The Chronicle of Skin & Allergy - October/November 2023

Contact allergens

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

n

Nickel remains the number one contact O ./N . 2023 allergen CT

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n Aluminum, the

New AD Tx options

American Contact Dermatitis Society’s Allergen of the Year in 2022, is present in Hep A, Hep B, HPV, and DTaP vaccines

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

by JOHN EVANS, Senior Editor, The Chronicle

N

◼ Dupilumab approved for pediatric patients over 6 months of age

see page 4

Psoriasis research

Advances in Txs for psoriasis n New topicals an option for patients who may be needle-phobic

by LOUISE GAGNON, Correspondent, The Chronicle

T

he ability of roflumilast to offer efficacy as a foam, oral forms of IL inhibitors under investigation, long-term data on the tyrosine kinase 2 (TYK2) inhibitor deucravacitinib, and data on the ability of spesolimab to prevent flares in generalized pustular psoriasis (GPP) are among the recent developments in psoriasis.

A versatile topical for plaque PsO The 0.3% foam formulation of the

phosphodiesterase-4 inhibitor roflumilast demonstrated efficacy in a study to treat the scalp and other hair-bearing areas of the body. It provided better efficacy than vehicle as measured by various outcomes including Body-Investigator Global Dr. Irina Assessment and Turchin Scalp-Investigator Global Assessment. The foam was also found to be well-tolerated.

“Because it is non-steroidal, there is not a concern about local adverse events,” said Dr. Irina Turchin, Assistant Professor in the Division of Clinical Dermatology & Cutaneous Science, Department of Medicine, Dalhousie University in Halifax and Memorial University in St. John’s, N.L., and a dermatology consultant for Horizon Health Network in Fredericton, N.B. “There is no irritation when it is used in the skin folds. It is very well-tolerated. The other thing that we have seen in our patients is the reduction in pruritus.”

Dr. Ashley O’Toole, a dermatolo-

ickel remains the king of contact allergens, Canadian regulations may have stemmed the rise of methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI), and there are increasing rates of sensitivity to hydroperoxides of linalool and limonene.

These were some of the findings from a recent summary of patch test results from the North American Contact Dermatitis Group (NACDG) (Dermatitis March-April 2023; 34(2):90-104) presented by Dr. Joel DeKoven during a webinar in April 2023. Dr. Dekoven was lead author on the paper.

Toronto-based Dr. DeKoven, a consultant dermatologist, Professor in the Department Dr. Joel DeKoven of Medicine at the University of Toronto and President of the NACDG, presented the findings at

Please turn to New Tx page 11

Wound care

Diabetic foot ulcers in Indigenous populations n Limb amputations three times more common in Northern Ontario

by KRISHNA RAU, Correspondent, The Chronicle

I

ndigenous communities have extremely high rates of type 2 diabetes and foot amputations, Dr. Gary Sibbald reported during a presentation at the second annual Indigenous Skin Spectrum Summit. More testing and foot examinations are needed in these communities.

Dr. Sibbald is a Professor of Please turn to ISSS page 8

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

Please turn to Contact page 18

For moderate to severe plaque psoriasis patients

PUT ON NOTICE B IMZELX® IS AVAIL ABLE FOR THEM

Pr

BIMZELX® (bimekizumab injection) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

Please consult the Product Monograph at https://ucb-canada.ca/sites/default/files/2022-03/bimekizumab-pm-ennon-nds_14%20Feb%202022.pdf for important information relating to contraindications, warnings and precautions, adverse reactions, drug interactions, dosing information, and conditions of clinical use which have not been discussed in this piece. The Product Monograph is also available by calling 1-866-709-8444.

Reference: 1. BIMZELX Product Monograph. UCB Canada Inc. February 14, 2022.

BIMZELX, UCB, and the UCB logo are registered trademarks of the UCB Group of Companies. © 2023 UCB Canada Inc. All rights reserved.

Oct./Nov. 2023 • 3

Vol. 29, No. 7

THE CHRONICLE of SKI N & A LLER GY

A Message from the Medical Editor

TOP of the MONTH

Vender on Psoriasis: Bimekizumab in biologic DMARD-naïve patients with active PsA: 52-week efficacy and safety Also, researchers assessed outcomes using patient reports in the validated Psoriasis Symptoms and Signs Diary through 12 weeks . . 10 CDA Debate: Should dermatologists counsel acne patients reagarding their diet?

Drs. Jessica Asgarpour and Tiffany Chen debate the pros and cons of counselling acne patients on their diet . . . . . . . . . . . . . . . . . . . . . . . . 14 Chronicle Postgraduate Educational Supplement In this issue’s postgraduate educational supplement, investigators completed a retrospective review of 18 patients diagnosed with locally advanced cutaneous squamous cell cancers (laCSCC) who were treated with cetuximab. Researchers found that cetuximab plus radiotherapy represents an active and tolerable treatment option for laCSCC including patients with contraindications for checkpoint inhibitor therapy . .21

Image from adobe.stock.com

More options for treating AD Canadian dermatologists discuss the latest options for the treatment of AD, including a new therapy approved for patients under six months of age. . . . . . . . . . . . . . . .4

Research

Atopic dermatitis linked to IBD From the News Resources of The Chronicle

New research shows that adults with atopic dermatitis (AD) have a 34% increased risk of developing new-onset inflammatory bowel disease (IBD) compared to individuals who do not have AD. That’s according to the results of a study from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, published in JAMA Dermatology.

In children that risk is even greater, with a 44% increased risk of developing IBD. In general, the researchers noted the severity of AD experienced by patients—whether they were adults or children—increased the risk of developing IBD. While not the first to examine connections between AD and IBD, this study evaluated more than one million participants (409,431 chil-

Oct/Nov 2023 • Vol. 29 No. 7 Published eight times per year by the proprietor, Chronicle Information Resources Ltd., with offices at 1460 The Queensway, Suite 212, Etobicoke, Ont. M8Z 1S4 Canada. Telephone: (416) 916-2476; Facs. (416) 352-6199.

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dren under one year of age to 18 years and 625,083 adults) with AD. It also differentiated between ulcerative colitis and Crohn’s disease.

“AD and IBD can cause changes in the microbiome, chronic inflammation, and the dysfunction in the skin and gut barrier respectively,” said senior author Dr. Joel Gelfand.

“There are also specific cytokines, certain kinds of proteins, that play a role in immune system activity and that seem to be related to AD and IBD. For example, we think dysfunction of types of T cells common to both AD and IBD, could be the culprits. Those need to be explored further to uncover both what’s happening at a microscopic level and what proteins or structures could be targeted to treat one or both conditions,” said Dr. Gelfand

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I

n this issue of THE CHRONICLE OF SKIN & ALLERGY, our reporters again highlight many of the advances in medical dermatology related to atopic eczema and psoriasis. The commentary from many Canadian experts relating to improve treatments for our patients is extremely positive on several fronts. Two other articles I would like to draw your attention to include an update on the top 10 contact allergens

by Dr. Joel DeKoven as well as Dr. Gary Sibbald’s review of the impact of diabetic foot ulcers and rate of amputation in Canada’s Indigenous population (both articles begin on page 1).

A very impactful, and a mustread, is the resident’s essay this month by Dr. Fabian Rodriguez-Bolalnos entitled “Hair love” (see page 19). In my opinion, his essay is both moving and educational not only for those of us who practice dermatology but for everyone involved in delivering healthcare.

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

Medical Editor

Editor, Cosmetic Dermatology

Wayne Gulliver, MD, FRCPC

Sheldon V. Pollack, 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

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 Assistant Editor Jeremy Visser Client Engagment Cristela Tello Ruiz

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Contacting The Chronicle

“Both hospital-based and community dermatologists were so excited to see the approval of spesolimab for generalized pustular psoriasis..prior to its availability, there was a huge unmet need for treatment for these patients.”

Dr. Ashley O’Toole, dermatologist, Peterborough, Ont. (see page 1)

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4 • Oct./Nov. 2023

THE CHRONICLE of SKIN & ALLERGY

Atopic dermatitis

Image from adobe.stock.com

More options available for treating AD ◼ Dupilumab now approved for use in patients as young as six months of age

by LOUISE GAGNON, Correspondent, The Chronicle

T

he approval of the biologic dupilumab to treat patients with atopic dermatitis (AD) as young as six months of age , the current availability of the biologic tralokinumab and the future availability of lebrikizumab, the approval of Janus kinase (JAK) inhibitors, new data on the safety of phototherapy to treat AD and on crisaborole as maintenance therapy, are all developments that are advancing treatment for patients with AD, according to Canadian dermatologists.

Dupilumab for patients six months and older The biologic dupilumab, which has been available for five years as an AD

treatment, now has approval in Canada for management of AD in patients who are as young as six months of age.

“It is reaching a cohort that we knew needed treatment, but was receiving limited Dr. Renée options,” said Dr. Beach Renée Beach, dermatologist and founder of DermAtelier on Avenue in Toronto. “I think and hope that it will mean better control of atopy for a group Dr. Loretta that is even more Fiorillo vulnerable than most patients.”

Dr. Loretta Fiorillo, Director, Division of Pediatric Dermatology, University of Alberta in Edmonton, agreed this expanded use of Dr. Joseph Lam dupilumab is a great benefit. “It’s extremely significant for the younger

population because atopic dermatitis is very, very prevalent in younger children,” said Dr. Fiorillo. “It’s extremely useful to have a drug now that we can use in babies six months and older.”

Still another biologic option for AD is the IL-13 inhibitor tralokinumab. An additional biologic that may make its way into the Canadian AD toolbox is also an IL-13 inhibitor, lebrikizumab.

“It is amazing [to have two biologics and another on the way],” said Dr. Beach. “For so long, this condition had so few options. I liken it to being in a desert and getting a drink of water, be it methotrexate or azathioprine or the other more traditional, non-specific immune modifiers. Now though, we are sitting at a restaurant, able to assess a menu of options and make an educated decision for targeted immune therapy to help a patient’s atopic dermatitis into remission.”

JAK inhibitors represent new oral treatments The approvals and availability of the systemic JAK inhibitors upadacitinib and abrocitinib signal new valuable tools to manage AD, observed Dr. Please turn to AD page 7

SUN Dermatology

CHANGING THE FACE OF ACNE CARE

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IN MODERATE TO SEVERE PLAQUE PSORIASIS

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COMPLETE CLEARANCE

HELP HER REACH IT

HELP HER KEEP IT

† Fictitious patient. May not be representative of all patients.

Indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

Complete clearance (PASI 100 response) was achieved at 12 weeks of treatment in 44% of SILIQ® patients (n=272) vs. ustekinumab 22% (n=65) (p<0.05, 1° endpoint, AMAGINE-2 study).1‡

CLINICAL USE: No dose adjustment is recommended in geriatric patients.

Not indicated in children <18 years of age.

