan./Feb. 2021; 38(1):164-180). That document noted that some retinoids have advantages in certain presentations.

“In terms of the topicals, for tretinoin, it is suggested that it is especially helpful for palmoplantar [ichthyosis]. Adapalene might be a less irritating option,” she said.

“Tazarotene is especially helpful for preventing or treating ectropion, especially in infants. It might be more irritating, but it will be interesting to see if there are new lotions developed that are less irritating and a better option.”

Topical trifarotene may have particular benefit in lamellar ichthyosis, as it increases expression of transglutaminase 1, which is deficient in this form of ichthyosis, Dr. Sibbald said. She noted trials were undertaken with topical formulations that have four times the potency of the currently marketed trifarotene cream, but were stopped early due to lack of benefit .

Among systemic retinoids, acitretin may be more beneficial in cases where there is peeling of the palms and soles, but “it does have a longer half life and higher risk of alopecia,” Dr. Sibbald said.

In contrast, oral isotretinoin has a shorter half-life but does cause more facial desquamation, she said.

Drug holidays may be a good option for pediatric patients treated with oral retinoids for ichthyoses, Dr. Sibbald said. “Especially in a patient who might improve naturally in the summer, you can stop the retinoid over the summer and then restart it.

There is no evidence that they lose the benefit of the retinoid when they do that, and it gives them some time off the medication.”

Non-proprietary and brand names of therapies: secukinumab (Cosentyx, Novartis); ixekizumab (Taltz, Lilly); dupilumab (Dupixent, Sanofi/Regeneron); tofacitinib (Xeljanz, Pfizer); intravenous immunoglobulin (various manufacturers); ustekinumab (Stelara, Janssen); topical ivermectin cream 1% (Rosiver, Galderma); topical trifarotene (Aklief, Galderma); acitretin (Soriatane, Miravo); isotretinoin (Accutane, Roche; Epuris, Cipher); tazarotene 0.045% (Arazlo lotion , Bausch Health); tazarotene 0.05 and 0.1% (Tazorac, Allergan); adapalene 0.1% (Differin, Galderma; Effaclar, La Roche Posay).

THERAPEUTIC INDEX AbbVie RINVOQ . . . . . . 2 Skyrizi. . . . . . . . 28 Dermtek Pharma Sebcur . . . . . . 15 Soluver . . 19 ERFA HQ 4% Gel . . . 10 Galderma Aklief . . 7 Miravo Blexten . . . . . . . .27 Pfizer Abrocitinab. . . . . .13 Sun Pharma Ilumya. . . . . . .5 UCB Corporate. . . . . . .9

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With your ongoing support, we continue to raise the bar in clinical research and development across chronic inflammatory skin conditions.

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Vender on Psoriasis Ronald B. Vender, MD, FRCPC comments on recent findings and developments, and answers clinicians’ questions

Secukinumab dosing in psoriasis patients weighing 90 kg or more Since obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment, investigators looked at the efficacy, safety and tolerability of secukinumab 300 mg every two weeks (Q2W) vs. secukinumab 300 mg every four weeks (Q4W) in patients with a higher body weight (Br J Dermatol 2022; doi:10.1111/bjd.20971).

A total of 331 patients with moderate-to-severe chronic plaque psoriasis weighing ≥90 kg were randomized to receive secukinumab 300 mg Q2W or secukinumab 300 mg Q4W. Patients who did not achieve PASI 90 at Week 16 on the Q4W regimen were reallocated to remain on the Q4W regimen or up-titrate to Q2W. Results showed that at Week 16, Q2W dosing (n=165) led to significantly higher PASI 90 responses vs.

Q4W [n=166; 73.2% vs. 55.5%, one-sided p-value=0.0003, odds ratio estimate (95% confidence intervals): 2.3 (1.4, 3.8). At Week 52, higher efficacy responses were maintained in the Q2W arm (n=165) vs. Q4W (n=83); PASI 75: 88.9% vs. 74.8%; PASI 90: 76.4% vs. 52.4%, PASI 100: 46.7% vs. 27.3%; IGA 0/1: 75.9% vs. 55.6% and DLQI 0/1: 66.1% vs. 48.8%. According to the investigators, PASI 90 non-responders at Week 16 who uptitrated to Q2W (n=31) showed higher efficacy responses at Week 32 (16 weeks post-up-titration, PASI 90: 38.7% vs. 16.5%) vs. those who remained on Q4W (n=40). Safety results were comparable across treatment arms and consistent with the established secukinumab safety profile.

The researchers concluded that secukinumab 300 mg Q2W demonstrated superior and sustained efficacy compared to Q4W in moderate-to-severe plaque psoriasis patients weighing ≥90 kg. Also, PASI 90 non-responders benefited from up-titration to a Q2W regimen.

of cytokine-gene-expression showed predominance of Th2/Th22 cytokines in EDE-lesions with a strong increase of IL-4, IL-22, and S100A7 levels in both Les and NLes skin compared to healthy skin. They noted a significant enhancement of IL-4, IL-22, and S100A7 in Les compared to NLes skin, and IL-26 levels were significantly increased compared to healthy skin. Low levels of IL-23A were found both in Les and NLes skin.

The researchers concluded that EDE is the result of the imbalance of Th2/Th22 response secondary to the blockade of IL-17A-activity. They reported that these EDE skin lesions primarily have Th2/Th22 features, with IL-22 playing a major role in pathogenesis.

This study has confirmed a long-standing concern with dermatologists who prescribe secukinumab. This first-to-class anti-IL 17 biologic has certainly had excellent success in treating patients with moderate to severe psoriasis, psoriatic arthritis and special site involvement such as nails, scalp and palmar-plantar psoriasis. However, it does have low biologic survival. Part of this decrease in efficacy seems to be in heavier patients. This study sponsored by the manufacturer showed that patients with a higher weight would benefit from more frequent dosing of secukinumab.

Other IL-17 inhibitors such as brodalumab have found better success in patients with Q2 week dosing. This study confirms that heavier patients would benefit from Q2 week dosing of secukinumab. Although patients who are using standard every fourweek dosing still benefit greatly with respect to PASI 75-90 and 100, the increased frequency of secukinumab every two weeks in heavier patients captures 15% (on average) more patients for PASI 75-90 and 100. One common misconception is that secukinumab does not work well in heavier patients. This study allows more frequent dosing. No safety concerns were found with this higher dosing either. This study confirms that heavier patients can be more effectively treated with more frequent dosing of secukinumab.

Eczematous drug eruption in patients with psoriasis on anti-interleukin-17A therapy The objectives of this study, published in Clinical and Experimental Dermatology (Dec. 4, 2021; https://doi.org/10.1111/ced.15052), were to describe the clinical and histologic features and skin cytokine profiles in patients with eczematous drug eruption (EDE), a spongiotic skin reaction in response to systemic medications such as tumour-necrosis-factor-α and interleukin-(IL)-17 inhibitors. To date, EDE has been described in patients receiving anti-IL17A monoclonal antibodies, with a prevalence of 2.2 to 12.1%.

The prospective study enrolled 289 psoriasis patients treated with two anti-IL17 monoclonal antibodies, ixekizumab and secukinumab. Eight (2.8%) patients developed EDE during the treatment period, from June 2019 to April 2021. A 5 mm lesional (Les) and a 3 mm non-lesional (NLes) skin sample was biopsied from all patients.

One section of the Les sample was sent for histological examination and one for evaluation of the cytokine profile.

The histology suggested a diagnosis of spongiotic dermatitis in all patients. The researchers reported that evaluation

Paradoxical psoriasis is an interesting concept that usually was related to TNF inhibitors causing plantar psoriasis or new onset psoriasis in patients who were using TNF inhibitors to treat non-psoriatic conditions such as inflammatory bowel disease. Although the pathways are similar for inflammatory bowel disease and psoriasis, the paradoxical occurrence of this disturbing disorder can be quite devastating for gastrointestinal patients using TNF inhibitors and who are under control for their inflammatory bowel disease. This can be difficult to treat but does not necessarily necessitate change in the biologic used to treat their gastrointestinal disease.

Quite often, it can be treated topically or with ultraviolet light and occasionally with the addition of traditional systemic medications.

This new concept of paradoxical disease is now stemming from a specific monoclonal antibody class that is used to treat psoriasis. The efficacy of anti-IL-17 monoclonal antibodies to treat psoriatic disease has been well established. However, paradoxical reaction such as these eczematous reactions have recently come to light.

This again is unusual because the pathway is completely different. The treatment of this paradoxical reaction can be quite difficult—if a change in biologic that treats dermatitis is introduced it is possible that the psoriasis returns. Time will tell with this early observation

We invite your comments and questions about this feature at www.derm.city. Dr. Ron Vender is a certified dermatologist with 29 years of clinical practice experience and over 75 clinical trials in psoriasis. He is founder and director of Venderm Innovations in Psoriasis, a center of excellence for Psoriasis offering a comprehensive management solution for individuals with psoriasis. www.psoriasis.vip

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Dr. Neil Shear, dermatologist and Professor Emeritus at the University of Toronto, speaks with many guests from the world of dermatology, including Dr. Boluwaji Ogunyemi, Dr. Marc Bourcier, and Dr. Rachel Asiniwasis, to hear their stories and insights. First season of eight episodes now available for listening and downloading.

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12 • February 2022

THE CHRONICLE of SKIN & ALLERGY

Tx: JAK inhibitors effective for treating AD patients Continued from page 1 at the University of Toronto.

