Abstract

Background: Psoriasis vulgaris, or plaque psoriasis, is a chronic systemic inflammatory disease characterized by scaly, erythematous plaques. It is associated with comorbidities such as cardiovascular disease, metabolic syndrome, depression, and anxiety, significantly affecting patients’ quality of life. Tildrakizumab, an IL-23 inhibitor, is approved for treating adults with moderate-to-severe plaque psoriasis.

Objectives: This real-world case series aims to illustrate diverse cases of moderate-to-severe psoriasis to highlight the clinical use of tildrakizumab by expert dermatologists. It seeks to answer: (1) How are experienced specialists utilizing tildrakizumab? (2) What are the patient outcomes on this injection regimen?

Methods: Expert dermatologists from four Canadian provinces (Saskatchewan, Alberta, Quebec, Ontario) contributed two patient cases each, ensuring diverse clinical settings and patient populations. Cases included the specialists’ clinical reasoning and patient outcomes at weeks 0, 4, 8, 12, and 16 post-tildrakizumab initiation.

Results: Seven real-world cases demonstrated the effective use of tildrakizumab in Canadian patients with psoriasis, including those with metabolic syndrome, psoriatic arthritis, malignancy history, and refractory disease. All patients experienced psoriasis improvement over the treatment period without notable adverse events.

Conclusions: Experts agreed that tildrakizumab is a safe, effective, and convenient treatment for psoriasis in Canada. Patients were highly satisfied with their outcomes and the therapy’s ease of use. These real-world cases provide valuable guidance for selecting tildrakizumab candidates seeking effective treatment with infrequent dosing suitable for various age groups, comorbidities, and busy lifestyles.

Keywords: psoriasis, real-world cases, IL-23 inhibitor, tildrakizumab

Funding/Disclosures: An unrestricted educational grant from SunPharma Canada supported the real-world case series. All authors contributed to the cases and development of the manuscript, reviewed it, and agreed with its content and publication.

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Introduction

Psoriasis is a systemic inflammatory disease with a heterogeneous skin presentation, affecting approximately 125 million people worldwide. ¹ Psoriasis vulgaris, the most common variant, accounts for approximately 85% of psoriasis cases in Canadians.² It typically presents as red, scaly, well-demarcated plaques or patches on the skin, which may appear violaceous or hyperpigmented in darker skin types.³ These plaques can affect the entire body but are frequently found on the scalp, face, intertriginous regions, nails, palms, and soles.⁴ The disease commonly manifests in adolescence or middle age (50–60 years) and follows a chronic course, rarely improving without treatment.¹

The etiology of psoriasis involves genetic, environmental, infectious, and lifestyle factors that contribute to the overactivation of the adaptive immune system. This leads to hyperproliferation of epidermal keratinocytes, vascular hyperplasia, and infiltration of T lymphocytes, neutrophils, and other immune mediators.^5-6 Interleukin 23 (IL-23) dysregulation has been identified as a key driver of psoriasis and autoimmune inflammation. Upon exposure to a trigger, TNF-α is released in the skin, activating dermal dendritic cells (DCs), which in turn produce IL-23. This cytokine activates Th17 cells and other inflammatory cells.⁷ Activated Th17 cells release pro-inflammatory cytokines—IL-17A/F, IL-22, IL-26, IFNγ, IL-6, TNF-α, and GM-CSF—resulting in keratinocyte hyperproliferation and an amplified inflammatory response.⁸ Notably, IL-23 plays a crucial role in both initiating and maintaining Th17 cell activation, IL-17 production, and the inflammatory feedback loop (Figure 1).⁸

Psoriatic arthritis (PsA), which shares a similar pathogenic mechanism, is the most prevalent comorbid condition, developing in up to 30% of psoriasis patients and potentially leading to joint destruction and lifelong disability.⁹ Furthermore, nearly half of psoriasis patients have been reported to have comorbid conditions such as cardiovascular disease (CVD), metabolic syndrome (MetS), anxiety, and depression.¹⁰ Systemic IL-23/Th17 inflammation in psoriasis has been linked to other inflammatory diseases, including CVD and MetS.⁹ Elevated Th17 and IL-17 levels have been observed in atherosclerosis patients, correlating with vascular inflammation, endothelial dysfunction, and atherosclerotic plaque formation.^11-12 Additionally, IL-23 and IL-23R levels are elevated within atherosclerotic plaques, indicating a role in disease progression.¹⁰ This corresponds with the increased incidence of myocardial infarction, ischemic heart disease, and severe vascular events in psoriasis patients.¹⁰

Obesity (BMI >30) has also been associated with psoriasis due to pro-inflammatory signaling from adipocytes, which contribute to disease pathogenesis via increased IL-6 and TNF-α production.¹³ These cytokines also promote insulin resistance, further exacerbating MetS and CVD.¹³ Given these systemic implications, effective psoriasis treatment may provide additional benefits, such as improving lipid-rich atherosclerosis and reducing non-calcified coronary plaque burden.¹²

Existing Treatments, Gaps, and Needs

Psoriasis has traditionally been managed with topical corticosteroids, but increasing recognition of its systemic nature necessitates systemic treatments. For mild psoriatic disease (3–5% body surface area [BSA]), topical corticosteroids, vitamin D3 analogs, calcineurin inhibitors, keratolytics, and phototherapy remain standard therapies.¹⁴ In moderate (BSA 5–10%) to severe (>10% BSA) cases, systemic treatments such as methotrexate, cyclosporine, and biologics targeting TNF-α (adalimumab, infliximab), IL-17 (secukinumab, ixekizumab, brodalumab), IL-12/23 (ustekinumab) and IL-23 (guselkumab, tildrakizumab, risankizumab) are commonly used. Additionally, small-molecule Janus kinase inhibitors such as deucravacitinib (approved for psoriasis) and tofacitinib as well as upadacitinib (approved for PsA) have expanded treatment options.¹⁵

Despite these advances, Canadian psoriasis patients remain largely dissatisfied with current treatments. In an online survey assessing awareness and use of available therapies, only 24% of respondents reported being “very satisfied” with their current regimen.¹⁶ Among Canadian dermatologists, key challenges in managing moderate psoriasis included treatment access, time to treatment, limited treatment choices, comorbidities, and patient acceptance.¹⁷ Notably, topical treatments remain the predominant approach for moderate psoriasis in Canada, whereas systemic therapies (including biologics) are underutilized. This contrasts with a study of 150 U.S. dermatologists, in which approximately 50% of moderate psoriasis patients were prescribed biologics.¹⁸

Tildrakizumab as a Psoriasis Treatment

Tildrakizumab is a high-affinity, humanized IgG1K monoclonal antibody that selectively targets IL-23 via its p19 subunit (Figure 1). It is indicated for adults with moderate-to-severe plaque psoriasis and is administered via subcutaneous injection every 12 weeks. The pivotal reSURFACE1 and reSURFACE2 phase 3, double-blind, randomized clinical trials evaluated the efficacy of tildrakizumab (100 mg and 200 mg) compared to placebo and the TNF-α inhibitor, etanercept.¹⁹ Patients received tildrakizumab at weeks 0, 4, and 16, while etanercept was administered twice weekly for the first four weeks and weekly thereafter. The primary endpoints included:

1. 1. The proportion of participants achieving ≥75% improvement in the Psoriasis Area and Severity Index (PASI 75).
   2. The proportion achieving a Physician’s Global Assessment (PGA) score of “clear” or “minimal,” with a ≥2-grade reduction from baseline at week 12.

In reSURFACE1, 59% of participants receiving tildrakizumab 200 mg, 55% receiving tildrakizumab 100 mg, 4% receiving placebo, and 48% receiving etanercept achieved a PGA 0/1 at week 12.¹⁹ Similar results were observed in reSURFACE2. Furthermore, pooled data revealed that tildrakizumab-treated patients with or without MetS had comparable response rates, making it a viable option for this population.¹⁹

Long-term data confirm tildrakizumab’s sustained efficacy. In the long-term extension trial, week 244 (5 years), 88.7%, 93.1%, and 114.7% of patients maintained PASI75, PASI90, and PASI100 responses, respectively.²⁰ Pooled phase 2 and 3 data indicate a favorable safety profile, with serious adverse events occurring in only 1.4% of tildrakizumab-treated patients versus 1.7% in the placebo group.^20-22 The most common adverse events were upper respiratory infections, injection reactions, and diarrhea.^21-22 Importantly, no increased risk was observed for cardiac disease, malignancy, suicidal ideation, inflammatory bowel disease, or demyelinating disorders.^21-22

Real-world evidence supports tildrakizumab’s effectiveness for moderate-to-severe plaque psoriasis in Canada.^{24, 25} In a 75-patient retrospective study, Abu-Hilal et al. demonstrated PASI75 in 95.7% of patients by week 48, regardless of prior biologic expsoure.²⁴ Long-term data confirm tildrakizumab’s sustained efficacy. At week 244 (5 years), 88.7%, 93.1%, and 114.7% of patients maintained PASI75, PASI90, and PASI100 responses, respectively.²⁰ Pooled phase 2 and 3 data indicate a favorable safety profile, with serious adverse events occurring in only 1.4% of tildrakizumab-treated patients versus 1.7% in the placebo group.^20-22 The most common adverse events were upper respiratory infections, injection reactions, and diarrhea.^21-22 Importantly, no increased risk was observed for cardiac disease, malignancy, suicidal ideation, inflammatory bowel disease, or demyelinating disorders.^21-22

Patients in these real-world studies also saw significant improvement in nail and scalp psoriasis during tildrakizumab treatment.^24,25 Gebauer et al. conducted a multicenter, randomized, double-blind, placebo-controlled, phase 3b study which showed that tildrakizumab was effective in treatment of scalp psoriasis with 49.4% of tildrakizumab-treated patients achieving a >2 improvement in Investigator Global Assessment (IGA) score by week 12 compared to 7.3% in the placebo group.²³

Considering psoriasis’ severe impact on quality of life, Costanzo et al. evaluated tildrakizumab’s effect on health-related quality of life metrics.²⁷ Their study revealed significant improvements in sleep, work productivity, and daily activities, with over 93% of patients expressing confidence in the treatment and an improved ability to lead a normal life.²⁷

Moderate-to-severe psoriasis is a systemic disease that warrants systemic, efficacious, and safe treatments to improve patient symptoms, quality of life, and overall health. Real-world cases provide invaluable guidance for both patients and physicians. Here, we illustrate how shared decision-making, and real-world clinical experience can facilitate successful tildrakizumab therapy across diverse patient populations in Canada.

Methods

Aim of the Project

This real-world case series is designed to illustrate a variety of patients with moderate-to-severe psoriasis treated with tildrakizumab in Canada. Cases showcase leading Canadian dermatologists’ real-world use of tildrakizumab, an advanced treatment for psoriasis. This series aim to answer the questions: 1) How are experienced specialist using tildrakizumab, and 2) How are their patients doing on the injection regimen? Expert dermatologists’ thought-process, reasoning, and rationales are detailed in the patient cases to serve as a guide for licensed providers who treat patients with moderate-to-severe psoriasis in Canada.

Steps in the Process

The project was conducted in the following five steps: 1) project definition and expert panel selection 2) data collection and preparation of patient cases, 3) patient case discussion and selection for publication 4) literature review to support selected cases 5) drafting, review, and finalization of the manuscript.

Role of the Panel

Our expert dermatologist panel consisted of 5 dermatologists practicing in Canada with extensive experience in caring for patients with moderate-to-severe psoriasis. Dermatologists were from 4 different Canadian provinces (Saskatchewan, Alberta, Quebec, Ontario) to capture geographical and provincial differences in dermatological practice. During an advisory meeting on November 17th, 2024, in Montreal, Quebec, expert dermatologists met to report on and discuss clinical cases using tildrakizumab in their clinical practice.

The panel used the following template to gather insight through a case-based approach:

a) Initial Steps in Treatment
____i. Patient-Focused Treatment Strategies
b) Treatment Options
c) Special Considerations
d) Advantages of Tildrakizumab for these Cases

Experts were asked to select two patient cases from their clinical practice to share and discuss. In the second half of the meeting, experts examined and collaborated to select seven real-world cases for inclusion in this publication. Experts agreed that real-world cases should represent common patient presentations and comorbidities to best illustrate tildrakizumab use in a wide range of patients. The publication was prepared and reviewed by the panel.

Tildrakizumab Administration

Before initiating tildrakizumab treatment, all patients completed a 28-day washout period for any prior systemic psoriasis therapies. Tildrakizumab was administered according to the prescribing information.²¹ Patients received two initial doses at weeks 0 and 4, followed by a dose at week 16 and subsequent doses every 12 weeks. All 100 mg doses were administered subcutaneously at the patient’s preferred injection site.

Experience Gathering and Psoriasis Outcome Measures

Suggested information and outcome measures to present included patient demographics, sex, weight, relevant medical history, concomitant medications, and comorbidities. In addition, patient psoriasis history was elicited by asking about the onset of psoriasis, type of psoriasis, location, and tried and failed therapies. At baseline, the patient’s psoriasis was evaluated using BSA and PASI scores. In addition, dermatologists were encouraged to ask patients how their psoriasis impacted their daily activities, social life, and self-image. Patients were evaluated at week 0 (baseline), week 4, week 8, week 12, and week 16 using BSA, PASI, and patient-reported qualitative measures such as treatment satisfaction and improvement in quality of life. Any adverse reactions were recorded and reported at each visit.

Body Surface Area (BSA)

BSA is a measure of the extent of skin involvement by psoriasis. According to the Joint American Academy of Dermatology-National Psoriasis Foundation guidelines, one severity measurement of psoriasis can be based on the percentage of BSA affected: less than 3% BSA is considered mild, 3-10% BSA is considered moderate and more than 10% BSA is considered severe.²⁹

Psoriasis Area Severity Index (PASI)

Another severity measurement is PASI which quantifies the extent and severity of psoriasis by accounting for intensity of redness, scaling, and plaque thickness. Scoring in each category will produce a score from 0 (no disease) to 72 (maximal disease severity).²⁹

Results

Selected Real-World Cases

The expert dermatologists selected seven cases to demonstrate the real-world use of tildrakizumab in a diverse group of patients with varying skin concerns, past treatment failures, severity, and comorbidities (Table 1).

Table 1. Summary of Real-World Patient Cases

Case 1. Use of Tildrakizumab in Previous Secukinumab Failure

A 34-year-old male, Fitzpatrick Skin Types (FST) IV, presented with severe plaque psoriasis involving his hands, legs, and arms. At baseline, he had a BSA of 12% and PASI score of 13.3. He had been diagnosed 3 years prior and had previously tried topical corticosteroids, methotrexate, phototherapy, and secukinumab, but his psoriasis persisted. The patient was also overweight and had psoriatic arthritis for which he took hydroxychloroquine and ibuprofen. He reported feeling self-conscious about his skin and stated that the itching affected his sleep. He avoided participating in sports due to fear of exposing his skin in public. The patient received his first dose of 100mg tildrakizumab. At week 4, he returned for his second 100mg loading dose but had not seen any improvement in his psoriasis (BSA 13%, PASI 15.6). By week 8, he noticed a reduction in plaque redness, though his BSA remained unchanged (BSA 13%, PASI 9.6). No further improvement was seen at week 12. The patient felt his condition had slightly improved and reported no discomfort or adverse events in the first 3 months of treatment. By week 16, he showed significant improvement with noticeable reductions in plaque redness, scaling, and thickness (BSA 3%, PASI 1.8) (Figure 2). The patient strongly agreed that his condition had improved and was satisfied with the treatment. Additionally, his psoriatic arthritis remained stable while on tildrakizumab, and he maintained his hydroxychloroquine regimen, despite the potential to exacerbate psoriasis, without any reported adverse effects.

Case 2. Biologic-Naïve Patient with Long-Standing, Severe Psoriasis

A 50-year-old female, FST III, presented with long-standing severe psoriasis. Diagnosed at age 14, she had previously tried topical corticosteroids, calcineurin inhibitors, vitamin D analogs, acitretin, and methotrexate without significant or lasting improvement. At presentation, her BSA was 40% and her PASI score was 16, with plaques affecting her torso, nails, and scalp. She avoided social activities, carefully selected clothes to hide her skin, and became less intimate with her husband due to embarrassment. The patient had developed depression due to her inability to live normally with her condition. She was started on tildrakizumab as a first-line biologic. At her week 4 visit, she reported modest improvement in plaque thickness and scaliness, with a 10% reduction in BSA (BSA 30%, PASI 12). Improvement continued at week 8 (BSA 20%, PASI 9) and week 12 (BSA 6%, PASI 4). By week 16, she had seen significant improvement with a BSA of 2% and PASI of 2 (Figure 3). She experienced no adverse events and tolerated the treatment without issues. The patient felt much more confident in her skin and was very satisfied with the therapy.

Case 3. Breast Cancer Survivor with Chronic, Lifelong Psoriasis

A 66-year-old overweight female, FST II, presented with lifelong psoriasis affecting her back and torso. She had suffered from psoriasis since her teenage years and had never achieved reliable control with any therapy. Previously, she had tried methotrexate, apremilast, phototherapy, topical corticosteroids, vitamin D analogs, and topical roflumilast. Additionally, the patient was a two-time breast cancer survivor, currently in remission for the past 10 years. She was apprehensive about starting systemic medications that might jeopardize her cancer remission, but she also felt very self-conscious about her skin and wanted to treat her psoriasis. Given tildrakizumab’s favorable safety profile, her dermatologist suggested trying the therapy. At baseline, the patient had a 10% BSA with a PASI score of 10.4. At week 4, she returned for her second loading dose and showed mild improvement, with a BSA of 8.5% and PASI of 8.4. Further improvement was noted by week 8 (BSA 2.5%, PASI 2) (Figure 4). At this time, she developed generalized pruritus, likely due to concomitant rosuvastatin use. The itching subsided after discontinuing rosuvastatin. The patient tolerated the treatment without any further adverse effects.

Case 4. Suboptimal Results with Tildrakizumab after Etanercept (TNF-α) Failure

A 65-year-old male presents to the clinic with refractory psoriasis. The patient has suffered from psoriasis for more than 30 years and had tried topical corticosteroids, tar, and vitamin D analogs as well as systemic etanercept. Topical treatments had provided some relief, but he had been on etanercept since 2004. In 2024, his psoriasis flared despite ongoing therapy. At that time, he had started a beta-blocker, bisoprolol and had been taking naproxen for PsA joint pain. Beta-blockers such as bisoprolol and non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, have been associated with increased risk of psoriasis and psoriasis flares.^{30, 31} The patient felt severely impacted by his psoriasis, which caused skin pain that affected his work, sleep, and daily activities. At his baseline visit, his BSA was 14%, and his PASI score was 15, with primarily extensor surface involvement and foot/sole involvement. He was started on tildrakizumab. At week 4, his BSA decreased to 9%, and his PASI score was 6.4. Despite mild improvement, the patient felt his condition was not improving and was dissatisfied with the effects of the first dose. He also developed cracks on his fingers that made holding objects uncomfortable. By week 8, the patient experienced significant improvement, with a BSA of 1.5% and PASI of 1.8. Although still not fully satisfied with the therapy, he reported dramatic improvement in his quality of life and felt less negatively impacted by his skin. At week 12, the patient had a flare with a BSA of 7% and PASI of 6.8. However, by week 16, his psoriasis had begun to resolve, with a BSA of 3% and PASI of 3.6 (Figure 5). Overall, he acknowledged mild improvement but expressed frustration with suboptimal results and continued psoriasis flares despite ongoing treatment.

Case 5. Tildrakizumab Used as a Safe and Effective Alternative to Systemic Immunosuppression

A 35-year-old male, FST IV, presented with a 4-year history of psoriasis. He had no other medical conditions. Since diagnosis, the patient had tried methotrexate, cyclosporine, topical calcineurin inhibitors (tacrolimus), and topical corticosteroids and vitamin D analogs. While on cyclosporine, the patient was concerned about the numerous side effects associated with the medication, and the other treatments were ineffective. At baseline, the patient had severe psoriasis affecting his torso, with a BSA of 55% and a PASI score of 29.8. His skin condition had a significant impact on his social life, self-image, and daily activities. He was started on tildrakizumab. By week 4, the patient saw improvements, with a reduction in BSA to 35% and a PASI score of 3.0. Continued improvement was observed at week 8, with a BSA of 10% and PASI of 2.9. By week 12, the patient was clear of psoriasis, with a BSA and PASI of 0 (Figure 6). He was very satisfied with the treatment and did not experience any adverse effects. He maintained these results through week 16 and continues to be treated with tildrakizumab.

Case 6. Tildrakizumab Used in Biologic-Naïve Patient with History of Prostate Cancer and Non-Hodgkin’s Lymphoma

A 69-year-old male, FST II, presented with long-standing plaque psoriasis. He was diagnosed about 15 years prior to presentation and had a 15% BSA and PASI score of 14.5. The psoriasis affected his feet, hands, elbows, legs and scalp. At the same time, the patient also had a history of hypertension, gastric reflux, non-Hodgkin’s lymphoma, and prostate cancer for which he was taking the following medications: pantoprazole, furosemide, candesartan, aspirin, and goserelin acetate. For his psoriasis, he had tried acitretin, calcipotriene/betamethasone, and clobetasol ointment. The patient was very bothered by his current regimen of topicals as the creams and ointments often rubbed off on his sheets and clothing. In addition, he often had people asking him about his skin and being concerned about it being infectious. At this time, he was started on tildrakizumab. Four weeks later, the patient began seeing some improvement in the scaling of his plaques. While his BSA remained unchanged, he saw reduction in PASI score to 10.7. He continued to see improvement and at week 8, he had a BSA of 8% and PASI score of 3.6. At week 12, the patient saw a reduction in BSA to 2% and a PASI score of 2.4. He eventually achieved a PASI score of 1 and BSA 1% by week 16 of treatment (Figure 7). No adverse effects were reported during his treatment.

Case 7. Tildrakizumab Used in Active Smoker with Severe Psoriasis

A 47-year-old female, FST II, presented with severe psoriasis affecting her back, nails, feet, legs, buttocks, and scalp. She had suffered from psoriasis for the past 25 years and had tried various topicals including calcipotriene/betamethasone foam, clobetasol ointment, tazarotene cream, coal tar, UV-B phototherapy and systemic treatments such as methotrexate. She also continued to smoke tobacco products and had hypertension, attention-deficit hyperactivity disorder (ADHD), and obesity. At baseline, the patient had a BSA of 26% and PASI score of 25.8. She felt very self-conscious about her skin and never thought that it would be possible for her to have clear skin. At this time, the patient was started on tildrakizumab. By week 4, the patient saw mild improvement in her psoriasis with a reduction in scaling; however, her BSA increased to 28%. The patient continued with treatment and saw noticeable results at week 8 when she returned to the office and was found to have a BSA of 22% and PASI score of 17.4 (Figure 8). At week 12, she had a BSA of 16% and PASI score of 8.7. By week 16, she further improved to have a BSA of 14% and PASI score of 8 (Figure 8). The patient was very enthusiastic about her results and felt hopeful about continuing with the treatment.

Discussion

This real-world case discussion provides valuable insights into the use of tildrakizumab as a safe, effective, and convenient therapy for Canadian patients suffering from moderate-to-severe psoriasis. All patients presented showed significant reductions in BSA and PASI by week 8 or week 16 of treatment.

In pivotal trials, 64% and 61% of patients on tildrakizumab (100mg) achieved PASI 75 by week 12 in reSURFACE1 and reSURFACE2, respectively This mirrors results from the real world, with 6 of the 7 patient cases showing significant improvement by week 12 or earlier. In reSURFACE2, etanercept was compared to tildrakizumab and demonstrated inferior results to tildrakizumab with only 48% of the etanercept group achieving PASI 75 compared to the 61% in the tildrakizumab group. One partial tildrakizumab responder in our series failed to respond to etanercept; however, he had mild improvements in his psoriasis after starting tildrakizumab demonstrating that IL-23 blockade may be more efficacious than TNF-α inhibition in some patients. Similarly, another patient had previously failed adalimumab before trying tildrakizumab. Our real-world cases, along with multiple real-world retrospective studies also confirm tildrakizumab efficacy in special psoriasis sites such as scalp, nails, palms and soles.^23-26 Importantly, tildrakizumab was also effective in patients with multiple comorbidities and refractory psoriasis. It also proved to be an effective treatment in overweight patients with BMI>25, which is critical in that approximately a third of patients with psoriasis meet criteria for MetS.³² Preliminary results from a recent study suggests that tildrakizumab may be effective in obesity by reducing levels of adipokines, immune modulating cytokines originating from adipocytes.³³ Taken together, tildrakizumab should be considered a first-line biologic given its efficacity in a variety of patients, psoriasis presentations, and safety profile.