CONTRAINDICATION: • Crohn’s disease MOST SERIOUS WARNINGS AND PRECAUTIONS: Suicidal ideation and behaviour: Suicidal ideation and behaviour, including completed suicides, have occurred in SILIQ patients. A causal association with SILIQ has not been established. Weigh the potential risk/benefit in patients with a history of depression and/or suicidal ideation or behaviour prior to prescribing. Refer patients with new or worsening suicidal ideation and behaviour to a mental health professional. Advise patients and caregivers to seek medical attention for manifestations of suicidal ideation or behaviour, new onset or worsening depression, anxiety, or other mood changes. Because of this risk, if an adequate response to SILIQ has not been achieved within 12 to 16 weeks, consider discontinuing therapy.

bauschhealth.ca PATIENT SUPPORT PROGRAM

For PASI 100 responders at Week 12, 72% of the patients who continued on SILIQ 210 mg Q2W maintained the response at Week 52.1‡

OTHER RELEVANT WARNINGS AND PRECAUTIONS: • Prescribers are to register in the SILIQ Patient Support Program before prescribing SILIQ, be educated on the appropriate use of SILIQ, and educate patients on benefits and risks of treatment, especially the risk of suicidal ideation and behaviour.

• Discontinue SILIQ if the patient develops Crohn’s disease while taking SILIQ. • SILIQ may increase risk of infections.

• Exercise caution when considering the use of SILIQ in patients with a chronic infection or a history of recurrent infection.

• Evaluate patients for tuberculosis (TB) prior to initiating SILIQ treatment. Do not administer SILIQ to patients with active TB. Initiate treatment for latent TB prior to administering SILIQ. Monitor SILIQ patients for signs and symptoms of active TB. • Live vaccines should not be given concurrently with SILIQ. Patients may receive inactivated or non-live vaccinations.

• Discontinue and initiate appropriate therapy if anaphylactic or other serious allergic reaction occurs.

• No adequate and well-controlled studies have been conducted in pregnant women.

• Caution in nursing women.

SILIQ® is a registered trademark of Bausch Health Companies Inc. or its affiliates.

Bausch Health, Canada Inc., 2150 St-Elzéar Blvd. West, Laval, Quebec H7L 4A8 © 2023 Bausch Health, Canada Inc. All rights reserved.

First and only biologic that selectively binds to and blocks IL-17 receptor A*

Oct./Nov. • 7

AD: Need to be mindful of morphological variations

READ MORE HERE:

At week 120, 61.1% of patients who received continuous SILIQ Q2W dosing were observed to achieve PASI 100.2§ The duration of the data presented here is beyond the duration of the data in the Product Monograph.

FOR MORE INFORMATION: Please consult the Product Monograph at https://pdf.hres.ca/dpd_pm/00051682.PDF for important information relating to adverse reactions, drug interactions, and dosing information that has not been discussed here. The Product Monograph is also available by calling 1-800-361-4261. ‡ AMAGINE-2 Study: A randomized, double-blind, active comparator trial in adult patients with moderate to severe plaque psoriasis, defined as a minimum body surface area of 10%, a PASI score ≥12, a static Physician’s Global Assessment score ≥3 on a severity scale of 0 to 5 in the overall assessment, and who were candidates for systemic therapy or phototherapy. Patients received either SILIQ (210 mg SC at Weeks 0, 1, and 2, followed by the same dose every two weeks through Week 12; n=612), ustekinumab (45 mg SC for patients ≤100 kg, or 90 mg SC for patients >100 kg at Weeks 0, 4, and 16 followed by the same dose every 12 weeks; n=300), or placebo (n=309).

The study included a phase during which patients originally randomized to receive SILIQ during the first 12 weeks were re-randomized to one of four SILIQ regimens at the Week 12 visit and placebo patients were crossed over to receive SILIQ 210 mg SC every two weeks. Patients receiving ustekinumab continued the same treatment until crossed over at Week 52 to SILIQ 210 mg SC every 2 weeks. § Open-label extension of AMAGINE-2 Study. Data presented are for patients who received continuous SILIQ 210 mg every 2 weeks from Week 3 through Week 120 (n=168).

REFERENCES: 1. SILIQ Product Monograph, Bausch Health, Canada Inc., June 2019.

2. Puig L, Lebwohl M, Bachelez H, et al. Long-term efficacy and safety of brodalumab in the treatment of psoriasis: 120-week results from the randomized, double-blind, placebo- and active comparator–controlled phase 3 AMAGINE-2 trial. Journal of the American Academy of Dermatology.

2020;82(2):352–9. * Comparative clinical significance unknown.

Continued from page 4 Beach. “I welcome them as additions to the arsenal of options against atopic dermatitis,” she said. “I am reassured based on the data, but still assess the risk-benefit in each patient I consider for this therapy. Monitoring patients with lab examinations including liver enzymes is my practice.”

The fact that JAK inhibitors such as upadacitinib are not injected is a plus, said Dr. Fiorillo. “It [upadacitinib] has several advantages over a biologic in the pediatric population,” said Dr. Fiorillo. “Number one, it is oral. There are many children, even adolescents, who do not want injections and who would rather take a pill.

As we treat the younger age group, oral administration becomes a major advantage. The second factor is that JAK inhibitors are very fast-acting. I had one patient who told me that she was doing better after the first dose of upadacitinib.”

The approval of upadacitinib and abrocitinib for patients 12 years and older is important, according to Dr. Joseph Lam, Clinical Associate Professor, Department of Pediatrics, Associate Member, Department of Dermatology and Skin Science, University of British Columbia, Vancouver. “I think these medications will be safe for the younger population,” said Dr. Lam. “Still, you need an open conversation with the family because of the worrisome list of side effects.”

Efficacy and safety of phototherapy and of crisaborole New research has underlined the safety of using ultraviolet B (UVB) phototherapy to treat AD with respect to long-term cancer risk.

One study involving 6,205 patients demonstrated the risks of skin cancer, non-melanoma skin cancer, and cutaneous melanoma did not increase among patients with AD who were treated with UVB phototherapy compared to those who did not receive it (J Am Acad Dermatol 2023 May 24;S0190-9622(23)00977-5).

“This Taiwanese study showed that the use of phototherapy does not increase the risk of skin cancer,” said Dr. Lam. “That is very useful to know.”

Another AD treatment that has demonstrated value as a maintenance therapy for less severe AD is crisaborole, noted Dr. Lam. In a study of nearly 500 patients, investigators aimed to evaluate the long-

term efficacy and safety of crisaborole.

They found the phosphodiesterase-4 inhibitor was effective and well tolerated for long-term maintenance treatment and flare reduction in adult and pediatric patients with mild-to-moderate AD (Am J Clin Dermatol 2023; 24(4):623–635).

“The study found a significant difference in the mean number of flarefree days for patients who received crisaborole versus vehicle,” said Dr. Lam. “There is some benefit to the use of it [crisaborole].”

Dr. Fiorillo noted the value of crisaborole, particularly where hand dermatitis is concerned. “I sometimes use it as an adjunct in a child who has very severe hand dermatitis and has deep scratch marks or fissures,” she said. “I will usually use a topical steroid first to heal the severity of the hand dermatitis, and as it improves, I will use crisaborole as a maintenance therapy.”

Ensuring diagnosis of AD in skin of colour Canadian dermatologists are wellequipped to identify AD in patients of all skin types, including deeper skin tones, according to Dr. Beach. “We are well-trained, and we need to continue to be mindful of morphological variations across skin tones,” said Dr. Beach. “An example would be seeing a more lichenoid variant of eczema in deeper skin tones and recognizing that ‘erythema’ can look violaceous or black in hue.”

Dr. Lam noted that not only is the phenotype across skin tones different, but that recent research has identified different endotypes involved in the presentation of AD in Asian patients compared to European-American patients and African-American patients (Allergol Int 2022 Jan;71(1):14-24). “What is happening underneath the skin is different,” said Dr. Lam. Non-psroprietary and brand names of therapies: dupilumab (Dupixent, Sanofi); tralokinumab (Adtralza, LEO Pharma); lebrikizumab (not approved in Canada); upadacitinib (Rinvoq, AbbVie); abrocitinib (Cibinqo, Pfizer); crisaborole (Eucrisa, Pfizer).

Clarification: An article in the September 2023 issue of The Chronicle of Skin & Allergy (Acne: Therapeutic Update 2023, page 4) misidentified the indication for topical clascoterone 1% cream.The heading on page 4, first column, should have read 'New therapy for acne. A corrected pdf version of the issue can be viewed at derm.city.

8 • Oct./Nov. 2023

THE CHRONICLE of SKIN & ALLERGY

ISSS: Programs available in wound care treatment Continued from page 1 medicine and public health at the University of Toronto, co-founder of Wounds Canada and the former director of the Wound Healing Clinic at Women’s College Hospital, Toronto. He is current director of the Project ECHO Ontario skin and wound care program.

Rates of diabetes are increasing across the world due to changes to diet, lifestyle, and way of life, said Dr. Sibbald. People are becoming much more susceptible to chronic diseases, especially type 2 diaDr. Gary betes or metabolic Sibbald syndrome.

But rates among Indigenous populations are growing at an even faster rate.

“Northern Ontario has three times the rate of diabetic foot amputations per 10,000 people than the Greater Toronto Area,” said Dr. Sibbald. “Long-term survival after major lower extremity amputation is low for all people, but even lower for the First Nations.”

High risk of diabetes Among Indigenous people, up to 80% of the population is at lifetime risk of diabetes. Among the general population, that figure is 50%, he said.

“We need to preserve Indigenous diets, lifestyles, cultures, and ways of life that can minimize the risk of these chronic diseases, including type 2 diabetes,” he said.

For remote Indigenous communities, Canada should be following the Diabetes Control Priorities for Developing/Low Resource Regions developed by Narayan V, et al, said Dr. Sibbald. There needs to be more effort toward glycemic control by using the hemoglobin A1C test, he said.

The test should show a patient's A1C levels at a seven or less. Average

blood sugar levels are at 17 or 18, which is far too high, he said. Blood pressure also needs to be controlled to help prevent foot ulcers.

In Canada, only 52% of people with diabetes receive an annual foot exam, he said. This is lower than in other Western countries. He recommended that physicians utilize the 60second foot screen to examine patients. This includes looking for a history of previous ulcer amputation, checking the pulse in the patient’s lower extremities and looking for deformities. About 8% of people have an aberrant dorsalis pedis pulse, so checking the posterior tibial is important, said Dr. Sibbald. Check for an active diabetic foot ulcer, he said.

Ingrown toenails or calluses could mean fissures, and fissures usually indicate neuropathy, he said.

Regular primary screening important Patients can use an infrared thermometer available online to monitor their foot care, he said. In random controlled trials, patients using the thermometer to measure five areas of their feet developed far fewer ulcers than those receiving standard care.

Dr. Sibbald also suggested checking cholesterol, drug use, smoking, and footwear as contributing factors in diabetes. The keys are prevention, regular primary care screening, patient's self-inspection, preventing recurrence by treating the cause and addressing the patient-centered concerns, and, perhaps, peer-led education programs.

The diabetic foot amputation sequence runs from diabetes to neuropathy, ulceration, perhaps vascular disease, infection, and amputation, he said.

A palpable pulse in the foot is roughly 80 mm of mercury or higher, and the ankle brachial pressure should be between 0.6 and 1.4, said Dr. Sibbald. Audible handheld

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Doppler can be done in a clinic, and in 80% of patients, it is possible to determine circulation without a vascular lab visit. If a physician can measure transcutaneous oxygen, it should be between 30 and 55 mm of mercury. The test is not affected by arterial calcification. It is a simple test that could indicate if a patient needs to be seen at a vascular lab, he said.