Atopic dermatitis Dupilumab has been a very successful addition to the atopic dermatitis (AD) armamentarium and is

being explored for its potential in treating other conditions such as prurigo nodularis, bullous pemphigoid and hand dermatitis, noted Dr. Lynde. “There are 89 clinical trials involving dupilumab,” he said.

“It’s being examined for so many different areas. We never thought we would potentially be using a biologic for some of these conditions.”

Dermatologists can consider

Camp Liberté was created by a group of dermatologists dedicated to offering children with moderate to severe skin conditions an opportunity to enjoy a summer camp experience. With locations in eastern and western Canada, Camp Liberté hosts more than 40 children per summer at no cost to parents, thanks to the support of generous donors.

More options in psoriasis Many non-steroidal topical agents are being explored as treatments for not only AD, but also for psoriasis, such as tapinarof and the PDE-4 in-

Our camps are fully equipped with volunteer dermatologists, residents and nurses to care for children with a wide range of skin conditions, including atopic dermatitis, epidermolysis bullosa, and alopecia areata.

Please turn to Tx page 16→

HOW CAN YOU HELP?

A gift to Camp Liberté provides Canadian children with skin conditions an opportunity to grow in confidence and self-esteem through a multi-cultural outdoor camping experience in a fun, safe, bilingual, environment.

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Le Camp Liberté a été créé par un groupe de dermatologues déterminés à offrir à des enfants qui ont des problèmes de peau variant de modérés à graves la possibilité de vivre l’expérience d’un camp d’été. Avec ses emplacements dans l’est et l’ouest du Canada, le Camp Liberté accueille plus de 40 enfants par été sans qu’il en coûte quoi que ce soit aux parents, grâce à l’appui de généreux donateurs.

Nos camps bénéficient des services complets de dermatologues, de médecins résidents et d’infirmières bénévoles qui s’occupent d’enfants aux prises avec un vaste éventail de problèmes de peau, y compris la dermatite atopique, l’épidermolyse bulleuse et la pelade.

COMMENT POUVEZ-VOUS AIDER?

Un don au Camp Liberté permet à des enfants canadiens qui ont des problèmes de peau d’accroître leur confiance en soi et leur estime de soi en vivant une expérience multiculturelle de camping en plein air offerte dans un environnement bilingue, sécuritaire et amusant.

using topical steroids in conjunction with the biologics such as dupilumab or the emerging therapy tralokinumab for moderate-to-severe AD to enhance patient response, said Dr. Lynde.

Janus kinase (JAK) inhibitors are becoming another class of agents offering benefit for the treatment of AD, and upadacitinib was the first approved in Canada. Other JAK inhibitors on the horizon include abrocitinib and baricitinib, and the small molecule rilzabrutinib is under study for AD. “There is selectivity in each of these molecules,” said Dr. Lynde.

Another class of therapies being investigated to treat AD are interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, noted Dr. Lynde, adding these are also being explored for any benefit in managing hidradenitis suppurativa (HS).

”

Chronicle Companies is pleased to support Camp Liberté with monetary and in­kind donations through Sandi’s Fund, estab­ lished to honour our late friend and colleague, Sandra Gail Leckie, RN. Sandi was a nurse, pharmaceutical industry execu­ tive and health educator who had a life long affinity for chil­ dren and children’s charities.

Chronicle Companies con­ tributes prots from the annual National Pharmaceutical Congress (www.pharmacongress.info) to Sandi’s Fund for Camp Liberté, and has partnered with Camp Liberté to provide communications assistance for this valuable philanthropic undertaking.

WE’VE ONLY SCRATCHED THE SURFACE ON KEY CYTOKINES IN

ATOPIC DERMATITIS Many cytokines, including IL-4, IL-13, IL-22, IL-31, and TSLP, contribute to this chronic, relapsing-remitting inflammatory skin disease.

A closer look has revealed that IL-4, IL-31 and TSLP contribute to itch, a symptom responsible for much of the disease burden.1–3

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References: 1. Evolution of Atopic Dermatitis in the 21st Century. Springer, 2019. 2. JAK-STAT Signaling in Diseases. CRC Press, 2020.

3. Weinstein M, et al. Atopic Dermatitis: A Practical Guide to Management. Eczema Society of Canada, 2020.

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14 • February 2022

Skin of Colour

THE CHRONICLE of SKIN & ALLERGY

Research

Research

SSC in Black children

MLA therapy in dark skin

n More common than previously thought

n Skin roughness also improved

From the News Resources of The Chronicle

From the News Resources of The Chronicle

Systemic sclerosis (SSC) may be more common in Black children than previously thought, according to findings published in Frontiers in Immunology (Nov. 9, 2021; 12:679531). This discrepancy may be due to limitations in current diagnostic criteria, the authors of the study note.

Researchers analyzed records from more than 4,000 patients.

Records included individuals aged between one and 94 years, who had presented at a specialist clinic between 2013 and 2018. Among those patients, 240 with symptoms of systemic sclerosis tested positive for SSCspecific autoantibodies.

One-fifth of those 240 people were less than 16 years old, and 90% of the young patients were Black. The investigators found that the average age of the children with SSC autoantibodies was less than eight years.

The research team also found that Black patients produce a different SSC-specific autoantibody than those seen in white patients. They write that this finding suggests current diagnostic criteria, based on biomarkers identified in studies that primarily included white populations, underestimate the rate of the disease in Black people.

Treating atrophic acne scars with a 1,064 nm picosecond laser using a fractionated microlens array (MLA) appears to be a safe therapeutic alternative for the treatment of these scars in dark-skinned individuals.

These findings were published in Lasers in Surgery and Medicine (Sept. 2021; 53(7):899-905).

In this study, 26 subjects with Fitzpatrick skin types III and IV and atrophic acne scars were treated with a 1,064 nm picosecond laser (spot size of 8 mm, fluence of 1.0 J/cm2, a repetition rate of 10 Hz) in combination with a microlens array handpiece for an average of three passes, for six monthly sessions.

Investigators observed a significant reduction of the scar volume from baseline at one, three and six months after the final treatment. At the six-month follow-up, 50% (13 of 26) of the subjects were rated as having at least 50% improvement of the scars, with the rate of improvement significantly increasing from the one-month follow-up to the sixmonth follow-up. Skin roughness also improved from baseline to six months.

Treatment Update U.S. HS PATIENTS OF COLOUR HAVE MORE SEVERE DISEASE In the U.S., patients with skin of colour and hidradenitis suppurativa (HS) have greater disease severity and higher healthcare utilization than other groups, according to recent findings.

Published in the Journal of the American Academy of Dermatology International (June 1, 2021; 3:42-52) the findings come from a retrospective analysis of HS patients at Stanford Hospital and Clinics.

The investigators compared demographics, disease severity, and healthcare utilization between races in adults identified to have at least two encounters with the medical system that were coded for HS. Validation was conducted using Optum's de-identified Clinformatics Data Mart Database of national insurance claims.

Examining the records of 939 HS patients seen at Stanford and 13,885 HS patients taken from the national dataset, researchers found that Black and Hispanic patients had greater healthcare utilization compared to white patients. The Hispanic patients at the Stanford clinic also had significantly increased disease severity compared to their white counterparts (χ2 p=0.009). As well, Hispanic patients entered tertiary care at an earlier age (Stanford mean: 30.8 years for Hispanics vs.

38.7 for Whites; p<0.001), while Black patients entered later (Stanford mean: 39.6 years).

PRABOTULINUMTOXINA SIMILARLY EFFECTIVE IN DARK SKIN FOR GLABELLAR LINE TX A single dose of 20U prabotulinumtoxinA as a treatment of glabellar lines was well tolerated in patients with skin of colour and had similar efficacy compared to patients without skin of colour.

In this post hoc analysis, published in Dermatologic Surgery (Apr. 2021; 47(4):516-521), researchers examined data from the pooled population of all 492 patients treated with 20U prabotulinumtoxinA in the two U.S. single-dose Phase III glabellar line clinical studies. The authors grouped the patients by Fitzpatrick skin type into a skin of colour (SoC) group (skin types IV, V and VI) and a without SoC group (skin types I, II and III). All participants had moderate-to-severe glabellar lines The investigators observed that fewer patients in the SoC group responded to the treatment—measured as a one-point or more significant improvement in the 4point Glabellar Line Scale—but the difference was not statistically significant. Rates of adverse events were similar between the two groups as well.

INFLAMMATORY GENE EXPRESSION Researchers say they have identified differences in gene expression in Black skin compared to non-Hispanic white skin, which may help explain differences in the prevalence and clinical features of inflammatory skin diseases..

The findings were published online ahead of print in Journal of Investigative Dermatology (Oct. 28, 2021).

In comparing baseline gene expression in full-thickness skin biopsies, the researchers identified 570 differentially expressed genes (DEG) in African American skin including immunoglobulins and their receptor; pro-inflammatory genes such as TNFα, IL-32; EDC (epidermal differentiation cluster) and keratin genes. The DEGs were functionally enriched for inflammatory responses, keratinization and cornified envelope formation.

When the investigators analyzed 3D human skin equivalents (HSE) made from African American and non-Hispanic white primary keratinocytes they found 360 DEGs, some of which were shared with skin, and enriched by similar functions. The AA HSE appeared more responsive to TNFα pro-inflammatory effects. Researchers also found a significant overlap between DEGs specific to African Americans in skin and HSE and the molecular signatures of skin in AD and psoriasis patients.