Unlike many existing therapies, tildrakizumab has a highly favorable safety profile. In clinical trials, there were no serious adverse events, and the most common adverse events included upper respiratory illness and injection site reactions.²¹ A pooled analysis of three randomized controlled clinical trials demonstrates that the rates of treatment-emergent adverse events (TEAE), serious TAE, and discontinuations due to adverse events were similar in both the tildrakizumab treatment and placebo group. Moreover, no reported cases of inflammatory bowel disease, candida infections or suicides were reported which are key counseling points for patients starting anti-IL-17 biologics. Additionally, no increased risk of malignancy was observed during tildrakizumab treatment. This is significant, as psoriasis increases the risk of lymphohematopoietic, head and neck, and gastrointestinal cancers, as well as non-melanoma skin cancers in patients who have previously received psoralen ultraviolet-A treatment. The increased cancer risk in this population makes carcinogenic treatments like methotrexate and cyclosporine less ideal compared to tildrakizumab.

Tildrakizumab does not harbor risks for MACE, VTE, or malignancy which makes it an appropriate first-line treatment for biologic-naïve and biologic-experienced patients.²¹ It may also be especially helpful in adult patients over the age of 50 with multiple comorbidities such as existing CVD, history of stroke or previous malignancies. One expert suggested tildrakizumab to be the ideal treatment for such as patient: the 70-year-old male with complex medical history including cardiovascular and cancer history (and perhaps a current smoker) who is seeking something to relieve his psoriasis symptoms and improve his quality of life. This is supported by pooled analyses of reSURFACE1 and reSURFACE2 which demonstrates efficacy, safety, and sustained responses in patients > 65 years through 244 weeks.³⁵ Safe use of tildrakizumab in the elderly population makes it an invaluable treatment for a population with high prevalence of comorbidities and polypharmacy. Experts agree that the only drawback of tildrakizumab is that some patients may require multiple doses before experiencing significant effects. This delay can be frustrating for patients who are hoping for quicker skin clearance.

Despite slow onset of action, patients are generally highly satisfied with tildrakizumab treatment. In the TRIBUTE study, researchers measured tildrakizumab impact on health-related quality of life and found that patients had significant improvement in their skin as well as their sleep, work productivity, activity level, and absenteeism.²⁷ Tildrakizumab is also convenient, with every 12-week dosing making it suitable for patients with busy work schedules or those who live between multiple locations. In Canada, it is ideal for the “snowbird” population who leave for months at a time to escape the winter. Most other biologics are dosed every 2, 4, or 8 weeks, which may impose time constraints on certain patients and their lifestyles. Less frequent dosing reduces the healthcare burden in Canada by decreasing the number of treatment administration visits.

Table 2. Clinical Pearls from Expert Canadian Dermatologists

Conclusion

The presented real-world cases reflect expert dermatologists’ clinical experience with tildrakizumab in treating Canadian patients with moderate-to-severe plaque psoriasis. The collective experience of these dermatologists suggests that tildrakizumab is a safe, effective, and durable treatment for a variety of patients. Tildrakizumab is an ideal therapy for older patients with multiple comorbidities who may not be candidates for therapies with a less favorable safety profile. The onset of action with tildrakizumab may vary, with some patients responding quickly while others may only experience results after 12 or 16 weeks. No adverse effects were reported in any of the patients.

Limitations

These patient cases represent outcomes under real-world conditions in patients with differing lifestyles and environments. The reported symptoms and measures were provided by dermatologists in their clinics and represent real-world data, rather than data from a randomized clinical trial under controlled conditions. Results are only reported up to the 16-week time point, which may not capture patients who required more doses of tildrakizumab to see improvement. Furthermore, the 16-week time frame does not account for potential future psoriasis flares.

Acknowledgement

The authors acknowledge and thank Anneke Andriessen PhD, for her assistance in preparing and reviewing this manuscript.

References

¹Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Beacon Dermatology, Calgary, AB, Canada

Conflict of interest: Leah Johnston does not have any conflicts of interest to disclose. Andrei Metelitsa has been an advisor and speaker for AbbVie, Eli Lilly, Galderma, Leo, Pfizer, Sanofi. Susan Poelman has been an advisor and speaker for AbbVie, Eli Lilly, Galderma, Leo, Pfizer, Sanofi.
Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that impacts approximately 10-15% of the population in the United States and Canada. Lebrikizumab is a novel systemic human monoclonal immunoglobulin G4 antibody that inhibits the activity of interleukin-13. In June 2024, lebrikizumab was approved by Health Canada for the treatment of moderate-to-severe AD in adults and adolescents who are 12 years of age and older, followed by US Food and Drug Administration approval in September 2024. This review provides an overview of data from clinical trials on the efficacy and safety of lebrikizumab in adult patients.

Keywords:atopic dermatitis, lebrikizumab, interleukin-13, IL-13, biologics, eczema, dermatitis

Introduction

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease that presents with pruritic, erythematous, eczematous patches and plaques that has a predilection for flexural sites. The estimated prevalence of AD in Canada and the United States is 8-16% in adolescents aged 12-17 years and 2-11% in adults.^1-7 Approximately 40% of AD patients have moderate-to-severe disease.⁷ AD has a significant negative impact on quality of life in individuals with the condition and is associated with increased rates of anxiety, depression, and sleep disturbances.⁸ Additionally, AD can be costly to manage for both patients and the healthcare system at large, and previous studies have found that AD has a major adverse impact on workplace productivity and absenteeism.⁸

First-line treatments for AD include emollients with use of wet wraps and topical agents including corticosteroids, calcineurin inhibitors, phosphodiesterase-4 inhibitors, and Janus kinase (JAK) inhibitors.⁹ Patients who do not achieve an adequate improvement with topical therapies alone or have severe, widespread AD at baseline may require narrowband phototherapy or systemic therapies to improve disease control.¹⁰ Currently, three monoclonal antibodies and two small molecule inhibitors have received Health Canada approval for the treatment of moderate-to-severe AD (Table 1).¹⁰ This review presents efficacy and safety data from clinical trials of lebrikizumab, the most recently approved treatment for AD in patients ≥12 years of age.

Table 1

Mechanism of Action

AD has numerous predisposing genetic and environmental factors that lead to a predominantly T‐helper type 2 (Th2) cell and type 2 innate lymphoid cell (ILC2)‐driven inflammatory response. Activation of Th2 and ILC2 cells leads to an increase in type 2 inflammatory cytokines, including interleukin (IL)‐4, IL‐5, IL‐13, and IL‐31.¹¹ IL‐4 is thought to primarily exert central effects by regulating the development of immune cells, such as Th2 cells, and promoting production of immunoglobulin E (IgE) by B cells. Conversely, IL‐13 primarily acts in the periphery and both cytokines are implicated in the pathogenesis of AD.¹² IL‐13 is overexpressed in AD lesions and non‐lesional skin compared to healthy controls and levels of IL‐13 in lesional skin correlate with AD severity.¹² IL‐4 and IL‐13 also contribute to cutaneous microbial dysbiosis and disruption of the skin barrier, with IL‐13 predominantly stimulating decreases in antimicrobial peptide and filaggrin protein levels and increasing local expression of IgE and migration of eosinophils.^11,13 Both IL‐4 and IL‐13 can bind to IL‐13 receptor α1 (IL‐13Rα1), inducing the formation of a heterodimeric receptor with the IL‐4 receptor α (IL‐4Rα) subunit and subsequently activating downstream JAK1 and tyrosine kinase 2 (TYK2)‐mediated pro‐inflammatory pathways.¹¹ IL‐13 also binds to IL‐13Rα2, which plays a negative regulatory role by stimulating IL‐13 degradation.^12‐14 Different IL‐13Rα2 receptor epitopes affect IL‐13 clearance rates, which has been observed in asthma studies.¹² Dupilumab binds to IL‐4Rα in IL‐4Rα/IL‐13Rα1 receptor complexes and decreases receptor signaling.^11,15 Although both lebrikizumab and tralokinumab are monoclonal antibodies that bind to IL‐13, lebrikizumab is known to have the highest binding affinity for IL‐13.¹² Lebrikizumab‐bound IL‐13 can still bind to IL‐13Rα1, but formation of IL‐4Rα/IL‐13Rα1 receptor complexes is blocked by lebrikizumab (Figure 1). Tralokinumab prevents IL‐13 from binding to IL‐13Rα1, which also subsequently inhibits IL‐4Rα/IL‐ 13Rα1 heterodimerization.^11,12,16 Tralokinumab also inhibits binding of IL‐13 to IL‐13Rα2, which does not occur with lebrikizumab.¹² In contrast, lebrikizumab‐bound IL‐13 is transported intracellularly after binding to Il‐13Rα2, where it co‐localizes and is subsequently degraded by lysosomes.¹² This mechanism promotes for clearance of IL‐13, while the underlying mechanism of tralokinumab inhibits this process and may lead to persistence of elevated IL‐13 levels.¹²

Figure 1

Production, Administration, Ingredients, Storage and Dosing

Lebrikizumab is a humanized IgG4 monoclonal antibody that consists of two identical heavy gamma chains and two identical light chains.¹⁷ Recombinant DNA technology is used to produce lebrikizumab in Chinese Hamster Ovary cells.¹⁷

Lebrikizumab is administered via subcutaneous (SC) 125 mg/mL (250 mg in 2 mL sterile solution) injections using either pre‐filled syringes or pre‐filled pens.¹⁷ The sterile solution in lebrikizumab is comprised of acetic acid, histidine, polysorbate 20, sucrose, and water. The medication should be stored in a refrigerator with a temperature between 2 and 8 degrees Celsius.

The initial loading dose of lebrikizumab is 500 mg (two injections) at baseline and 2 weeks,¹⁷ followed by administration every 2 weeks in 250 mg SC doses until 16 weeks. After 16 weeks, the dosing frequency can be decreased to every 4 weeks.¹⁷ In some cases, patients who achieved partial responses may be recommended to continue 250 mg every 2 weeks until 24 weeks.¹⁸

Pharmacokinetics

Serum levels of lebrikizumab peak at 7-8 days after SC injections and the estimated bioavailability is 86%.^17,19 Metabolism of lebrikizumab is theorized to occur through the same protein catabolism pathways that typically degrade endogenous antibodies.^19,20 No dose adjustments are required for patients with hepatic or renal insufficiency, or geriatric patients (≥65 years of age).¹⁷

Contraindications to Lebrikizumab

Lebrikizumab is contraindicated in patients with known allergies or hypersensitivity to any ingredients in its formulation.¹⁷ Clinical trials for lebrikizumab have not been conducted in pediatric patients <12 years of age or >12 years who weigh less than 40 kg, and therefore, it is not currently approved by Health Canada for use in these individuals.¹⁷ Lebrikizumab is not currently recommended in pregnant individuals due to a lack of safety data in humans.¹⁷ As lebrikizumab is an IgG4 antibody, it is able to cross the placenta. However, studies in pregnant monkeys that tested lebrikizumab at exposure levels that were 18 to 22‐fold higher than the dosages used in humans, no adverse fetal effects were observed.¹⁷ Fetal serum levels of lebrikizumab were approximately 30% of maternal serum levels.¹⁷ Recent clinical practice guidelines suggest that dupilumab is likely to be safe during pregnancy and other biologics targeting similar pathways are expected to have similar pregnancy safety profiles, though this conclusion cannot be drawn due to the current lack of safety data.²¹

Clinician-Reported Efficacy Data from Phase 2 and 3 Clinical Trials in AD

Three phase 2 clinical trials have been conducted to evaluate the efficacy of lebrikizumab in adults with moderate-to-severe AD (Table 2).^16,22,23 Following completion of phase 2 trials, which demonstrated efficacy for improving AD as well as high safety and tolerability, six phase 3 clinical trials of lebrikizumab have been completed.^24-31 Additional long-term phase 3 efficacy and safety trials are currently being conducted.^32,33

Table 2

The ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) monotherapy, randomized, phase 3 placebo-controlled trials further demonstrated the efficacy of lebrikizumab as a treatment for AD.^24-26 The ADvocate trials enrolled both adolescents ≥12 years of age and adults.^24-26 The primary outcome in both trials was the proportion of participants who achieved an Investigator Global Assessment score (IGA) of 0 or 1 at 16 weeks, representing complete or near complete clearance of AD.²⁴ The secondary efficacy outcome was the proportion of participants who achieved Eczema Area and Severity Index (EASI)-75, indicating ≥75% improvement from baseline, at 16 weeks. In ADvocate1, 43.1% of the lebrikizumab group and 12.7% of the placebo group achieved an IGA score of 0 or 1 at 16 weeks (P < 0.001).²⁴ EASI-75 was achieved by 58.8% and 16.2%, respectively (P < 0.001).²⁴ In ADvocate2, 33.2% of the lebrikizumab group and 10.8% of the placebo group had IGA 0/1 scores at 16 weeks (P < 0.001), and EASI-75 was achieved in 52.1% and 18.1%, respectively (P < 0.001).²⁴ After 16 weeks, patients in the ADvocate1 and ADvocate2 trials who received treatment with lebrikizumab were randomized to either continue 250 mg every 2 weeks, switch to lebrikizumab 250 mg every 4 weeks, or discontinue treatment with lebrikizumab.²⁵ The primary efficacy endpoint, IGA 0/1, was maintained in 71.2% of the lebrikizumab every 2 weeks group, 76.9% of the lebrikizumab every 4 weeks group, and 47.9% of the group that was switched to placebo after week 16.²⁶ The group that received lebrikizumab 250 mg every 4 weeks had the highest proportion of participants who maintained EASI-75 at the end of 52 weeks of treatment (81.7%), compared to 78.4% of patients in the lebrikizumab 250 mg every 2 weeks group and 66.4% of the lebrikizumab discontinuation group.²⁵ No fluctuations in maintenance of EASI-75 occurred in 70.8% of the lebrikizumab every 2 weeks group, 71.2% of the lebrikizumab every 4 weeks group, and 60.0% of the lebrikizumab withdrawal group.²⁶ During the maintenance treatment period (weeks 16 to 52) in the ADvocate1 and ADvocate2 trials, 12.4% of the lebrikizumab every 2 weeks group, 16.1% of the lebrikizumab every 4 weeks group, and 18.3% of the lebrikizumab withdrawal group required treatment with topical therapies to optimize control of their AD.²⁵

The ADhere trial (NCT04250337) was a 16‐week, phase 3 randomized, placebo‐controlled trial of lebrikizumab, combined with low to mid‐potency topical corticosteroids and/or topical calcineurin inhibitors, which participants were instructed to use on an as‐needed basis.²⁷ The primary endpoint, attainment of IGA 0/1 at 16 weeks, occurred in 41.2% of patients in the lebrikizumab 250 mg every 2 weeks group and 22.1% of the placebo injection group (P = 0.01).²⁷ EASI‐75 was achieved in 69.5% of lebrikizumab and 42.2% of placebo group patients (P < 0.001).²⁷ The mean proportion of topical therapy‐free days at 16 weeks was numerically greater in the lebrikizumab group, but this difference was not statistically significant.²⁷

The ADjoin (NCT04392154) trial is a phase 3, long-term, efficacy and safety trial that is pending completion. Preliminary data from this trial demonstrated that 76% of the ADvocate1 and ADvocate2 trial participants and 79% of the ADhere trial participants maintained IGA 0/1 after 2 years of treatment with lebrikizumab at 250 mg every 4 weeks maintenance dosing.²⁸ This data suggests that lebrikizumab is an effective long-term therapy for maintaining complete or near-complete clearance of AD in patients who have optimal responses at 16 weeks.²⁸

Clinician-Reported Efficacy Data from Phase 3 Trials in Pediatric Patients with AD

The ADore trial (NCT04250350) analyzed the effects of lebrikizumab exclusively in adolescent patients between 12 and 17 years of age with moderate‐to‐severe AD.²⁹ Patients received 500 mg loading doses of lebrikizumab at baseline and week 2, followed by 250 mg every 2 weeks throughout the 52‐week trial.²⁹ The primary endpoint was safety and the proportion of participants who discontinued lebrikizumab due to adverse events. At 4 weeks, 28.6% of patients achieved EASI‐75, which rose to 73.2% at week 16 and continued to steadily increase to 81.9% at the end of the 52‐week trial.²⁹ IGA 0/1 was achieved in 14.4% at week 4, 46.3% at week 16, and 62.6% at week 52.²⁹ Rescue therapies were needed in 27.2% of participants.²⁹ The ADorabale‐1 (NCT05559359) and ADorable‐2 (NCT05735483) trials, two phase 3 placebo‐controlled randomized controlled trials (RCTs) in children aged ≥6 months, are currently in progress.^32,33

Subset efficacy analyses from the ADvocate1, ADvocate2, and ADhere trials found that data collected from adolescent patients were consistent with overall population outcomes.³⁰

Effects of Lebrikizumab on Vaccine-Induced Immune Responses

The ADOPT-VA trial (NCT04626297) was a phase 3 placebo-controlled RCT that was conducted to analyze responses to non-live vaccines in patients receiving treatment for AD with lebrikizumab.³¹ No differences in response rates between the lebrikizumab and placebo groups were observed following the meningococcal conjugate vaccine and the tetanus toxoid booster vaccine.³¹ Improvements in AD severity and symptoms were similar to results from other lebrikizumab trials.³¹

It is recommended that patients receive age-appropriate live vaccinations prior to starting lebrikizumab, as they are contraindicated during treatment.¹⁷

Patient‐Reported Outcomes

Across published phase 2 and 3 trials, patients who received lebrikizumab 250 mg every 2 weeks had significantly higher rates of achieving a ≥4‐point decrease in Pruritus Numerical Rating Scale severity scores compared to the placebo groups.^16,24,27,31 At 52 weeks, more than 60% of participants in the ADvocate1 and ADvocate2 trials maintained this improvement.²⁶ Additionally, sleep loss and the interference of pruritus with sleep were significantly better with lebrikizumab compared to placebo,³⁴ Furthermore, these improvements were associated with higher Dermatology Life Quality Index ratings.³⁵ Patients in the ADvocate1 and ADvocate2 trials who received treatment with lebrikizumab also experienced significant improvements in depression and anxiety ratings compared to placebo.³⁶

Safety Data

A pooled safety analysis of the eight clinical trials of lebrikizumab for AD found that the rates of adverse events (AEs) were 49.2% in participants who were treated with lebrikizumab 250 mg every 2 weeks and 53.1% in participants who received treatment with a placebo, of which 2.3% and 4.4% were classified as severe AEs, respectively.³⁷ AEs leading to treatment discontinuation occurred in 2.3% of lebrikizumab 250 mg every 2 weeks and 1.4% of placebo group participants.³⁷

Conjunctivitis was the most common treatment-emergent adverse event (TEAE) in the lebrikizumab groups (6.5%).³⁷ Allergic conjunctivitis was reported in 1.8% of the lebrikizumab 250 mg every 2 weeks groups and in the TREBLE RCT, more than half (53%, n=8/15) of all instances of conjunctivitis were allergy-related.^22,37 Approximately 20% of patients in both the lebrikizumab and placebo groups had a past history of conjunctivitis at baseline, but only 1.8% of the placebo groups developed the condition during the trials.³⁷ Targeting IL-13 signaling is theorized to interfere with maintenance of the conjunctival mucosa by decreasing levels of conjunctival goblet cells, thereby increasing the risk of conjunctivitis.³⁷ Other TEAEs that were more common in participants who received lebrikizumab included nasopharyngitis (4.4%), headache (4.4%), dry eye (1.4%), allergic rhinitis (1.0%), and injection site reactions (2.5%).³⁷ No participants developed anaphylaxis or hypersensitivity reactions.³⁷ Eosinophilia occurred more frequently in the placebo groups (0.8%) than the lebrikizumab every 2 weeks groups (0.6%).³⁷

The lebrikizumab every 2 weeks groups developed herpes zoster (0.6%) and herpes simplex (0.3%) infections at higher rates compared to the placebo groups, in which no cases were reported.³⁷ Eczema herpeticum was not reported in patients receiving lebrikizumab every 2 weeks, while the incidence was 0.7% in the placebo groups.³⁷ Lebrikizumab could theoretically increase the risk of helminth infections, though this was not observed in the lebrikizumab every 2 weeks trial groups.^17,37 No confirmed opportunistic infections occurred in any of the lebrikizumab or placebo groups.

Non‐melanoma skin cancers (NMSC) occurred in 0.3% of the lebrikizumab 250 mg every 2 week groups and 0.5% of the placebo groups.³⁷ No other malignancies were observed during the 16‐week trial period in the lebrikizumab 250 mg every 2 weeks and placebo groups.³⁷ In a pooled analysis of all participants who received lebrikizumab with any dosing protocol (including a single dose at baseline), 0.3% of participants developed NMSC and 0.4% developed other malignancies, including prostate cancer (n=1), cutaneous T‐cell lymphoma (n=2), endometrial adenocarcinoma (n=1), invasive breast cancer (n=1), a neuroendocrine tumor (n=1), and metastatic pancreatic carcinoma (n=1).³⁷ All malignancies were classified as unrelated to lebrikizumab by the study investigators and were similar to expected malignancy rates.³⁷

Data from Clinical Trials for Asthma

Asthma is a common comorbidity of AD and in patients with both moderate‐to‐severe asthma and AD, consideration should be given to systemic therapies that can optimize management of both conditions. Some phase 2 and 3 trials of lebrikizumab found reductions in rates of asthma exacerbations and hospitalizations in adolescents and adults with poorly controlled asthma, though other studies have failed to demonstrate consistently significant results.^38‐40

Efficacy Comparison of Lebrikizumab to Other Biologics and Small Molecule Inhibitors for AD

A 2024 network meta‐analysis of RCTs that investigated biologics and small molecule inhibitors for moderate‐to‐severe AD found that lebrikizumab, along with dupilumab and tralokinumab, had intermediate efficacy and the most favorable safety profiles.⁴¹ While JAK inhibitors, including upadacitinib and abrocitinib, have demonstrated the highest efficacy in improving AD, they were associated with significantly higher rates of AEs. Compared to dupilumab, lebrikizumab has shown a slightly reduced but non‐significant difference in reducing EASI scores from baseline, though dupilumab was associated with a higher chance of achieving EASI‐50 and IGA 0/1 at 16 weeks.^42,43 Lebrikizumab showed comparable or superior performance to tralokinumab for clinician and patient‐reported efficacy measures.^41,42

A comparative study that analyzed propensity‐matched participant cohorts based on week 16 EASI and % BSA scores from the ADvocate trials and the SOLO‐CONTINUE dupilumab phase 3 RCT found that lebrikizumab every 4 weeks showed comparable or superior maintenance of efficacy outcomes between week 16 and week 52.⁴³ Lebrikizumab may be advantageous due to the less frequent dosing schedule during the maintenance phase, as the FDA‐approved maintenance frequency of dupilumab is every 2 weeks.⁴³

Conclusion

Lebrikizumab is a novel monoclonal IgG4 antibody that targets IL‐13 and prevents IL‐4Rα/IL‐13Rα1 receptor signaling and is approved by Health Canada for the treatment of moderate‐to‐severe AD in adolescents 12 years or older and adults. Lebrikizumab has comparable efficacy to other monoclonal antibody treatments for AD, including dupilumab and tralokinumab, requires less frequent monthly maintenance doses than dupilumab after 16 weeks, and is associated with a lower rate of adverse events compared to JAK inhibitors. Lebrikizumab is a promising option for the treatment of moderate‐to‐severe AD given its favorable safety profile, durable efficacy in long‐term follow‐up studies, and major improvements in pruritus, sleep, and overall quality of life in patients with AD.