Dr. Sibbald recommended using the Levine technique in cases of infection. The first step is to clean the wound and examine for normal granulation, then rotate the swab through 360 degrees to extract fluid.

If it is relatively dry, it may not be infection. He also suggested using the NERDS (Non-healing, Exudate, Red friable tissue, Debris (Discoloration) and Smell) and STONEES (Size increasing, Temperature elevation, Os (probes to bone), New breakdown, Erythema/edema, Exudate and Smell) criteria. With both, if the patient shows any three of the signs, infection is indicated, he said. With NERDS, treat topically, and with STONEES, treat systemically.

For plantar pressure redistribution, the gold standard is a cast, he said. But a cast is expensive and may interfere with driving and be dangerous in winter. Cheaper de-

vices, such as a half shoe, can be extremely effective, he added.

Programs available to train clinicians in wound care Dr. Sibbald said there are programs available in the north that offer micro-credentials in wound care and treatment. The programs, run by educational institutions, government ministries, and healthcare organizations, allow physicians to take 30 hours of courses and can be done virtually. He said he is also involved in developing toolkits to help physicians in the north address diabetic foot care.

Bottom Line: Remote northern Indigenous communities have skyrocketing rates of type 2 diabetes and of foot amputations from diabetic ulcers. These communities need more testing for blood sugar levels and blood pressure. Patients with diabetes need regular foot exams for diabetic ulcers. Physicians should follow the 60-second foot screen and encourage patients to do more self-inspection. It’s important to follow established techniques such as Levine, NERDS and STONEES in cases of suspected infection.

THERAPEUTIC INDEX Bausch Health Siliq . . . . . . . . 6, 7

Pfizer Cibinqo. . . . . . 12-13, 11

Dermtek Pharma Reversa . . . . . . 28

Sun Pharma Corporate . . . . . . . . 5 Ilumya . . . 17, 16

Janssen Bioadvance. . . . . . . . 27 Tremfya . . . . . . . . 9

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Reference: TREMFYA®/TREMFYA ONE-PRESS® (guselkumab injection) Product Monograph. Janssen Inc. November 8, 2022.

The image depicted contains models and is being used for illustrative purposes only.

19 Green Belt Drive | Toronto, Ontario | M3C 1L9 | www.janssen.com/canada © 2023 Janssen Inc. | All trademarks used under licence. | CP-378319E

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

Speed of clinical improvement in the real-world setting from patient-reported Psoriasis Symptoms and Signs Diary: Secondary outcomes from the Psoriasis Study of Health Outcomes through 12 weeks This study set out to compare the speed of clinical improvement of approved biologics on the symptoms and signs of moderate to severe psoriasis assessed by patients using the validated Psoriasis Symptoms and Signs Diary (PSSD) through 12 weeks (J Eur Acad Dermatol Venereol 2023 May 5. doi: 10.1111/jdv.19161. Online ahead of print).

The researchers assessed the outcomes based on patient reports in the validated Psoriasis Symptoms and Signs Diary (PSSD) through 12 weeks.

Utilizing the PSSD seven-day recall period, patients assessed the symptoms (itch, skin tightness, burning, stinging, and pain) and signs (dryness, cracking, scaling, shedding/flaking, redness, and bleeding) of their psoriasis (0–10). Eligible patients (n=1,654) had comparable baseline PSSD scores. From Week 1, the anti-IL17A cohort achieved significantly larger score improvements in PSSD summary scores and a higher proportion of patients showed clinically meaningful improvement (CMI) compared to the other biologics cohort through 12 weeks, the researchers report. Lower PSSD scores were associated with a greater proportion of patients reporting their psoriasis as no longer impacting their quality-of-life (DLQI 0,1) and a high level of clinical response (PASI 100). They note that results also indicate a relationship between an early CMI in PSSD score at Week 2 and PASI 100 score at Week 12.

Results showed that treatment with anti-IL-17A biologics, particularly ixekizumab, resulted in rapid and sustained patient-reported improvements in psoriasis symptoms and signs compared to other biologics in a real-world setting.

The Psoriasis Study of Health Outcomes (PSoHO) is an international, prospective, non-interventional study that compares the effectiveness of anti-interleukin (IL)-17A biologics versus other biologics, together with pairwise comparisons of ixekizumab versus five individual biologics in patients with PsO. This is a very advanced international registry that compares IL-17 with other biologics to determine health outcomes. In addition to DLQI, PSSD score is an interesting measure that looks at psoriasis symptoms and signs according to the patient and not the physician. Although the DLQI can determine how a patient interacts with their social media or family environment, the Psoriasis Signs and Symptoms Diary allows patients to express the discomfort they may have directly in their skin and the signs they observe.

This way of measuring is different than what we are used to in terms of improvement of quality of life, but it looks at what the patient experiences on a day-to-day basis. It is certainly an important factor. In Australia, the guidelines determine that intractable itch is an indication for a biologic along with moderate to severe skin disease.

This itch factor has not been instituted in many other countries, if any, and Australia should be commended for recognizing the importance of this symptom. This study showed that IL-17s—because of their rapid improvement compared to other biologics— could be a benefit for those who suffer from many symptoms of psoriasis.

Bimekizumab in biologic DMARD-naïve patients with active PsA: 52-week efficacy and safety Bimekizumab (BKZ), a monoclonal IgG1 antibody targeting interleukin (IL)-17F and IL-17A, has shown remarkable efficacy in biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active psoriatic arthritis (PsA) at the 16-week mark. This study in Annals of the Rheumatic Diseases (doi:10.1136/ ard-2023-224431) provides insights into the long-term efficacy and safety of BKZ up to Week 52.

The BE OPTIMAL trial consisted of a 16-week double-blind, placebo-controlled phase followed by a 36week treatment-blind phase. Patients were randomized to receive subcutaneous BKZ 160 mg every four weeks, placebo with a switch to BKZ at Week 16, or adalimumab (ADA) 40 mg every two weeks. Efficacy outcomes were assessed using American College of Rheumatology (ACR) response criteria 20/50/70, Psoriasis Area and

Severity Index (PASI) 75/90/100 (for patients with baseline psoriasis affecting 3% body surface area), and minimal disease activity (MDA) with non-responder imputation.

The results revealed that BKZ maintained ACR 20/50/70, PASI 75/90/100, and MDA responses from Week 16 to Week 52, consistent with earlier findings.

Patients who switched to BKZ at Week 16 also exhibited improved efficacy, achieving similar results to those initially randomized to BKZ by Week 52.

In terms of safety, the majority of patients experienced at least one treatment-emergent adverse event (TEAE) during BKZ treatment, which was similar to the rate observed with ADA. Serious TEAEs occurred in a small percentage of BKZ-treated patients (6.6%), and there was one reported death (0.1%). Candida infections were more common in the BKZ group (7.7%) compared to ADA (0.7%), but all cases were localized and non-serious.

BKZ demonstrated sustained efficacy in biologicnaïve PsA patients from Week 16 to Week 52, with an acceptable safety profile. No new safety concerns emerged during the study, supporting the continued use of BKZ as a treatment option for PsA. At the time of this writing bimekizumab was not approved by the FDA in the United States but it is approved in Europe and in Canada for the treatment of moderate to severe psoriasis. It is also approved for the treatment of psoriatic arthritis in Europe, but not in Canada at this time. This important study shows that this interleukin 17 inhibitor is effective in treating psoriatic arthritis with responses as early as 16 weeks maintaining out to week 52.

This comparative study was done versus adalimumab, which is the standard of care for psoriatic arthritis for most rheumatologists. However, the difference in skin efficacy is very different from that of bimekizumab versus adalimumab. Adverse events are uncommon with most biologics however with bimekizumab candidiasis can be seen but cases are almost always localized, non-serious, and easily treated. It is uncommon to stop therapy due to oral candidiasis associated with bimekizumab. Further studies using bimekizumab in biological experienced patients are being done and results should be available shortly.

We invite your comments and questions about this feature at www.derm.city. Dr. Ron Vender is a certified dermatologist with more than 30 years of clinical practice experience and over 100 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

Oct./Nov. 2023 • 11

THE CHRONICLE of SKIN & ALLERGY

New Tx: New biologic therapy for GPP fills unmet need Continued from page 1 gist at Skin Centre for Dermatology in Peterborough, Ont., a sub-investigator in clinical trials, and Adjunct Professor at Queens University in Kingston, Ont., agreed about the flexibility of roflumilast.

“Roflumilast is a long-awaited new topical for psoriasis that truly is a ‘one-size fits all’ topical treatment for patients,” said Dr. O’Toole. “This non-steroidal treatment introduces a novel mechanism of action for the topical management of psoriasis, and it serves to meet an unmet need for patients looking for an effective, versatile, simple, once-daily topical for psoriasis. It has been extremely Dr. Ashley well-received by patients in my clinic so far.”

O’Toole Dr. O’Toole added that it is encouraging to see the accumulating evidence of roflumilast’s efficacy in scalp psoriasis. “I am excited to see the growing body of evidence for the management of scalp psoriasis, which is a difficult-to-treat area,” said Dr. O’Toole. “In my experience, patients in clinical trials with scalp disease found it an effective and pleasing option.”

Spesolimab for GPP Recent data demonstrated that high-dose spesolimab Dr. Ron was superior to placebo in preventing GPP flares, with an Vender 84% reduction in the risk of flare development over 48 weeks and no flares observed after week four.

“Both hospital-based and community dermatologists were so excited to see the approval of spesolimab for generalized pustular psoriasis,” said Dr. O’Toole. “Prior to its availability, there was a huge unmet need for treatment for these patients. Although thankfully it is rare, GPP is an extremely difficult disease to manage and has severe physical and psychosocial implications for patients.”

Dr. O’Toole noted that she would use this therapy for a first presentation of GPP or for flare management and added that she looks forward to the emergence of data supporting the potential use of the biologic as a maintenance therapy.

Important safety information for CIBINQO Clinical use Can be used with or without medicated topical therapies for atopic dermatitis.

Limitations of use: use in combination with other JAK inhibitors, biologic immunomodulators, or potent immunosuppressants, such as methotrexate and cyclosporine, has not been studied and is not recommended.

Most serious warnings and precautions Serious infections: patients may be at increased risk for developing serious bacterial, fungal, viral and opportunistic infections that may lead to hospitalization or death; more frequently reported serious infections were predominately viral. If a serious infection develops, interrupt treatment until the infection is controlled. Risks and benefits of treatment should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Monitor for signs and symptoms of infection during and after treatment, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Malignancies: lymphoma and other malignancies were observed in patients taking JAK inhibitors to treat inflammatory conditions and were more frequently observed in patients with rheumatoid arthritis (RA) during a clinical trial with another JAK inhibitor versus TNF inhibitors.

Thrombosis: including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients taking JAK inhibitors to treat inflammatory conditions. Many of these events were serious; some resulted in death. Consider risks and benefits prior to treating

Dr. Ron Vender, a dermatologist in Hamilton, and Director of Dermatrials Research Inc. and Venderm Consulting, agreed about the impact of spesolimab on the management of GPP. “It [spesolimab] has good potency,” said Dr. Vender. “It shows promis-

am excited to see the growing body of evidence for the management of scalp psoriasis, which is a difficult-to-treat area”

“I

⏤Dr. Ashley O’Toole ing results in preventing flares in generalized pustular psoriasis.”