PAPULAR ACNE SCARS ASSOCIATED WITH KELOIDS Papular acne scarring is significantly more common in individuals with keloid scars, a finding researchers say may provide insight into papular scars as an under-recognized form of acne scarring.

Published in Dermatologic Surgery (Oct. 2021; 47(10):13471351), these findings come from a retrospective study of 416 patients with acne scars. The investigators classified the scars into three types—atrophic, papular, and keloid type—based on clinical photographs, and analyzed the clinical and histologic features of papular acne scars.

Among all the patients included in the study, 410 patients (98.56%) had atrophic scars, 53 patients (12.74%) had keloid scars, and 46 patients (11.06%) had papular acne scars. Twenty patients (4.81%) had both papular and keloid acne scars.

When the researchers conducted histologic analysis, they identified fibrotic tissue in both keloid and papular acne scars, with the fibrosis of the papular scar limited to the upper dermis.

In their conclusion, the authors write that the association between papular and keloid acne scars can suggest the decision for scar treatment.

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16 • February 2022

THE CHRONICLE of SKIN & ALLERGY

Continued from page 12 hibitor known as PF-07038124.

Another biologic that is now available to prescribe for moderateto-severe plaque psoriasis is tildrakizumab, a therapy that can get psoriatic skin clear or almost clear, explained Dr. Lynde.

Canadian dermatologists should prepare for the fact that biosimilars will be increasingly available, particularly for well-established biologic agents such as etanercept and adalimumab, said Dr. Lynde.

The tyrosine kinase (TYK)-2 inhibitor deucravacitinib, which is prescribed in rheumatology, is also being explored as a possible treatment for psoriasis, noted Dr. Lynde.

An unmet need is in the management of palmoplantar pustulosis, a condition that Dr. Lynde noted is very common among Japanese patients. The IL-17 inhibitor brodalumab is being studied for this specific indication.

Acne therapy The topical trifarotene cream has provided therapeutic value in the management of acne, according to Dr. Lynde. “It’s highly effective for acne that presents on the face, the trunk, and the back,” he said.

Tazarotene lotion, which was approved by Health Canada in August 2021, is another topical agent that offers an advantage for patients with acne, noted Dr. Lynde.

Some possible acne treatments under investigation include a topical gel combining tretinoin and benzoyl peroxide, and a topical gel consisting of clindamycin and adapalene, which is being explored to manage moderate-to-severe acne. A novel oral agent under study for the treatment of acne is a fatty acid synthase inhibitor, which offers “a completely different mechanism of action,” said Dr. Lynde.

Image from stock.adobe.com

Tx: New ways to treat conditions such as melanoma

American dermatologists have been able to offer their patients with acne the androgen receptor inhibitor clascoterone. It was approved by the U.S. FDA in the summer of 2020, but it has not been approved for prescription in Canada.

Less common conditions HS is also a disease state that has gained much interest with respect to the exploration for new therapies.

One of the therapies under investigation for the management of HS includes the injectable ruxolitinib, pointed out Dr. Lynde.

Possible treatments for chronic hand dermatitis include a topical JAK1 inhibitor, referred to as ARQ252 and the topical JAK inhibitor delgocitinib, noted Dr. Lynde.

Vitiligo is another condition for which there has been an absence of effective therapies, but selective JAK inhibitors such as ruxolitinib, cerdulatinib, and ritlecitinib are being explored as possible future options, said Dr. Lynde.

Melanoma is a condition where historically dermatologists could offer little hope to patients in terms of a curative treatment, but there are now more than 800 upcoming, recruiting or active studies in melanoma, and the future for effective treatment is bright, according to Dr. Lynde. “The field of onco-dermatology has made quite a difference,” he said.

Non-proprietary and brand names of therapies: dupilumab (Dupixent, Sanofi/Regeneron); tralokinumab

(Adbry, LEO Pharma); upadacitinib (Rinvoq, AbbVie);abrocitinib (not approved in Canada); baricitinib (Olumiant, Lilly); rilzabrutinib (not approved in Canada); tapinarof (not approved in Canada); tildrakizumab (Ilumya, Sun Pharma); deucravacitinib (not approved in Canada); brodalumab (Siliq, Bausch Health); trifarotene cream (Aklief, Galderma); tazarotene lotion (Arazlo, Bausch Health); tretinoin/benzoyl peroxide gel (not approved in Canada); clindamycin/adapalene gel clascoterone (not approved in Canada); ruxolitinib (Jakavi, Novartis); delgocitinib (not approved in Canada); cerdulatinib (not approved in Canada); ritlecitinib (not approved in Canada).

Message from the Medical Editor Continued from page 3 Cullingham and Purdy provide updates on JAK inhibitors, while Dr. Barankin introduces readers to a new class of drugs—the TYK-2 inhibitors. (It’s interesting to note that a recent psoriasis genome wide association study has identified a TYK-2 gene associated with psoriasis). Dr. Rao joins his colleagues in highlighting the importance of JAK inhibitors across a multitude of dermatologic conditions, noting that their efficacy and safety are truly remarkable.

In pediatric dermatology, there are now two IL-17 blockers available for pediatric patients with psoriasis.

According to Dr. Cathryn Sibbald, these agents have rapid onset and lead to improved outcomes compared to the biologics we presently have available. She also points out the importance of screening for psoriatic arthritis even in pediatric patients. Dr. Sibbald also describes the rare psoriasis-like reactions to the biologic dupilumab, which can easily be treated with mid-po-

tency topical steroids. She notes that for the treatment of ichthyosis, the new retinoid trifarotene may be useful (see page 1).

During the Maddin Lecture at Derm Update, it was suggested that many of the current unmet needs in dermatology could be helped with significant scientific breakthroughs arising from the use of genome-wide association studies. We’ve seen breakthroughs in psoriasis identifying the link between psoriasis and genes such as TNF, IL-23, IL-17, and TYK-2. Similar studies could produce potential targets in other disorders with familial tendency including atopic dermatitis, HS and vitiligo. I anticipate a bright future for further therapeutic innovations as we continue to understand the immunopathogenesis of these disorders.

As always, THE CHRONICLE team invites and welcomes your comments on this issue, or any other topic in dermatology, at www.derm.city.

—Wayne P. Gulliver, MD, FRCPC, Medical Editor

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18 • Febraury 2022

THE CHRONICLE of SKIN & ALLERGY

Maddin Lecture: Therapy options growing for HS Continued from page 1 Maddin Lecture at Derm Update 2021 in Montreal, Dr. Gulliver described his career path and highlighted several of the advances he and colleagues have made in pursuit of gaining insights into psoriasis.

Newfoundland and Labrodor is considered a fertile resource for genetic research because of its isolation and homogeneity, making its people a focus for the identification of genes in some diseases, such as psoriasis, explained Dr. Gulliver. Families of English, Scottish and Irish ancestry have resided in the province for more than 300 years.

Dr. Gulliver and colleagues Dr. Wayne looked at single nucleotide polyGulliver morphisms (SNPs), one of the most common type of genetic variation among people. One of the first investigations Dr. Gulliver was involved with was a 1992 study involving 100 patients with psoriasis. It was observed than 87% of patients had a positive family history for psoriasis.

“We saw that HLA-Cw6 played an important role, and if you were HLA-Cw6 positive, you got psoriasis at a younger age,” said Dr. Gulliver, who received the lifetime achievement award from the Canadian Dermatology Association in 2021.

Apart from HLA-Cw6, Dr. Gulliver and colleagues identified a second gene, which was tumor necrosis factor (TNF)-alpha. “We predicated back in 1994 that TNF-alpha played a role in psoriasis,” he said. “We were just waiting for a drug that targeted it.”

TNF-alpha target Infliximab and alefacept were early breakthrough agents that produced what was at the time regarded as significant clearance of psoriasis, said Dr. Gulliver. In a double, placebo-controlled trial,

two courses of alefacept were administered to treat chronic plaque psoriasis. A total of 28% of patients achieved Psoriasis Area Severity Index (PASI) 75 while 56% achieved a PASI 50 during treatment and follow-up control after the first course (J Am Acad Dermatol 2002 Dec; 47(6):821833).

Fast forward to contemporary times where most emerging agents are held to a higher standard, with therapies being measured by PASI 90 and PASI 100 responses. “There has been an evolution,” said Dr. Gulliver, referring to the advances in efficacy of treatment in the last decade. “Psoriasis has come a long way—we can reach PASI 100.”

One of the major undertakings in research involved more than 100 investigators who conducted genome-wide association scans and identified 15 psoriasis susceptibility loci, noted Dr. Gulliver. One of the findings from this large-scale investigation was the identification of tyrosine kinase 2, a therapeutic target that plays a role in several autoimmune conditions.

One of the observations that Dr. Gulliver and colleagues have made is that patients with psoriasis face an elevated risk of death compared to individuals who don’t have psoriasis. A cross-sectional study concluded that patients with psoriasis died at a significantly younger age than individuals without psoriasis. The study also showed that patients who had an earlier onset of disease (age 25 or less) compared to those with a delayed onset (older than 25 yeas), died at a younger age. Individuals with psoriasis were also hospitalized more often for system disorders than individuals without psoriasis (J Cutan Med Surg Jan-Feb 2011; 15(1):37-47).