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¹Center for Clinical Studies, Webster, TX, USA
²Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there is no conflict of interest.
Funding sources: None.

Abstract:
Nanodermatology has been an emerging area of research and drug development in the last two decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has yielded potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery. Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been more frequently explored for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been increasingly investigated to improve efficacy of various drugs via enhanced delivery to the target site. Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but these formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to boost drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects. Enhanced drug delivery utilizing nanoparticles has been successfully trialed for treatment of psoriasis, vitiligo, acne vulgaris, and atopic dermatitis in many research studies, however more investigation is needed prior to utilization in humans.

Keywords:nanodermatology, nanoparticles, enhanced drug delivery, nanocarriers

Introduction

Nanodermatology has been an emerging area of research and drug development in the last decades. Nanodermatology lies at the intersection of nanotechnology, chemical engineering, biophysics, and pharmacology. Increasing research has exhibited potential benefits of nanotechnology in the treatment of various skin conditions via enhanced transdermal drug delivery.¹

Nanoparticles, defined as particles ranging from 1 to 1000 nanometers, have been increasingly investigated for their potential role in targeted drug delivery systems. Nanocarriers, which include liposomes, ethosomes, and vesicle carriers, have been more frequently explored in order to improve the efficacy of various drugs via enhance delivery to the target site.

Many dermatologic conditions are preferentially treated with topical formulations to locally target the affected area and reduce systemic absorption, but topical formulations are limited in their penetration. The ability of topical formulations to effectively deliver active ingredients to the target site is uncertain, therefore nanoparticles have been increasingly investigated as an approach to increase drug delivery to the deeper layers of the skin, improve absorption, and decrease adverse effects.²

This article will discuss the promising application of nanotechnology as a route of increased transdermal drug delivery in order to treat various common dermatological conditions, including psoriasis, vitiligo, acne vulgaris and atopic dermatitis, as well as nanoparticle utilization in sun protection.

Psoriasis

Psoriasis is a common inflammatory skin disorder, affecting over 125 million people worldwide, that can range in presentation from erythematous plaques to pustules. Traditionally, mild psoriasis can be treated with topical medications, including corticosteroids, betamethasone/calcipotriol, calcineurin inhibitors, and retinoids.³ However, moderate to severe disease often requires systemic treatments such as methotrexate, cyclosporine, and biologic agents. These systemic treatments often come with the risk of significant adverse effects.

Multiple drug‐loaded nanoparticles and nanocarriers have been found to have promising potential in the treatment of psoriasis, while minimizing the risk for adverse effects and maximizing transdermal drug delivery.⁴ Tazarotene (TZ), a topical antipsoriatic retinoid with significant irritation potential, was loaded into fluidized spanlastic nanovesicles that measured about 260 nanometers. When compared to commercially available topical tazarotene, researchers found that the nanovesicles not only showed higher antipsoriatic activity in human subjects but also demonstrated deeper penetration during ex vivo testing.⁵ Tacrolimus, an immunosuppressive agent that has often been used topically to treat psoriasis, exhibits poor cutaneous bioavailability, particularly in hyperkeratotic plaques. Therefore, topical tacrolimus ointment was compared to a micelle nanocarrier tacrolimus formula. The micelle formula showed increased tacrolimus delivery into the stratum corneum and epidermis when compared to the traditional topical tacrolimus ointment.⁶

In addition to improved delivery of classic topical treatments, researchers have been utilizing nanotechnology to investigate the transdermal delivery potential of drugs traditionally used as systemic therapy, such as methotrexate and cyclosporine. Both methotrexate and cyclosporine are typically reserved for severe psoriasis due to the significant risks of toxicity and adverse effects. However, when combined with nanotechnology, these drugs can be applied topically, therefore greatly minimizing the risk for systemic adverse effects.⁴

Cyclosporine, a calcineurin inhibitor, is incredibly effective as a systemic therapy for psoriasis, but unfortunately, its use comes with risks of nephrotoxicity, neurotoxicity, metabolic disruptions, and immunosuppression.⁷ In an imiquimod induced psoriatic plaque on mice, cyclosporine‐loaded liposomes were more effective at reducing psoriatic features than cyclosporine gel.⁸

Like cyclosporine, systemic methotrexate has shown great utility in the treatment of psoriasis, however there is risk of significant side effects. In an in vivo skin deposition study, methotrexate niosomes, or non‐ionic surfactant vesicles, resulted in a greater percentage of drug deposition in the skin when compared to a simple methotrexate topical solution.⁹ Similarly, gold nanoparticles loaded with methotrexate led to improvement of scaling, erythema, epidermal thickness, and parakeratosis in mice models with imiquimod induced psoriasis. The methotrexate‐gold nanoparticles also showed deeper penetration when compared to topical methotrexate. Additionally, after treatment there was no significant difference in the blood count, AST, and ALT of the treatment group when compared to the control.¹⁰

Nanoparticles have not only allowed for greater skin penetration and drug delivery than classical topical treatments, but they have also allowed researchers to create topical formulations of systemic medications that come with risk of significant adverse effects. More research is needed to compare the efficacy of systemic therapy with nanoparticle formulations.

Vitiligo

Vitiligo, an acquired disorder characterized by the development of depigmented macules, is thought to be caused by autoimmune destruction of melanocytes. Treatment is typically focused on preventing progression and inducing some degree of repigmentation. Recent investigation into the utility of nanodermatology has led to exciting treatment potential.

Berberine, an isoquinoline alkaloid, despite exhibiting potential benefit as a topical vitiligo treatment, has limited utility due to its poor skin permeability. In order to improve delivery, berberine was loaded into hyalurosomes, which are modified nanovesicles that have enhanced skin penetration abilities and are non‐irritating. In human skin studies, berberine hyalurosomes showed greater permeability and greater drug retention when compared to a conventional berberine gel. In a vitiligo‐induced mouse model, the berberine loaded hyalurosomes showed a significant return of normal pigmentation that was greater than the conventional berberine gel.¹¹

Psoralen in combination with ultraviolet light (PUVA) is a common treatment for vitiligo. However, psoralen has weak percutaneous permeability. Resveratrol, a sirtuin activator, has the potential to manage vitiligo by reducing oxidative stress, therefore psoralen and resveratrol were loaded into ultra deformable liposomes and used as combination antioxidants in PUVA therapy for vitiligo. This combination not only demonstrated greater skin penetration but also showed significant melanin stimulation and tyrosinase activity. Administration of a nanocarrier loaded with resveratrol and psoralen in combination with UV light therapy stimulated pigment and reduced oxidative stress, making it a promising potential therapy for vitiligo.¹²

While the mechanism of vitiligo is not completely understood, oxidative stress is believed to play a significant role in the disease. Platinum and palladium have been investigated for their strong antioxidant properties as they are inducers of superoxide dismutase.¹³ PAPLAL, a topical cream consisting of platinum and palladium nanoparticles, has been shown to be an effective treatment for vitiligo that was refractory to first‐line therapies including narrow band UVB and topical corticosteroids.¹⁴

Acne Vulgaris

Acne vulgaris is one of the most common skin conditions, affecting up to 90 percent of adolescents with presentation ranging from mild to severe. The pathophysiology is multifactorial, making treatment complicated. Therapeutic options for mild to moderate acne typically consists of topical agents, including retinoids, antibiotics, benzoyl peroxide, and salicylic acid, whereas treatment for severe acne consists of oral therapy with isotretinoin, antibiotics, or hormonal agents.¹⁵

While topical tretinoin is an effective treatment, its use is limited by low water solubility and high instability in air and heat. Its use also comes with the risk of significant skin irritation and dryness. Therefore, nanocarriers have been investigated to achieve greater photostability and lower irritation potential. Tretinoin was encapsulated into solid lipid nanoparticles which improved its photostability and showed significantly less irritation when compared to the gel formula in an animal model.¹⁶

Similar to tretinoin, adapalene has been widely used in the treatment of acne vulgaris since gaining US FDA approval in 2016, however it has limited bioavailability in the hair follicle and its use also comes with the risk of irritation and dryness. Adapalene was successfully encapsulated into tyrosine derived nanospheres (TyroSphere™). In ex vivo follicular penetration studies, the tyrospheres significantly enhanced adapalene delivery to the pilosebaceous unit, when compared with commercially available adapalene. In vitro irritation studies also demonstrated decreased irritation potential of the tyrosphere formula.¹⁷

Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that presents with dry, eczematous, erythematous patches, and pruritus. AD is likely mediated by a combination of epidermal changes, increased immunoglobulin E levels, and T-helper 1 and 2 proliferation which leads to elevated levels of inflammatory cytokines. Traditionally, topical corticosteroids have been the treatment of choice for acute flares, however long-term use of topical corticosteroids can cause skin atrophy.

Liposomes, composed of phospholipids, have a strong affinity for the stratum corneum, allowing for increased skin permeability and uptake. Both betamethasone 17‐valerate (BMV), a moderate potency corticosteroid, and diflucortolone valerate (DFV), a high potency corticosteroid, were loaded into liposomes. The liposomes showed 2.68 to 3.22 times greater retention in the stratum corneum and epidermis when compared to the commercially available BMV and DFV creams. In pharmacodynamic evaluation, the liposome formula showed greater anti‐inflammatory activity when compared to the commercial creams, despite the liposome gel having 10 percent less active drug than the commercial cream. This result was thought to be due to enhanced delivery and decreased systemic absorption. Finally, in rat models, AD was induced by dinitrofluorobenzene, and the liposomes formulas not only showed lower erythema, edema, and scratching behaviors, but also to the commercial creams.¹⁸

In a similar study, chitosan nanoparticles were loaded with hydrocortisone (HC) and hydroxytyrosol (HT). These nanoparticles exhibited deeper penetration and a higher concentration of drug in the epidermal layer. This could reduce the dose and frequency of drug application needed for effective treatment, which could decrease the risk of adverse effects. Systemic adverse effects of glucocorticoids include hypocalcemia and hyperglycemia. When commercially available hydrocortisone was repeatedly applied to rat models, they showed a significant decrease in serum calcium concentration and an increase in serum glucose concentration, while the HC‐HT nanoparticle solution did not cause any biochemical derangements. This demonstrates that utilizing a nanoparticle drug delivery system could potentially reduce systemic adverse effects of glucocorticoids, while also increasing skin penetration.¹⁹

While corticosteroids have been considered the first‐line for AD, other topical calcineurin inhibitors, like tacrolimus and pimecrolimus, are being increasingly utilized in AD. Calcineurin inhibitors are often considered safer for long‐term use and use on sensitive areas like the face, but they often cause an uncomfortable burning sensation at the site of application. Tacrolimus has a high molecular weight and poor water solubility which limits its permeability. To reach therapeutic dosing, larger quantities of topical tacrolimus must be applied, which increases the risk of irritation. Chitosan nanoparticles were used as the carrier for tacrolimus. The nanoparticle solution led to greater drug retention in the stratum corneum, epidermis, and dermis than the commercially available cream. In AD induced rat models, AD was successfully managed with the nanoparticle solution containing one‐third the dose in the commercially available cream.²⁰

Sunscreen

Sunscreen commonly contains minerals like zinc oxide and titanium dioxide as the primary active sun protection agents. However, sunscreens with these ingredients are typically opaque and white, which lends cosmetic concerns to many users. Many cosmeceutical companies have begun incorporating nanoparticles into their sunscreens in an attempt to create a more desirable and better tolerated formula.

Sunscreens with zinc oxide and titanium dioxide nanoparticles have been shown, in an in vitro study, to provide enhanced sun protection. Additionally, sunscreen containing nanoparticles demonstrated improved texture with no residual white cast when compared to creams with zinc oxide and titanium dioxide particles.²¹

However, some studies have shown that zinc oxide and titanium dioxide nanoparticles lead to an alteration in the recommended UVA/UVB ratio. Currently, the FDA recommends that at least one‐third of the overall sun protection factor should be against UVA. Reducing the size of the zinc oxide and titanium dioxide particles confers an increased UVB protection at the expense of UVA protection. In order to mitigate this, some researchers have recommended that using various sizes of particles in one formulation, for example using micro and nano zinc oxide (20‐ 200 nanometers) particles and nano titanium dioxide (20‐35 nanometers) particles may remedy this discrepancy. However, more research is needed to determine the ideal size of particles to adhere to the recommended 3 to 1 UVB/UVA ratio.²²

Concerns

As nanoparticle use increases both in treatment of skin disease and in cosmetics, there are concerns regarding the long-term health effects and potential toxicities. The potential for nanoparticles to accumulate in the skin and contain harmful impurities are important considerations regarding toxicity.²³

Due to rising concerns that nanoparticles are depositing into deeper layers of the skin and causing cellular damage, multiple studies have sought to determine the long-term effects of utilizing nanoparticles in various formulations. One study found that both coated and uncoated zinc oxide nanoparticles localized primarily in the stratum corneum with limited penetration into viable epidermis. This study also found that the nanoparticles did not alter the skin barrier function or the redox state of the viable epidermis.²⁴ There are also concerns regarding the ability of titanium dioxide to induce DNA damage and potentially act as a carcinogen.²⁵ However, the carcinogenic effects of titanium dioxide are typically seen after subcutaneous injection or inhalation of nanoparticles.²⁶

There is conflicting data regarding the penetration of zinc and titanium nanoparticles, and thus the ability for these nanoparticles to cause damage. However, despite the conflicting data, the consensus appears to be that nanoparticles in sunscreens and skin care do not pose a health risk, however more research and collaboration is needed between the scientific and cosmetic communities as many cosmetic companies do not advertise their products as containing nanoparticles.^25,27

Conclusion

Nanoparticles, defined as a particle ranging from 1 to 1000 nanometers, have shown extremely encouraging potential in targeted drug delivery systems in the treatment of various dermatologic diseases and conditions. Not only do nanoparticles or nanocarriers exhibit increased penetration and retention of existing topical drugs, but they also have been employed to create topical formulations of drugs that are primarily given as systemic therapy. This allows drugs like methotrexate and cyclosporine to be used topically and without the risk of severe adverse effects. Overall, the utilization of nanoparticles as an enhanced drug delivery system is an incredibly promising area of research with exciting implications in the treatment of many common dermatologic conditions. Nanocarriers appear to be safe, however more research and development is needed as the majority of current research is being done in animal models. It is also important for cosmeceutical and scientific communities to collaborate on research, particularly when it comes to utilization of nanoparticles in sunscreens. Cosmetic companies should also be encouraged to publish or advertise the use of nanoparticles in their products.

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Abstract

Background: Atopic dermatitis (AD) is a heterogeneous disease characterised by epidermal barrier dysfunction and immune dysregulation. It commonly presents with pruritus and eczematous lesions that significantly impact quality of life. Abrocitinib is a JAK inhibitor approved for treatment of refractory, moderate-to-severe AD in patients 12 years and older.

Objectives: This real-world case series intends to illustrate a variety of moderate-to-severe AD patient cases to help guide discussions around abrocitinib and describe its treatment strategies used by experts in the field.

Methods: Expert panel members were recruited from across Canada to discuss varying clinical AD phenotypes seen in their clinic. Guided by literature, the panel shared their opinions and insights to provide a holistic view of the overarching question, “Which patients are good abrocitinib candidates?”

Results: The panel reported on ten real-world patient cases that detailed the use of abrocitinib in biologic naïve patients, refractory AD patients, complex medical patients, and those with differing treatment goals. Cases aim to demonstrate the broad use of abrocitinib in patients with AD, offering a learning point with each real-world case.

Conclusions: Each presented real-world case reflects the panel’s clinical experience. Panel members concluded that abrocitinib is a fast-acting, safe, and efficacious therapy for a wide variety of AD patients with differing disease severities and comorbidities. Treatment with abrocitinib may cause transient nausea that frequently resolves by taking it with food. Overall, patients are highly satisfied with the treatment.

Keywords: atopic dermatitis, real-world cases, JAK inhibitor, abrocitinib

Disclosures and Acknowledgment: The authors conducted the real-world series, supported by an educational grant from Pfizer Canada. The authors acknowledge and thank Sophie Guénin, MSc, for her assistance in preparing this manuscript.

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Introduction

Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease characterized by epidermal barrier breakdown, immune dysregulation, and significantly reduced quality of life (QoL).¹ Approximately 3.5% of the total Canadian population and 25.4% of the pediatric Canadian population is affected with AD.^1,2 This relapsing condition may present as dry, erythematous, sensitive skin or pruritic, excoriated, eczematous, and painful patches with weeping erosions and prurigo nodules.¹ About one-third of AD patients are affected by atopic comorbidities such as asthma, food allergy, and hay fever.³

Patients with AD report impaired quality of life that limits their daily lives and social interactions.³ Pruritus is reported as the most burdensome symptom of AD, with 95% of patients reporting itch as the most important indicator of treatment response.⁴ Other burdensome symptoms included excessive dryness, scaling, inflamed skin, skin pain, and sleep disturbance.⁴ Impaired barrier function in AD is largely attributed to filaggrin dysfunction.⁵ Meanwhile, immune dysregulation in AD largely stems from T-helper (Th)2 cell cytokines, interleukin (IL)-4 and IL-13, in its acute phase and Th1 skewing in chronic disease.⁶ IL-22 and IL-17-producing T cells have also been implicated in the pathogenesis of AD.⁶

Systemic Treatment for Moderate-to-Severe AD

The consensus-based European guidelines for the treatment of AD recommend proactive therapy with topical calcineurin inhibitor (TCI) or topical glucocorticosteroids (TCS) for moderate AD along with narrow band (nb) UVB phototherapy, psychosomatic counseling, and climate therapy.⁶ For severe AD, the guidelines recommend hospitalization in specific cases, systemic immunosuppression with cyclosporine, short-course oral glucocorticosteroids, methotrexate, azathioprine, or mycophenolate mofetil.⁷ Biologic monoclonal antibody therapies such as dupilumab are also recommended for severe AD patients.⁷

Dupilumab is an anti-IL-4-receptor α monoclonal antibody that inhibits the signaling of both IL-4 and IL-13.⁶ Since the guidelines were published in 2018, an additional monoclonal antibody therapy, tralokinumab, an IL-13 inhibitor, has been approved for AD treatment in Canada, as well as two janus kinase inhibitors (JAK) inhibitors (JAKi): abrocitinib and upadacitinib.⁶

Newer topicals such as the topical PDE4 inhibitor, crisaborole, has also been recently introduced for AD treatment, and ruxolitinib, a topical JAK inhibitor, not yet available in Canada.^6,7

Abrocitinib & JAK Inhibitors (JAKis)

JAKis are a new class of systemic treatments for AD that function by blocking downstream cytokine inflammatory signaling.⁶ Abrocitinib and upadacitinib are once daily, oral JAK1 inhibitors that block IL-4 and IL-13, cytokines involved in the pathogenesis of AD, downstream.^8,9 Abrocitinib is available in three doses: 50 mg, 100 mg, and 200 mg, and is approved for moderate-to-severe AD patients aged 12 and older.⁹ In pivotal trials JADE MONO-1 and JADE-MONO-2, abrocitinib demonstrated significant pruritus reduction within two weeks.^10,11 In a phase 3 comparative clinical trial, JADE-COMPARE, abrocitinib 200 mg demonstrated greater IGA response and itch response at endpoint than dupilumab.¹² As with all JAK inhibitors, abrocitinib has inherited a black box warning for thrombosis, major adverse cardiovascular events (MACE), and malignancy. Despite this, clinical trial safety analysis at 48 weeks of both the 100 mg and 200 mg abrocitinib dosage groups showed only 0% to 0.3% incidence of the following: nonmelanoma skin cancer (NMSC), malignancy, MACE, or VTEs.¹³

Upadacitinib is approved for the treatment of AD, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease, ankylosing spondylitis, and non-radiographic axial spondylarthritis.⁹ In refractory moderate-to-severe AD, upadacitinib is approved in Canada for ages 12 and up with two dosing options: 15 mg and 30 mg; recommendations suggest initiating treatment at 15 mg prior to titrating up to 30 mg.¹⁴

As more treatments become available, it will be important for clinicians to partner with patients in a treat-to-target (TTT) paradigm to identify the optimal AD treatment for each patient.¹⁵

Methods

Aim of the Project

This real-world case series illustrates a variety of patients with moderate-to-severe AD treated with abrocitinib. The cases outline the TTT paradigm and demonstrate patient-provider partnerships that highlight patient priorities and ideal treatment options. Expert panelists’ thought processes, reasoning, and rationales are detailed in the following patient cases to serve as a guide for licensed providers who treat patients with AD.

Steps in the Process

The project was conducted in the following five steps: 1) project definition and expert panel selection 2) data collection and preparation of patient cases, 3) patient case discussion and selection for publication 4) literature review to support selected cases 5) drafting, review, and finalization of the manuscript.

Role of the Panel

The panel consisted of 10 dermatologists practicing in Canada who commonly care for patients with AD. Panelists were chosen from 3 provinces in Canada to capture geographical and provincial differences in dermatological practice. During the Dermatology Update conference on April 30^th, 2023, in Vancouver, panelists met to report on and discuss clinical cases of AD patients who were suitable candidates for abrocitinib treatment.

The panel used the following template to gather insight through a case-based approach:

Panelists were asked to select two patient cases from their clinical practice to share and discuss. In the second half of the meeting, panelists examined and collaborated to select ten real-world cases for inclusion in the publication. Panel members agreed that real-world cases should focus on common AD scenarios encountered in the clinic. The publication was prepared and reviewed by the panel.

Experience Gathering and Atopic Dermatitis Outcome Measures

Suggested information and outcome measures to present included patient demographics, concomitant medications, comorbidities and Investigators’ Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (PP-NRS), and patient-reported Dermatology Life Quality Index (DLQI) at weeks 0, 2, and 4 (+/- 5 days) of abrocitinib treatment (Appendix 1). Panelists were also requested to report patient compliance, treatment satisfaction, and any adverse events experienced.

Results

Selected Real-World Cases

The panel selected ten cases to demonstrate the real-world use of abrocitinib in a diverse group of patients with varying skin concerns, past treatment failures, severity, and comorbidities. The findings reflect real-world clinical use of oral abrocitinib and patient treatment outcomes.

Case 1: The recalcitrant, severe AD patient with intense pruritus

A 31-year-old Caucasian, Fitzpatrick Skin Type (FST) 1, female struggling with severe, recalcitrant AD for the past 18 years presented with reported worsening anxiety, avoidance of social activities, and sleep interruption due to debilitating pruritus. Intense pruritus led to diffuse excoriations and multiple skin infections. Her EASI was 22, and DLQI 20. Over the years, the patient had tried TCS, TCI, crisaborole, nbUVB phototherapy, and systemic therapies: prednisone, methotrexate, and intramuscular triamcinolone injection. She had developed striae on her abdomen and arms from frequent TCS use and continued to suffer from intractable itch. The patient started dupilumab but discontinued it after three months due to repeated flu-like symptoms and nasopharyngitis. Having failed first, second-, and third-line therapies for AD, the patient was started on abrocitinib, 200 mg daily. The rationale for beginning abrocitinib at the higher dose was the failure of previous treatment and the patient’s primary complaint of incessant itch. Within eight weeks, she saw rapid improvement; her EASI was 8 and DLQI 4. At week 16, her EASI was 2 and DLQI 0. When asked about her experience, the patient reported that abrocitinib had “life-changing” effects after only one month of treatment. No adverse events occurred, and the patient was reduced to 100 mg abrocitinib daily without exacerbation.

Learning point: Abrocitinib is a fast-acting, effective, and safe treatment option for patients with longstanding, recalcitrant AD. It may be an option for patients who have failed many prior therapies. Abrocitinib therapy can improve patients’ QoL and reduce the need for TCS and other adjunct therapies, thereby sparing patients from the undesirable adverse effects of these treatments.

Case 2. The biologic-naïve patient

Since early childhood, a 55-year-old Caucasian (FST1) salesman with hypertension, hypercholesterolemia, and prediabetes had suffered from severe AD that affected extensive parts of his head, neck, trunk, and extremities. Since starting amlodipine and rosuvastatin for his comorbid conditions, the patient reported worsening xerosis and diffuse erythema.