Patients who have GPP can have very severe disease that needs attention, stressed Dr. Turchin. “They can get really sick,” she said. “They often have systemic symptoms that may get to the point where they may need hospitalization and even be in the ICU. We now have this treatment [spesolimab] that is effective and really would be life-changing for many patients with this disease.”

Deucravacitinib and other TYK-2 inhibitors under development Data on extended use of deucravacitinib are highly positive, according to Dr. Vender.

There were significantly greater improvements in clearance of psoriasis with deucravacitinib Please turn to New Tx page 16

patients who may be at increased risk. In a clinical trial in patients ≥50 years of age with RA, a higher rate of all-cause mortality and thrombosis occurred in patients treated with another JAK inhibitor versus TNF inhibitors. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

Major adverse cardiovascular events (MACE): including non-fatal myocardial infarction, were observed more frequently in patients ≥50 years of age with RA during a clinical trial comparing another JAK inhibitor versus TNF inhibitors.

Other relevant warnings and precautions • Driving or operating machinery • Dose-dependent increase in blood lipid parameters, lipid monitoring and management • Hematological abnormalities • Use with potent immunosuppressants • Vaccination • Monitoring and laboratory tests • Fertility • Women of childbearing potential • Pregnancy and breastfeeding • Geriatrics For more information Consult the Product Monograph at http://pfizer.ca/pm/en/CIBINQO.pdf for important information regarding adverse reactions, drug interactions and dosing, which have not been discussed in this piece. The Product Monograph is also available by calling 1-800-463-6001.

References: 1. CIBINQO Product Monograph, Pfizer Canada ULC. 2. Bieber T, et al. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N Engl J Med 2021;384:1101–12.

† Results from a phase 3 randomized, double-blind, placebo-controlled, double-dummy, parallel group, multicentre study of CIBINQO in combination with background medicated topical therapies in

patients aged ≥18 years with moderate-to-severe atopic dermatitis who had an inadequate response to topical therapy or had received systemic therapy, excluding dupilumab. 2:2:2:1 randomization to CIBINQO 200 mg (n=226), CIBINQO 100 mg (n=238), dupilumab (n=243) or placebo (n=131) for 12 weeks. CIBINQO dose: 200 mg or 100 mg taken orally once daily. Dupilumab dose: 300 mg administered subcutaneously every other week after a loading dose of 600 mg at baseline. Matching placebo was dosed accordingly.

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CIBINQO is indicated for the treatment of patients 12 years and older with refractory moderate-to-severe atopic dermatitis, including the relief of pruritus, who have had an inadequate response to other systemic drugs (e.g., steroid or biologic), or for whom these treatments are not advisable.

A new, highly selective oral JAK1 inhibitor for moderate-to-severe AD*

Once-daily dosing Flexibility to start patients 12–64 years of age with a 100 or 200 mg dose based on individual goal of therapy and potential risk for adverse reactions. Exceeding 200 mg per day is not recommended.

Consult the Product Monograph for complete dosing and administration information.

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1-855-935-FLEX (3539) 0RQGD\ WR )ULGD\ DPȁ SP (67 7 Refer to the page in the bottom-right for additional safety information and for a web link to the Product Monograph discussing: • The most serious warnings and precautions regarding: serious infections; malignancies; thrombosis; major adverse cardiovascular events • Other relevant warnings and precautions regarding: driving and operating machinery; dose-dependent increase in blood lipid parameters, lipid monitoring and management; hematological abnormalities; use with other potent AD=atopic dermatitis; JAK1=Janus kinase 1. * Clinical significance unknown.

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Significantly more CIBINQO patients achieved ≥75% improvement in the EASI score from baseline (defined as EASI-75) at Week 12 vs. placebo † 1,2

Patients who achieved EASI-75 response (%)

CIBINQO 200 mg n=226

CIBINQO 100 mg n=238

dupilumab 300 mg n=243

placebo n=131

‡ p<0.0001 vs. placebo (multiplicity-controlled).

100 90 80 70

65.5

60 50 40 30

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58.1

30.0

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Rapid and significant itch relief was seen as early as Week 2 vs. placebo as measured

by PP-NRS4 (2º endpoint) † 1,2

Patients achieving a PP-NRS response with ≥4-point improvement from baseline

§ % 31.8

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CIBINQO 100 mg

CIBINQO 200 mg

vs. 26.4% vs. 13.8% dupilumab 300 mg

placebo

Significantly more CIBINQO 200 mg patients achieved PP-NRS4 vs. dupilumab as early as Day 4 and remained higher through Week 2 Proportion of PP-NRS4 responders with CIBINQO 100 mg was similar to dupilumab at Week 2 and over time. § p<0.001 vs. placebo (multiplicity-controlled). ¶ p<0.0001 vs. placebo (multiplicity-controlled). || p<0.0001 vs. dupilumab (multiplicity-controlled); statistical comparison between either CIBINQO dose and dupilumab was only performed on the proportion of patients achieving PP-NRS4 at Week 2.

Adapted from Product Monograph.

EASI-75=Eczema Area and Severity Index; PP-NRS=Peak Pruritis Numerical Rating Scale.

CIBINQO is only indicated in patients who have had an inadequate response to other systemic drugs or for whom these treatments are not advisable. Over 50% of patients in these studies did not have prior exposure to systemic therapy.

Contact your Pfizer representative to learn more about CIBINQO

See additional safety information and study parameters on page 11 xx

14 • Oct./Nov. 2023

THE CHRONICLE of SKIN & ALLERGY

CDA Debate: Shoul counsel their acne p Two dermatologists debate the science

D

uring the ‘Controversies in Dermatology’ panel at the Canadian Dermatology Association’s 2023 annual scientific sessions in Toronto, Drs. Jessica Asgarpour and Tiffany Chen tackled the question of whether dermatologists should be counselling their acne patients about diet. Their debate focused on the science regarding high-glycemic index (GI) diets and dairy.

PRO: Dr. Jessica Asgarpour is a dermatologist in practice in Toronto and a sub-Investigator for Probity Medical Research Inc. She is also a clinical associate at Women’s College Hospital in Toronto.

There is a plausible mechanism for dairy and high GI foods contributing to acne, and there is enough evidence in the literature to support counselling acne patients on their diet, Dr. Asgarpour said in her presentation.

She noted that two populations of Indigenous people in Papua New Guinea and Paraguay were studied in the 1990s and found to experience no acne.

“These Indigenous populations had no influence from Western culture,” she said. “They did not eat any high glycemic index foods or dairy. They just ate fish, meat, vegetables, and fruit. In good examinations of 1,300 subjects, not one of them had a pimple.”

At the time, Dr. Asgarpour said, researchers hypothesized this lack of acne might have a genetic basis. “Then more recently, researchers replicated these studies with the populations exposed to a Western diet, and subsequently [some of] these subjects do have acne. So, it is not just genetics [that contributed to the prior lack of acne].”

She noted that mechanistically, dairy and high GI foods both increase insulin and insulin-like growth factor (IGF)-1. These in turn inhibit the FOXO1 transcription factor, stimulating the mTORC1 pathway and causing hyperkeratinization and increased sebum production—both key contributors to acne.

“We also know that insulin-like growth factor 1 can stimulate the testes, the adrenal gland, as well as the ovaries to over-produce testosterone precursors as well as testosterone to bind to the androgen receptor. That ultimately, again, causes sebum production and causes that plug in the hair follicle unit,” she said.

For dairy, it is suspected that the proteins in milk—whey and casein— are insulinotropic, causing a spike in insulin. “Milk and dairy also can cause hormonal effects,” Dr. Asgarpour said. “Essentially, milk does have the precursors of testosterone.”

This potential hormonal impact of dairy may explain the bad reputation of skim milk, she said, as skim milk has less estrogen than whole milk, and estrogen is protective against acne.

To support her position, Dr. Asgarpour cited two literature reviews.

The first, (Int J Dermatol, June 2021; 60(6):672-685), included 53 articles related to a potential association between high GI foods, dairy, and acne.

Within that review, there were three randomized controlled trials (RCTs) examining the relationship between high GI foods and acne, and no RCTs related to dairy. Of the three RCTs, two supported a link between a high GI diet and acne. Both showed a clinically significant difference in acne symptoms, one also found a histological difference in sebaceous gland size, and one found a biochemical difference in IGF1 levels.

This review also included 42 observational studies, all but two of which supported a link between diet and acne.

The second, (JAAD Int March 29, 2022; 7:95-112), looked at 34 articles.

Of those 34, six were interventional trials and 28 were observational. Two of the interventional trials were also included in the first review. Three separate RCTs supported that high GI foods did worsen acne, and one RCT did not support the association.

“When you combine the two systematic reviews, out of the seven RCTs, five of them did support a high glycemic index diet causing acne,” Dr. Asgarpour said. “In all of the observational studies between the two systematic reviews, there were more than 75 per cent that supported an association between dairy, glycemic index food and acne.”

“We also know that diet can affect treatment,” Dr. Asgarpour said.

“When we have patients on doxycycline, we counsel not to take dairy because this can chelate the doxycycline and decrease its absorption.”

Oct./Nov. 2023 • 15

THE CHRONICLE of SKIN & ALLERGY

ld dermatologists patients about diet? behind diet as a contributor to acne

CON: Dr. Tiffany Chen is a lecturer at the University of Toronto and an associate dermatologist at Sunnybrook Health Sciences Centre.

The literature supporting a link between acne and the consumption of dairy or high-GI foods has several limitations. Until more robust studies are conducted, physicians would be doing a disservice to their acne patients if they generally recommended restricting these foods, said Dr. Tiffany Chen.

Dr. Chen noted that most current dermatology guidelines for acne management do not advocate any specific dietary treatment advice for patients with acne. “In its 2016 acne management guidelines The American Academy of Dermatology explicitly tackles this question head-on, and states in no uncertain terms that given the current data, no specific dietary changes are recommended,” she said.

A 2015 Cochrane Systematic Review also found insufficient evidence to support a low glycemic diet and concluded that further evidence is required, she said.

“So why is this association still a little half-baked? It comes down to the quality of the data,” said Dr. Chen. “There are very few interventional controlled studies. And in the systematic review that was published in the JAAD [Journal of the American Academy of Dermatology] last year, they specifically focused on glycemic index and dairy, because these are really the two components of a diet that have the most clearly delineated pathways in terms of how they affect hormones and acne pathogenesis.”

More than 80% of the studies included in the JAAD review were observational, with only five randomized control trials (RCTs) identified, Dr. Chen said. And none of the RCTs looked at dairy, and three of the RCTs were interpretations of the same patient data.

“Without having controlled experiments, where diet is manipulated, it's very difficult for us to draw direct cause and effect conclusions,” she said. “We also know that dietary reporting is very unreliable and very im-

precise. Very few studies have used more objective ways of recording diet, such as longitudinal food diaries or daily interviews. Instead, they relied on questionnaires or asked people to think back to what they had eaten weeks prior, months prior, or even years prior. Many studies asked adult women what they had eaten back in high school.”

The evidence linking dairy consumption and acne is the weakest, Dr. Chen said. Many studies do not support a link between overall dairy consumption and the skin condition, with the signal instead coming from skim milk in particular. “Perhaps there's a different hormonal composition of skim milk and lower levels of estrogen. But I think this still needs to be fully elucidated,” she said. She also noted that the iodine content of milk, which can vary based on production and handling could be a factor, as iodine is a known trigger for acne flares.