That observation was also made by U.S. investigators: A cohort study that looked at the risk of mortality in patients with psoriasis found that severe psoriasis is linked with an increased risk of death (Arch Dermatol 2007 Dec; 143(12):1493-

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Another insight had to do HLA-Cw6 status and its impact on psoriasis severity, noted Dr. Gulliver. It was observed that patients who were HLA-Cw6 positive were more likely to have their psoriasis go into remission whereas those who were HLA-Cw6 negative were more likely to experience a psoriasis flare or remain stable.

Research conducted by Dr. Gulliver and other researchers has highlighted that psoriasis frequently presents with comorbidities. The risk of developing metabolic syndrome is five times more likely for individuals who have psoriasis compared to those who do not (Arch Dermatol Res 2006; 298(7):321-328).

As genetic research in psoriasis is advancing and integrating components such as artificial intelligence, more insights into the chronic condition and likely other conditions will be revealed, according to Dr. Gulliver.

“I see psoriasis as a key to the lock of many other diseases,” said Dr. Gulliver. “By studying psoriasis, we should be able to find genes that are targets for things like diabetes, hypertension, hyperlipidemia and Crohn’s disease.”

Advancing the understanding of HS Dr. Gulliver noted that medical treatment of hidradenitis suppurativa (HS), another chronic condition, has progressed to include more choices in the last decade. “It is an exciting area of research,” he said.

Therapies for HS now include biologics as options in addition to standard treatments like oral or topical antibiotics, noted Dr. Gulliver, describing the development by an international group of researchers and clinicians of an HS treatment algorithm in 2016 (Rev Endocr Metab Disord 2016; 17:343–351).

“HS patients who failed treatments like antibiotics can be put on a biologic,” said Dr. Gulliver.

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In support of achieving Indigenous health equality, the Indigenous Skin Spectrum Summit will educate healthcare providers as to the latest and best research and frame it in the specific context of Indigenous communities.

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POSEDUCATIONAL TGRAD UATE SUPPLEMENT Real-world assessment and treatment of locally advanced basal cell carcinoma: Findings from the RegiSONIC disease registry

Aleksandar Sekulic,1 Simon Yoo,2 Ragini Kudchadkar,3 Julie Guillen,4 Gary Rogers,5 Anne Lynn S. Chang,6 Scott Guenthner,7 Bernard Raskin,8 Keith Dawson,9 Yong Mun,10 Laura Chu,11 Edward McKenna,9 Mario Lacouture12 Department of Dermatology, Mayo Clinic, Scottsdale, Ariz.; 2Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago; 3Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta; 4UCSF Dermatology and Laser Surgery Center, University of California, San Francisco; 5Surgical Dermatology, Tufts New England Medical Center, Boston; 6Dermatology, Stanford University School of Medicine, Stanford, Calif.; 7Dermatology Center of Indiana/Indiana Clinical Trials Center, Plainfield, Ind.; 8UCLA School of Medicine, Los Angeles; 9Medical Affairs, Genentech, South San Francisco, Calif.; 10Biostatistics, Genentech, South San Francisco, Calif.; 11Oncology, Genentech, South San Francisco, Calif.; 12Dermatology, Memorial Sloan Kettering Cancer Center, New York 1

ABSTRACT Background: Limited information is available regarding real-world treatment patterns and their effectiveness and safety in patients with locally advanced basal cell carcinoma, including patients not typically represented in clinical trials. The purpose of the current study was to describe how clinicians diagnose and treat locally advanced basal cell carcinoma in the United States.

Methods: This prospective, multicenter, observational registry study included patients with newly diagnosed, Hedgehog pathway inhibitor–naive locally advanced basal cell carcinoma without basal cell carcinoma nevus syndrome (n=433) treated at 75 U.S. academic and community practices, including dermatology, Mohs surgery, and medical oncology sites. The main outcomes of this study were treatment patterns and associated effectiveness and safety for patients with locally advanced basal cell carcinoma in real-world settings.

Results: Determination of locally advanced basal cell carcinoma was mainly based on lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), and location (46.2%). Within 90 days of determination of locally advanced disease, 115 patients (26.6%) received vismodegib, 251 (58.0%) received surgery/other (non-vismodegib) treatment, and 67 (15.5%) had not yet received treatment (observation). Vismodegib-treated patients had a higher prevalence of high-risk clinical features predictive for locoregional recurrence than those with non-vismodegib treatment or observation. Clinical response rate was 85.1% with vismodegib and 94.9% with non-vismodegib treatment (primarily surgery). The most common adverse events with vismodegib were ageusia/dysgeusia, muscle spasms, alopecia and weight loss. Rates of cutaneous squamous cell cancers were comparable between vismodegib and non-vismodegib treatment.

Conclusions: This prospective observational study offers insight on real-world practice, treatment selection, and outcomes for a nationally representative sample of U.S. patients with locally advanced basal cell carcinoma. For patients with lesions that were not amenable to surgery, vismodegib treatment was associated with effectiveness and safety that was consistent with that observed in clinical trials.

Reprinted with permission ©2022 Sekulic et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Content has been edited to conform with the Canadian Press Publication Style Guide.

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INTRODUCTION

onmelanoma skin cancer is the most common malignant neoplasm diagnosed in the United States.1 Most basal cell carcinomas (BCCs) are diagnosed early, when surgery is curative; however, an estimated 1% to 10% progress to advanced (i.e., locally advanced or metastatic) disease because of delays in treatment, aggressive subtypes, or recurrence/progression after surgery.2–4.

The disease course of advanced BCC is highly variable, and few treatment options are available. Mohs micrographic surgery has been used to treat locally advanced BCC and might be used in conjunction with lymph node dissection in patients with lymph node involvement.5,6 In patients experiencing recurrence after repeated surgical treatments or with lesions not amenable to surgery, radiation therapy may be effective;6,7 however, its usefulness is limited by lesion location, previous use of radiation, and presence of genetic syndromes, including BCC nevus syndrome (BCCNS; also known as Gorlin syndrome).7,8 There is historically no standard chemotherapy regimen for advanced BCC, although use of platinum agents has been reported.9 A key molecular driver of BCC is inappropriate activation of the Hedgehog signalling pathway via mutations in the tumour suppressor patched gene (PTCH1) and consequent activation of the smoothened gene (SMO).8,10 The development and approval of targeted Hedgehog pathway inhibitors (HPIs) provide new options for patients with locally advanced BCC and BCCNS.11–14 Information regarding the relative effectiveness, safety and patterns of treatment of locally advanced BCC outside structured clinical trials is scarce.

RegiSONIC (An Observational Study of Treatment Patterns and Effectiveness and Safety Outcomes in Advanced Basal Cell Carcinoma and Basal Cell Carcinoma Nevus Syndrome Patients), an advanced BCC registry conducted in the United States, is designed to prospectively evaluate how clinicians diagnose and treat advanced BCC and to characterize the effectiveness, safety and use of systemic (HPIs and chemotherapies) and local (surgery, radiation, destructive, and topical) treatments in realworld clinical practice, with broad inclusion criteria to capture treatment patterns and outcomes for patients not typically enrolled in clinical trials.

Herein, we describe baseline characteristics, diagnosis, and treatment patterns and outcomes in a subset of patients with newly diagnosed locally advanced BCC without BCCNS who were HPInaive at baseline. This group of patients constituted the largest cohort of patients in the registry who were available for analysis.

MATERIALS AND METHODS Study design RegiSONIC was a multicentre, prospective, observational, three-cohort study with an enrollment of 503 patients with advanced BCC or BCCNS treated in 75 U.S. academic and community sites, including dermatology, Mohs surgery and oncology practices. Treatment, procedures and clinic visit schedules were at the discretion of the treating physician, consistent with routine clinical practice.

The study was conducted in accordance with U.S. Food and Drug Administration regulations, International Conference on Harmonization E6 Guidelines for Good Clinical Practice, and applicable local, state and federal laws. The protocol was reviewed and approved by the following centralized or local institutional review boards: Atlantic Health System; California Pacific Medical Center IRB; Cleveland Clinic IRB; Colorado Multiple Institutional Review Board; Columbia University Institutional Review Board; Cooper Health System IRB; Emory University IRB; Icahn School for Medicine at Mount Sinai; Loma Linda University IRB; Marshall University IRB; Mayo Clinic IRB; Memorial Sloan Kettering Cancer Center; New England Institutional Review Board; Northeast Hospital Corporation; Northwestern University; Nova Southeastern University; Partners Healthcare System; Springfield Committee for Research Involving Human Subjects; Stanford University IRB; Sterling IRB; University of Arizona IRB; University of California, Irvine Institutional Review Board; University of California, San Diego; University of Miami; University of Minnesota IRB; University of Mississippi Medical Center IRB; University of North Carolina Chapel Hill; and Western Institutional Review Board. All patients provided written informed consent. This study was registered with ClinicalTrials.gov (number, NCT01604252).

Study population Eligible patients were adults (aged ≥18 years) with advanced BCC as determined by the treating clinician within 90 days before enrollment or with BCCNS at study entry. Although this

POSTGRADUATE EDUCATIONAL SUPPLEMENT

Figure 1: Study disposition. aBCC, advanced basal cell carcinoma; BCCNS, basal cell carcinoma nevus syndrome; HPI, Hedgehog pathway inhibitor; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma. study had three patient cohorts (Fig. 1), only those enrolled in the largest cohort (Cohort 1) were included in this analysis.

These patients had advanced BCC without BCCNS, had not been previously treated with an HPI, and had not participated in an advanced BCC- or HPI-related clinical trial within 90 days before enrollment.