While biologic naïve, he had previously tried various moisturizers, TCS, TCI, phototherapy, and oral antihistamines with only modest benefit. Despite the multimodal treatment approach, the patient continued to have frequent visits to the Emergency for infections and exacerbations. His condition greatly impacted his work and social interactions as well as his psychological and sexual health. Given his frequent business travel, busy family life, and needle aversion, the patient expressed interest in a convenient, effective treatment that would improve his worsening xerosis and eliminate the requirement for additional therapies. For these reasons, the patient was started on 100 mg abrocitinib. Within two weeks, the patient’s IGA score reduced from 3 to 2, EASI score from 4 to 2 and PP-NRS score from 8 to 3. Two weeks later, the patient saw continued improvement with an IGA score of 1, EASI score of 1, and PP-NRS score of 2. Rapid reduction in itch made the patient extremely satisfied with abrocitinib monotherapy. He did not experience any adverse events and was “thrilled” with his outcome. The patient remains on abrocitinib 100 mg with the option to increase to 200 mg, if necessary.

Learning point: JAKi is an option for biologic-naïve patients for whom self-injection does not correspond to their lifestyle. Patients who travel frequently or lead busy lifestyles may have difficulty transporting subcutaneous injections that must be stored in cool temperatures or having the proper setting to self-inject. Further, some patients are needle-phobic and would prefer an effective, oral treatment option.

Case 3. The patient with post-inflammatory hyperpigmentation

A 29-year-old Southeast Asian (FST4) female presented with sensitive skin, longstanding AD and significant post-inflammatory hyperpigmentation (PIH) around her eyes and on her arms. She had been treated with multiple courses of prednisone with a good response but would predictably flare 2-4 weeks after steroid discontinuation. Having suffered from AD since infancy, she reported the post-inflammatory hyperpigmentation from AD as her most bothersome symptom. Previous treatments included TCS, TCI, and crisaborole. She saw a slight improvement in her skin and pruritus with topical therapy in conjunction with oral antihistamines. Despite mild improvement, she was still desperate for a long-term, effective solution. Her primary care physician had recently made her aware of abrocitinib and encouraged her to seek evaluation by a dermatologist. As a young, single female without any plans for pregnancy in the near future, the patient was a good candidate for abrocitinib and was started on abrocitinib 100 mg. Her IGA was 3 at baseline, EASI score was 4, and PP-NRS score was 8. By week 4, her IGA, EASI, and PP-NRS scores were all 1, and she felt happy and hopeful that PIH marks would continue to fade with time. No compliance issues or adverse reactions were reported.

Learning point: Patients with skin of colour are at increased risk for PIH. Consistent AD treatment with abrocitinib and control of AD, results in PIH improvement and improved mood and QoL. It also reduces inappropriate, long-term use of oral corticosteroids. In females of childbearing age, it is also important to inquire about pregnancy and/or contraceptive use. Pregnancy is a contraindication for abrocitinib use. It should be recognized that contraceptive use may lead to low risk of VTE. Family planning should be discussed with all patients of childbearing potential who are contemplating treatment with abrocitinib.

Case 4. The atopic patient with barriers to treatment access

A 22-year-old (FST2) male with lifelong AD and comorbid atopic diseases (hay fever, asthma, and urticaria) presented with worsening pruritus. Physical exam revealed symmetric, generalized excoriated red, scaly patches with significant lichenification on his bilateral extremities, face, scalp, and back. Working as a dishwasher, the patient reported wearing gloves most of the day to protect his skin from irritating soaps or dryness. Despite his precautions, his skin began impacting his ability to work. He reported skin burning, discomfort, unbearable itch, and skin pain, which frequently disrupted his sleep. At presentation, while on methotrexate, his EASI was 23, IGA score 4, and DLQI 18, with 31% of his body surface area (BSA) affected by AD (Figure 1A [back – face]). Throughout his lifetime, the patient had tried lifestyle modifications such as fragrance-free, hypoallergenic detergent, gentle cleansers, moisturizer application every 2 hours as well as TCS, TCI, calcipotriol gels, oral antihistamines, systemic corticosteroids, and 1-year of methotrexate. Given the severity of the patient’s AD and worsening QoL, the plan was to begin biologic monoclonal antibody therapy. Unfortunately, the patient could not gain access to dupilumab or tralokinumab through his insurance, compassionate drug program, or patient assistance programs. Fortunately, the patient was able to access 100 mg abrocitinib and was thus started on this oral therapy in lieu of biologic therapy. The 100 mg dose was chosen since the patient and his mother were risk-averse and wished to try the 100 mg dose first, increasing to 200 mg only if the 100 mg dose was not sufficient. Two weeks prior to starting abrocitinib, the patient was given his first shingles vaccine. At his 11-week follow-up visit, the patient reported no skin pain and minimal itch with only slight residual erythema on his face (EASI 1.1, IGA 1) (Figure 1B [face – back]). He reported that he could sleep through the night and was able to stop using topical therapies and antihistamines. Of note, the patient experienced mild initial nausea and abdominal pain that abated within the first few weeks of treatment. He had his second shingles vaccine after commencing abrocinitib treatment.

Learning point: Abrocitinib is readily accessible to some patients who are unable to gain coverage for monoclonal antibody therapies such as dupilumab and tralokinumab. While addressing itch, abrocitinib also effectively targets skin pain. It is important to consider shingles vaccination prior to abrocitinib start. The second dose of the vaccine can be given 1-6 months later.¹⁶ Nausea may also be an important adverse effect to discuss with patients. Nausea is frequently transient and can be improved by taking abrocitinib with food.

Figure 1: 22-year-old male with severe AD
(Photos courtesy of Lyn Guenther MD, FRCPC)

Case 5. The complex medical patient with persistent AD-related pruritus

The retired aerospace worker, two-time widower, and former smoker the 63-year-old man, has atopic triad and comorbid anxiety, depression, hyperlipidemia, hypertension, and a history of stroke. He presented with persistent AD, severe pruritus, and atopic keratoconjunctivitis (AKC). His concomitant medications included: citalopram, atorvastatin, ezetimibe, perindopril, and clopidogrel. Despite his other conditions, the patient was most concerned with his pruritus as it had prevented him from sleeping, exercising, socializing, dating, and working. He had only slept through the night three times in the past year. Embarrassed by his skin, he has not been in a swimming pool for over ten years. His EASI was 50, DLQI 26, IGA 4, PP-NRS 10, and BSA 49% (Figure 2A [face – back – legs]).

Having tried numerous moisturizers, TCS, 12 years of nbUVB phototherapy, antihistamines (up to 4 times approved dosing), and multiple cycles of prednisone, he continued to suffer from his skin condition. He was enrolled in a lebrikizumab clinical trial, which helped his AD and pruritus but did not clear his face and neck. However, during the clinical trial, he suffered a non-treatment-related posterior cerebral artery infarct, which has deterred him from future biologic use. The patient redeveloped generalized erythema, lichenification, and scaling off the biologic.

The rationale for starting abrocitinib stemmed from numerous conversations with the patient, during which he highlighted his preference for QoL over mere survival. He was desperately seeking to sleep through the night and regain control of his life. Use of immunosuppressants such as methotrexate and cyclosporine were contraindicated in this patient due to his heavy alcohol use and hypertension, respectively. Given his AKC, dupilumab, and tralokinumab were eliminated as options to reduce the risk of worsening his ocular involvement. The lower perceived rates of MACE and VTE events with abrocitinib compared to upadacitinib led to the patient being started on abrocitinib. Two weeks prior to starting abrocitinib, he received his first dose of the shingles vaccine. The decision was made to start at 50 mg of abrocitinib to mitigate any potential risk for drug interactions or adverse cardiovascular events. He reported that during his first week on abrocitinib, he was able to sleep itch-free every night and noticed smoother skin texture. After one month of monitoring without any adverse events nor appreciable changes in blood values, the patient was increased to 100 mg abrocitinib. After two weeks on 100 mg abrocitinib, the patient’s EASI was reduced to 6.4, DLQI to 6, IGA to 2, PP-NRS to 1.5, and BSA to 10% (Figure 2B [face – back – legs]). The patient remains on 100 mg of abrocitinib with good control of AD, itch, and good tolerability.

Learning point: Assessment of risks and benefits with a patient remains an important consideration in the TTT paradigm for AD treatment. While extra precautions must be considered in a complex medical patient, their complexity does not preclude them from abrocitinib therapy. Titration of the abrocitinib dose, starting at 50 mg, may also help minimize any potential risk while simultaneously allowing patients to benefit from treatment.

Figure 2: 63-year-old medically complex male with anxiety, depression, hyperlipidemia, hypertension, and a history of stroke
(Photos courtesy of Lyn Guenther MD, FRCPC)

Case 6. The busy professional biologic naïve patient needing a fast-acting therapy

A 38-year-old lawyer of Asian (FST4) descent presented to the clinic in search of a rapid solution for his AD. He had no significant past medical history other than lifelong AD. At presentation, his DLQI was 28, EASI was 50, and IGA was 4 (Figure 3A [face – legs]). He had only previously tried betamethasone 0.1% cream and prednisone with mild, transient improvement after each therapy. Despite being naïve to systemic therapies beyond prednisone, he wanted a quick, easy solution to his skin condition that would not impact his busy schedule and allow him to enter conference rooms with confidence. Understanding the patient’s aggressive treatment goals, the provider started him on 200 mg of abrocitinib with concomitant use of tacrolimus ointment 0.1% twice daily, as needed. Four weeks later, the patient returned with 90% skin clearance, including complete clearance on his face and only post-inflammatory erythema remaining on his extremities (Figure 3B face – legs]. At his 6-month follow-up, he had clear skin (Figure 3C [legs]). While he was given the option to reduce to the 100 mg dose, the patient has been reluctant to decrease the dosage given his rapid, lasting response to the current abrocitinib 200 mg regimen.

Learning point: The 200 mg dose of abrocitinib may be an optimal first-choice therapy for select patients. The JAKi allows for fast results, and the ease of a once-daily pill makes it an ideal option for working professionals with hectic lives. The 100 mg and 200 mg abrocitinib dosing options also allow patients to choose how aggressively they would like to treat their AD while relying on their provider to help them weigh the risks and benefits.

Figure 3: 38-year-old biologic naïve male
(Photos courtesy of Andrei Metelitsa MD, FRCPC)

Case 7. The dupilumab failure AD patient

A 62-year-old (FST3) male with generalized AD since adolescence was initiated on 100 mg of abrocitinib therapy. Having struggled most of his adult life with daily TCS and emollient regimens, the patient was frustrated as his AD had a determinantal impact on his daily activity, social life, sports participation, and sleep. He had previously tried one year of dupilumab treatment with an inadequate response. Prior to starting abrocitinib, his EASI was 12, IGA 3, and PP-NRS 8. After two weeks on abrocitinib, the patient had an EASI of 3.2, IGA 1, and PP-NRS of 1. Despite reporting nausea from therapy, he expressed 8 out of 10 satisfaction, given his dramatic skin response. At his 4-week follow-up, the patient had an EASI of 2.1, IGA 1, and PP-NRS of 1, with resolution of his nausea and no further adverse events.

Learning Point: Abrocitinib is an ideal step-up therapy for patients who have an inadequate response to dupilumab. The differing mechanisms of action of abrocitinib and dupilumab make the trial of abrocitinib worthwhile in a patient who may have failed IL-4 receptor blockade. Nausea, when and if it occurs, often resolves spontaneously.

Case 8. The patient intolerant to dupilumab

Struggling with AD since childhood, a 47-year-old female (FST4) with mild asthma and severe AD presented after 16 months of dupilumab therapy. While dupilumab was effective for the first year, her skin failed to maintain its initial response. She had also developed persistent conjunctivitis secondary to dupilumab use. AD covered her trunk, face, and proximal extremities and often caused her to miss work and avoid romantic and social relationships. She struggled to sleep through the night without scratching. In the past, she had tried topical tacrolimus and clobetasol without any lasting improvements. The rationale for starting 100 mg abrocitinib was intolerance and failure to maintain response to dupilumab. On Day 0, her EASI was 35, IGA 4, and PP-NRS score 8. Upon starting abrocitinib treatment, the patient reported mild nausea that improved when the tablet was taken with food. By week 4, the nausea had resolved, and the patient had an EASI of 16, IGA of 2, and PP-NRS of 3. She reported feeling more confident in her skin, with reduced pruritus and improved sleep and quality of life. Without experiencing any other side effects, the patient remains on 100 mg of abrocitinib and is highly satisfied with the treatment.

Learning Point: The side effect profile for abrocitinib does not include conjunctivitis or any other ocular effects, making it ideal for patients sensitive to the adverse reaction of dupilumab or tralokinumab or patients with comorbid ocular conditions. Lastly, nausea is a common adverse effect of abrocitinib therapy that usually resolves with time and may be mitigated by taking the medication with food.

Case 9. The patient with adult-onset AD

The 49-year-old (FST2) male presented with a 4-year history of adult-onset AD. He had a remote history of alcohol-induced pancreatitis but no other comorbidities. Expressing high levels of frustration with his inadequate sleep and intractable itch, the patient wanted rapid control of his pruritic skin. He had tried TCS, TCI, and cyclosporine without sustained skin improvement, and he experienced deterioration of his kidney function from cyclosporine. His EASI was 25, IGA 4, and PP-NRS score 9. The rationale for starting abrocitinib was that the patient was desperate for rapid control. While upadacitinib was considered for rapid pruritus relief, the patient’s history of alcoholism made abrocitinib a safer option as it does not require monitoring of liver function tests. After four weeks of abrocitinib 100 mg daily use, the patient no longer required use of TCS and had an EASI of 1.2, IGA of 2 and PP-NRS of 4. He was extremely satisfied with treatment and tolerated the treatment without any adverse events.

Learning Point: Immunosuppressants such as cyclosporine and methotrexate have long been used to treat AD, although Health Canada does not approve them for treating AD. In addition, these immunosuppressants are often associated with kidney toxicity (cyclosporine), liver and bone marrow toxicity (methotrexate) as well as malignancy (both medications). Thus, long-term use of these immunosuppressants is not appropriate for long-term use in AD patients. In addition, the increasing availability of efficacious, safe, and targeted treatments for AD makes the use of broad immunosuppressants inappropriate.

Case 10. The AD patient switching from another JAK inhibitor

The 21-year-old (FST4) male university student presented with severe AD involving his torso and limbs. His AD first presented in childhood. He had a positive family history of atopic disease. Having tried TCS, crisaborole, and a 2-year course of methotrexate without improvement, the patient was started on upadacitinib. While the upadacitinib helped to significantly clear his skin, he developed acneiform lesions on his face which led to treatment cessation. His AD returned upon upadacitinib cessation (EASI 24, IGA 4, and BSA 30%). A healthy young man, the patient was offered to start at the higher 200 mg dose of abrocitinib, which should allow for faster control of his AD and a quicker return time to being more productive at school. At his 4-week follow-up, the patient had an EASI of 1.2, IGA of 2, and BSA of 3%, with the most considerable improvement on his face and neck. The patient reported mild nausea a few hours after taking abrocitinib; however, the nausea abated when he started taking it with food. Interestingly, he did not experience acne on abrocitinib.

Learning Point: Abrocitinib is a good treatment option for patients who had adverse reactions to another JAKi. There is a low risk of acne as an adverse reaction to abrocitinib versus upadacitinib. Thus, if a patient develops acne on one JAKi, it does not preclude them from trying abrocitinib.

Discussion

Real-world cases provide highly impactful insight into patient and provider experience with a new treatment. Without a cure, the AD treatment goal is aimed at reducing symptoms to a level that has minimal or no impact on patient QoL. In the patient cases discussed above, all patients had previously tried and failed topical therapies such as TCS, TCI, and various emollients and moisturizers. While some had tried systemic therapies, a few were naïve to systemic AD therapies prior to starting abrocitinib. Each patient discussed had a complete or near complete response by week 4 of abrocitinib therapy and reported significant satisfaction with treatment. This real-world case discussion provides invaluable insight into abrocitinib use in a diverse population of Canadian patients suffering from moderate-to-severe AD.

Biologic Naïve Patients

The 2018 consensus-based European guidelines for the treatment of adult AD only recommend the use of dupilumab in severe AD.⁶ While JAKi’s were not yet approved when these guidelines were released, clinical experience suggests that many practices do not recommend JAKi until a patient has failed all other standard therapies, such as dupilumab and other immunosuppressants. However, panel members discussed five cases of biologic-naïve patients with safe, efficacious, and accessible treatment with abrocitinib. The patients’ successful treatment with abrocitinib as a second-line therapy after topicals suggests that requiring a patient to cycle through a biologic prior to a JAKi may be unnecessary. Biologic naïve patients reported being “thrilled” and “very satisfied” with abrocitinib oral dosing that provided rapid itch relief and improvement in QoL.

Dupilumab Failed/Intolerant Patients

Another recurring rationale for initiating a patient on abrocitinib therapy was previous inadequate response or intolerance to dupilumab treatment. Three patients presented had previously been on dupilumab and stopped either due to inefficacy, failure to maintain response, or secondary conjunctivitis. Switching to abrocitinib after prior dupilumab therapy had no effect on the JAKi’s efficacy. Each patient saw near complete response to abrocitinib on either 100 mg and 200 mg dosing approaches. Failure to maintain response to dupilumab may stem from the monoclonal antibody’s ability to trigger the development of anti-drug antibodies (ADA).¹⁷ Some reports show a 7.61% ADA incidence in dupilumab studies, which may be higher in sporadic dupilumab injectors.¹⁸ Abrocitinib, a small-molecule JAK inhibitor, does not trigger the production of ADAs, which may contribute to greater maintenance of initial response.¹⁸ In one-year clinical trials, JADE EXTEND for abrocitinib and LIBERTY AD CHRONOS for dupilumab, 60.5% of patients on abrocitinib 200 mg exhibited an IGA 0/1 at week 48 while only 40% of patients on dupilumab 300 mg weekly and 36% of patients on dupilumab 300 mg biweekly exhibited an IGA score of 0/1 at week 52.^19,20

Jumping JAKi’s and Adverse Reactions

To date, two systemic JAKi’s, upadacitinib and abrocitinib, are indicated in Canada for AD treatment. The most common adverse reactions to abrocitinib include nasopharyngitis, nausea, headache, herpes simplex, increase in blood creatinine phosphokinase, dizziness, urinary tract infection, fatigue, acne, and vomiting. Acne occurred in 4.7% of patients on 200 mg abrocitinib and 1.6% of patients on 100 mg abrocitinib in placebo-controlled trials.⁸ While upadacitinib shares many similar adverse reactions to abrocitinib, 16% of patients on 30 mg and 10% on 15 mg of upadacitinib developed acne during placebo-controlled clinical trials.¹⁴ Case 10 illustrates that patients who develop acne on upadacitinib may not have this adverse event on abrocitinib.

In the real-world cases presented, nausea was the most common adverse event experienced by four patients in the series. The nausea was reported to subside over time or when counseled to take abrocitinib with food. Reactivation of the varicella-zoster virus (VZV) has also been reported in approximately 1% of abrocitinib-treated patients.¹³ The panel suggests shingles vaccination in conjunction with JAKi use. Two presented cases reported that first dose shingles vaccination occurred two weeks prior to abrocitinib start.

Dosing Approach

Abrocitinib is unique in that it offers three potential dosing strategies: 50 mg, 100 mg, and 200 mg.⁸ Depending on preference, patients and providers may choose to start at a higher dose and titrate down or start at a lower dose and titrate up. Considering patient factors, disease factors, and concomitant medications, providers should work with their patients to choose the best dosing strategy for them.

Abrocitinib is predominately metabolized by CYP2C19 (~53%) and CYP2C9 (~30%); thus, co-administration of abrocitinib with a strong CYP2C19 and CYP2C9 inhibitor is not recommended and may increase the risk of adverse reaction to abrocitinib.⁸ Case 5 had a history of cerebral infarct and anxiety treated with CYP2C19 inhibitor, clopidogrel, and CYP2C19 substrate, citalopram, respectively. Despite his complex medical history, because of the impact of his severe AD on his QoL and sleep (he only slept three nights/year pre-abrocitinib), he was initiated on 50 mg of abrocitinib to assess safety. He tolerated the regimen without any adverse reactions. The 50 mg abrocitinib allows for further dose titration in patients with poor renal function or who are poor CYP2C19 metabolizers.

While extra caution must be taken, the panel agreed that patients with complex medical histories should not be excluded as potential candidates for abrocitinib without first evaluating the risks and benefits and having a thorough discussion with these patients.

Future Directions

The panel agreed that patient testimonials are highly impactful and educational. Patients are often enthusiastic about sharing their experiences. In the future, it will be important to direct discussions toward more complex AD cases to help healthcare providers choose appropriate dosing strategies and treatment regimens with the proper precautions. Further investigation into AD-associated PIH in individuals with sensitive skin may also help elucidate therapy plans for all skin types. Lastly, one panel member suggested further training of other medical specialties outside of dermatology in order to earlier recognize and appropriately treat AD patients. In particular, emergency medicine (EM) practitioners come in frequent contact with AD patients suffering from recurrent infections or exacerbations. Educating EM providers may allow for faster AD treatment and reduced patient suffering.

Conclusion

The real-world cases presented reflect the expert panel’s clinical experience with abrocitinib for the treatment of patients with moderate-to-severe AD. The panel’s cumulative insight suggests that abrocitinib is a safe, effective, and rapid-acting AD therapy that may be used in all Fitzpatrick skin types and disease stages. Through a multi-option dosing approach, abrocitinib fosters a TTT paradigm that allows patients and providers to form successful, individualized AD treatment plans.

Limitations

The presented cases represent real-world experience with abrocitinib. All outcome measures were reported from providers in the clinic and reflect real-life data rather than data from a controlled, clinical trial environment. Actual experience with abrocitinib may differ with each patient and/or provider. Our expert panel included general dermatologists and did not include specialized pediatric dermatologists. Thus, this discussion does not provide real-world experience in a pediatric setting. Off-label use of abrocitinib is up to the discretion of treating healthcare providers.

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ayaa Alkhaleefa, Taylor Evart Woo, and Laurie Parsons have no relevant disclosures. Funding sources: None.

Abstract: Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Dupilumab was approved by the US Food and Drug Administration in September 2022 and Health Canada in July 2023 for the treatment of PN. Dupilumab is a human monoclonal immunoglobulin G4 antibody that binds the interleukin (IL)-4 receptor alpha subunit, blocking intercellular signalling of IL-4 and IL-13. Inhibition of these cytokines downregulates the inflammatory response and improves disease severity and pruritus. Two randomized controlled trials have shown dupilumab to be effective in reducing pruritus and lesion count in patients with PN. The approval of dupilumab for PN represents the first approved therapy for PN and may indicate a paradigm shift in the way this condition is treated.

Keywords: dupilumab, Dupixent®, immunomodulator, biologic, prurigo nodularis, nodular prurigo, clinical trial

Introduction

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by prurigo nodules, a cutaneous reaction pattern in which pruritus is a central component.^1,2 It presents with papulonodules distributing along the trunk and extensor surfaces and ranges from few to hundreds of lesions.^2,3 It is among the dermatoses that demonstrate the “butterfly sign”, where skin on the upper back is spared.⁴ The mean age of patients with PN is 50.9 years, and it is slightly more common in females who have darker skin phototypes.⁴ PN may be associated with underlying systemic diseases, including chronic obstructive pulmonary disease, congestive heart failure, chronic nephritis, type 2 diabetes mellitus, or the human immunodeficiency virus (HIV) infection. Clinical features of PN include intense pruritus that is present constantly, intermittently, or paroxysmally for ≥6 weeks. The diagnostic workup for PN includes a complete blood cell count with differential, liver and renal function tests, diabetes screening, thyroid function testing, infectious etiologies including viral hepatidies, and excluding other systemic etiologies.³

The pathogenesis of PN involves immune and neural dysregulation.^3-5 Biopsy of prurigo lesions show dense dermal, interstitial, and perivascular infiltrates in the dermis.³ These infiltrates primarily consist of increased numbers of T-lymphocytes, mast cells, and eosinophilic granulocytes. These collections of immune cells generate a robust inflammatory response releasing interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins, and neuropeptides causing an intractable itch. In addition, there is upregulation of several neuropeptides such as calcitonin gene-related peptide and substance-P. Upregulation of neuropeptides promotes their secretion into cutaneous tissue via nerve fibers, ultimately causing neurogenic inflammation.