Other limitations of the existing research Dr. Chen identified are generalizability and misclassification bias.

Most of the participants in the observational studies were women, and most of the RCT participants were men, so conclusions drawn from these somewhat homogenous populations may not apply to the more diverse general population.

Much of the acne recorded in the existing studies was self-diagnosed by patients and not independently verified by a dermatologist or a physician, she said.

While nutrition has an important impact on skin and general health, especially when it comes to low glycemic index and low glycemic load, physicians should not support a connection between dairy and high GI foods and acne, said Dr. Chen.

Focusing on diet as an acne risk factor could draw attention away from other drivers of the condition, she said. As well, there is a chance that physicians validating the diet-acne connection without strong supporting evidence could inadvertently drive patients toward non-traditional sources of information and pseudoscience.

16 • Oct./Nov. 2023

New Tx: Oral therapy, deucravacitinib, good alternative for needle phobic patients Continued from page 11 compared to placebo and apremilast at 16 weeks, compared to apremilast at 24 weeks, with improvements being maintained through 52 weeks.

“We have long-term results [with deucravacitinib],” said Dr. Vender. “They [results] are very promising in terms of efficacy and safety. Also, there are other TYK2 inhibitors that are in development, with some starting Phase III clinical trials.”

According to Dr. O’Toole, deucravacitib’s oral formulation and the lack of required lab monitoring are advantages.

“I have found it an effective option and easy transition for patients who are needle-phobic or for those who prefer a simple once-daily pill,” said Dr. O’Toole.

“Personally, I have seen it work well for patients even with difficult to treat palmoplantar and scalp psoriasis. Patients and I really like how there is no required monitoring while on this medication as opposed to the traditional systemic options.”

Dr. Turchin noted deucravaticinib is a valuable addition to the psoriasis toolbox.

“It really complements our current armamentarium for psoriasis treatments,” said Dr. Turchin. “It is another oral medication. It was shown to have improved efficacy over apremilast.

It is safe for patients, and it offers the option of not having to have injections.”

Oral forms of biologic agents under study Oral agents, one targeting IL-17A

and the other targeting the IL-23 pathway, are in development and will represent alternatives to injectable biologics to manage psoriasis.

“This is an advantage for patients who are needle-phobic and for patients who desire an oral medication,” said Dr. O’Toole.

“Some patients want a quick-on, quick-off medication, as opposed to an injection that may be in their system for about eight to 12 weeks.”

Dr. Turchin echoed that substitutes for injectable biologic therapies for psoriasis hold much appeal.

“It is super interesting that we are now looking at this world [of oral agents for psoriasis],” said Dr. Turchin. “They are potentially game changers in psoriasis management. Injections are not for everyone. Having that flexibility and convenience of oral medications would be changing the landscape of psoriasis management for many patients.”

The future availability of biologic agents in oral form is a thrilling prospect for dermatologists treating psoriasis, noted Dr. Vender.

“This was the biggest news coming out of the World Congress of Dermatology in July,” said Dr. Vender, citing JNJ77242113, which demonstrated responses in PASI 75, 90, and 100 at 16 weeks. “There were extremely promising 16-week results in a Phase II study.”

In addition, Dr. Vender noted that proof-of-concept data with an IL-17A inhibitor demonstrated changes in PASI scores in adults with mild-to-moderate psoriasis after six weeks.

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ʈɃǼǺǼǽɃ[éÃɃT§ Ù ɉɃÊÙɃªåÝɃÝé ݪ ª Ùª ÝɃ à Ƀ ą¼ª å ÝɈɃ All rights reserved.

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Non-proprietary and brand names of therapies: roflumilast 0.3% (Zoryve, Arcutis); deucravacitinib (Sotyktu, BristolMyers Squibb); spesolimab (Spevigo, Boehringer Ingelheim); apremilast (Otezla, Amgen).

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18 • Oct./Nov. 2023

THE CHRONICLE of SKIN & ALLERGY

Contact allergens: Nickel sensitivity on the rise Continued from page 1 the GLIDE (Great Lakes Immunodermatology Exchange) 4.5 webinar.

The report data came from more than 4,000 patients tested at three Canadian and 10 U.S. centres between Jan. 1, 2019 and Dec. 31, 2020. A majority of the patients were female, and the mean age was 47.7 years. The patients were patch tested to a screening series of 80 allergens, with 70% being positive to one or more allergens.

The top 10 contact allergens in order were: 1. Nickel 2. Methylisothiazolinone 3. Fragrance mix 1 4. Hydroperoxides of linalool 5. Benzisothiazolinone 6. MCI/MI 7. Propolis 8. Myroxylon pereirae 9. Cobalt 10. Formaldehyde Nickel is once again the number one contact allergen, rising to 18.2% of patients sensitized from 16% in 2017-2018, Dr. DeKoven said, and “followed by methylisothiazolinone second [13.8%] and fragrance mix one [12.8%].”

There have been some notable movements in the rankings, he noted. Hydroperoxides of linalool moved to fourth place (11.1%) from fifth place in the earlier review (9.1%). “Benzothiazolinone has moved up to the fifth position [10.4%]; propolis [#7, 8.7%] has cracked the top 10 where it was not in there before,” Dr. DeKoven said.

“MCI/MI, fortunately, dropped down to nine per cent occupying the sixth position, he said. In

Acne Dx Quiz

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the 2017-2018 report, MCI/MI was the third-most common contact allergen, at 11.0%.

Formaldehyde was almost completely out of the top 10, now in 10th place (6.8%) from its earlier place in sixth position (7.4%).

The changes in the rankings of different preservatives are notable, Dr. DeKoven said.

“This is the first time we've seen any sort of drop in methylisothiazolinone since we started testing it in 2013/2014,” he said.

That decrease comes after the Government of Canada prohibited MI and MCI/MI in leave-on personal care products in 2018, and restricted its inclusion in rinse-off products, noted Dr. DeKoven.

In the Canada-specific data from 2019/2020, the positivity rate to MI was 12.7%, compared to 15.2% for the 2017/2018 data.

This decrease “was found to be statistically significant, and I think clinically significant as well,” he said. However, in the U.S., where MI and MCI/MI are not similarly regulated in personal care products, there was virtually no change in rates of positivity.

The state of preservatives Looking specifically at preservatives, in the 2019/2020 rankings methylisothiazolinone is followed by two other isothiazolinones—benzothiazolinone at 10.4% and MCI/MI at 9.0%.

“Then we have formaldehyde [6.8%] and quaternium-15 [3.8%] rounding out the top five [preservatives],” Dr. DeKoven said.

Sodium metal bisulfite is now sixth at 3.3%, which Dr. DeKoven said is a fairly high percentage.

“Parabens, which are always talked about by various companies, were extremely low at 0.4 per cent. So it's almost the most non-reactive preservative that we're testing to,” he said. “And phenoxyethanol, fortunately, was at 0.1 per cent. I say fortunately, because phenoxyethanol is being used more and more in place of other preservatives such as methylisothiazolinone.”

Dr. DeKoven said that physicians should remember that methylisothiazolinone is used in more than 1,500 personal care products in the U.S., including shampoos, conditioners, body washes, facial hand cleansers, slime, and sunscreen. Individuals buying sunscreens in the U.S. might develop reactions.

Also, methylisothiazolinone may be found in products that can come into contact with skin even though they are not personal care products, he said. These products can include water-based paints, glues, glue sticks, and children’s play slime.

Non-cosmetic personal care products such as waterless hand cleansers used by automotive technicians and machinists are not covered by Canada’s regulations on MI and MCI/MI, Dr. DeKoven said.

Other isothiazolinones are currently permitted in personal care products and cosmetics in Canada. “So far, they haven't been incorporated into cosmetics in Canada. But this is a potential pitfall in the future,” Dr. DeKoven said.

Other notable preservatives Dr. DeKoven mentioned are sulfites and persulfates. He noted that

sulfites are used in many products as antioxidants, preservatives, and bleaching agents. Sulfites are used in cosmetic products and hair dyes, but also in pharmaceutical preparations including antifungal creams, ophthalmic solutions, and injectable products such as local anesthetics containing epinephrine, he said.

Persulfates are still used in some hair bleaches, Dr. DeKoven said, but now some individuals are more likely to have more widespread allergic contact skin reactions through their use as shock treatments for hot tubs and swimming pools.

Fragrances The usual fragrance allergens, fragrance mix I and II and Balsam of Peru, remain prominent, Dr. DeKoven said.

“But hydroperoxides of linalool and limonene seem to be taking on increasing importance as possible contact allergens,” he said. The NACDG also tests reactions to Ylang-ylang, cinnamic aldehyde, and other essential oils.

“Major components of essential oils have become very popular,” Dr. DeKoven said. “Hydroperoxides of linalool have gone up to 11.1 per cent from 8.9 per cent and hydroperoxides of limonene are now at 3.5 per cent. “So we have those two in the top five of fragrance positivity in the NACDG findings.”

There is some controversy about hydroperoxides of linalool and limonene as contact allergens, Dr. DeKoven said, as no research has been able to isolate the hydroperoxides in actual products or on the surface of the skin of individuals using these products. It is not clear if the increasing rates of patch test positivity is an epiphenomenon unrelated to the presence of linalool or limonene in products or represent a genuine contact allergy, he said.

Other important allergens Aluminum was the American Contact Dermatitis Society’s Allergen of the Year in 2022, and is present in all Hepatitis A, HPV and DTaP vaccines in North America, and Hepatitis B vaccines in Canada, said Dr. DeKoven. The metal can result in local or generalized reactions that can last six months to years, he said. In a group of Swedish patients with local skin reactions, 85% were found to be patch test positive. “However, the good news is when [the Swedish patients] were re-patch tested five to nine years later, more than 75 per cent were negative.

So there is hope for children who get these reactions to aluminum in vaccines.”

The last allergen Dr. DeKoven mentioned was isobornyl acrylate, which was the allergen of the year in 2020. This agent was present in the plastic hub of glucose monitors and insulin pumps and migrated into the adhesive patients used to affix the devices to their skin, he said.

Isobornyl acrylate was added to the NACDG’s test series in 2023, Dr. DeKoven said, and it appears to be present in other skin-contacting consumer products. “There have been published reports about the [Apple] Air Pod Pro and Pro Max [earbuds] causing reactions,” he said.

Photo by: Dr. Thomas Brinkmeier via Wikimedia Commons

Correct answerC. Papulopustular

Oct./Nov. 2023 • 19

THE CHRONICLE of SKIN & ALLERGY

Perspectives/2023 The Chronicle of Skin & Allergy, in partnership with the Dermatology Industry Taskforce on Inclusion, Diversity and Equity (DiTiDE), sponsored a short essay competition for Canadian dermatology residents in 2022.

This contest was open to any resident enrolled in a dermatology training program at a Canadian medical school, with enrolment confirmed by their Program Director. Entrants submitted a 350- to 500-word composition reflecting on matters relating to inclusion, diversity, and equity. Eight winners were announced.

The selected essays will be published in each issue of The Chronicle during 2023.

Dr. Fabian Rodriguez-Bolanosi of Women’s College Hospital was recognized for his essay “Hair love”.

DiTiDE is a volunteer working group composed of Canadian life sciences managers and executives, dermatologists, patient association leaders, and allied parties committed to improving the patient experience and outcomes of under-represented skin types and underserved ethnicities through developing physician education and resources.