Determination of whether BCC was advanced, selection of target lesions and choice of treatment were at the discretion of the treating clinician. Target lesions were recorded and measured at baseline and assessed at each follow-up visit. Response was assessed by the treating physician according to their method of choice.

Data collection Data that included medical conditions/procedures, changes in concomitant medications, disease status/tumour response, Eastern Cooperative Oncology Group (ECOG) performance status, treatment status and adverse events (AEs) were collected quarterly. All patients were required to complete annual

study visits over a three-year follow-up period. Patients were followed until completion of three years of follow-up, death, withdrawal of consent, loss to follow-up, or study termination, whichever occurred first, and analyses included data up to the last data collection timepoint for all enrolled patients.

AE collection was limited to serious AEs (fatal, life-threatening, requiring hospitalization, resulting in significant disability, or otherwise considered medically significant by the clinician), AEs leading to treatment discontinuation, or protocol-defined AEs of interest (muscle spasms, arthralgia, alopecia, dysgeusia/ageusia, unintentional weight loss, fatigue grade ≥2, gastrointestinal events grade ≥2, cardiovascular events, amenorrhea, and squamous cell carcinoma [SCC]).

Statistical analysis The objectives of this study were to characterize factors associated with advanced BCC diagnosis, initial treatment choices, treatment effectiveness and safety and changes in treatments in pa-

tients with locally advanced BCC without BCCNS (Cohort 1) in real-world clinical practice. Given the potential for multiple and varied treatments during follow-up, three treatment groups were defined based on treatment received within 90 days after locally advanced BCC diagnosis, regardless of any subsequent treatment: 1) vismodegib (received vismodegib alone or in combination with other treatments within 90 days of diagnosis), 2) non-vismodegib treatment (received treatments other than vismodegib [eg, surgery, radiation, photodynamic therapy, topical treatment, other systemic therapy] within 90 days of diagnosis), and 3) observation (did not receive treatment within 90 days of diagnosis, but may have received treatment thereafter).

Descriptive analyses were conducted to summarize patient and clinical disease characteristics at baseline, characterize treatment patterns, and assess effectiveness and safety outcomes of treatment using statistical software (SAS, version 9.2 or later; SAS Institute Inc., Cary, N.C.).

RESULTS Patients Between June 2012 and August 2015, 503 eligible patients were enrolled at 75 U.S. academic and community practices, including dermatology, Mohs surgery and medical oncology sites; 439 patients were enrolled in Cohort 1, nine patients in Cohort 2, and 55 patients in

Table 1: Baseline demographics in patients with locally advanced basal cell carcinoma in Cohort 1.

Cohort 3 (Fig. 1). Overall, 37 eligible patients declined to participate. To reduce the risk of selection bias, investigators were encouraged to invite all eligible patients to participate in the study. Data from 433 HPI-naive patients with newly diagnosed, locally advanced BCC without BCCNS enrolled in Cohort 1 are presented; four patients with metastatic disease and two patients whose disease could not be adequately subclassified were excluded from this analysis.

At data cutoff (August 31, 2017), median follow-up duration was 23.6 months (range 0.03–45.04). All 433 patients had discontinued the study, including 69 patients (15.9%) who completed the study with three years of follow-up. The most common reasons for study discontinuation were sponsor decision to terminate the study (150 patients; 34.6%), loss to follow-up (83 patients; 19.2%), and patient decision to withdraw (55 patients; 12.7%).

Patient demographics Most patients were aged ≥65 years (56.8%; median, 67 years), and most (62.6%) were men (Table 1). Almost all patients were white (99.5%) and had sun-sensitive skin phototypes (Fitzpatrick skin type I–III; 90.4%).

Compared to those who received non-vismodegib treatment, vismodegib-treated patients and those who underwent observation were more likely to be men (57.8% vs. 67.8% and 71.6%). Vismodegib-treated patients were more likely than those in the nonvismodegib treatment and observation groups to be current or former smokers (54.8% vs. 41.8% and 46.3%) and to be less educated (high school graduate or less; 40.0% vs. 31.9% and 32.8%) and were less likely to be regular sunscreen users (24.3% vs. 33.5% and 31.3%). Patients who received non-vismodegib treatment were more likely to have good baseline performance status than vismodegib-treated patients and those who underwent observation (ECOG performance status 0: 59.3% vs. 42.2% or 43.1%). Evaluation of medical history included all dermatologic and non-dermatologic medical conditions as well as non–BCC-related surgeries and proce-

Table 2: Baseline demographics in patients with locally advanced basal cell carcinoma in Cohort 1.

Table 3: Baseline disease characteristics in patients with locally advanced basal cell carcinoma in Cohort 1. dures in patient medical records. These were extracted and coded using Medical Dictionary for Regulatory Activities version 20.0. There were no identifiable factors in medical history associated with treatment choice. Performance status (ECOG) was extracted for the most recent assessment before study enrollment and change in performance status was assessed at each follow-up visit.

Diagnosis and disease characteristics For most patients (369; 85%), determination of locally advanced BCC was based on multiple factors, most commonly lesion size (79.6% of patients), histopathology (54.3%), extent of involvement (49.0%), location (46.2%), recurrence (26.7%) and likelihood of curative resection (25.3%) (Table 2).

When determination of locally advanced BCC was based on lesion size, lesions measured ≥20 mm in 63.0% of patients; when based on recurrence, 40.9% of patients experienced ≥2 recurrences; when based on location, the lesion site was the face in 69.8% of patients. Evaluation of variables that may reflect lack of access to care or undertreatment (i.e., health insurance coverage, psychiatric disorders/dementia and BCC treatment history) did not provide any insight into factors contributing to the development of advanced BCC (S1 Table).

At baseline, 23.3% of patients had multiple clinically visible advanced lesions (Table 3), with a median of three lesions per patient. Target lesions were located on the head/neck in 63.6% of patients and were most commonly

nodular (64.6%) or morpheaform/infiltrative (27.4%).

Disease characteristics differed across treatment groups, with a higher prevalence of clinical features predictive for increased risk of locoregional recurrence in vismodegib-treated patients and patients in the observation group compared with those who received non-vismodegib treatment, including lesion size ≥20 mm (73.5% and 62.8% vs. 59.0%), curative resection unlikely (49.1% and 28.8% vs. 13.5%), and recurrent disease (37.7% and 47.0% vs.

16.3%). However, distribution of lesions across anatomic sites, particularly highrisk areas of the head/neck, were comparable across groups. More patients in the vismodegib group had medical contraindications to surgery or radiotherapy or were expected to have significant cosmetic/functional deficits with local treatment.

Treatment Of the 433 patients, 115 (26.6%) were included in the vismodegib group, 251 (58.0%) in the non-vismodegib treatment group, and 67 (15.5%) in the observation group (no treatment within 90 days of enrollment). Median follow-up duration was 25.4 months (range 0.16– 39.56), 22.8 months (range 0.03–45.04), and 21.2 months (range 0.03–44.25), respectively.

Patients in the vismodegib group generally remained on vismodegib and, in some cases, restarted vismodegib after intervals of a few to several months off treatment (Fig. 2A). Most patients receiving vismodegib (108 patients; 93.9%) had ≥1 interruption or

change in treatment, most commonly because of AEs (36 patients), maximum benefit achieved (21 patients), patient decision (19 patients) or treatment holiday (14 patients). The median duration of vismodegib treatment was 6.31 months (range 0.03–31.97).

Of 251 patients in the non-vismodegib treatment group, most (198 patients [78.9%]) received only surgery (e.g., Mohs surgery, cryosurgery, excision); 53 patients (21.1%) received other non-vismodegib treatments (e.g., topical therapy, radiation, other systemic therapy) within 90 days after locally advanced BCC diagnosis. After 90 days, few patients received other treatments, although patients might have undergone multiple surgeries (Fig. 2B). Most patients (287; 98.4%) had ≥1 interruption or change in treatment, most commonly because maximum benefit was achieved (196 patients).

Of 67 patients in the observation group, several patients received treatment after 90 days (Fig. 2C), most commonly surgery (19 patients; 28.4%), vismodegib (six patients; 9.0%), radiation (five patients; 7.5%), or topical treatment (three patients; 4.5%).

Response assessment and effectiveness Disease assessment at baseline and during treatment consisted primarily of clinical evaluation (93.5%, 90.3%, and 88.9% of patients in the vismodegib, non-vismodegib treatment, and observation groups, respectively), and less frequently, histopathologic evaluation (6.5%, 16.6%, and 13.9%, respectively) or diagnostic imaging (8.6%, 1.1%, and 0, respectively) (S1 Fig). Clinical evaluation was based on visual parameters, such as lesion size (S2 Fig); complete response assessment was most commonly based on lack of clinically visible evidence of BCC (>60%) (S3 Fig). Patients in the non-vismodegib treatment group, most of whom underwent surgery, were more likely to have only one posttreatment disease assessment than vismodegib-treated patients (26.6% vs 5.7%).

Among 101 evaluable vismodegibtreated patients, the clinical response rate was 85.1%, with complete response in 63.4%. Median duration of response was 17.5 months, and disease recurrence was reported in 23.8% of patients.

Among 198 evaluable patients in the non-vismodegib treatment group, most of whom underwent surgery, clinical and complete response rates were 94.9% and 91.4%, respectively. Disease recurrence was reported in 2.0% of patients.

Safety Because AE collection was limited to serious AEs or AEs of interest unless an AE caused treatment discontinuation, nonserious AEs were less likely to be col-

lected in the non-vismodegib treatment group, as most patients in that group underwent surgery and frequently had only one posttreatment assessment following an assessment of complete response.