Treatment options for PN involve addressing potential underlying causes, providing symptomatic relief, and breaking the itchscratch cycle.^3,6 The first-line topical therapy for PN is high potency topical corticosteroids, such as betamethasone valerate 0.1% tape.³ Other treatment options include topical calcineurin inhibitors, topical capsaicin, neuromodulators (gabapentinoids, cannabinoids, or anesthetics), antidepressants, phototherapy, and immunosuppressants. However, many treatments for PN are commonly used off-label and there exists variability in dosing regimens, leading to varying degrees of efficacy and clearance rates.⁷

Dupilumab represents the first and only US FDA and Health Canada approved medication for the treatment of PN.⁸ Dupilumab is a human monoclonal immunoglobulin G4 antibody that works by binding the IL-4 receptor alpha subunit shared by the IL-4 and IL-13 receptor complexes (Figure 1). Binding to this subunit inhibits both the inflammatory and pruritic processes, which are integral components in managing the itch-scratch cycle. IL-31 is a cytokine that is associated with the immune cascade and is believed to contribute towards symptoms of intense pruritus in PN.^4,6

Supporting Evidence for Dupilumab Monotherapy

The clinical trials involved in the regulatory approvals of dupilumab for PN, PRIME and PRIME2, showed significant improvement in the treatment of extreme pruritus and reduction in lesion count. The clinical investigations included two 24-week randomized, double-blind, placebo controlled, multicenter, parallel-group trials.^9,10 Adults aged 18-80 years (n=311) with ≥20 nodules and pruritus were included. Pruritus was graded using the Worst-Itch Numeric Rating Scale (WI-NRS), where 0 indicated no itch and 10 indicated insupportable itch. Only patients with WI-NRS score of ≥7 prior to commencement of dupilumab were investigated. Additional inclusion criteria included a history of failing a 2-week course of medium-to-superpotent topical corticosteroid or when topical corticosteroids were not medically advisable. Both clinical trials assessed the effect of dupilumab in reducing the number of lesions along with pruritus improvement. Efficacy was assessed by a reduction in WI-NRS by ≥4 points and Investigator’s Global Assessment PN-Score (IGA PN-S) of 0-1, which is equivalent to a reduction in the number of nodules down to 0-5. Patients received either dupilumab 600 mg subcutaneously on day 1 followed by 300 mg once every other week for 24 weeks on a background therapy of topical corticosteroids/topical calcineurin inhibitors at a stable dose, or a matching placebo drug. The mean age of patients was 49.5 years, and 65% of subjects were female. At baseline, the WI-NRS score was 8.5, and 66% of patients had 20-100 nodules while 34% had more than 100 nodules. In addition, 43% of patients had a history of atopy.

The first clinical trial (PRIME) showed that 38.7% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 9.2% of patients who received placebo (Table 1).⁹ The second clinical trial (PRIME2) showed that 32.1% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 8.5% of patients who received placebo (Table 2).¹⁰ Overall, dupilumab demonstrated efficacy in treating both the extreme pruritus and for reducing the number of PN nodules over a 24- week period.

Safety

Dupilumab appears to be safe for the treatment of PN. The most common side effects include 1-2% of patients who developed injection site reactions, which was more likely to occur with the initial loading dose. In addition, 8.6% of patients (n=152) had headache, 5.3% of patients (n=152) had nasopharyngitis, 4% (n=152) of patients developed conjunctivitis, and 3% (n=152) of patients developed herpes infection, dizziness, myalgias, and diarrhea.^9,10 Serious adverse events, including neurodermatitis occurred in 1.3% of patients (n=152). The following serious adverse events occurred in <1% of the patient sample: coronavirus disease of 2019 pneumonia, musculoskeletal chest pain, papillary thyroid cancer, asthma, interstitial lung disease, pelvic inflammatory disease, acute pyelonephritis, lipoma, and uterine leiomyoma. The aforementioned adverse effects were not considered related to the study intervention, except for sepsis and mesenteritis which occurred in one patient in the placebo group.¹¹

Combination Therapy Studies

Studies exploring combination therapies with dupilumab are limited. Kabbani et al. shared a case study of a 49-year-old woman who had psoriasis and PN and was successfully treated with a combination of dupilumab and ustekinumab.¹² Ustekinumab is a human monoclonal antibody that is used to treat plaque psoriasis, psoriatic arthritis, and inflammatory bowel disease.¹³ It specifically inhibits the inflammatory response caused by IL-12 and IL-23. After 3 months of ustekinumab 45 mg every 12 weeks and dupilumab 600 mg loading dose followed by 300 mg every 2 weeks, the patient had complete resolution in her pruritus. After 10 months on this combination therapy, she achieved complete clearance of her nodules. The patient has been on this combined therapy for 4 years, and has maintained her clinical response in remission. The combination therapy has been well tolerated, and there have been no safety concerns reported.

Special Populations

Safety and efficacy of dupilumab for pediatric patients younger than 18 years of age with PN have not been established.^9,10 PN has an incidence of 21.6 per 100,000 children and is commonly associated with atopic dermatitis.¹⁴ Few case reports have highlighted the use of dupilumab in pediatric patients. For example, a 7-year-old boy who had PN was treated with dupilumab 400 mg followed by 200 mg every 2 weeks. He was also using topical corticosteroids at the time. After 4 weeks of dupilumab therapy, the patient noted improvement in his prurigo lesions and no new lesions developed. By 12 weeks, the patient reported resolution of pruritus, and at the 1 year follow-up there were only a minimal number of active skin lesions and almost no excoriations. Overall, further clinical trials are required to determine the efficacy and safety of using dupilumab for PN in the pediatric population.

Conclusion

Dupilumab is an effective treatment for adult patients who have PN. Most notably, therapy improves the severe pruritus associated with this condition. Dupilumab has been shown to have a promising safety-profile and represents a paradigm shift in the way patients with PN are treated. However, further research is also required to determine the efficacy and safety of dupilumab for PN in the pediatric population.

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Abstract

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease affecting 2-4% of the Canadian population. Lifelong management is required. While most psoriasis vulgaris cases are mild-to-moderate (>80%) and do not require systemic treatment, these cases can still be particularly challenging to treat as topical therapies present limitations, including efficacy and administration, leading to poor long-term treatment compliance and unsatisfactory treatment responses. The intent of this paper is to provide physicians with a clinically relevant review of the currently available and newly developed topical therapies for psoriasis, the practice guidelines for topical management of mild-to-moderate psoriasis, and the common pitfalls and mitigation strategies to encourage long-term treatment compliance.

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Introduction

Psoriasis is a common immune-mediated skin disease affecting ~2-4% of the population in North America.¹ In nearly one-third of cases, disease begins during the first 2 decades of life and follows a chronic and persistent course, resulting in high cumulative lifetime disability.² Psoriasis is divided into 4 major clinical forms, including plaque psoriasis, guttate psoriasis, erythrodermic psoriasis and pustular psoriasis.³ Plaque psoriasis represents >90% of cases and will be the focus of this review. Classically, plaque psoriasis affects the trunk as well as the extensor surfaces of the elbows and knees; it can also affect other body sites, giving rise to regional variants such as scalp, face, intertriginous, palmoplantar, genital and nail psoriasis.³

Because psoriasis is often localized to visible and/or special body sites (knees, elbows, trunk and scalp) and is commonly associated with pain and itch, it often causes significant physical and psychological burdens.⁴ Stigmatization is common and contributes to poor health-related quality of life (HRQoL), elevated risk of multiple health comorbidities, and increased barrier to treatment.⁵ Indeed, a recent Global Burden of Disease (GBD) study ranked psoriasis as the second contributor to all skin-related Disability Adjusted Life Years (DALYs).⁶ The GBD study highlighted an increase in prevalence and morbidity of psoriasis globally, with North America and Europe being particularly affected, emphasizing the significant burden that psoriasis imposes on both individuals and society as a whole.⁶

Mild, moderate, and severe psoriasis are defined as plaques affecting <3%, between 3-10%, and >10% of body surface area (BSA), respectively.¹ Much progress has been realized in regards to managing severe disease with the approval of numerous advanced systemic therapies, including biologics and small molecules.⁷ Unfortunately, in contrast to severe disease, there has been very limited advancement in the management of mild-to-moderate disease, which affects >80% of the psoriatic patient population.^8,9 Mild psoriasis is typically managed with lifelong skin-directed topical therapies.¹⁰ Topical therapies are also often used to treat severe psoriasis vulgaris, either as monotherapy or as an adjunct to phototherapy and/or systemic therapy.¹⁰

The most commonly used topical therapies in psoriasis include corticosteroids, vitamin D3 analogues, retinoids, calcineurin inhibitors, keratolytics and tar. Multiple fixed-ingredient combination products have become commercially available in the last 20 years with the aim to overcome challenges related to lack of efficacy, compliance and adverse events.¹¹

Our objective is to review: 1) the currently available and newly developed topical therapies, both single and fixed-dose combination products; 2) clinical practice guidelines specific to the topical treatment of psoriasis; and 3) common pitfalls and mitigation strategies when managing psoriasis with topical therapies. While we recognize the importance of behavioural modification and skin care in the management of psoriasis vulgaris of all severities, we refer the reader to the review article by Ko et al. on the topic.¹²

Literature Search

This narrative literature review included studies that examined currently available therapies for psoriasis from 2010 to present. The review was conducted using the PubMed and Embase databases with the following search terms: (psoriasis) AND [(corticosteroids) OR (topical corticosteroids) OR (topical corticosteroids AND salicylic acid) OR (topical corticosteroids AND coal tar) OR (calcipotriol) OR (calcitriol) OR (tacalcitol) OR (pimecrolimus) OR (tacrolimus) OR (tazarotene) OR (retinoids) OR (corticosteroid* AND calcipotriol) OR (corticosteroid* AND calcitriol) OR (corticosteroids AND tazarotene) OR (roflumilast) OR (tapiranof) OR (topical treatment)] as either keywords or MeSH terms. Clinicaltrials.gov website was also searched for ongoing Phase II and III clinical trials. References of identified manuscripts were manually extracted to identify additional articles. Only articles published in English were considered. Articles were included if they reported on treatment of psoriasis in humans, regardless of study type. All publications were independently assessed by SG and EN first by screening titles, then abstract, followed by full-length manuscripts. Any discrepancies were discussed and resolved.

Topical Therapies for Psoriasis – Our Current Toolbox

Psoriasis is a chronic disease that requires a life-long treatment. Most patients are managed with topical treatments, therefore, it is important to recognize all presently available therapeutic options, taking into account their respective efficacy, safety profile, and usage considerations. Currently, available treatments that will be discussed include topical corticosteroids (TCS), vitamin D3 analogues, calcineurin inhibitors (TCI), tar-based preparations, retinoids, and combination therapies.¹³ These therapies can be used to induce skin clearance and to maintain disease control.¹⁴ Monotherapies with dithranol and salicylic acid will not be discussed, as their clinical use is limited. A clinical timeline of topical therapies for psoriasis is provided in Figure 1. This section will first discuss efficacy and safety considerations of monotherapies followed by combination treatments. Novel therapies, established or previously published guidelines for topical medications use and general recommendations to improve compliance are discussed in following sections.

Monotherapies

Topical Corticosteroids (TCS)

TCS have been used to treat psoriasis for over 60 years.¹⁵ TCS exert broad anti-inflammatory, immunosuppressive, and antimitotic effects.¹⁶ The most recent systematic review that we have identified focusing on TCS efficacy and safety in psoriasis dates back to 2012.¹⁵ It included 50 randomized controlled trials (RCTs), of which only 11 were placebo controlled. Potent and ultra-potent TCS were used in different formulations to induce and/or maintain disease control. Only 5 studies used the Psoriasis Area and Severity Index (PASI) assessment tool to measure efficacy outcomes. The mean percentage change in the PASI from baseline to 4-8 weeks ranged from 45-60%. However, the overall reported efficacy rating varied greatly depending on the study. An added benefit of occlusion was suggested (1 study), whereas no efficacy difference was established between different vehicles (2 studies). Three studies confirmed that weekend (or episodic) TCS treatment after achieving skin clearance was valuable to prevent plaque recurrence in 30-40% of patients at 6 months.

Since this publication, we identified 2 additional RCTs.^17,18 Desoximetasone 0.25% spray twice daily (BID) demonstrated statistically significant clinical success compared to the vehicle as measured by Physician Global Assessment (PGA) score 0/1 at 4 weeks (39% vs. 7%, respectively).¹⁷ Efficacy was better among compliant patients who received reminders compared to those that were not reminded, suggesting that compliance is an important barrier to treatment success.^18-20 Another RCT compared once daily (QD) halobetasol propionate 0.05% cream vs. halobetasol propionate 0.01% lotion suggesting similar efficacy at 2 weeks.²¹

Despite corticosteroid-sparing alternatives and combination therapies (discussed below) being commercially available, TCS remain widely used because of the low cost of some products as well as their versatility. They are available in a wide range of vehicles and potencies, ranging from I (ultra-high potency) to VII (low potency). Available vehicles include creams, lotions, foams, gels, ointments, shampoo, sprays, and solutions²² (Table 1). Typically, potent to ultra-potent TCS (class I-II) (e.g., clobetasol propionate) are used for thick plaques on the trunk/limbs or special sites, such as the scalp and palmoplantar regions; moderate potency TCS (class III-IV) (e.g., betamethasone valerate; triamcinolone acetonide) are suitable for thinner plaques on the trunk/limbs, whereas mild potency TCS (class VI-VII, e.g., desonide; hydrocortisone) are recommended for intertriginous areas, genitals and/or face.²² Milder potency preparations are also usually preferred to manage psoriasis in pediatric or pregnant patients.^23,24 The choice of the vehicle is made by the treating physician together with the patient. While some vehicles are preferred based on the anatomic site being treated and desired potency, patient preference is of utmost importance since this enhances treatment compliance. An RCT of vehicle preference among various TCS preparations assessed adherence to treatment and improvement of HRQoL among patients with psoriasis between spray, cream, ointment, gel, lotion, foam, and solution.²⁵ It was found that patient preference was highly variable, with less messy products favoured.²⁵ There was no overwhelming agreement on the effect of TCS vehicles in terms of efficacy, hence treatment should be individualized.

Table 1. Topical Corticosteroid Classes of Potency

Adverse events (AEs) with TCS use are generally rare, but may occur with prolonged and/or inappropriate use. These include local AEs such as skin atrophy, telangiectasia, striae, poor wound healing and infections. When used on the face or acne-prone skin, acne exacerbation or de novo periorificial dermatitis/folliculitis may occur.²⁶ Furthermore, even class VII TCS used on eyelids for prolonged periods can lead to cataracts and/or glaucoma.²⁷ Systemic AEs related to hypothalamic-pituitary axis (HPA) suppression are exceedingly rare.^28,29 Two systematic reviews/meta-analyses evaluated TCS safety in psoriasis. Literature identified was reassuring, with <5% risk of skin atrophy³⁰ and <5% rate of HPA suppression when TCS were used long-term.³¹ TCS withdrawal reactions, such as Red Skin Syndrome or topical steroid addiction, have also been reported with discontinuation of prolonged, frequent use of moderate to high potency TCS.³² These severe reactions are rare and are more likely to occur with use on special areas, such as the face and the genitals. A recent review article concluded that TCS are generally safe and effective when used correctly for short periods of time or with short breaks in longer treatments.³² Beside AEs, additional TCS related limitations include potential tachyphylaxis and corticophobia. Whether tachyphylaxis truly exists is debated among experts, as diminished efficacy over time may be related to low adherence to treatment among patients, especially when long-term treatment is required.³³ Corticophobia among patients and health care providers remains omnipresent and is a major barrier for treatment efficacy beyond inherent limitations associated with the drugs of this class.³⁴

Vitamin D3 Analogues

The introduction of Vitamin D3 analogues ~30 years ago was met with much enthusiasm due to their steroid-sparing effect.³⁵ Commercially available vitamin D3 analogues in Canada are calcipotriol and calcitriol ointments. Vitamin D3 analogues may be used as monotherapy, as an adjunct to TCS, or as fixed-dose combination therapy. They work by regulating gene transcription, modulating keratinocyte proliferation, and differentiation.³⁶ The mechanism of action also involves the inhibition of T cell proliferation and downstream inflammatory mediators.³⁶

There are several systematic reviews published assessing the efficacy of vitamin D3 analogues compared to vehicle or TCS.^37-41 As monotherapy, 1 review reported treatment success (defined as >90% reduction in the PASI score) with vitamin D3 analogues ranging from 4-40% after 6-12 weeks of therapy.³⁷ Another reported a decrease in the PASI ranging from 27.8-60.4% with calcipotriol monotherapy.³⁸ Further, BID use of vitamin D3 analogues was found to be at least as effective as TCS and more effective than placebo at 8 weeks.^38,39 A systematic review focused on efficacy of vitamin D3 analogues in pediatric psoriasis patients found 5 studies reporting improvement in PASI from baseline ranging from 17.3-94%, 1 study reporting improvement in Psoriasis Scalp Severity Index (PSSI) of 32.1%, and 1 study reporting 100% clearance of skin lesions.⁴⁰

In the last 10 years, only 2 new double-blind, vehicle-controlled phase III RCTs evaluated the efficacy and safety of calcipotriol 0.005% foam BID for mild-to-severe psoriasis (defined as plaque psoriasis involving 2-20% BSA) compared to vehicle.⁴² Both studies demonstrated significant treatment success, defined as the Investigator’s Static Global Assessment (ISGA) scores of 0/1 at 8 weeks. The primary outcome was achieved in 15% vs. 7% of calcipotriol vs. vehicle patients in the first study and 28% vs. 6% in the second study.⁴²

The use of vitamin D3 analogues in psoriasis has been shown to be safe and well-tolerated, with less AEs than TCS. AEs are generally comparable to the vehicle, with application site reactions occurring in less than 2% of subjects.⁴² Specifically, these include stinging, burning, and peeling of the skin.^37,43 Calcitriol may cause less irritation in sensitive areas compared to treatment with calcipotriol.⁴⁴ When used appropriately (maximum recommended dose of 100 g per week of calcipotriene or 200 g per week of calcitriol), the risk of hypercalcemia is very low.⁴³ Hypercalcemia risk was studied in 3 studies, occurring at a rate <1%.³⁷

Retinoids

Vitamin A and its naturally occurring and synthetic derivatives are referred to as retinoids.⁴⁵ They were introduced as a treatment for cutaneous disorders in the 1960s and, with the development of safer synthetic retinoids, have become widely used.⁴⁵ There are many topical retinoids used in dermatology, however, only tazarotene has been studied and indicated for psoriasis. While tazarotene lotion 0.045% is the only formulation commercially available in Canada, it is indicated for acne and used off-label for psoriasis. Tazarotene binds and modulates activity of retinoic acid receptors (RAR)-β and -γ, thereby decreasing inflammation and keratinocyte proliferation.⁴⁶

There were 2 systematic reviews assessing the efficacy of topical retinoids in psoriasis. The first contained 4 studies comparing tazarotene 0.05% or 0.1% gel or cream to placebo, finding tazarotene to be more effective in improving symptoms in the short-term (6-12 weeks).³⁹ However, the more recent systematic review comparing the same interventions found that symptom clearance as measured by Investigator’s Global Assessment (IGA) ranged from 5.5-6.2% with tazarotene 0.05% and 0.1% cream at 12 weeks, which was not better than placebo.⁴⁷ In the last 10 years, there have been no new published RCTs assessing the efficacy of topical retinoid monotherapy in psoriasis. Most clinical trials have focused on combination therapy of tazarotene and TCS.

The most common AEs associated with use of tazarotene are cutaneous local irritations such as peeling, erythema, itching, and burning at the site of application.⁴⁶ Cutaneous absorption of topical retinoids is limited, and there are no known systemic toxicities. However, as retinoids are teratogenic, women of childbearing age must use appropriate contraception.⁴⁶

Calcineurin Inhibitors (TCI)

Topical calcineurin inhibitors (TCI) have been approved since the early 2000s for the treatment of mild-to-moderate atopic dermatitis. While not indicated for psoriasis, TCI are often used off-label for facial and intertriginous psoriasis to avoid TCS-related AEs.⁴⁸ The available formulations are pimecrolimus 1% cream and tacrolimus 0.1% and 0.03% ointments. TCI bind to immunophilins, which lead to a decreased release of interleukin (IL)-2 and interferon (INF)-γ and thereby decreased T cell proliferation.⁴⁹

Systematic reviews assessing the efficacy of TCI for psoriasis confirmed tacrolimus superiority to placebo, TCS and calcitriol in treating facial and intertriginous psoriasis with treatment duration of 8 weeks.^50,51 However, pimecrolimus was inferior to standard psoriasis treatments.^50,52 One systematic review looked at the synergistic effect of TCI and TCS, which found that there was no additional benefit by combining these agents as opposed to TCS alone.⁵³

In the last 10 years, there have been 2 new RCTs published assessing the efficacy of TCI in psoriasis. The first studied the use of pimecrolimus 1% cream in the treatment of intertriginous psoriasis compared to placebo, finding that 71.4% in the treatment group reported an IGA of 0/1 at 8 weeks.⁵⁴ The second assessed tacrolimus 0.1% ointment in the treatment of nail psoriasis on 1 hand, using the other hand as a control. At 12 weeks, there was statistically significant improvement in the treated hand as evaluated by the Nail Psoriasis Severity Index (NAPSI) score.⁵⁵

AEs for topical TCI include skin irritation and discoloration to the site of application.⁵⁶ In 2006, a black box warning was issued for a potential link with skin cancer and lymphoma.⁵⁶ However, as a result of subsequent large-scale studies disproving this association,⁵⁷ Health Canada lifted the black box warning in 2021.⁵⁸ The systematic reviews and RCTs found similar rates of AEs between treatment and placebo groups,^51,54 however patients should be counselled regarding transient burning sensation when prescribed tacrolimus ointment to improve treatment adherence.

Tar

Historically, coal tar was considered a classic anti-psoriatic therapy and was used as a first-line agent for more than 2,000 years to treat psoriasis and other skin diseases.⁵⁹ Recent studies shed light into the mechanism of action of tar, suggesting modulation of epidermal differentiation and anti-inflammatory effects are likely achieved through activation of the aryl hydrocarbon receptor (AHR).⁵⁹ The efficacy of coal tar or its distillate, liquor carbonis detergens (LCD), in treating psoriasis was seldom formally evaluated. The limited available data suggests inferior efficacy to other commercially available agents. Specifically, a Cochrane Review (last updated in 2013), identified tar (including LCD) as generally less effective than TCS and vitamin D3 analogue monotherapies.⁴¹ Safety has been another important concern. As the “crude” word suggests, coal tar contains >10,000 organic compounds, including carcinogenic chemicals, such as benzene.⁵⁹ However, carcinogenic potential has not been proven.⁶⁰ Over-the-counter tar-containing products are available in different formats including lotions, creams, ointments, and shampoos, however, its application can be messy by staining hair, skin, nails, and clothing with a very unpleasant odour.⁶¹ While it can be compounded with TCS and other active ingredients to enhance effectiveness and penetration, currently it is primarily used in shampoos for the treatment of scalp psoriasis.⁶¹

Combination Therapies

Combination therapies were developed to improve treatment efficacy as it provides 2 mechanisms of action simultaneously and may have additive or synergistic effects.⁶² Further, they may decrease AEs related to each ingredient alone and are therefore better tolerated than monotherapy.⁶² Specifically, vitamin D3 analogues and retinoids decrease the risk of skin atrophy, whereas TCS decreases the irritation associated with vitamin D3 analogues and retinoids. Additionally, most fixed-dose combination topical therapies are prescribed to be applied QD as opposed to BID, thereby potentially improving long-term compliance. Commonly prescribed fixed-dose combination topical therapies include TCS and salicylic acid, TCS and vitamin D3 analogues (commercially available since 2001 as ointment, 2012 as gel, and 2016 as aerosol) as well as TCS and retinoids (commercially available as lotion since 2020).