The 2nd annual short-essay competition for Canadian dermatology residents is now open for entries. Details are available at http://derm.city/for-residents.

Hair love DURING ONE OF MY ROTATIONS I HAD THE PRIVILEGE TO PARTICIPATE IN THE HAIR CLINIC. The majority of patients I met there were women dealing with hair loss. Hair loss can be devasting to patients, regardless of age, sex, or ethnicity. This experience taught me the importance of hair care and styling practices in the assessment of these patients. My lack of knowledge in the subject became very obvious from the beginning.

There is an Oscar-winning short film called “Hair Love”. This movie is centred around a family from the Black community and a little girl’s morning struggle to style her hair. Her father tried to help but he was scared of the challenge at first. This story resonated with me and my interactions with patients in that clinic. I was facing the same situation, I had to ask about hair care practices, something I had little knowledge of, especially regarding afro-textured hair.

One of the first patients I saw, who I will refer to as “Susan”, was coming to the clinic because of longstanding progressive hair loss. Susan, a Black woman in her early 50s, had previously met with other dermatologists and was told that the diagnosis was traction alopecia due to hair styling practices. She did not accept this to be true, given that she denied applying any traction to her hair. I, on the other hand, felt somewhat uneasy because I did not want to upset her with what could be perceived as impertinent questions, since I knew she had felt dismissed in the past.

When I asked her to remove her wig she was hesitant for a moment, but finally did, although I could sense her discomfort. I reassured her by telling her that she was in the right place and that I believed her. After our assessment was completed, the diagnosis of frontal fibrosing alopecia was made. I was asked to take some biopsies of the scalp for diagnostic confirmation.

While I was doing the procedures, Susan began to cry. I asked her if she was in pain but her response was that she was just very moved. She told me that it was the first time she felt heard and understood. In the end, we were able to provide some comfort and treatment. This encounter reminded me of the importance to be an active listener and to always have a curious mind.

When I got home from the clinic I started to read about hair styling practices and products. I also re-watched the movie “Hair Love” later that day.

There are two quotes from the movie that will stick with me that apply to medicine and life in general: “All it takes is some confidence and willingness to get started”, and “… you can make the journey with a little bit of work and a whole lot of love.”

Dr. Fabian Rodriguez-Bolanos completed his medical training and residency in dermatology in Costa Rica. He moved to Canada in 2016 to pursue a fellowship in advanced medical at Sunnybrook Hospital. He went on to retrain in dermatology at the University of Toronto. Currently he is a fellow in Mohs surgery at Women’s College Hospital in Toronto.

Support for Perspectives/2023 comes from Dermtek Pharma

Ensuring peoples’ well-being, from generation to generation, since 1985. Proud to be a family-owned, all-Canadian provider of dermatologic treatments, including Reversa™. Visit: www.dermtek.ca

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POSTGRADUATE EDUCATIONAL SUPPLEMENT Effectiveness and toxicity of cetuximab with concurrent RT in locally advanced cutaneous squamous cell skin cancer: A case series Mark Chang,1 Wolfram Samlowski,2,3,4,* and Raul Meoz2,3 University Medical Center of Southern Nevada, Las Vegas, Nev. 2 Comprehensive Cancer Centers of Nevada, Las Vegas, Nev.

1

Department of Internal Medicine, University of Nevada, Las Vegas (UNLV), Las Vegas, Nev. 4 Department of Internal Medicine, University of Nevada, Reno, Nev. * Corrresponding author: wsamlowski1@gmail.com

3

ABSTRACT Background: Treatment for locally advanced cutaneous squamous cell cancers (laCSCC) remains poorly defined. Most laCSCC tumours express high levels of epidermal growth factor receptors (EGFR). Cetuximab has activity in other EGFR expressing cancers and enhances the effectiveness of radiotherapy.

Methods: A retrospective review of institutional data identified 18 patients with laCSCC treated with cetuximab induction and concurrent radiotherapy. The loading dose of cetuximab was 400 mg/m² IV. Subsequent weekly doses of 250 mg/m² IV were infused throughout the period of radiation. The treatment doses ranged from 4500 to 7000 cGy, with a dose fraction of 200 to 250 cGy. Results: The objective response rate was 83.2% with 55.5% complete responses and 27.7% partial responses. Median progression-free survival was 21.6 months.

Progression-free survival was 61% at one year and 40% at two years. With longer follow-up, some patients developed a local recurrence (16.7%), distant metastases (11.1%) or a second primary cancer (16.3%). Cetuximab was well tolerated, with 68.4% patients experienced only mild acneiform skin rash or fatigue (Grade 1 or 2). Radiotherapy produced expected side effects (skin erythema, moist desquamation, mucositis).

Discussiom: Cetuximab plus radiotherapy represents an active and tolerable treatment option for laCSCC, including patients with contraindications for checkpoint inhibitor therapy.

INTRODUCTION asal cell and squamous cell (keratinocyte-derived) skin cancers are extremely common. It is estimated that the incidence is 3.3 to 5.4 million patients each year in the U.S.1 Due to their frequency, these cancers are not reportable in the NCI Surveillance, Epidemiology, and End Results (SEER) cancer registry. The incidence of keratinocyte-derived skin cancers has increased steadily over decades.1 Cutaneous squamous cell carcinoma (CSCC) represents approximately

B

20% of keratinocyte-derived skin cancers with an estimated 3 to 7% of CSCC patients developing recurrent invasive, regionally metastatic, or distant metastatic disease.2 Precise data concerning the incidence of keratinocytederived skin cancers, as well as the number of patients with more advanced stage disease and their outcome are not readily available. Karia estimated that in 2012 between 5604 to 12,572 CSCC patients developed nodal metastasis (~4% of estimated CSCC patients), resulting in 3,932 to 8,791 deaths (~1.5% mortality).3 In general, CSCC is predominantly a disease of elderly, fair skinned, heavily

Reprinted with permission ©2023 2023 Chang, 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 Chronicle.Academy develops bespoke structured learning programs for clinicians providing in-depth education to professionals in the healthcare industry.

sun-exposed Caucasians. Known risk factors for aggressive CSCC behaviour include tumour-related factors, such as head and neck primary sites, indistinct infiltrative borders of the lesion, rapid growth, tumor diameter >2 cm, invasion to >2.0 mm depth, and perineural extension.2 Host factors that are thought to predict more aggressive behavior include immunosuppression (e.g., organ transplantation, co-morbid conditions such as HIV, indolent lymphomas, and CLL) and tumour recurrence after previous surgery or radiotherapy.4 A number of staging systems have been defined to try to identify high risk individuals for more aggressive therapy and close monitoring.5 These include the American Joint Commission for Cancer (AJCC), Union for International Cancer Control (UICC) and the Brigham and Women’s Hospital staging systems.6,7 In the Brigham and Women’s staging system, T2b or T3 tumours appear to be highrisk and have a greater than 20% risk of lymph node involvement.8,9 Treatment options for laCSCC remain poorly defined. In the past, after failure of the initial resection, radiotherapy with or without added chemotherapy was frequently utilized.2,10,11 Since the average advanced CSCC patient is elderly, often with significant comorbid medical conditions, aggressive chemotherapy proved to be poorly tolerated.

The epidermal growth factor receptor (EGFR) is overexpressed in virtually all squamous cell skin cancers.12 As single agents, EGFR inhibitor monoclonal antibodies cetuximab and panitumumab have shown modest efficacy in phase II clinical trials in patients with metastatic cutaneous squamous-cell carcinoma, but durable responses have been uncommon.13-16 There is, however, an extensive literature concerning treatment squamous cell carcinoma of the head and neck (SCCHN) showing that the EGFR directed monoclonal antibody cetuximab plus radiotherapy has significant activity in this EGFR-driven cancer.

Since there was no established standard therapy for laCSCC patients in 2014, we began treating patients with bulky unresectable tumours with cetuximab and concurrent radiotherapy due to their potential synergy. This was reasonable because most of our patients had primary tumours involving head and neck primary sites. It should be noted, that while synergy of cetuximab plus radiotherapy has been demonstrated in SCCHN, formal evaluation of additive or synergistic benefit in CSCC has not yet been established versus radiotherapy alone. More recently, PD-1

directed monoclonal antibodies such as cemiplimab and pembrolizumab have received U.S. FDA approval for treatment of recurrent, unresectable, or metastatic CSCC.17,18 Unfortunately, even today, many patients are not candidates for treatment with PD-1 antibodies, due to organ transplants and underlying autoimmune conditions.19 Thus, additional treatment options are needed.

We performed a retrospective review of treatment outcome and toxicity in our patients who received concurrent cetuximab and radiotherapy to show an additional potentially effective treatment option for patients with laCSCC. The goal is also to provide data to inform the design of potential prospective clinical trials.

RESULTS Eighteen eligible patients were identified. Patient characteristics are shown (Table 1). Of the 18 patients identified, 16 were male (88.8%) and two were female (11.1%). The median age of patients was 76±11 years (SD) with an age range of 47 to 92 years. Seventeen patients were Caucasian and one was African American.

The median number of cetuximab doses was 8.0±3.7 (SD). The range was 4 to 18. The median cumulative dose of cetuximab was 4,750±2,872 mg. The median duration of cetuximab therapy was 1.9±6.2 months and ended with completion of radiotherapy.

The response rates for concurrent therapy with cetuximab plus radiation therapy included 10 patients (55.5%) who achieved an objective complete response (CR), four (27.7%) had a partial response at the treated site (Table 2).

Thus, the objective response rate (CR + PR) was 83.2%. An example of a typical response is shown, (Figure 1), demonstrating dramatic remission of bulky scalp tumours, including in-transit metastases, following concurrent treatment. This patient achieved a durable complete response after treatment, which continues at over two-year follow-up.

Median progression free survival was 21.6 months at a median follow-up of 18 months (range of 0.9–70 months) (Table 2). The apparent drop-off in the PFS graph after 21 months is due to the diminishing number of patients at risk for progression. Only one patient eventually relapsed within the treatment site (5.5%), two relapsed with marginal recurrences at the edge of the irradiated field (11.1%), three progressed in regional lymph nodes or in-transit metastases (16.6%). With longer follow-up,

POSTGRADUATE EDUCATIONAL SUPPLEMENT second primary cancer, non-Hodgkin’s lymphoma (NHL). This patient was able to restart Erbitux and radiotherapy after being treated with chemotherapy and achieving remission of her NHL. Only one patient was ever hospitalized for toxicity. This patient developed syncope due to dehydration while undergoing treatment but was able to continue regimen after recovery (Grade 3 toxicity).

DISCUSSION

Table 1: Patient characteristics and treatment. *Electron beam therapy. Abbreviations: UPN: unique patient number; M: male; F: female; C: Caucasian; AA: African American; B&W: Brigham and Womens; HTN: hypertension; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; DM: diabetes mellitus; Afib: atrial fibrillation; CKD: chronic kidney disease; UC: ulcerative colitis; CA: cancer; BPH: benign prostatic hypertrophy; DVT: deep venous thrombosis; TIA: transient ischemic attack; FX: radiotherapy fraction; RT: radiotherapy.