In the vismodegib group, AEs were reported in 104 patients (90.4%). The most common all-grade AEs (≥20% of patients) were ageusia/dysgeusia (71 patients; 61.7%), muscle spasms (66 patients; 57.4%), alopecia (58 patients; 50.4%) and weight loss (29 patients; 25.2%). Serious AEs occurred in 29 patients (25.2%), and 24 (20.9%) patients discontinued treatment because of AEs. Cutaneous SCCs were reported in 14 patients (12.2%), with an exposure-adjusted incidence rate of 0.06 cases per patient-year.

In the non-vismodegib treatment group, AEs were reported in 65 patients (25.9%). Serious AEs occurred in 35 patients (13.9%). Cutaneous SCCs were reported in 31 patients (12.4%), with an exposure-adjusted incidence rate of 0.07 cases per patient-year.

DISCUSSION In this prospective, observational study, we identified distinct treatment patterns of real-world patients with locally advanced BCC who were given different treatments based on initial clinical presentation. The availability of vismodegib highlighted the need to better define locally advanced BCC. Historically, “advanced” BCCs (although rarely described as such) were those necessitating complex treatment beyond usual standard of care (i.e., surgery) or recurring repeatedly despite adequate local treatment.15,16 Clinical trial eligibility criteria have defined locally advanced BCC based on lesion size, extent of local invasiveness, tumour location, expected morbidity or mortality from local treatment, low likelihood of curative resection, contraindication to local treatment or number of recurrences.16 Many of these criteria are subjective, and little is known about how physicians make the determination of locally advanced BCC in clinical practice.

Data from this prospective, observational study indicate that locally advanced BCC determination was typically made based on multiple factors. Lesion size was the most common criterion for determination of locally advanced BCC (almost 80% of patients), frequently in conjunction with histopathology, extent of involvement, or tumour location (around 50% of patients each). Consensus criteria for defining locally advanced BCC as inappropriate for surgery or radiotherapy were recently described and might assist in standardization of locally advanced BCC determination in clinical practice.17 Delays in diagnosis and treatment can contribute to development of advanced BCC.2–4 Barriers to accessing care

POSTGRADUATE EDUCATIONAL SUPPLEMENT rily determined on the basis of clinical evaluation with infrequent use of histopathology or imaging in the realworld setting. Median duration of response was comparable to those observed in ERIVANCE-BCC (26.2 months) and STEVIE (23.0 months), given differences in follow-up time across studies.11,12 Outcomes observed in patients who received non-vismodegib treatment (most commonly, surgery) should be interpreted with caution, as many patients had only one follow-up visit. Nevertheless, the observed recurrence rate for these patients is within the range reported in randomized clinical trials or observational studies of surgical outcomes.3,24– 28

Figure 2: Basal cell carcinoma. Representative treatment patterns among randomly selected patients treated within the first 90 days with vismodegib (n=40, A), non-vismodegib treatment (n=40, B), and observation (n=28, C). Vismodegib=received vismodegib within 90 days of diagnosis; non-vismodegib treatment=received interventions other than vismodegib within 90 days of diagnosis; observation=received no intervention within 90 days of diagnosis. Bar lengths represent duration from date of locally advanced basal cell carcinoma diagnosis to study termination, death, or data cutoff; > denotes death; X denotes initial progression; * denotes surgery. may include lack of health insurance and history of mental illness. In the current study, insurance coverage was high across the study population and was consistent with coverage rates in the general U.S. population.18 Additionally, prevalences of psychiatric disorders and dementia in the study population were similar across treatment cohorts and similar to or lower than prevalences in the general population.19–21 Although data on prior treatment history for the target BCC were available for only a subset of patients, rates of nontreatment were generally low across cohorts. Thus, evaluation of variables that may reflect lack of access to care or undertreatment did not provide any insight into factors contributing to the development of advanced BCC in this patient population.

Results also indicate that initial treatment choices for locally advanced BCC are dictated primarily by tumour size, number of tumours, extent of involvement, histopathology and

anatomic location of BCC lesions, which is consistent with anecdotal observations.22 Vismodegib was the only HPI available throughout study accrual (June 2012 through August 2015), with sonidegib receiving approval in July 2015. Patients treated with vismodegib were clearly different from patients treated with other modalities (predominantly surgery; 78.9%), with a higher prevalence of poor-risk features. In particular, vismodegib was chosen more frequently for patients with multiple or larger lesions (≥20 mm), consistent with considerations of disfigurement and potentially higher risk of recurrence after surgery for patients with larger lesions or lesions located in the periocular, paranasal or scalp regions.23 Given the different clinical presentations of vismodegib-treated versus non–vismodegib-treated patients, outcomes should not be compared between treatment groups. However, outcomes for each treatment appear

consistent with those reported in the literature with clinical trial populations that typically exclude patients with comorbidities, the elderly or patients with poor performance status. The clinical response rate in vismodegib-treated patients was consistent with investigator-assessed response rates in the pivotal ERIVANCE-BCC study (60.3%) and STEVIE safety study (68.5%), although the complete response rate was higher than that observed in clinical studies (31.7% in ERIVANCE-BCC and 33.4% in STEVIE), which likely reflects more rigorous methods of response assessment in clinical trials relative to the real-world setting.11,12 In these clinical studies, determination of response used formal structured assessments based on physical examination and radiology per Response Evaluation Criteria in Solid Tumors (RECIST), with histopathological confirmation of complete response in the ERIVANCE-BCC study. In contrast, our data suggest that response is prima-

In general, the safety profile of vismodegib was manageable and similar to that reported in clinical trials.29,30 The most common AEs were ageusia/dysgeusia, muscle spasms, alopecia and weight loss. Concerns have been raised regarding an increased risk of cutaneous SCC with vismodegib, with conflicting findings from retrospective cohort analyses.31,32 In this observational study, cutaneous SCC was collected prospectively as an AE of interest and vismodegib treatment did not appear to be associated with an increased risk of SCC. To our knowledge, this report represents the first prospective evaluation of the incidence of cutaneous SCCs in vismodegib-treated patients, including a concurrent group of patients managed primarily by surgical excision serving as a control. Whereas Fitzpatrick skin types were comparable across groups, regular sunscreen use was slightly more common in the non-vismodegib treatment group.

Overall, treatment patterns showed that vismodegib-treated patients often received vismodegib over multiple intervals during follow-up, although a few patients initially treated with vismodegib subsequently underwent surgery. Several reports suggest that neoadjuvant vismodegib might shrink tumours, thereby allowing less extensive surgery with lower risk for morbidity.33–35 These data suggest the need to further explore the potential utility of HPIs in the neoadjuvant setting.

Strengths of this study are the inclusion of a nationally representative sample of patients from a range of U.S. academic and community practices, including dermatology, Mohs surgery and medical oncology sites. As a result of broad inclusion criteria, the registry included patients who would typically be excluded from clinical trials. Moreover, patient participation was extensive, with only 37 eligible patients declining to participate over the three-year accrual period.

Limitations of this study include those commonly associated with observational studies in the real-world set-

ting, such as nonrandomized treatment assignment, lack of standardized assessment, and variation in treatment practices across centres. Moreover, patients were seen by a variety of different providers, including dermatologists, Mohs surgeons and oncologists. Such diversity contributes to challenges in describing treatment patterns for patients with locally advanced BCC in the real-world setting. The relatively high rate of patient decision to withdraw (12.7%) was comparable to rates observed in clinical trials of vismodegib and other published long-term BCC studies.29,30,36–38 Loss of patients to follow-up is high in BCC studies and probably reflects the older age of BCC populations and the fact that BCC is typically not immediately lifethreatening.36–38 In addition, follow-up of patients was limited because of the sponsor’s decision to close the study two years earlier than originally planned.

tion=received no intervention within 90 days of diagnosis. https://doi.org/10.1371/journal.po ne.0262151.s003 (PDF) S1 Table. Health insurance coverage, history of psychiatric disorders/dementia, and BCC treatment history in patients with locally advanced basal cell carcinoma in Cohort 1.

Abbreviations: BCC, basal cell carcinoma; laBCC, locally advanced basal cell carcinoma. aSpecific diagnoses occurring in two or more patients are reported.

Vismodegib=received vismodegib within 90 days of diagnosis; non-vismodegib treatment=received interventions other than vismodegib within 90 days of diagnosis; observation=received no intervention within 90 days of diagnosis. https://doi.org/10.1371/journal.po ne.0262151.s004 (PDF) S1 Data. https://doi.org/10.1371/journal.pone.02 62151.s005 (PDF)

CONCLUSIONS

ACKNOWLEDGMENTS

The RegiSONIC study offers useful insight on real-world practice and treatment selection in patients with locally advanced BCC and highlights differences in disease characteristics that may drive choice of treatment. Effectiveness and safety of vismodegib in the realworld setting was consistent with that observed in clinical trials.

The authors thank the patients, families, and investigators who participated in RegiSONIC; Anne Morris, registry epidemiologist, for contributions to data analyses; Diana Chen, medical director, for contributions to study development and initiation; E. Dawn Flick, senior director of registries, for contributions to the study design and implementation; Cheryl Schwab, clinical operations lead, for work with sites to ensure fidelity to the study protocol; and Elizabeth Mandel, data management lead, for ensuring data quality. Medical writing assistance for this manuscript was provided by Melanie Sweetlove, MSc, of ApotheCom (San Francisco, Calif.) and funded by F. Hoffmann-La Roche Ltd.