Topical Corticosteroids and Keratolytics

Keratolytic agents, such as salicylic acid and urea, can improve the efficacy of TCS, especially for thicker plaques, by enhancing penetration and improving skin barrier. They are commercially available in combination as salicylic acid 3.0% and betamethasone dipropionate 0.05% ointment and salicylic acid 2.0% and betamethasone dipropionate 0.05% lotion. Additional alternatives can be compounded. There were several RCTs assessing combination therapy of salicylic acid and TCS showing superiority to monotherapy of either salicylic acid or the TCS alone.^53,63 However, 2 RCTs compared combination therapy of TCS and salicylic acid to calcipotriol monotherapy, with no clinical difference.⁶⁴ HRQoL was however improved with the combination therapy and was preferred by patients.⁶³ Only 1 RCT assessed urea in combination with TCS, which found a greater percentage of patients with an improved clinical score compared to monotherapy (47% vs. 33%).⁶³ Similarly, recent data showed that even simple moisturizers containing lipid-ceramides improve the efficacy of TCS.^65,66 In the last 10 years, there have been no newly published RCTs assessing the efficacy of topical salicylic acid and TCS combination therapy in psoriasis. Although rare, there is a risk of salicylic acid toxicity with topical application.⁶⁷

Calcipotriol and Betamethasone Dipropionate Fixed-Dose Combination

Calcipotriol 50 μg/g and betamethasone dipropionate 0.5 mg/g (Cal/BD), available in ointment, gel, and foam formulations in Canada, allows for both anti-inflammatory and anti-proliferative effects. A large Cochrane systematic review published in 2013 assessed the efficacy of combination therapies in psoriasis. Cal/BD was superior to placebo^41,68 and monotherapy (Cal or BD alone) in all but 1 RCT as early as after 2-8 weeks of treatment.⁴¹

In the last 10 years, there have been many new RCTs assessing the efficacy of Cal/BD for psoriasis focusing on the newer foam formulation, which when used QD for 4-12 weeks demonstrated a significant decrease in PASI from baseline of ~70%, superior to vehicle or either monotherapy.^69-72 Further, approximately half of participants achieved an IGA of 0/1.⁷³ Two studies compared Cal/BD to betamethasone valerate 0.1% dressing, showing in the first trial no significant efficacy difference at 4 weeks with Cal/BD ointment⁷⁴ and the second trial demonstrated superiority of the Cal/BD foam (at 4 weeks).⁷⁵ Several additional RCTs re-iterated the superiority of Cal/BD therapy vs. vitamin D3 analogue monotherapy.^76,70,77-80

Several RCTs focused on Cal/BD vehicle.^71,72,81 RCTs comparing different vehicles have shown better efficacy and superior HRQoL improvement with the use of Cal/BD foam compared to gel or ointment formulations^71,72,81 and cream compared to suspension.⁸² However, RCTs assessing vehicle preference as determined by patients did not find any significant preferences when comparing gel vs. foam, gel vs. ointment, and ointment vs. topical suspension, determining that individual patient preference should dictate treatment.^83-85 One real-world study found that patients using gel reported greater satisfaction compared to ointment due to ease of use.⁸⁶

One RCT focused on psoriasis relapse prevention following clinical clearance, defined as PGA score 0 or 1 (clear or almost clear).⁸⁷ In this study, both treatment arms received Cal/BD QD for 4 weeks initially to achieve skin clearance and were subsequently randomized into Cal/BD or vehicle biweekly as maintenance treatment. Patients that applied Cal/BD proactively experienced 3.1 relapses per year vs. 4.8 relapses (defined as PGA score 2 or higher) seen in the vehicle group. Median time to first relapse was also longer in the proactive management group (56 vs. 30 days) suggesting that proactive approach may be an interesting alternative to reactive approach for interested patients and could potentially be cost-effective.⁸⁷ As expected, both active treatment and proactive maintenance with Cal/BD were well-tolerated and no cases of skin atrophy were reported in either group.⁸⁷

Tazarotene and Halobetasol Fixed-Dose Combination

The only combination treatment of retinoid with TCS commercially available in Canada is halobetasol 0.01%/tazarotene 0.045% (HP/TAZ) lotion. A systematic review published in 2012 included 7 studies assessing the combination of retinoids (in general) with TCS, supporting superiority of combination as opposed to retinoid monotherapy at 4 weeks.⁸⁸ A recently published systematic review of 5 RCTs demonstrated treatment success, defined as at least 2-grade improvement from baseline in the IGA score and IGA score of 0 or 1 (clear or almost clear), of 32.8-52.5% for HP/TAZ compared to 33.3-34% for HP alone and 18.6% for TAZ alone with treatment duration of 2-8 weeks.⁸⁹

There have been several new RCTs published in the last 10 years assessing efficacy and safety of retinoids and TCS combination therapy. A combination tazarotene 0.05%/betamethasone diproprionate 0.05% (TAZ/BD) applied QD was superior to either agent used as monotherapy in 2 studies.^90,91 Treatment success of QD topical HP/TAZ lotion measured by the proportion of patients achieving IGA 0/1 ranged from 31.3-57.8% with treatment durations of 8-12 weeks,^92-99 which was significantly more effective than vehicle or either ingredient alone. The most frequent AEs reported were dermatitis, pruritus, pain, and irritation,^92,93,98 occurring in 6-20.8% of study participants.^91,97 A single RCT analyed the sensitization and irritation potential of HP/TAZ lotion with treatment duration of 4-6 weeks, finding that the topical did not induce contact sensitization and caused only minimal skin irritation, but significantly less than tazarotene alone.¹⁰⁰

Topical Therapies for Psoriasis – The Pipeline

As reviewed above, our current toolbox of topical therapy options is limited to TCS and a handful of other agents, such as vitamin D3 analogues, retinoids, tar or their combination. While the marketing of steroid-sparing monotherapies and fixed-dose combinations with TCS represents a major step forward in the management of psoriasis, these treatment options possess limitations in terms of efficacy, AEs, cost, patient satisfaction, and real-world adherence. Hence, there remains an unmet need for new topical therapies.¹⁰¹

There is an exciting topical therapy pipeline in psoriasis (Table 2), roflumilast and tapirnarof will be discussed in this section as phase III RCT data was recently published. Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor that has been developed into 0.3% cream and foam formulations. Crisaborole, a topical PDE-4 inhibitor, was approved in 2016 for atopic dermatitis in adults and children.¹⁰² Its use has been investigated for psoriasis in phase II RCTs, however, despite demonstrating efficacy and safety, results were not published. Rather, focus has shifted to roflumilast, a more potent PDE-4 inhibitor by 25-300X based on in vitro studies.¹⁰² PDE-4 inhibition suppresses the breakdown of cyclic adenosine monophosphate (cAMP), decreasing the presence of proinflammatory cytokines involved in the pathogenesis of psoriasis, similar to apremilast used systemically or topical crisaborole.¹⁰³ Phase I and II RCT data have demonstrated that roflumilast cream QD was superior to the vehicle when used for 2-8 weeks.^104-106 Phase III RCT data regarding roflumilast 0.3% cream efficacy and safety has been recently published.¹⁰⁷ DERMIS-1 and DERMIS-2 were parallel double-blind RCTs including 439 and 442 patients, respectively. Patients aged ≥2 years with psoriasis affecting 2-20% BSA were recruited and randomized 2:1 into either roflumilast 0.3% cream or vehicle applied QD for 8 weeks. The primary outcome was IGA 0/1 response plus ≥2 grade improvement from baseline, which was achieved in 37.5-42.4% of roflumilast-treated patients vs. 6.1-6.9% vehicle-treated patients. Improvement of PASI ≥75% from baseline (PASI75) was achieved in 39.0-41.6% vs. 5.3-7.6% of roflumilast-treated vs. vehicle-treated patients, respectively. It was also shown to be effective for the treatment of intertriginous psoriasis (68.1-71.2% vs. 13.8-18.5%). The incidence of AEs was comparable to the vehicle, with the most commonly reported events being diarrhea and headache in the roflumilast group. Further, AE profiles were similar in individuals aged 12–17 years relative to adults.¹⁰⁷ Currently, roflumilast is approved by the US Food and Drug Administration (FDA) and Health Canada.

Table 2. Topical antipsoriatic agents undergoing clinical trials

Tapinarof is an AHR-modulating agent that acts as an anti-inflammatory compound. It has a similar mechanism of action to tar, which also activates AHRs, however it does not contain carcinogenic chemical compounds.¹⁰⁸ Tapinarof is able to regulate innate and adaptive immune responses, affecting Th17 and regulatory T cells. It also has an important role in the development and maintenance of the skin barrier and upregulating barrier genes, such as filaggrin. Lastly, tapinarof inhibits the migration of T cells, decreasing the presence of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, INF-γ, IL-2, IL-13 and IL-17A.¹⁰³ Phase III RCT data has been recently published. In 2 parallel double-blind RCTs including >600 patients each, adults with mild-to-severe psoriasis (PGA 2-4, BSA 3-20%) were recruited and randomized 2:1 into either tapiranof 1% cream or vehicle applied QD for 12 weeks. The primary endpoint was IGA 0/1 and 2-point reduction from baseline at 12 weeks, which was achieved in 35.4-40.2% of tapinarof-treated patients vs. 6.0-6.3% of vehicle-treated patients.¹⁰⁹ While it was generally well-tolerated, increased rates of pruritus, contact dermatitis and folliculitis were seen in the active treatment group. A second RCT found that significantly more participants achieved a 75% reduction in the PASI score from baseline (PASI75) with tapinarof (50.4%) compared to calcipotriol (38.5%) and placebo (13.9%) when used QD for 12 weeks.¹¹⁰ Tapinarof has been recently approved by the FDA.

Treatment Guidelines for Topical Antipsoriatic Agents

Treatment guidelines for severe psoriasis and psoriatic arthritis are beyond the scope of this manuscript. This section will focus on reviewing guidelines specific to the treatment of mild-to-moderate psoriasis or treatment focused on topical agents.

Current guidelines for the treatment of mild-to-moderate psoriasis recommend topical therapies which include monotherapy with TCS, vitamin D3 analogues, TCI, retinoids, anthralin, and tar as well as combination therapies as first-line options. In Canada specifically, treatment guidelines were initially published in 2011. At this point, Grade A recommendation for first-line topical therapies included TCS or vitamin D3 analogues (i.e. calcipotriol) monotherapy or Cal/BD fixed-dose combination therapy. The treatment guidelines noted that additional topical therapy options were superior to placebo (e.g., retinoids alone or in combination with TCS, 15% LCD) and may be used on a case-by-case basis.^10,111 An update of these treatment guidelines was published in 2016 adding topical calcitriol as an additional first-line topical therapy option for mild psoriasis.^10,111

The American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) have put forth the most recent guidelines in North America in 2020 focusing on topical therapies.¹⁴ The AAD-NPF guidelines do not mention specific recommendations for first-line topical therapy options, but rather provide guidance for use within each class. For TCS, Grade A recommendations include using class I to V agents for up to 4 weeks for body psoriasis (excluding intertriginous areas) and class I to VII agents for scalp psoriasis. The use of TCS for prolonged periods (>12 weeks) may be done under the supervision of a physician (Grade C). However, gradual reduction in frequency of TCS is suggested upon clinical improvement, but without defined tapering protocol. Following clinical improvement, maintenance of response can be achieved by using a steroid-sparing agent (e.g., vitamin D3 analogues or TCI) or by using TCS intermittently (e.g., biweekly, this is also known as proactive approach). Additional recommendations made in regards to TCS use were as follows: the use of emollient was suggested to reduce itching and desquamation and to prevent relapse after TCS discontinuation (Grade B). As well, topical salicylic acid alone or in combination with TCS was recommended as an alternative to TCS monotherapy to achieve clear skin (8-16 weeks of treatment, Grade B).

AAD/NPF guidelines recommended vitamin D3 analogue monotherapy and/or in combination with TCS (e.g., Cal/BD fixed-dose combinations) to induce clearance of scalp psoriasis (4-12 weeks treatment, Grade A), facial psoriasis (up to 8 weeks treatment, Grade B, caution to favour class VI-VII TCS agents) or body psoriasis (up to 52 weeks treatment, Grade A). Topical retinoids (e.g., tazarotene) were recommended either as monotherapy, fixed-dose combination (e.g., HP/Taz) or in combination with narrowband ultraviolet light phototherapy (NB-UVB) (Grade B) for plaque psoriasis and nail psoriasis. However, HP/Taz was preferred (Grade A) to induce clear skin (8-16 weeks treatment) due to better efficacy and tolerability.

The off-label use of TCI (e.g., tacrolimus and pimecrolimus) was recommended by AAD/NPF guidelines for facial and inverse psoriasis to achieve clinical improvement (Grade B recommendation) and to maintain response (Grade C recommendation). They also suggested a combination of tacrolimus/6% salicylic acid for body psoriasis (Grade B recommendation).

Grade B recommendation was also stated for short contact anthralin use (≤2 hours per day, up to 8-12 weeks treatment) and Goeckerman therapy (coal tar and NB-UVB) for mild-to-moderate plaque psoriasis.¹⁴ Coal tar preparations received Grade A recommendation as well.

Real-world Limitations with Topical Treatments and Strategies to Improve Compliance

As highlighted above, all current topical therapies come with limitations. Patient compliance is certainly among the most important barriers to success. Adherence rates with current topical therapies are low, estimated to range from 50-70% in general.¹⁰¹ The compliance rates for TCS are even more variable and in some instances are thought to be as low 8%, due to prevalent corticophobia among dermatology patients.^101,112 Adherence is an important concept that must be evaluated in patients as it is directly associated with better clinical outcomes. A recent RCT demonstrated that a decrease in adherence rate of 10% was associated with a 1-point increase in disease severity.¹¹³

Various interventions were studied to improve compliance. Three RCTs integrated reminders in the forms of BID telephone calls, text messages, or smartphone application to remind and motivate patients to use their topical therapy.^20,114,115 In all studies, adherence improved and almost doubled compared to non-interventional arms (65% vs. 38% adherence).¹¹⁵ This translated into significantly better clinical outcomes, such as reduction in PGA.^20,115 Another RCT developed a web-based application to educate patients with videos, graphics, and text.¹¹⁶ While knowledge was improved, this did not translate to increased treatment adherence.¹¹⁶ Four RCTs approached adherence by offering more clinical support, such as teaching from nursing staff or internet-based reporting.^117-120 Compared to standard of care, these clinical trials demonstrated that additional support resulted in greater clinical outcomes as early as 4 weeks, which were sustained at 3 months.^117-120

Vehicle selection is an important component of efficacy and adherence. Good vehicles can accelerate barrier restoration and enhance efficacy of active agents by promoting penetration and sustained drug release.¹²¹ As discussed above, RCTs assessing patient satisfaction have found that treatment preferences are heterogeneous and may even change over time.^83,122 Factors that may influence preferences included age, sex, comorbidities, disease duration, and prior treatments.¹²² Therefore, a vehicle should be selected to maximize efficacy and meet the diverse needs of the patient while considering bodily location of psoriasis, probability of improvement, and delivery method. An additional very important attribute for a topical therapy to improve patient adherence is convenience. While it may be patient-specific, an agent that does not need to be applied often (QD or less often), is universal (e.g., same product that can be applied anywhere on the skin), is cosmetically acceptable (texture, colour, and odour) and is affordable will likely promote higher patient adherence and thereby achieve better clinical success rates.

As discussed in the guideline review section above, the first aim of psoriasis treatment is to achieve clear/almost clear skin with a topical agent of choice (combined physician/patient decision for agent selection). Prior to fixed-dose combination topical therapies, in order to increase efficacy while mitigating AEs, different strategies were used. These included rotational treatment where patients alternated between 2 agents, usually a TCS and a corticosteroid-sparing molecule;¹²³ or a sequential treatment approach where a superpotent agent (usually TCS class I-II) was used initially with subsequent step down to either a milder TCS, steroid-sparing molecule or a rotational treatment. However, nowadays fixed-dose combination topical therapies are more popular for their additive efficacy, simplicity, and convenience.¹²³ Once acceptable control is achieved, discussion of relapse prevention is important.

Because psoriasis is chronic and likely to recur upon discontinuation of the topical therapy, it is important to educate the patient about the chronicity of the disease and its treatment at the initial and subsequent visits. Two approaches following initial improvement of psoriasis are commonly used in clinical practice to maintain response over longer-term: the proactive and reactive approaches. Combined physician-patient decision-making may opt for either a proactive approach which consists of using the same agent to achieve clear skin (or another topical) intermittently (e.g., biweekly) to psoriasis-prone areas in order to prevent recurrence, or a reactive approach where all treatments are discontinued upon clinical resolution and restarted promptly with first signs of disease recurrence.

Conclusion

The vast majority of our psoriasis patients have a mild-to-moderate disease requiring topical therapies life-long. Consequently, the availability of safe, effective, and convenient products is essential to achieve and maintain clear/almost clear skin and promote long term treatment adherence. In this review, we provided clinicians an up to date safety and efficacy data of commercially available topical products as well as imminent pipeline topicals. North American guidelines for topical treatment of mild-to-moderate psoriasis are summarized as well as clinical tips are provided.

¹Diplomate of the American Board of Dermatology, Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Medicine University of Toronto, Onco-dermatologist, Princess Margaret Cancer Centre, Director, Toronto, ON, Canada.
²Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine, Division of Dermatology, Laval University, Director Melanoma and Skin Clinic, Le Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, Quebec City, QC, Canada.
³Medical Oncologist, Medical Oncology Disease Site Lead for Melanoma/Skin Oncology, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre. Assistant Professor, Department of Medicine, University of Toronto, Associate Member, Department of Immunology, University of Toronto, Toronto, ON, Canada
⁴Radboud UMC, Nijmegen and Andriessen Consultants, Malden, The Netherlands.
⁵Fellow of the Royal College of Physicians of Canada, Associate Professor, Department of Oncology, McGill University; Director, Division of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada.
⁶Fellow of the Royal College of Physicians of Canada, Diplomate of the American Board of Dermatology, Associate Professor, Department of Medicine University of Toronto, Toronto, ON, Canada, Lynderm Research, Markham, ON, Canada.

Abstract
The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) quality of life by offering tools to healthcare professionals for preventing, reducing and/or managing cutaneous adverse events (cAEs).
Immunotherapy, specifically immune checkpoint inhibitors (ICIs), for cancer patients is both increasing in indications and use. Similarly, the incidence and onset of cutaneous immunotherapy-related adverse events (cirAEs) vary based on the class and dose of immunotherapy administered, the type of cancer, and factors related to the patients. Dermatologists will increasingly see side effects from immunotherapy.

The CaSMO advisors developed a practical primer on prevention, identification, and treatment, including skincare for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.
A modified Delphi approach was used for the cirAEs practical primer’s development. Recommendations given by the CaSMO advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions.

According to the CaSMO group, the management of cirAEs starts with physician awareness and patient education on the occurrence of toxicities, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before immunotherapy begins and ongoing thereafter as part of the lifestyle.

Keywords: Immunotherapy, cutaneous adverse events, immune checkpoint inhibitor, skin toxicity, psoriasis, pruritus, morbilliform, eczema, bullous pemphigoid

Disclosures
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this manuscript. This work was supported by an unrestricted educational grant from La Roche-Posay Canada. All authors contributed to the manuscript, reviewed it and agree with its content and publication.

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Introduction

In 2021 an estimated 229,200 Canadians were diagnosed with cancer.¹ In Canada, of the four most commonly diagnosed types of cancer (lung, breast, colorectal, and prostate), excluding non-melanoma skin cancer, lung cancer is the most lethal and expected to cause more deaths than the other types combined.^2,3

Immunotherapy activates the body’s immune system to fight cancer. Immune checkpoint inhibitors (ICIs) prevent the deactivating signal by blocking the T-cell shut-off receptors and ligands from binding to each other, thereby disrupting signaling so that T cells remain active and can then recognize and attack cancer cells.^4,5 ICIs are approved for treatment across almost every type of solid-organ tumors, many hematologic malignancies, and in many instances, first-line therapy.^4,5 In 2019, in the United States, approximately 40% of oncology patients were eligible for treatment with immunotherapy.⁶ ICIs may be administered as a single agent (anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab, and avelumab)) or as combination immunotherapy (ipilimumab and nivolumab) and even as a combination with other agents.^4-6

Oncology patients treated with immunotherapy may experience cutaneous immunotherapy-related adverse events (cirAEs) at any time during and after the cancer treatment, severely impacting the quality of life (QoL) and potentially cancer treatment outcomes.^7-24 The incidence and onset of cirAEs vary depending on the drug class, the type of cancer, and factors related to the patient.²⁵ Adverse skin reactions occur in 14%–47% of patients treated with ICIs, ranging from mild and localized to debilitating and widespread in 1%–3% of patients and even potentially causing death.^15,16,26-30 Nivolumab-related cirAEs, including isolated pruritus, occurred in approximately 13–20% of patients, of which 0.7% of patients reported grade three or higher cAEs.^29-33 Pembrolizumab-induced cirAEs occurred in 9%–27% of patients, of which 1%−4% of patients reported grade three or higher cirAEs.^34,35

Frequently occurring cirAEs include pruritus without primary dermatologic findings (isolated pruritus), lichen planus or lichenoid drug eruptions, psoriasiform reactions, eczematoid eruptions, morbilliform eruptions, and bullous diseases, primarily bullous pemphigoid.^7-24  

The cirAEs may indicate a therapeutic response. A multicenter retrospective study on patients with non-small-cell lung carcinoma (NSCLC) receiving nivolumab showed that AEs and cirAEs were a strong predictor of survival outcomes, and those presenting with more than 2 AEs showed more benefit than patients with fewer AEs.¹⁴  Vitiligo occurs in some patients with melanoma receiving ICIs (Figure 1), and this is significantly associated with both progression-free-survival (PFS) and overall survival (OS) which indicated a two to four times lower risk of disease progression and death.^32,36

Major guidelines^10-12 recommend the use of systemic steroids for grade 2 or higher “rash” contrary to evidence showing the use of systemic steroids reduces the anticancer effect of ICIs.³³  A secondary analysis of a randomized trial on stage III melanoma patients with cirAEs showed that patients who received treatment with systemic steroids for 30 days or longer had lower OS than those without steroid treatment.³³  Another multicenter retrospective analysis of patients treated with anti-PD-1 therapy showed that high-dose glucocorticoids used to treat AEs were associated with poorer PFS and OS.³⁵

Scope of the Canadian Skin Management in Oncology Project

The Canadian skin management in oncology (CaSMO) project was developed to improve cancer patients’ (both active and survivors) QoL by offering tools for preventing and managing cAEs.^37-39 A general management algorithm to reduce the incidence of all cutaneous toxicities and maintain healthy skin using general measures and over-the-counter agents³⁸ and an algorithm to reduce and treat acute radiation dermatitis³⁹ were previously published. These algorithms aim to support all healthcare providers treating oncology patients, including physicians, nurses, pharmacists, and other medical providers.^38,39 The next step in the project was to develop a practical primer on prevention, identification, and treatment for cirAEs, focusing on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid.