Table 2: Treatment outcome. Abbreviations: UPN: unique patient number; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; PFS: progression free survival; OS: overall survival; D-2nd primary: died of second primary cancer; A-NED: alive: no evidence of disease; D-other: died of non-cancer related causes; DOD: died of CSCC; NSCLC: non-small cell lung cancer; COPD: chronic obstructive pulmonary disease. two patients developed distant metastases (11.1%) and three patients developed aggressive 2nd primary neoplasms (16.6%) (one of these also had a concurrent regional recurrence of CSCC). Progression-free survival was 61% at one year and 40% at two years. (Figure 2).

Of the 18 patients in our study, eightg (44.4%) have died and 10 (55.5%) remain alive. Median overall survival was 60.7% months (range 3.5 to 62.5 months) (Figure 3). It should be noted that causes of death included comorbid age-related conditions in three patients (16.7%), one of whom also had concurrent progression of metastatic CSCC (5.5%), and three others developed aggressive secondary neoplasms (16.7%).

Cetuximab treatment was well tolerated. A total of five patients experi-

enced no significant cetuximab-related side effects (27.8%). A total of 12 patients (66.7%) developed mild acneiform skin rash controllable with oral and topical antibiotics, or fatigue (reaching at most Grade 1 or 2 toxicity). Radiotherapy produced typical side effects (skin erythema, moist desquamation, and oral mucositis). Three patients had no apparent side effects from radiotherapy (16.7%). Eight patients (44.4%) experienced mild radiation skin changes at the site of radiotherapy. More severe radiation toxicity was seen in other patients, with moist desquamation or other more severe skin toxicity (33.3%), oral cavity mucositis (33.3%), auditory canal inflammation (one patient). In several patients there were overlapping toxicities. Delayed wound healing at the

prior tumour site also was observed after regression of bulky tumours, although this was not precisely quantified. Seven patients required a brief treatment break lasting one to two weeks due to radiation dermatitis, moist desquamation, oral pain, and mucositis.

Patient number 16 was the only patient to have therapy interrupted more than once for a total of four treatment breaks.

Sixteen patients were able to complete planned treatment with minimal side effects. Two patients (Number 5 and 7) had their treatments discontinued early due to increasing skin toxicity.

Despite early discontinuation of therapy in patient 5, after resolution of radiation-induced skin changes, she was found to have achieved a complete response. Patient number 7 developed a

The majority of CSCC are small and localized, and thus are easily managed by dermatologists and surgeons, including Mohs microsurgical approaches. Highrisk CSCC are usually managed with aggressive surgical resection including peripheral and deep margin assessment.1 After resection of high-risk patients, adjuvant radiotherapy is frequently added, based on data from small case series. Unfortunately, no larger or randomized studies of adjuvant radiotherapy have been performed in CSCC, to date. There have been additional recent advances in treatment options for laCSCC such as the PD-1 antibodies pembrolizumab and cemiplimab.17,18 Additional treatment options are needed, especially for patients who have contraindications to checkpoint inhibitor treatment, such as those with solid organ transplants and autoimmune disease.

EGFR expression is present in normal keratinocytes and is expressed at increasingly higher levels in most patients with laCSCC and in lymph node metastases from CSCC.12,20-23 In keratinocyte cultures, epidermal growth factor (EGF) stimulates cell proliferation and suppresses markers of terminal differentiation.24 EGF stimulated proliferation can be blocked by EGFR antibodies and EGFR tyrosine kinase inhibitors.24 In vitro and murine models have shown that EGF activation of malignant epithelial cells induces signal transducer and activator of transcription 3 (STAT-3) activation, which drives carcinogenesis.25,26 EGFR blockade abrogates this response.25 Additional preclinical research has shown that EGFR blockade may inhibit telomerase activity in CSCC and thus suppress tumour cell survival.27 Thus, inhibition of the EGFR signalling pathway seemed to be an attractive treatment option in laCSCC. Cetuximab is an IgG1 monoclonal antibody, which binds with high affinity to human EGFR. This antibody blocks binding of EGF and other ligands to the EGFR. Cetuximab also induces internalization and downregulation of EGFR and induces enhanced antitumor immune responses via antibody dependent cell-mediated cytotoxicity.28 In vitro exposure of squamous cell carcinoma (SCC) cell lines derived from head and neck cancer patients to cetuximab inhibited proliferation in a time and dose-dependent manner.29 Since cetuximab causes tumour cells to accumulate in G1 of the cell

Figure 1: Example of treatment response. Patient 17 Pre-treatment scalp photograph (A). Patient 17 scalp photograph at 14 months post-treatment with cetuximab/RT (B).

Figure 3: Overall survival of all 18 patients.

Figure 1: Progression-free survival of all 18 patients. Censored patients are indicated by hash marks. cycle, radiosensitivity is enhanced.29 Numerous studies have evaluated cetuximab plus RT in SCCHN. Bonner, et al conducted a randomized trial comparing RT alone with RT plus cetuximab, in the treatment of stage III or IV nonmetastatic, measurable SCC of the oropharynx, hypopharynx, or larynx.30,31 The median duration of locoregional control (primary endpoint) was 24.4 months among patients treated with cetuximab plus RT and 14.9 months among those given RT alone. RT plus cetuximab significantly prolonged progression-free survival and overall survival. The five-year OS rate was 45.6% in the cetuximab plus RT group and 36.4% in the RT alone group.30,31 Despite similarities in histology, there has been only limited testing of EGFR antibodies such as cetuximab and panitumumab in CSCC. Published clinical trials of cetuximab and panitumumab in recurrent or refractory CSCC have shown only limited activity as monotherapy.13-16 Durable responses or remissions have proven elusive.13-16 The oral 1st generation EGFR inhibitor Erlotinib has demonstrated virtually no clinical activity in CSCC.32 There is only limited data published concerning the effectiveness of combining cetuximab with radiotherapy in laCSCC. Joseph, et al published eight patients with laCSCC treated with cetuximab plus concurrent radiotherapy.33 At 25 months follow-up, five patients remained in a complete remission.

One patient relapsed after a partial response. Two patients died (one of due to progression of disease, the other of an unrelated cause). Treatment in this group of patients proved well tolerated, with most toxicities ≤ grade 2, and no toxicities of grade 4/5 reported. Preneau reported a series of patients treated with cetuximab in combination with either radiotherapy, carboplatin or as monotherapy.16 The response rate in cetuximab and radiation treated patients (n=5) was reported as 80% versus 33% for cetuximab alone. The PFS was a disappointing 1.6 months and overall survival only three months for the cetuximab plus radiotherapy patients.16 Samstein and colleagues reported 12 laCSCC patients with concurrent cetuximab and radiotherapy.34 Complete and partial response was noted in 36% and 27% (response rate, 64%). Median progressionfree and overall survival were only 6.4 and 8.0 months, respectively. Grades 3 to 4 adverse events were noted in 83% of patients; 67% required hospital admission for adverse events. A total of 51% had longer-term disease control with a short median follow-up (seven months). Lu and Lien published a series of patients receiving either cisplatin and RT (15 patients) or cetuximab plus RT (eight patients) for laCSCC. With two-year median follow-up, both PFS (50 vs. 30%) and OS (73 vs. 40%) appeared to favor the cetuximab/RT group.35 The activity of cetuximab therapy in conjunction with radiotherapy in SCCHN encouraged us to use this ap-

proach for treatment of laCSCC. This was particularly attractive, as most of our patients had primary tumours originating in head and neck sites. We report 19 patients with laCSCC who had progressed after prior surgery, but who had not received prior systemic therapy or radiation therapy. These patients were treated with a consistent treatment approach combining cetuximab with concurrent radiotherapy. We found an objective response rate of 83.2% with 55.5% complete responses and 27.7% partial responses. The median progression-free survival was 21.6 months, with a median follow-up of 18 months. A total of 60% of patients were progression free at one year. Median overall survival was 60.7%.

Our data demonstrate that cetuximab plus radiotherapy represents an active treatment option for laCSCC, with manageable toxicity. This treatment option can be considered in patients with laCSCC, including those with contraindications that preclude checkpoint inhibitor therapy, such as organ transplants and autoimmune disease. The overall frequency of complete responses and duration of responses is high enough to be of interest for potential comparison to checkpoint-inhibitor based therapy. Our current study is intended to be hypothesis generating, with a goal of providing preliminary data to supporting development of comparative clinical trials. Potential limitations of our data include a relatively small number of treated patients, the retrospective nature of the analysis, and six-year span of patient accrual. Challenges for future treatment refinements included a small number of patients who failed either at the treatment site or at the margins of the planned radiation. The latter may suggest expansion of planned treatment volumes. Additional challenges include patients who developed regional and distant metastases from CSCC or aggressive second neoplasms.

MATERIALS AND METHODS Patient population A retrospective review of medical

records was performed of patients uniformly treated with cetuximab by a single physician (WS) at a single institution.

These patients were treated over a sixyear period between 2014 to 2020. Patients with locoregionally advanced or recurrent cutaneous squamous cell skin cancer (CSCC) treated with cetuximab and concomitant radiotherapy were identified by a search of a HIPAA-compliant electronic medical record system, IKnowMed (McKesson, Inc., Houston Tex.).

Clinical data were extracted from the chart into a spreadsheet and de-identified. The following information was extracted from the record: Gender, age, date of diagnosis, primary site, and stage at diagnosis using UICC 8th edition.6 Characteristics of cetuximab treatment were recorded, including number of doses and cumulative cetuximab dose administered, start and end dates for cetuximab treatment and any cetuximab-associated toxicity. Data related to radiotherapy were also extracted including start and end date of radiotherapy, elapsed time (days), fraction size, cumulative radiotherapy dose (Gy) and any associated toxicities. Best response, date of relapse and progression sites were identified. Both PFS and OS were calculated from cetuximab start date, cause of death was also recorded if patient was deceased. This study design was deemed exempt from full IRB review by the Western IRB chair.

The data cut-off date for data analysis was 12/31/20.

Exclusions included patients with squamous cell carcinoma of the head and neck (SCCHN) with oral, pharyngeal, or laryngeal primary sites. Patients with recurrent or metastatic CSCC after prior radiotherapy or other prior systemic treatments or those who were not treated with concurrent cetuximab plus radiotherapy were excluded.

Cetuximab treatment The initial loading dose of cetuximab was 400 mg/m² IV infused over two hours. Subsequent doses of 250 mg/m² IV were infused over 60 min each week, starting prior to the initiation of radiotherapy and continuing throughout the

POSTGRADUATE EDUCATIONAL SUPPLEMENT entire period of radiation therapy. All patients were seen weekly for close monitoring and lab monitoring during concurrent therapy. Patients were supported with hydration and magnesium replacement as required. Side effects of therapy were treated with symptomatic measures such as topical and oral antibiotics for the frequent cetuximab-induced rash, oral lidocaine for mucositis.

All patients underwent referral and evaluation for concomitant radiation therapy. The treatment consisted of electron beam fields designed to completely encompass superficial skin lesions in most patients, including a 1 to 2 cm margin. The dose ranged from 5000 to 6600 cGy at 200 to 250 cGy per fraction. Field reduction usually after 5000 cGy. If the regional lymph nodes were involved, or the skin tumour invaded facial structures, 3D conformal radiation therapy or IMRT was used with 6MeV photons, bolus used as needed to bring the dose to the surface.

For nodal disease, a boost to carry the involved nodes to a total of 6600 to 7000 cGy was used.