SUPPORTING INFORMATION S1 Fig. Methodology used for disease assessment.

Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging. Vismodegib=received vismodegib within 90 days of diagnosis; nonvismodegib treatment=received interventions other than vismodegib within 90 days of diagnosis; Observation=received no intervention within 90 days of diagnosis. https://doi.org/10.1371/journal.po ne.0262151.s001(PDF) S2 Fig. Parameters used to determine response assessment.

Abbreviations: BCC, basal cell carcinoma; laBCC, locally advanced basal cell carcinoma; mBCC, metastatic basal cell carcinoma. Vismodegib=received vismodegib within 90 days of diagnosis; non-vismodegib treatment=received interventions other than vismodegib within 90 days of diagnosis; Observation=received no intervention within 90 days of diagnosis. https://doi.org/10.1371/journal.po ne.0262151.s002 (PDF) S3 Fig. Criteria for assessment of complete response.

Abbreviations: BCC, basal cell carcinoma. Vismodegib=received vismodegib within 90 days of diagnosis; non-vismodegib treatment=received interventions other than vismodegib within 90 days of diagnosis; Observa-

Data Availability All relevant data are in the paper and its Supporting information files.

Funding F. Hoffmann-La Roche/Genentech, Inc. funded the RegiSONIC study and participated in the study design; data collection, analysis, and interpretation; preparation and revision of the manuscript; and decision to submit the manuscript for publication.

Competing interests A. Sekulic has no conflict of interest to declare. S. Yoo has no conflict of interest to declare. R. Kudchadkar has served on advisory boards and received honoraria from Bristol-Myers Squibb and has received grants/research funding from Merck. J. Guillen has no conflict of interest to declare. G. Rogers has no conflict of interest to declare. A.L.S. Chang has served as a clinical investigator for research studies funded by Roche/Genentech, Merck, Novartis and Regeneron. S.

Guenthner has served on advisory boards and received grants/research funding and honoraria from Genentech, Pfizer, AbbVie, Amgen, LEO Pharma, Lilly, Dermira, Sun Pharma, UCB, Vanda and Janssen. B. Raskin has no conflict of interest to declare. K. Dawson, Y. Mun, L. Chu, and E. McKenna are employees of Genentech and hold stock/stock options in Roche/Genentech. M. Lacouture has received royalties from Legacy Healthcare Services, Apricity Health, Azitra, Deciphera, Galderma, Johnson & Johnson, NCODA, Novocure, Kyowa Kirin, Loxo, Merck Sharp & Dohme, Janssen, Menlo Therapeutics, Novartis, QED Therapeutics, F. Hoffmann-La Roche, Amgen, AstraZeneca, Genentech, Seagen, Lutris, Paxman Collers, OnQuality Pharmaceuticals and Takeda Millennium and has received research funding from Veloce, US Biotest, Lutris, Paxman and Novocure.

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13. Sekulic A, Migden MR, Oro AE, et al: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366(23):2171–2179.

14. Migden MR, Guminski A, Gutzmer R, et al: Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015; 16(6):716–728.

15. Sekulic A, Mangold AR, Northfelt DW, LoRusso PM: Advanced basal cell carcinoma of the skin: targeting the hedgehog pathway. Curr Opin Oncol 2013; 25(3):218–223.

16. Maly TJ, Sligh JE: Defining locally advanced Basal cell carcinoma. J Drugs Dermatol 2014; 13(5):528– 529. S1545961614P0528X. 17. Peris K, Licitra L, Ascierto PA, et al: Identifying locally advanced basal cell carcinoma eligible for treatment with vismodegib: an expert panel consensus. Future Oncol 2015; 11(4):703–712.

18. Berchick ER, Hood E, Barnett JC: Health insur-

ance coverage in the United States: 2017 Washington, DC, USA: United States Census Bureau; 2018 [cited 1 Apr 2021]. https://www.census.gov/content/dam/Census/library/publications/2018/demo/p60264.pdf 19. National Institute of Mental Health. Statistics: Mental illness. Bethesda, MD, USA: National Institutes of Health; 2021 [updated Jan 2021; cited 1 Apr 2021]. https://www.nimh.nih.gov/health/statistics/mental-illness.shtml 20. National Institute of Mental Health. Statistics: any anxiety disorder. Bethesda, MD, USA: National Institutes of Health; 2021 [updated Jan 2021; cited 1 Apr 2021]. https://www.nimh.nih.gov/health/statistics/a ny-anxiety-disorder.shtml 21. Alzheimer’s Association: 2021 Alzheimer’s disease facts and figures. Alzheimers Dement.

2021; 17(3):327–406. Epub 2021/03/24.

22. Lewin JM, Carucci JA: Advances in the management of basal cell carcinoma. F1000Prime Rep 2015; 7:53.

23. Marzuka AG, Book SE: Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J Biol Med 2015; 88(2):167–179.

24. Chren M-M, Torres JS, Stuart SE, Bertenthal D, Labrador RJ, Boscardin WJ: Recurrence after treatment of nonmelanoma skin cancer: a prospective cohort study. Arch Dermatol 2011; 147(5):540–546.

25. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R: Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5year follow-up. J Am Acad Dermatol 2005; 53(3):452–457.

26. Leibovitch I, Huilgol SC, Selva D, Richards S, Paver R: Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years. J Am Acad Dermatol 2005; 53(3):445–451.

27. Mosterd K, Krekels GA, Nieman FH, et al: Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 2008; 9(12):1149–1156.

28. Smeets NW, Krekels GA, Ostertag JU, et al: Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet 2004; 364(9447):1766–1772.

29. Sekulic A, Migden MR, Lewis K, et al: Pivotal ERIVANCE BCC study: 12-month update of efficacy and safety of vismodegib in advanced basal cell carcinoma. J Am Acad Dermatol 2015; 72:1021–1026.

30. Basset-Seguin N, Hauschild A, Grob JJ, et al: Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial.

Lancet Oncol 2015; 16:729–736.

31. Bhutani T, Abrouk M, Sima CS, et al: Risk of cutaneous squamous cell carcinoma after treatment of basal cell carcinoma with vismodegib.

J Am Acad Dermatol 2017; 77(4):713–718.

32. Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL: Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol 2016; 152:527–532.

33. Alcalay J, Tauber G, Fenig E, Hodak E: Vismodegib as a neoadjuvant treatment to mohs surgery for aggressive Basal cell carcinoma. J Drugs Dermatol 2015; 14(3):219–221.

34. Ally MS, Aasi S, Wysong A, et al: An investigatorinitiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma. J Am Acad Dermatol 2014; 71(5):904–911.

35. Chang AL, Atwood SX, Tartar DM, Oro AE: Surgical excision after neoadjuvant therapy with vismodegib for a locally advanced basal cell carcinoma and resistant basal carcinomas in Gorlin syndrome. JAMA Dermatol 2013; 149(5):639–641.

36. van Loo E, Mosterd K, Krekels GA, et al: Surgical excision versus Mohs’ micrographic surgery for basal cell carcinoma of the face: a randomised clinical trial with 10 year follow-up.

Eur J Cancer 2014; 50(17):3011–3020.

37. Pandeya N, Purdie DM, Green A, Williams G: Repeated occurrence of basal cell carcinoma of the skin and multifailure survival analysis: follow-up data from the Nambour Skin Cancer Prevention Trial. Am J Epidemiol 2005; 161(8):748–754.

38. Maciel PC, Veiga-Filho J, Carvalho MP, Fonseca FE, Ferreira LM, Veiga DF: Quality of life and self-esteem in patients submitted to surgical treatment of skin carcinomas: long-term results. An Bras Dermatol 2014; 89(4):594–598.

• February 2022

Journal Club

THE CHRONICLE of SKIN & ALLERGY

Research of Note

Diagnostic Quiz

COVID -19 RISK HIGHER IN AD PATIENTS

R

Photo courtesy of Wikimedia Commons

esearchers conducted a large cohort case-control study to evaluate the risk of Covid19 infection in patients with atopic dermatitis (AD). Using data from the U.S. National Institutes of Health (NIH) All of Us cohort, the investigators analyzed the association between AD and Covid-19 in 11,752 AD cases and 47,008 matched controls.

They found that AD patients were more likely to have a Covid-19 diagnosis (4.2% vs. 2.8%; p<0.001), and AD remained significantly associated with Covid-19 (odds ratio, 1.29; p<0.001) after adjusting for demographic factors and comorbidities using a multivariate analysis.

R Fan, AC Leasure, W Damsky, JM Cohen: Association between atopic dermatitis and COVID-19 infection: A case-control study in the All of Us research program, in JAAD International (March 2022; 6:77-81)..

A. Atopic dermatitis B. Seborrheic dermatitis C. Psoriasis D. Contact dermatitis

HS RAISES RISK OF COMPLICATIONS DURING PREGNANCY

R

esearchers conducted a retrospective cohort analysis comparing the risk of adverse pregnancy and maternal outcomes among women with and without hidradenitis suppurativa (HS). They also evaluated the influence of comorbid conditions. Compared to control pregnancies (n=64,218), HS pregnancies (n=1,862) had a higher risk of spontaneous abortion (15.5% vs. 11.3%), preterm birth (9.1% vs. 6.7%), gestational diabetes mellitus (11.6% vs. 8.4%), gestational hypertension (6.1% vs. 4.4%), preeclampsia (6.6% vs. 3.8%), and cesarean section (32.4% vs. 27.1%).