Table 1: Immunotherapy classes, molecules, and indications

CTLA-4 impinges on many features of T-cell biology.^43,44  The CTLA-4 signaling pathway and the PD-1/PD-L1/PD-L2 signaling pathway are critical checkpoints that are used to down-regulate the body’s immune system that tumors often exploit and activate, thereby evading the body’s immune system.^43,44 CTLA-4 dampens T-cell responses via cell-intrinsic and extrinsic pathways. Intrinsic events include, among others, inhibition of protein translation, recruitment of phosphatases, activation of ubiquitin ligases, inhibition of cytokine receptor signaling, and inhibition of lipid microdomain formation on the surface of T-cells. Cell extrinsic events include the competition for CD28 in binding to its ligands CD80/86, the removal of CD80/86, the release of suppressive indoleamine-dioxygenase, and the modulation of Treg function. Antibodies to CTLA-4 may facilitate T-cell tumor entry and alter the movement in tumors and rates of egress.^43,44

cirAEs can present as almost any dermatologic condition, but most are inflammatory dermatoses.^7-11,26 The median time to onset of cirAEs is four weeks but has a broad range from 2 to 150 weeks, including beyond treatment discontinuation.^15,17,45

cirAEs of any grade have been reported at 30-40% of patients receiving PD-1/PD-L1 and approximately 50% of patients treated with ipilimumab.³¹  Maculopapular rash and pruritus are common cirAEs related to these treatments.³¹

A systematic literature review on cancer treatment with pembrolizumab and nivolumab observed that the most frequently occurring cirAEs were inflammatory dermatitis, pruritus, and vitiligo.⁴⁶ The rate of any-grade cirAEs with pembrolizumab and nivolumab was reported at 16.7% (RR=2.6) and 14.3% (RR=2.5), respectively.⁴⁶ The cirAEs may be associated with pruritus and comprised of erythematous macules, papules, and plaques, predominantly low-grade and localized to the trunk and extremities.⁴⁶ Challenges with reports of cirAEs are accurate descriptions and diagnoses of the specific dermatoses as many are simply reported as “rash”. Additional cirAEs comprised pruritus [incidence pembrolizumab and nivolumab was 20.2% (RR=49.9) and 13.2% (RR=34.5) respectively] and vitiligo [incidence, 8.3% (RR=17.5) and 7.5% (RR=14.6) respectively].⁴⁵ The researchers noted that knowledge of cirAEs is critical in delivering optimal cancer treatment, maintaining therapeutic agent dose, and health-related QoL.⁴⁶

The advisors agreed that cirAEs are likely an indicator of ICIs treatment efficacy and should be managed with topical treatment and judicious, ideally steroid-sparing systemic treatment where possible.^33,35-38

Approaches to the most common immunotherapy-related cAEs

The advisors discussed and selected the most common cirAEs: isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, morbilliform (maculopapular) eruptions, and bullous pemphigoid eruptions.^7-25,27-30

According to the advisors, the management of cirAEs starts with patient education on the occurrence of cirAEs, preventive measures, and skincare using gentle cleansers, moisturizers, and sunscreen started before ICIs treatment begins and ongoing during survival as part of the lifestyle.^9-25

Diagnosis of cirAEs

When diagnosing the cirAEs, other etiologies such as an infection, an effect of other agents, or other skin conditions should be ruled out.^8-11 

Biopsies play a role in accurately diagnosing the cirAEs when morphology is not clear. Histopathologically, cirAEs can be categorized into four broad groups, group 1: Inflammatory skin disorders, which reflect acute, subacute, or chronic inflammation of various patterns associated with variable epidermal changes, including psoriasiform or lichenoid interface chronic dermatitis.^16,50-53 Group 2: ICIs-related bullous skin lesions such as bullous pemphigoid or dermatitis herpetiformis, group 3: Keratinocyte alteration—Grover’s disease⁵⁴/acantholytic dyskeratosis, and group 4: Immune-reaction mediated by alteration of melanocytes such as regression of nevi, tumoural melanosis, and vitiligo.^29,36,48-52 For this review, we will only be focusing on the selected cirAEs.

When assessing the severity of cirAEs, grading systems’ trial limitations need to be considered.⁹ The Common Terminology Criteria for Adverse Events (CTCAE) classification is typically used; however, in the case of clinical trials, clinicians should be cognisant of the version the trial is using as different versions of CTCAE have different definitions and categorizations.²⁶

A general approach to prevention or reduction of cirAEs as well as initial management of the previously published CaSMO algorithm is displayed (Figure 2) for reference.³⁸  

Isolated Pruritus

Immunotherapy-related isolated pruritus occurs frequently and has a significant impact on QoL (Figure 3).^{7-25,31,46,55-57}  Diagnostic criteria for pruritus have been described as core symptoms, including duration of pruritus (more than six weeks) and a history of signs of scratching.^63,64 Associated criteria comprise a range of clinical manifestations, symptoms, functions, and emotions. The function includes the extent of impaired QoL, sleep loss, and days of absence from work. Emotions include possible psychological reactions such as, depression, anxiety, anger, and helplessness.⁶⁴

Isolated pruritus should be a diagnosis of exclusion once other causes such as pre-bullous pemphigoid, bites, or other drug reactions are ruled out.

A stepwise approach includes starting with over-the-counter topical agents, topical prescription agents, systemic drugs, and phototherapy.^63,64 General principles before starting topical and/or systemic treatment comprise skincare using gentle cleansers and moisturizers, especially in the presence of xerosis.^63,48

The CaSMO algorithm educates on general measures such as avoiding skin irritants, scented products, temperature extremes, sun, and the use of sun-protective clothing (e.g., brim hats and sunglasses). The information should be provided before immunotherapy starts, and this is especially important for isolated pruritus.³⁸ The daily skincare regimen should be reinforced with emphasis on gentle cleansers, skin moisturization, and sun protection – similar counseling to a patient with atopic dermatitis.^37,38,47  

A prurigo nodularis 4-tier treatment ladder⁶⁴ addresses neutral and immunologic mechanisms that may be applicable to ICIs-induced pruritus.⁶⁴ Immunologic mechanisms are more likely to be the underlying mechanism in ICIs-induced pruritus. Patients can enter the treatment ladder at any tier and move up or down the ladder based on their clinical presentation.⁶⁴  Immunologic tier 1 is more likely mechanisms can be treated with TCS, TCI, or topical calcipotriol.⁶⁴  Moisturizers, including antipruritics such as pramoxine 1% or formulations with menthol or camphor, may be used as an adjunct therapy.⁶⁴ 

For tier 2 neural mechanisms of pruritus medications include selective nor­epinephrine reuptake inhibitors (SNRIs) (i.e., mirtazapine) and gabapentinoids (gabapentin and pregabalin), which have antipru­ritic properties.^63,64  Second-generation histamine H1 receptor antagonists were shown to be effective and safe for patients receiving ICIs.⁶⁴ 

Additional second-line systemic therapies such as neurokinin 1 inhibitors (i.e., aprepitant) and inhibi­tors of interleukins (ILs) 4, 13 may be considered for the tier 3 immunologic mechanisms approach.⁶⁴ When evaluating the need for systemic or topical treatment, possible interactions with cancer therapy are assessed together with concomitant conditions and cirAEs.^{9-11,15,16,23,24 37,38,47}

Clinicians should take caution using systemic steroids and immunomodulators for patients receiving cancer treatment with ICIs (Table 2).^9-11

Table 2: Isolated pruritus

Psoriasiform Eruptions

T helper (Th) cells producing interleukin (IL)-17, IL-22, and tumor necrosis factor (TNF) drive the pathogenesis of psoriasis by orchestrating inflammation in the skin triggering proliferation of keratinocytes and endothelial cells.⁶⁵ Besides Th17 cells, other immune cells that are capable of producing IL-17-associated cytokines participate in psoriatic inflammation.^66-70  ICIs are thought to be driven through the TH17 pathway, and this may have implications on the development of psoriasis but also on the use of systemic psoriasis medications.^64,65,71,72

Immunotherapy with anti-PD1 and anti-PDL1 can exacerbate psoriasis, although more severe flares were noted in patients treated with durvalumab.^65-68,70,71

A personal or family history of psoriasis is a significant risk factor that should be identified before starting immunotherapy.^65,66,68 These patients require regular skin monitoring enabling early diagnosis and treatment of psoriatic exacerbations.^65,66,68 Prompt diagnosis can prevent a severe impact on QoL of this cirAE that may compromise therapeutic protocols and final cancer prognosis (Figure 4).^53,65,66 A skin biopsy to confirm the diagnosis, although not required, includes parakeratosis, hypogranulosis, regular acanthosis, suprapapillary plate thinning, and neutrophils at various layers of the epidermis.^68,70

Psoriasiform cirAEs can affect skin, nails, and joints and significantly impact QOL.^65-71 Psoriasis can be associated with arthritis as patients have a greater-than-expected incidence of psoriatic arthritis when it occurs as a cirAE of cancer treatment.^33,65,66 The choice of therapy takes many factors into account, including the extent and area of involvement, lifestyle, other health issues, and medications. First-line treatments include topical treatment with TCS, TCI, calcitriol, or a combina­tion of a super potent TCS with calcipotriol or tazarotene can be given.^65-71  For recalcitrant cases, consider adjuvant narrowband ultraviolet B therapy or oral treatment such as systemic retinoids [acitretin] or apremilast.^72-75  Although there is no direct evidence in ICIs treated cancer patients, methotrexate is immunosuppressive and may reduce the therapeutic effect of ICIs, similar to systemic steroids that have been shown to reduce RFS and OS.^32,33,35

Acitretin or apremilast is preferred over methotrexate; however, there is an absence of data for apremilast on the effect it may have on the anticancer treatment.^68-75  If the lesions persist, treatment with biologics may be required to treat psoriasiform cirAEs. IL-23 agents (gulselkumab, risankizumab, tildrakizumab) are considered most targeted and have the least direct evidence of immunosuppression (e.g. infection and TB reactivation). However, the risk/benefit needs to be considered before starting treatment with biologics (Table 3).^76-86

Lichen Planus

Immunotherapy-induced lichen planus is a pruritic, papulosquamous disease that can affect skin, hair, and nails (Figure 5). Treatment is required, especially if pruritic when it can severely impact QoL.^{7-19,27,33,46,63,77,78} When examining the patient exclude guttate psoriasis, mucositis, and bullous disease. Specific investigations include a detailed medical history and medication use, liver function tests including hepatitis C status, and, if required, a skin biopsy.⁷⁹

Pruritus may be treated with second-generation histamine H1 receptor antagonists (e.g., blistane, rupatadine, cetirizine and fexofendadine).^63,64,79 A retrospective analysis of clinical data investigating if commonly used medications might influence responses to checkpoint inhibitors. The researchers found that concurrent use of second-generation histamine H1 receptor antagonists correlated with significantly improved survival outcomes in those with melanoma or lung cancer. In addition, the antihistamine was effective for treating pruritus in cirAEs.^63,64,79 The choice of therapy takes many factors into account, including the extent and area of involvement, other health issues, and medications.^{8-11,67-69,78,80} First-line treatment includes moisturization and sun avoidance, antihistamines, TCS, and TCI.^80,81 Other second-line treatments include oral retinoids (acitretin), apremilast, sulfasalazine, metronidazole, hydroxychloroquine (especially for scalp or presentation with arthritis).⁸⁰ Additionally, narrowband or broadband UVB or PUVA may be used. Treatment with cyclosporine should be avoided as it may exert effects on the immune system (Table 4).^25,31,78

Table 4: Lichen planus

Eczematous Eruptions

Eczematous eruptions (EE) are associated with altered immune function, epidermal barrier dysfunction, genetic and environmental factors, and poorly understood interaction between these factors.^82-85 EE presents clinically as relapsing erythematous and pruritic patches of skin with varying severity (Figure 6).^9-11,82-85  Skin biopsies may be taken if the condition is extensive or not responding to therapy or if the diagnosis is in doubt.^9-11 Canadian and US guidelines for topical treatment of atopic dermatitis include education and avoiding triggers, routine skincare with gentle cleansers and moisturizers, and EE management foundation regardless of disease severity and prescription treatment.^82,83 Conventional moisturizers contain occlusives, humectants, and emulsions. Newer moisturizers designed to restore skin barrier defects include distinct ratios of lipids that resemble physiological compositions.^{36,38,47,82,83} If EE is not controlled with a moisturizer alone, TCS, TCI, or crisaborole ointment, an anti-inflammatory inhibitor of PDE4, is recommended while continuing skincare.^9-11,82-86   Treatment with crisaborole ointment achieved early sustained control of atopic dermatitis flares (reduced pruritus, erythema, exudation, excoriation, induration/papulation, and lichenification).^84,85  The topical PDE4 inhibitor offered a safe alternative to TCS and TCI.^84,85

For those not adequately controlled with topical treatment, nbUVB may be considered.^82,83 Dupilumab is a humanized monoclonal antibody against the shared alpha subunit of IL-4 and IL-13 receptors, blocking these cytokines commonly found in atopic dermatitis-affected skin. The use of dupilumab may be considered for extensive, moderate-to-severe EE. Two large, long-term RCTs demonstrated its efficacy and safety.^{9-11,82,83,86}  

Another option is tralokinumab (IL-13 inhibitor) which was shown to be effective and safe for the treatment of severe atopic dermatitis.⁸⁷

Treatment with the biologic is preferred to methotrexate which is an immunosuppressive and may reduce the anticancer effect.^9-11 TCS, TCI, and crisaborole can be used with any systemic treatment to address an EE flare (Table 5).^82-85,93

Morbilliform (maculopapular) Eruptions

These cirAEs may present as pruritic, nontender, erythematous papular, and macular eruptions on various body locations.^37,38,46,47 Physical examination focusing on the morphology and the distribution, starting on the trunk and then spreading to limbs, of the presented morbilliform eruptions is required to distinguish between the various cirAEs (Figure 7).^37,38,46,47 Laboratory tests may be needed and include a complete blood count, electrolytes, renal and liver function, and inflammatory markers.^37,38,46,47 Peripheral blood eosinophilia (≥500 eosinophils/microL) may be caused by numerous conditions, including allergic, infectious, inflammatory, and neoplastic disorders (Table 6).^37,38,46,47  Mild to moderate conditions may be treated with general skin care measures, TCS, TCI, and oral histamine H1 receptor antagonists to reduce pruritus.^63,64,94 Generally, this condition can be managed with aggressive topical treatment; however, for very severe and symptomatic cases, ICIs-treatment may be held, and a short course of systemic corticosteroids may be indicated.⁹⁴ 

Table 6: Morbilliform eruptions

cirAE BP can occur at any time, including after discontinuation of ICI. The onset to developing BP is within days or weeks of ICI exposure or may be delayed several months after starting ICI.³¹ Upon diagnosis ICIs is to be held and may require permanent discontinuation.^3,15,46 In milder cases, aggressive topical treatments with class I TCS may be as effective as systemic steroids.⁹²  cirAE BP may require systemic treatment and temporary, if not permanent, cessation of immunotherapy.^3,15,46 Systemic corticosteroids may be used the achieve control quickly while waiting for steroid-sparing treatments to take effect.^88,90-92 Non-immunosuppressive systemic treatment includes oral tetracycline-class antibiotics combined with oral niacinamide 500 mg twice a day, omalizumab, IVIg, and dupilumab.^31,88,90-92 However, steroid-sparing agents that are immunosuppressive may be required in order to control BP ongoing, including methotrexate, mycophenolate mofetil or rituximab.⁹¹ While rituximab may be immunosuppressive, it works on B-cells and may not hinder the T-cell activation from ICIs. In patients with cirAE BP, obtaining disease control as quickly as possible is ideal not only for improved QoL, and decreased morbidity but also if treatment is to be reinitiated (Table 7).^93,95

Table 7: Bullous eruptions

Limitations

The details provided on the mode of action of ICIs were limited to what is clinically relevant for this primer on cirAEs. Clinical studies on prescription medications and skin care for cirAEs frequently are case reports, case series, or have small sample sizes. For this reason, grading the evidence resulting from the literature searches was irrelevant. Therefore, recommendations given by the CaSMO project advisers are based on information from the guidelines, algorithms, consensus papers, and systematic reviews coupled with their clinical experience and resulting from discussions. More work is required to identify the best practice evidence-based management of cirAEs.

Summary and Conclusions

Immunotherapy for cancer patients is fast-developing into the standard of care for many malignancies. Although many publications are available on cirAEs, publications on the treatment using prescription medications and skincare are scarce.

The CaSMO practical primer focuses on isolated pruritus, psoriasiform eruptions, lichenoid eruptions, eczematous eruptions, and bullous pemphigoid. The practical primer addresses the need for physician awareness, patient education on the occurrence of cirAEs, prompt diagnosis, prevention, treatment, and ongoing skincare started before ICI.

References

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Charles W Lynde MD, FRCPC¹, James Bergman MD, FRCPC², Loretta Fiorillo MD³, Lyn Guenther MD, FRCPC⁴, Marissa Joseph MD, FRCPC, FAAD⁵, Jill Keddy-Grant MD⁶, Ian Landells MD, FRCPC⁷, Danielle Marcoux MD, FRCPC⁸, Catherine McCuaig MD, FRCPC⁹, Michele Ramien MD¹⁰, Wingfield Rehmus MD MPH FAAD¹¹

Introduction

Atopic dermatitis (AD) is a lifelong pruritic, inflammatory skin disease associated with altered immune function and epidermal barrier dysfunction.^1-3 The chronic and recurring cyclic waxing and waning nature of AD leads the patient to treatment fatigue and imposes a significant burden on both the patients’ and caregivers’ quality of life (QoL).¹ AD frequently appears early in childhood and affects over 20% of children and up to 3.5% of adults.^2,3 Measurements of the prevalence of AD can differ, and this variability can be impacted by geographic location, population studied, and definition of AD used. A Canadian study showed that the adult prevalence of AD is up to 3.5% and that AD may be more prevalent among First Nations populations.² This research further revealed that men were less affected than women and that AD decreases with age. Additionally, the study noted that the severity of AD varies per region.² In many countries, the prevalence of AD is on the rise, especially in young children from developing lower-income countries in South East Asia and Latin America.⁴ Although the role of race and ethnicity in the pathophysiology of AD remains unclear, a higher incidence of AD was observed in Black American children (17.3%) compared to White children (10.4%).⁴

The pathophysiology includes skin barrier defects, inflammatory cytokines, and immune abnormalities. ADs’ etiology is multifactorial and involves an incompletely understood interaction between genetic factors, immune system dysfunction, skin barrier disorders, genetic and environmental stressors.^5,6 Most of the patients with AD have mild disease; however, 10% – 20% of children with AD are categorized as severe, and these rates are slightly higher in adults.²

There is a need for a variety of therapeutics targeted to different levels of severity.^6,7 A treatment paradigm that recognizes that patients may oscillate between degrees of severity and integrates topical and systemic therapies may align more closely with clinical reality.^8,9 AD treatment is often challenging due to the disease itself, treatment fatigue, and patient/caregiver concerns. Patients and caregivers frequently have concerns about medication safety and adverse events (AEs) as well as the long-term use of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI).⁹ Crisaborole ointment is an effective and safe alternative to TCS and TCI.⁹ Sharing best clinical practice standards, addressing challenges in treatment application, and methods to improve patient adherence to therapy may improve treatment results.⁹

This paper aims to review best clinical practices in treating AD patients, explore optimal use of crisaborole in mild to moderate disease, and provide expert guidance for the real-world use of crisaborole ointment to improve patient outcomes. This papers’ target audience is general practitioners, pediatricians, pediatric dermatologists, and dermatologists who treat patients with AD.

Methods

The project used a modified Delphi communication technique for interactive decision-making for medical projects, adapted from face-to-face meetings to suit a virtual platform.^10-12 The meeting was virtually convened on May 8, 2021, and the expert panel consisted of eleven dermatologists, including nine pediatric dermatologists from diverse geographical regions within Canada, who commonly treat patients with AD. In preparation for the meeting, a literature review surrounding crisaborole for the treatment of mild-moderate AD was conducted, and the panel members were surveyed regarding the use of crisaborole ointment for the treatment of AD.

The literature review and the pre-meeting survey results were presented at the virtual meeting. During the meeting, the experts were divided into three breakout groups to discuss and adopt draft recommendations for the real-world use of crisaborole ointment that were prepared from the literature searches by CWL and AA. The three groups presented their adapted versions of the recommendations to the larger group following the breakout session. The adapted recommendations were then collated and edited if necessary. The panel then voted and adopted the recommendations using evidence coupled with expert opinion based on the clinical experience of the advisors. The meeting summary and subsequent review of the manuscript were performed online (Figure 1).

Literature Review

Searches for English-language literature [2015– 2020] took place on April 14, 2021, on PubMed and Google Scholar as a secondary source. The data gathered by the literature review prioritized clinical studies published on the use of crisaborole, articles describing the current best practice in AD, and the most recent clinical guidelines, consensus papers and, algorithms. Excluded were duplications, articles of insufficient quality [small sample size, flawed methodology], and the most recent reviews were used in the case of review articles.

The searches yielded sixty-two papers deemed clinically relevant to current best practices of crisaborole use in AD. After removing duplicates and articles of insufficient quality, thirty publications remained: Four on epidemiology, ten reviews, three consensus papers and algorithms, four guidelines, five clinical studies, and four systematic reviews, meta-analyses, or posthoc analyses.

Results

The literature review indicated that the guidelines, algorithms, and consensus papers for topical AD treatment had not changed significantly over the past decade apart from adding crisaborole ointment and removing the black box for topical calcineurin inhibitor (TCI) treatment.^{7-9, 13-21}

A consensus paper and algorithm that explored the need for practical solutions to improve AD care was developed and published by the authors’ panel.⁸ The consensus statements and algorithm for topical treatment and maintenance of AD were integrated into the panels’ recommendations presented in this publication.

The DERMA (D: Diagnosis/Distribution; E: Education/Emollients; R: Red/Itchy; M: Medication/Maintenance; A: Assessment /Adherence) AD Algorithm targets a broad base of health care professionals treating patients with AD. The consensus statements and DERMA AD algorithm for topical treatment and maintenance of AD reflected current practice and were integrated into the panels’ recommendations (Figure 2).

Clinical Evidence of Crisaborole

Crisaborole is a small molecule, anti-inflammatory nonsteroidal PDE4-I inhibitor for the treatment of AD, which has demonstrated safety and efficacy in patients with mild-to-moderate AD.^22-30 Two percent crisaborole ointment was first approved by the American Food and Drug Administration (FDA) in December 2016 and then in 2018 by Health Canada for mild-to-moderate AD patients aged 2 years and over and in March 2020 (USA) and May 2021 (Canada) for patients aged 3 months and over.²⁵

The efficacy and safety studies on crisaborole used various clinical assessment scales such as Investigator Static Global Assessment (ISGA), Atopic Dermatitis Severity Index (ADSI), Eczema Area, and Severity Index (EASI) score, and Patient-Oriented Eczema Measure (POEM).

A randomized, double-blind, intra-patient controlled study (for the first 14 days) was continued as an open-label study applying crisaborole to all lesions. The study, including 40 patients of 18 years-old and older, demonstrated significant changes from baseline in crisaborole-treated lesions, ISGA, and pruritus NRS improvement from day fifteen assessment onwards.²³ The study also showed normalization of the genomic skin profile (approximated normal skin), inhibition of inflammatory genes known to be induced through degradation of cAMP by PDE4, and reduction in epidermal hyperplasia and TEWL.²³

The safety and efficacy of crisaborole treatment over 28 days were shown in two identical randomized, double-blind, vehicle-controlled studies including 1,522 patients with mild-to-moderate AD of 2 years and over.²² Significantly more patients treated with crisaborole than vehicle reached the primary endpoint (ISGA: clear, almost clear) than those treated with the vehicle at day 29 assessment.²² A long-term, open-label, single-arm 48 weeks safety study that included 517 patients of 2 years and over showed similar safety results as in a previous study that included adult AD patients.^22,24 In the long-term open-label study, nine patients (1.7%) withdrew due to AEs such as a stinging sensation after applying the ointment.²⁴ Another phase four open-label, single-arm study on 137 infants aged 3 months to less than 24 months of age demonstrated that crisaborole is safe and effective. ISGA of clear or almost clear was achieved at day 29 assessment by 30.2% of patients.²⁵ The study further indicated that improvements exceeded the minimal clinically significant difference in total POEM score at day eight and day twenty-nine.²⁵ The POEM subscale data further revealed improved sleep and pruritus, markedly improving patients’ and their caregivers’ quality of life.²⁵ Crisaborole yielded a rapid and statistically significant reduction in pruritus within four days.^26-28 Notably, in two vehicle-controlled studies, the vehicle effect on pruritus was considerable.^26,28

A pooled analysis of four studies of mild-to-moderate AD patients demonstrated efficacy and local tolerability of crisaborole treatment. After crisaborole use, most patients had mild to no pruritus from the first assessment through the remainder of treatment.²⁷

In a further study, treatment with crisaborole resulted in a marked improvement in QoL for patients and their parents, caregivers, and families.²⁸

A post hoc analysis of 2 phase 3 studies showed the effectiveness of crisaborole compared to the vehicle in significantly alleviating mild-to-moderate AD severity (per ADSI), and percentage of body surface area (%BSA) affected.²⁹

Finally, a systematic literature review and network meta-analysis comparing efficacy and safety profiles of crisaborole ointment, 2%, versus other topical treatments for mild-to-moderate AD showed crisaborole was superior to vehicle and pimecrolimus 1% cream, and comparable to tacrolimus, 0.1% or 0.03% ointments, concerning ISGA 0/1 at 28-42 days.³⁰ Additionally, the systematic review showed that the AEs rates for application site burning/stinging were much higher for TCIs than for crisaborole.³⁰ The studies included different patients, and endpoints varied, so comparative assessment of medications from this meta-analysis is difficult. Head to head comparative studies are needed to see objective scientifically-grounded efficacy comparison.