Data analysis Extracted information was accessed and recorded in a de-identified manner into a password-protected Excel spreadsheet (Microsoft, Redmond, Wash.) for analysis and calculation of descriptive statistics. Progression-free and overall survival were evaluated via KaplanMeier analysis.36 Toxicity was graded using the CTCAE 1.1 criteria.37

ABBREVIATIONS AJCC: American Joint Commission for Cancer; CR: complete remission; CSCC: cutaneous squamous cell carcinoma; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; laCSCC: locally advanced cutaneous squamous cell carcinoma; NHL: non-Hodgkin lymphoma; PFS: progression-free survival; PR: partial response; SCCHN: squamous cell carcinoma of the head and neck; UICC: Union for International Cancer Control.

DATA AVAILABILITY The data underlying this article will be shared upon reasonable request to corresponding author.

AUTHOR CONTRIBUTIONS Conceptualization, M.C., W.S., and R.M.;

methodology, M.C., W.S., and R.M.; validation, M.C., W.S., and R.M.; formal analysis, M.C. and W.S.; investigation, M.C., W.S., and R.M.; resources, W.S., and R.M.; data curation, M.C., W.S., and R.M.; writing—original draft preparation, M.C.; writing—review and editing, M.C., W.S., and R.M; visualization, W.S.; supervision, W.S., and R.M.; project administration, W.S.; All authors have read and agreed to the submitted version of the manuscript.

ACKNOWLEDGMENTS We appreciate the patients, families, clinic staff, and referring physicians who made this case series possible. The helpful editorial suggestions of Suzanne Samlowski, M. Arch. are also appreciated.

CONFLICTS OF INTEREST Authors have no conflicts of interest to declare. No external funding was procured for this research.

ETHICAL STATEMENT This study design was deemed exempt from full IRB review by the Western IRB chair.

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15. Montaudié H, Viotti J, Combemale P, Dutriaux C, Dupin N, Robert C, Mortier L, Kaphan R, Duval-Modeste AB, Dalle S, De Quatrebarbes J, Stefan A, Brunet-Possenti F, et al: Cetuximab is efficient and safe in patients with advanced cutaneous squamous cell carcinoma: a retrospective, multicentre study. Oncotarget 2020; 11:378–385.

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17. Rischin D, Migden MR, Lim AM, Schmults CD, Khushalani NI, Hughes BGM, Schadendorf D, Dunn LA, Hernandez-Aya L, Chang ALS, Modi B, Hauschild A, Ulrich C, et al: Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing. J Immunother Cancer 2020; 8:e000775.

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28. Specenier P, Vermorken JB: Cetuximab in the treatment of squamous cell carcinoma of the head and neck. Expert Rev Anticancer Ther 2011; 11:511–524.

29. Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59:1935–1940.

30. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354:567–578.

31. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK: Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010; 11:21–28.

32. Gold KA, Kies MS, William WN Jr, Johnson FM, Lee JJ, Glisson BS: Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial. Cancer 2018; 124:2169–2173.

33. Joseph K, Alkaabi K, Warkentin H, Ghosh S, Jha N, Smylie M, Walker J: Cetuximab-radiotherapy combination in the management of locally advanced cutaneous squamous cell carcinoma. J Med Imaging Radiat Oncol 2019; 63:257–263.

34. Samstein RM, Ho AL, Lee NY, Barker CA: Locally advanced and unresectable cutaneous squamous cell carcinoma: outcomes of concurrent cetuximab and radiotherapy. J Skin Cancer 2014; 2014:284582.

35. Lu SM, Lien WW: Concurrent radiotherapy with cetuximab or platinum-based chemotherapy for locally advanced cutaneous squamous cell carcinoma of the head and neck. Am J Clin Oncol 2018; 41:95–99.

36. Stalpers LJA, De Meere JMM, Kaplan EL: [The mortality in Amsterdam from 1554 to 2021].

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37. U.S. Department of Health and Human Services.

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NIH, National Cancer Institute, 2010.

Chronicle Companies is pleased to support Camp Liberté with monetary and in kind dona ons through Sandi’s Fund, established to honour our late friend and colleague, Sandra Gail Leckie, RN. Sandi was a nurse, pharmaceu cal industry execu ve and health educator who had a life long a nity for children and children’s chari es.

Chronicle Companies contributes proÞts from the annual Na onal Pharmaceu cal Congress (www.phar macongress.info) to Sandi’s Fund for Camp Liberté, and has partnered with Camp Liberté to provide com munica ons assistance for this valuable philanthropic undertaking

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.

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.

HOW CAN YOU HELP? A gift to Camp Liberté provides Canadian children with skin conditions an «« ÀÌÕ ÌÞ Ì }À Ü V w`i Vi > ` Ãi v iÃÌii Ì À Õ} > Õ Ì VÕ ÌÕÀ> outdoor camping experience in a fun, safe, bilingual, environment.

Donate Now! / Faites un don dès maintenant!

campliberte.ca 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. à V> «Ã Lj jwV i Ì `ià ÃiÀÛ Vià V « iÌà `i `iÀ >Ì }ÕiÃ] `i édecins réà `i Ìà iÌ `½ wÀ mÀià Lj jÛ ià µÕ ý VVÕ«i Ì `½i v> Ìà >ÕÝ «À Ãià >ÛiV un vaste éventail de problèmes de peau, y compris la dermatite atopique, l’épidermolyse bulleuse et la pelade.

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”

26 • Oct./Nov. 2023

THE CHRONICLE of SKIN & ALLERGY

Journal Club Research of Note

Diagnostic Quiz

TARGETING NLRP3 INFLAMMASOME IN HS PROMISING nvestigators identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in hidradenitis suppurativa (HS) skin vs healthy skin. The immune transcriptome was distinct and more heterogeneous than healthy skin. They found significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages, and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1 and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1 and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation.

Photo courtesy of Wikimedia Commons

I

A. Vitiligo B. Idiopathic guttate melanosis C. Hypopigmented mycosis fungoides D. Pityriasis versicolor

B Moran, CM Smith, A Zaborowski, M Ryan, J Karman, RW Dunstan, et al: Targeting the NLRP3 inflammasome reduces inflammation in hidradenitis suppurativa skin, in the British Journal of Dermatology (Oct. 2023; 189(4):447–458).

THE EDITORS invite your participation in this

I

HE Burks, JL Pokorny, JL Koetsier, QR Roth-Carter, CR Arnette, P Gerami, et al: Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration, in Journal of Cell Biology (Sept. 21, 2023; 222(11):e202212031.

regular feature of the journal.

Please send all images and correspondence to: Medical Editor, The Chronicle of Skin & Allergy 1460 The Queensway, Suite 212, Etobicoke, Ont. M8Z 1S4 Telephone: (416) 916-2476 E-mail: health@chronicle.org

Correct answer D. Pityriasis versicolor

PARACRINE CROSSTALK BETWEEN KERATINOCYTES, MELANOMA CELLS CONTRIBUTES TO MELANOMA PROGRESSION n this paper researchers provide evidence that melanoma cells hijack intercellular communication by secreting factors that keep Dsg1 expression low in the surrounding keratinocytes. This low expression of Dsg1 causes keratinocytes to generate paracrine signals that enhance melanoma spread through CXCL1/CXCR2 signalling. The evidence suggests paracrine signaling from melanoma cells increases levels of the transcriptional repressor Slug, and decreases expression of the Dsg1 transcriptional activator Grhl1. This data supports paracrine crosstalk between melanoma cells and keratinocytes resultsin chronic keratinocyte Dsg1 reduction that contributes to melanoma cell movement associated with tumor progression.

What THE LAY PRESS is saying about . . .

Dermatology news your patients may be reading 'SKIN FLOODING' TIKTOK TREND DIVIDES DERMATOLOGISTS An article from WalesOnline (Sept.

19, 2023) discusses the TikTok viral beauty trend “skin flooding,” where hydrating skincare products are layered on the skin. According to the publication, dermatologists are divided on the practice, with some saying it could be beneficial and others warning that it may damage the skin's natural barrier, leading to dryness and itching. They even caution against unnecessary product layering, citing potential harmful reactions between ingredients. Dr. Dave Reilly, a London, UK-based skincare research scientist, is among those cautioning against excessive layering. Instead, Dr. Reilly advises a simpler routine: gentle cleansing, applying a hydrating serum with ingredients like hyaluronic acid or glycerin, using a serum with hydrating components such as niacinamide or polyglutamic acid, and finally, applying a moisturizing lotion, cream, or ointment to seal in moisture. This routine can be done twice a day for those with dry skin.

ONTARIO’S SHORTAGE OF DERMATOLOGISTS IS A CRISIS According to a report in CityNews (Aug. 21, 2023), a shortage of dermatologists in Ontario is causing long wait times, leading to people lining up as early as 5 a.m. outside a dermatology clinic in Toronto’s Distillery District. Dr. Davindra Singh, founder of AvantDerm, highlights the increasing demand, with more than 100 people in the morning lineup. He says AvantDerm operates one of the few rapid-access clinics in the province. Patients only need a doctor’s referral and a health card. Without this clinic, some would have to wait up to one year for an appointment. People come from across the GTA and even farther, including Vancouver, due to lengthy waitlists for dermatologists. Government data indicates only 251 dermatologists serve Ontario’s over 15 million residents.

Dr. Singh calls for measures to attract more dermatologists and assist primary care providers in managing their workload.

PEOPLE OF COLOUR RECEIVE SPECIAL TX AT UNIQUE CLINIC An article in New Canadian Media (Sept. 19, 2023) reports that The Ottawa Hospital has launched Canada’s first Skin of Colour Dermatology Specialty Clinic at its Civic Campus. Dr. Reetesh Bose, a dermatologist and the clinic’s founder, emphasizes that immigrants and refugees diagnosed with skin conditions such as psoriasis and eczema often have their symptoms aggravated by Canada’s dry, cool climate. The clinic addresses the needs of individuals with non-white skin, including South Asian, Chinese, Black, Filipino, Latin American, Arab, Southeast Asian, West Asian, Korean, and Japanese backgrounds. Dr. Bose emphasizes the importance of focusing on diverse skin types in dermatology to ensure accurate diagnoses and timely treatment, especially for serious conditions like melanoma. Common skin conditions in immigrant populations include psoriasis, eczema, scarring alopecia, keloids, lupus, and vitiligo, which may impact individuals of various skin colours and ethnicities.

CONSUMER TIPS ON RESOLVING COMEDONAL ACNE According to an article in Allure (Sept. 7, 2023), comedonal acne tends to cluster on the chin, nose, or forehead. Unlike inflammatory acne, comedonal acne lacks redness and swelling but can be visually unappealing. The condition is caused by sebum, dead skin cells, bacteria, and dirt that clogs pores. Effective treatments include retinoids, salicylic acid, and benzoyl peroxide. Salicylic acid cleansers penetrate pores, retinoids promote cell turnover, and benzoyl peroxide acts as an antibacterial agent. Open comedones, or blackheads, have openings on the skin’s surface, while closed comedones appear as flesh-coloured bumps due to no air exposure. Both result from clogged pores linked to excess sebum and hormonal fluctuations. Salicylic acid cleansers and topical retinoids treat open and closed comedones. Microdermabrasion can reduce their appearance, and androgen inhibitors may help regulate hormone-related comedonal acne.

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