After investigators adjusted for comorbidities, the relative risk of some pregnancy and maternal outcomes was reduced. In the fully adjusted model, HS pregnancies were independently associated with spontaneous abortion (odds ratio, 1.20; 95% CI, 1.04-1.38), gestational diabetes mellitus (odds ratio, 1.26; 95% CI, 1.07-1.48), and cesarean section (odds ratio, 1.09; 95% CI, 1.004-1.17).

THE EDITORS invite your participation in this regular feature of the journal.

Please send all images and correspondence to: Medical Editor, The Chronicle of Skin & Allergy 555 Burnhamthorpe Road, Suite 306, Toronto, Ont. M9C 2Y3.

Telephone: (416) 916-2476 E-mail: health@chronicle.org

L Fitzpatrick, J Hsiao, R Tannenbaum, A Strunk, A Garg: Adverse pregnancy and maternal outcomes in women with hidradenitis suppurativa, in Journal of the American Academy of Dermatology (Jan. 2022; 86(1):46-54)

Correct answer A Atopic dermatitis

26

What THE LAY PRESS is saying about . . .

WIFE CIRCLES HUSBAND ’S MOLES OF CONCERN A 20-year-old woman was worried when new moles started appearing on her husband’s body. According to the site BuzzFeed (Jan. 05, 2022), she sent her husband to the dermatologist with spots of concern marked and circled so that the doctor wouldn’t miss them.

When her husband returned from the doctor, she was pleasantly surprised by what she saw: the dermatologist had responded to her notes, and written additional comments next to her notations. Most of the moles were of no concern but one was indeed early-stage skin cancer.

TWITTER CONNECTS CANUCKS EQUIPMENT MANAGER WITH WOMAN WHO SAVED HIS LIFE In late October, 2021, at the inaugural home game for the NHL’s expansion Seattle Kraken, spectator Nadia Popovici was seated behind Brian Hamilton, the assistant equipment manager for the Vancouver Canucks. During the game, she tried to get his attention for a reason that went beyond the action on the ice. Hamilton told CTVNews (Jan. 2, 2022) that Popovici held her phone to the glass with a message that said that the mole on the back of his neck was cancer. He later went to the doctor and within a week, the mole, which turned out to be Type II malignant melanoma, was removed. Popovici, who had spent time volunteering in hospitals and is about to enter medical school, had saved his life. “She extended my life,” Hamilton said.

“The words out of the doctor’s mouth were if I ignored that for four to five years, I wouldn’t be here.”

JADA PINKETT SMITH TALKS ABOUT ALOPECIA Actress and “Red Table Talk” host Jada Pinkett Smith is making the best of her hair loss. Pinkett Smith first went public about her battle with alopecia in 2018 and has since been sharing updates with fans through social media.

A short article by CNN.com (Dec. 29, 2021) reported on a video the actress shared on her verified Instagram account. The video showed her closely shaved hair and a new line that looks like a scar on her scalp. She also said that she decided to talk about the line on her scalp so that people won’t think she’s had brain surgery.

OBESITY APPEARS TO INCREASE SUNBURN DIAGNOSIS A recent study published in the Journal of Investigative Dermatology (Nov. 26, 2021) found that obesity is associated with sunburn diagnosis, with increasing effect estimates found for increasing body mass index (BMI). The researchers stated that a positive association between obesity and objectively determined sunburn supports the theory that sunburn may explain some of the increased risk of melanoma among patients with obesity. They also said that other mechanisms, particularly biologic, may contribute to these skin cancer risks as well. While the study may be a stepping stone to researching the connection between skin cancer and obesity, it had some limitations-weight and height were self-reported, race and ethnicity data were unavailable, and the study only included insured individuals.

Indications: Seasonal Allergic Rhinitis BLEXTEN® (bilastine) is indicated for the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) in patients 4 years of age and older with a body weight of at least 16 kg.

Chronic Spontaneous Urticaria BLEXTEN® (bilastine) is indicated for the relief of the symptoms associated with chronic spontaneous urticaria (CSU) (e.g. pruritus and hives), in patients 4 years of age and older with a body weight of at least 16 kg.

Contraindication: • History of QT prolongation and/or torsade de pointes, including congenital long QT syndromes Relevant warnings and precautions: • QTc interval prolongation, which may increase the risk of torsade de pointes • Use with caution in patients with a history of cardiac arrhythmias; hypokalemia, hypomagnesaemia; significant bradycardia; family history of sudden cardiac death; concomitant use of other QT/QTc-prolonging drugs

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bilastine tablets 20 mg

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MILLION PATIENTS WORLDWIDE

PRESCRIPTION ANTIHISTAMINE COVERED BY MOST PRIVATE INSURANCE PLANS • P-glycoprotein inhibitors may increase plasma levels of BLEXTEN® in patients with moderate or severe renal impairment; co-administration should be avoided • BLEXTEN® should be avoided during pregnancy unless advised otherwise by a physician • A study was performed to assess the effects of BLEXTEN® and bilastine 40 mg on real time driving performance compared to placebo.Bilastine did not affect driving performance differently than placebo following day one or after one week of treatment.

However, patients should be informed that very rarely some people experience drowsiness, which may affect their ability to drive or use machines.

For more information: Please consult the product monograph at https://www.miravohealthcare.com/wp-content/uploads/2021/08/ Blexten-PM-ENG-Aug2021.pdf for important information relating to adverse reactions, drug interactions, and dosing information which have not been discussed in this piece. The product monograph is also available by calling 1-866-391-4503.

As of August 31, 2021, the estimate from internal data of patient exposure is based on units sold of the defined daily dose of 20 mg bilastine and the mean treatment duration of 3 weeks.

Reference: 1. Blexten® Product Monograph. Aralez Pharmaceuticals Canada Inc. 2021.

bilastine tablets 20 mg Aralez Pharmaceuticals Canada Inc.* 6733 Mississauga Road, Suite 800 Mississauga, Ontario L5N 6J5 *d/b/a Miravo Healthcare

© 2022. BLEXTEN is a registered trademark of FAES used under license by Aralez Pharmaceuticals Canada Inc.

In the IMMERGE study, patients on SKYRIZI achieved non-inferiority and superiority vs. secukinumab for percentage of patients achieving PASI 90 at Week 16 and Week 52, respectively (SKYRIZI: 73.8% [n=121/164] and 86.6% [n=142/164] vs. secukinumab: 65.6% [n=107/163] and 57.1% [n=93/163] at Weeks 16 and 52, respectively) (treatment difference at Week 16: 8.2% [96.25% CI: -2.2, 18.6]; at Week 52: 29.8% [95% CI: 20.8, 38.8; p<0.001]; co-primary endpoints).1*

SKYRIZI demonstrated superior skin clearance 1,2 (PASI 100) vs. secukinumab at Week 52 The percentage of patients achieving PASI 100 with SKYRIZI was 65.9% vs. 39.9% with secukinumab at Week 52 (treatment difference: 26.2%, 95% CI: 15.9, 36.5; p<0.001; SKYRIZI: n=164; secukinumab: n=163; first-ranked secondary endpoint).

SKYRIZI (risankizumab injection) is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Clinical use: Efficacy and safety in pediatric population (<18 years of age) have not been evaluated.

Limited data available for geriatrics (≥65 years of age).

Relevant warnings and precautions: • Infections including tuberculosis • Vaccinations • Hypersensitivity • Pregnant or nursing women • Women of childbearing potential

For more information: Please consult the Product Monograph at www.abbvie.ca/content/dam/ abbvie-dotcom/ca/en/documents/products/SKYRIZI_PM_EN.pdf for important information relating to adverse reactions, drug interactions, and dosing information which have not been discussed in this piece.

The Product Monograph is also available by calling us at 1-888-704-8271.

PASI: Psoriasis Area and Severity Index; CI: Confidence Interval. * IMMERGE was a phase 3, international, multicentre, randomized, open-label, efficacy assessor-blinded, active-comparator study of up to 88 weeks total duration. The study included a 30-day screening period, and eligible patients (n=327) were randomized in a 1:1 ratio (SKYRIZI: n=164; secukinumab: n=163) via a centralized Interactive Response Technology system to open-label treatment with risankizumab or secukinumab for up to 64 weeks. Risankizumab was administered as two subcutaneous (SC) injections of 75 mg (150 mg total) at Weeks 0, 4, and every 12 weeks thereafter until the last dose at Week 40, except for patients in France who received additional doses at Weeks 52 and 64 to allow for continuous treatment until it was commercially available for patients in France. Secukinumab was administered as two SC injections of 150 mg (300 mg total) at Weeks 0, 1, 2, 3, 4, and every 4 weeks thereafter until the last dose at Week 48. The non-inferiority margin for PASI 90 at Week 16 was 12%.

References: 1. Warren RB, et al. Efficacy and safety of risankizumab vs. secukinumab in patients with moderate-to-severe plaque psoriasis (IMMerge): Results from a phase 3, randomised, open-label, efficacy assessor-blinded clinical trial. Br J Dermatol 2020;doi:10.1111/bjd.19341. 2. Papp K, et al. Canadian guidelines for the management of plaque psoriasis. 1st ed. June 2009. 3. SKYRIZI Product Monograph.

AbbVie Corporation. Available at: www.abbvie.ca/content/dam/abbvie-dotcom/ca/en/documents/products/SKYRIZI_PM_EN.pdf.

© AbbVie Corporation Printed in Canada CA-SKZD-210053A – October 2021

abbvie.ca 1-888-703-3006