Crisaborole works better for mild than moderate disease, where it provides a faster reduction of pruritus and other AD symptoms relieve.^9,25-30 Crisaborole is not typically used with TCI due to potential irritation, but the combination may be suitable for steroid-phobic patients and those at high risk of sequelae.⁹

It is advisable to avoid crisaborole application on significantly flared skin due to possible irritation. Crisaborole ointment can be beneficial for dermatitis of the hands and feet due to the potential for deeper penetration into inflamed, thicker lichenified skin as a result of the smaller molecular size of crisaborole. There appears to be less irritation of the hands and feet, and the good safety profile of crisaborole justifies application in infants and children.^9,25-30

Statements and Recommendations

Statement 1: Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function. When AD is not controlled by behavioral measures such as skincare and avoidance of triggers, treatments such as TCS, TCI, and more recently, PDE4-I should be considered. It is important to use topical agents in conjunction with moisturizers and gentle cleansers.

The complex multifactorial pathogenesis of AD includes genetic and environmental factors.⁵ The skin barrier in AD is dysfunctional, and this defective skin barrier leads to water loss from the skin and the ingress of irritants, pathogens and allergens resulting in further inflammation.⁷ As the dysfunctional barrier at baseline is further disrupted, an inflammatory immune response is upregulated, which further disrupts the barrier leading to a feedback loop.^6,31,5,6

AD presents clinically as recurrent scaly erythematous and pruritic papules and plaques of skin with varying severity. This morphology, in addition to pruritus and family history of atopy, are important diagnostic criteria.^7,32 Specific signs of AD include oozing, scaling, crusting, erythema, edema, and lichenification, which, together with the body surface area involved and the impairment of daily activities, help determine AD severity (Figure 3-5).
Most patients with AD present with mild disease and can be adequately treated with frequent moisturization and topical therapy such as TCS, TCI, or crisaborole.^{3,5,7,8,12-21}

Educating patients and caregivers about the condition, avoiding triggers, and daily skincare regime, including gentle cleansers and moisturizers, is a vital part of the approach.^{7-9, 13-21}

AD is a chronic disease, and as a result, adherence to therapy is a major obstacle. Education and patient support and can improve adherence and, in turn, outcomes. It is important to remember that AD education is not a one-and-done phenomenon. Ongoing reinforcement of the treatment plan and goals is needed. Clinicians need to explain the condition, the rationale for treatment, optimal treatment use, and demonstrate the application process in their office.^8,9 During the detailed conversation, solicit the patients’ or caregivers’ input and questions to enable their active role in the process.⁹ This will help manage expectations, adherence to treatment, and maintenance of the lifelong chronic disease.⁹ Actions to improve patient adherence with treatment include detailed but easy to follow information and options to revisit the information by reading materials or trusted websites (Box 1).^8,9,15,19

Box 1: Patient and caregivers information and education about crisaborole

Statement 2: Crisaborole, 1% ointment, is a nonsteroidal anti-inflammatory PDE4-I with demonstrated efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any body site. It may be especially beneficial for:

• Sensitive areas prone to thinning from TCS such as the face, intertriginous areas, and genitals
• Hand, feet, palms, and soles, where the small molecular size may allow potential deeper penetration

A previous publication by the panel reviewed various cases that reflect real-world clinical use of crisaborole aimed to clarify its optimal use as monotherapy, combination therapy, sequential therapy, and maintenance therapy.⁹ Crisaborole can provide a good and safe alternative to TCS and TCI, such as in cases of steroid or TCI avoidance, and can be used in mild-to-moderate AD patients from 3 months of age upwards.²⁵

The case studies discussed in the article suggested that crisaborole treatment was effective and well-tolerated for pediatric AD of the face, hands, and feet of infants, toddlers, young children, and adults where therapy with TCS or TCI had failed.⁹ One of the cases was a 5-year-old boy with moderate-to-severe AD of his hands that was painful and severely impacting daily activities, such as playing and interacting with other children. After eight weeks of crisaborole use, his hand palms and wrists involvement had almost entirely cleared.⁹

The advisors recommend that the smaller molecular size of crisaborole may allow better penetration into the skin to the site of inflammation.⁹ The advisors also indicated that there might be a cumulative effect of adding crisaborole for hands and feet that can benefit from its optimal penetration as part of a combination regimen with TCS and TCI in moderate-to-severe AD cases.⁹

Statement 3: Crisaborole may be used as a first-line topical agent and is also a good choice when previous treatment has yielded suboptimal results when TCS side effects constitute a significant concern, and in the case of TCS/TCI phobia.

TCS and TCI hesitancy exists among all cultures and likely contribute to AD treatment failure.³³ Widely available biased unreliable, and inaccurate sources of information about eczema and topical therapies such as TCS and TCI are not helpful for AD patients and hinder physicians ability to educate and treat appropriately.³³ Clinicians must inquire about and if present must thoroughly discuss the patients and caregivers’ concerns about TCS and TCI and emphasize that these treatments are vital and, if used appropriately, safe and effective.^{5,7,8,9,12-21} Providing the patient with trusted websites can give balanced information, thus addressing the issues that are adding to patients concerns, especially in those with TCS and TCI phobia.^15,19

If patients or caregivers continue to have safety concerns surrounding TCS/TCI treatment, then crisaborole can offer a safe alternative even in infants as young as three months of age.²⁵ In this situation, offering a safe and effective alternative to TCS or TCI may improve treatment adherence and patient outcomes.⁹

Statement 4: When starting topical therapies such as crisaborole, consider the following:

• Test the patients’ tolerability with a sample before a prescription to determine the degree of stinging
• Avoid its initial use on severely inflamed or open areas of skin
• Limit its use to areas less likely to sting/burn
• Use the product in combination with a refrigerated moisturizer

The recommendations are supported by the advisors’ clinical experience⁹, a post hoc analysis of 2 phase 3 studies²⁹, and a systematic literature review comparing efficacy and safety profiles of crisaborole and other topical treatments in mild-to-moderate AD.³⁰ Crisaborole is used in mild-to-moderate AD, but it is best to avoid application on severely inflamed and open areas if possible to minimize stinging.^29,30

Testing the patients’ tolerability in-office before prescribing crisaborole provides an opportunity to teach the patient about the appropriate application of the medication and identifies the uncommon patient who has more prominent stinging and thus may not tolerate the medication. The application also helps to identify the patient who has mild discomfort. Proper education and guidance can minimize the symptoms and allow then to get past the short-term symptom. Application in the office and identifying these subgroups will instill greater confidence in the medication and make it more likely that the prescription will be filled and utilized rather than abandoned after one application.

Improved knowledge about the central roles a defective skin barrier and dry skin may play in AD increasingly recognizes the benefits of daily and ongoing use of mild cleansers and moisturizers.³⁴ The use of a gentle cleanser that employs advanced vehicles with a near-physiologic pH (4.0–6.0) may help maintain skin barrier function by optimizing skin surface pH levels.³⁴ Utilizing moisturizers to optimize the barrier decreases water loss, decreases inflammation, and improves the skin’s barrier and natural moisturizing factors. Moisturizers that contain skin lipids such as ceramides have shown benefits over standard emollients when used for AD patients.³⁵

In an algorithm for South and East Asian AD patients, moisturizers were included as a standard measure when using topical treatments for AD, such as pimecrolimus.³⁶ A refrigerated moisturizer used in combination with crisaborole ointment may prevent irritation, burning, or stinging.⁹

Statement 5: TCS, TCIs, and PDE4-I may induce application site pain such as burning and stinging. Information and education on measures to prevent or treat these side-effects, such as testing/limiting application sites and concomitant use of a refrigerated moisturizer, can help optimize results and decrease skin irritation.

Few AEs such as irritation, burning, and stinging were reported in clinical studies using crisaborole but seem to be occurring more frequently in clinical practice.^16,9

Clinical trials report stinging or burning occurring in up to 8%, but the symptoms are usually transient, and 1.7% of patients withdrew due to these symptoms. In practice, clinicians have anecdotally noted that the rate of stinging seems to be greater than that reported in clinical trials, but generally, the stinging is mild and transient.^16,9 Topical medications can sting due to the stabilizers and preservatives in the vehicle cream or due to the medication itself. TCIs can sting, and this stinging is often correlated to the degree of inflammation in the area. Clinicians often apply TCS initially to calm down the AD, after which the TCI is better tolerated. Whether this technique applies to crisaborole is not clear but should be answered by future reports/ studies.^8,9

Before starting crisaborole therapy, inform and educate the patient and caregiver on measures that may prevent or quickly resolve irritation, burning, or stinging if it occurs.⁹ Best practice tips of the panel include the use of crisaborole with daily skincare, such as a gentle cleanser and a refrigerated moisturizer.⁹ Apply a patient age-appropriate regimen and patient education.⁹ Identifying patients prone to skin irritation may benefit from an in-office trial with a sample before prescribing the ointment.

Survey Results

A pre-meeting survey was conducted among the panel to share best practice standards and clinical pearls they use in prescribing crisaborole to mild-to-moderate AD patients. All eleven advisors completed the survey. Demographics, number of visits of AD patients, the severity of AD, and treatment are shown in Table 1. When asked: If Crisaborole is not your first choice, indicate why not? stinging (63% [7]), burning (40% [4]) and costs (91% [10]) were frequently mentioned. Six physicians also answered crisaborole was not used for other reasons, which included: Lack of payer coverage, Need to be off-flare to initiate the treatment to get a good response, It is not as effective and does not work as quickly as TCS or TCI, Other medications are effective and more readily available and with which there is more clinical experience. The advisors noted to specifically use crisaborole for various body locations such as the face (72% [8]), hands (91% [10]), eyelids (55% [6]), intertriginous areas (63% [7]), genitals (63% [7]), and feet (81% [9]). According to the advisors, they hypothesize that the small molecular size of crisaborole appears to allow better penetration on areas with thicker skin.

Table 1: Pre-meeting survey results
N=11
Topical corticosteroid (TCS), atopic dermatitis (AD)

When asked the main reasons to prescribe crisaborole, all (100% [11]) answered that there is a need for a nonsteroidal alternative. Other answers included TCS phobia (91% [10]) and TCI phobia (63% [7]) and suboptimal results with previous therapy (63% [7]).

When stinging or burning occurred with crisaborole use, the advisors discontinued the treatment more frequently in children than adults. For preventing and managing AEs, the advisors provided education before starting crisaborole treatment. Some tested patients’ tolerability to the treatment in the office prior to a prescription to determine the degree of stinging. Further, they recommended measures to reduce stinging, such as concomitant use of a gentle cleanser and refrigerated moisturizer, cooling the ointment in the fridge, and concomitant TCS or TCI use (Figure 6). Finally, the advisors agreed to avoid the application of crisaborole on severely flaring skin.

When asked about the patients’ response to crisaborole treatment within four weeks, forty percent of responders noted that on average, 20-50% of patients had improved, and 50% of the panel noted an improvement in over 50% of their patients (Figure 7 and 8).

Limitations

Measures to reduce burning and stinging that may occur when using crisaborole were developed using the authors’ expert opinion and clinical experience, and further studies are needed to support the possible benefits of these measures.

Conclusions

The review explored best clinical practices of crisaborole for mild to moderate AD patients and provided expert guidance for the real-world use of crisaborole ointment.

Atopic dermatitis is a common chronic inflammatory disorder in which patients experience a waxing and waning disease state that is punctuated by episodes of flares. If their disease is quiescent, then the patient continues good skincare by utilizing moisturizers and avoiding irritants. Patients will escalate and add topical medications at the first sign of a flare. Since every patient has a distinct disease course, some patients may never be fully clear while others clear between episodes. Recognition that patients with AD have a disease that often varies in severity and location on their body allows physicians to choose the appropriate treatments based on their clinical experience. The physician needs to educate their patient to escalate therapy accordingly at the first sign of disease in order to prevent severe flares. An eczema treatment plan is a necessity to ensure a smooth transition of therapy from baseline to flare. For mild to moderate AD patients, three topical options can be prescribed to control inflammation. Traditionally these medications have been divided into first and second-line therapy. However, the expert panel believes that the choice of a specific agent should be decided by the clinician based on factors such as disease severity, location, physician experience with the product, cost, and patient preference.

Crisaborole is a nonsteroidal PDE4-I with demonstrated safety and efficacy in patients aged three months and older with mild to moderate AD. It is a well-tolerated alternative to TCS or TCI and can be used on any cutaneous non-mucosal body site. It may be especially beneficial for areas with thicker skin, such as hands and feet, possibly due to improved penetration to the site of inflammation as a result of its small molecular size. There are no concerning serious safety signals associated with crisaborole. Crisaborole does cause a burning sensation in 8% of patients, but this is usually transient and may be minimized by the concomitant application of cool moisturizers. Consideration of in-clinic test site application of crisaborole to high-risk individuals may help identify those at risk and allow patient education, which may decrease the side effect and in turn improve adherence and outcome.

¹Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
²Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest:
Joseph Lam has served as an advisory board member for Bausch Health, Leo Pharma, Pfizer Canada and Sanofi-Genzyme.
He is on the speaker’s bureau for Pfizer Canada. He has received a research grant from the Eczema Society of Canada. Aryan Riahi has no conflicts to declare.

Abstract:
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory condition marked by pruritus and traditionally treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole 2% ointment (a topical phosphodiesterase-4 inhibitor) is a newer topical agent for the treatment of AD. Crisaborole is indicated for treating mild-to-moderate AD and evidence from phase 3 and phase 4 trials show that crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age. The most common side effects are pain and paresthesia at the application site. Treatments with tolerable safety profiles such as crisaborole may provide an alternative to patients with TCS phobia. The role of crisaborole in AD therapy may become clearer as multiple phase 4 trials are currently underway and their results are poised to answer more questions, including its safety profile for patients as young as 3 months of age, potential use as a steroid-sparing agent, and direct comparisons to TCS and TCI, which are the current mainstay treatments of mild-to-moderate AD.

Key Words:
crisaborole, Eucrisa, atopic dermatitis, eczema, topical treatment, phosphodiesterase-4 inhibitor, corticosteroids

Introduction

Atopic dermatitis (AD) is a chronic, relapsing, and inflammatory condition affecting the skin. Clinical features include xerosis, oozing, crusting, and erythema. Pruritus is a hallmark manifestation of AD that can cause frequent scratching, leading to skin infections and lichenification.¹ The face, scalp and extensor surfaces are commonly involved in infancy, while there is prominent flexural involvement in older children and adults.² While some patients experience resolution by adolescence, others have symptoms that persist into adulthood.³ AD has been estimated to affect 15-30% of children and 10% of adults in industrialized nations.⁴ The economic burden of AD has been estimated to be $3.8 billion per year.⁵ Due to the chronic nature of AD and limitations of current available topical agents, especially for pediatric use, there remains an unmet need for novel AD therapies to address long-standing treatment gaps. Crisaborole 2% ointment (Eucrisa™) is a Health Canada and US FDA-approved topical phosphodiesterase-4 (PDE4) inhibitor for treating mild-to-moderate AD. Evidence from phase 3 and 4 trials demonstrate crisaborole is an effective agent with a well-tolerated side effect profile for children >2 years of age.⁶

Overview: Diagnosis and Pathogenesis

The diagnosis of AD is clinical. Skin biopsy and laboratory testing such as serum immunoglobulin E (IgE) levels are not routinely performed in the evaluation of suspected AD, but may be useful in ruling out other skin conditions.⁷ Adverse impacts from AD are wide ranging and include impairments to general health, quality of life, and mental health, with the financial cost of disease management posing a significant concern for patients and their families. Scratching may expose patients to secondary infections, which can exacerbate the severity of AD.⁸ The differential diagnosis for AD includes irritant or allergic contact dermatitis, serborrheic dermatitis, psoriasis, and scabies. Intractable, chronic itch is a hallmark of AD. Scratching may expose patients to secondary infections, which can exacerbate the disease severity.⁶

The pathogenesis of AD is determined by numerous factors including abnormalities in the skin barrier, a skewed T helper type 2 (Th2) immune response, impaired innate immunity, and changes in the resident microbial flora of the skin.⁹ The epidermis of patients with AD is prone to increased transepidermal water loss.¹⁰ The filaggrin (FLG) protein, which is produced by keratinocytes and encoded by the FLG gene, serves a critical role in skin barrier formation.¹¹ Patients with AD have lower levels of expression of skin barrier-related proteins including FLG-2, corneodesmosin, and enzymes necessary for skin hydration and water retention at the stratum corneum.¹² In addition to a barrier defect, the underlying immune system is also dysregulated in patients with AD. The innate immune response depends on toll-like receptors, which are stimulated by tissue damage and microorganisms, and enhance the strength of tight junctions to prevent allergen and microorganism penetration.¹³ Grouping patients with AD into one endotype may be overly simplistic. AD has a variety of endotypes depending on age groups, ethnicities, FLG mutations, and IgE levels.¹⁴ These include Asian versus European American, adults versus children, and presence or absence of family history of FLG mutations.¹⁴ Since increased Th2 cell levels are common across the spectrum of AD, targeting this factor should theoretically be therapeutic for all phenotypes of AD. However, phase 3 trials of dupilumab, an interleukin (IL)-4 and IL-13 blocker targeting the Th2-mediated pathway, was only able to reduce the Investigator’s Global Assessment score of patients down to 1 or 0 in 36-38% of cases.¹⁵ This suggests that other immune mediators outside of Th2 cells may be involved in the pathogenesis and treatment of AD.

Treatment Options for Atopic Dermatitis

The goals of treatment for AD are to achieve symptom reduction and prevent exacerbations. This approach is balanced with minimizing the risks of therapy. The mainstay therapy of AD is topical corticosteroids (TCS).¹⁶ An alternative to TCS is topical calcineurin inhibitors (TCI). Both treatments elicit potential side effects if used improperly. The face and skin folds are areas at high risk for atrophy with inappropriate use of TCS. High potency TCS also pose the risk of systemic toxicity, such as adrenal suppression in pediatric populations, especially if used under occlusion, e.g., diapered area.^17,18 TCI medications such as topical tacrolimus ointment and pimecrolimus cream do not carry the risk of skin atrophy, but may burn and sting on application. Patient education is needed as topical tacrolimus and pimecrolimus come with an FDA black box warning for increased risk of malignancies such as lymphoma.^19,20 Since the regulatory manadate to include the black box warning was institued in 2005, there has been mounting evidence to support the safe use of TCIs and the increased risk of malignancy remains theoretical. Prior to topical crisaborole, no new topical molecules have been approved to treat AD over the last 15 years.

Severe AD may warrant the use of ultraviolet-B (UVB) phototherapy or systemic immunosuppressant therapy such as cyclosporine, methotrexate, or mycophenolate mofetil when the patient is refractory to topical treatments.²¹ In 2019, both the FDA and Health Canada approved dupilumab for treating patients with AD >12 years of age who suffer from moderate-to-severe AD when topical therapies are ineffective or not advised.^22-24 Dupilumab is a fully human monoclonal antibody that binds to the IL-4 receptor and inhibits signaling of IL-4 and IL-13.²⁵

Crisaborole 2% is a topical PDE4 inhibitor indicated for the treatment of mild-to-moderate AD. Studies have shown that crisaborole 2% ointment improves AD signs such as exudation, excoriation, lichenification, and especially pruritus. Unlike TCS and TCI therapies, systemic exposure to crisaborole is limited.²⁶ The most common side effects are pain and paresthesia at the application site.²⁷

Crisaborole‘s Mechanism of Action

Crisaborole inhibits the action of PDE4. Pharmaceutical interest in phosphodiesterase enzymes, including crisaborole, was sparked by their role in nucleotide signaling pathways, leading to the development of specific novel inhibitors.²⁸ Elevated PDE4 enzyme levels have been associated with a chronic inflammatory state.²⁹ Since PDE4 is expressed by immune cells and keratinocytes, inhibition of PDE4 increases intracellular levels of cyclic adenosine monophosphate (cAMP) which inhibits the nuclear factor kappa B (NF-kB) pathway and the release of tumor necrosis factor (TNF)-alpha and pro-inflammatory cytokines that have a causal role in AD and psoriasis.²⁹

Crisaborole’s boron chemistry allows for formation of a low molecular weight molecule that penetrates human skin effectively.³⁰ Systemic exposure and risk of adverse effects from crisaborole is generally avoided due to the molecule’s rapid metabolism to inactive metabolites that do not affect cytokine release or the activity of PDE4.²⁹

Completed and Ongoing Studies of Crisaborole

Crisaborole’s safety profile and efficacy has been evaluated through 2 double-blind vehicle-controlled controlled phase 3 clinical trials. These studies assigned patients aged 2 years and older with mild or moderate AD as per Investigator’s Static Global Assessment (ISGA) scoring for treatment with either 2% crisaborole ointment or vehicle for 28 days. Results collected on day 29 demonstrated that 51.7% of patients receiving crisaborole had an ISGA of clear (0) compared to 40.6% of vehicle-treated patients (P = 0.05) and 48.5% of patients had ISGA of almost clear (1) compared to 29.7% of those treated with vehicle (P < 0.001).⁷

Two randomized, double-blind, vehicle controlled phase 3 studies with 759 and 763 participants demonstrated that crisaborole improves pruritus compared with vehicle (56.6% vs. 39.5%; P < 0.001) as early as day 2 of therapy (34.3% vs. 27.3%; P = 0.013).³¹

TCS are routinely used as therapy for flare-ups in AD.³² However, only short-term TCS use is recommended to minimize local and systemic adverse effects such as striae, telangiectasia, cutaneous atrophy, and acne.³³ As for TCI, both Health Canada and FDA initially advised against the use of long-term TCI therapy due to the unclear risk of malignancy.^19,20 Health Canada has subsequently removed the black box label for primecrolimus.³⁴ However, patients may continue to be apprehensive about using TCIs given their previous black box labeling. More research, including investigations on long-term maintenance, is needed to determine optimal topical treatment options for AD with favorable safety profiles. There is a phase 3 randomized, double-blind, vehicle-controlled study being conducted with 700 patients with mild-to-moderate AD.³⁵ Patients will receive crisaborole twice a day for a maximum of 8 weeks to identify responders, defined as ISGA score of 0 or 1 with 2-grade improvement from baseline or 50% improvement from baseline based on Eczema Area and Severity Index (EASI50) scoring. Non-responders will be discontinued after the 8-week run-in period. Maintenance treatment consists of once daily administration of crisaborole QD. Flares defined as ISGA ≥2 will be treated with twice daily crisaborole for up to 12 weeks. Completion of the trial is anticipated by July 2022.³⁵

The efficacy and safety profile of crisaborole is currently being investigated in phase 4 trials. A randomized, double-blind, vehicle-controlled study is evaluating the efficacy and safety of 3 different application rates of crisaborole ointment 2% in adults with mild-to-moderate AD.³⁶ Each patient will have 4 application areas and receive 1 of 4 treatments ranging from vehicle to 3 different application rates of crisaborole. Patients will be randomly assigned to treatment with topical crisaborole (application rates A, B, or C) or vehicle, once daily, for 2 weeks. The results of this study, with a projected completion of June 2020, may demonstrate whether the efficacy and safety of crisaborole is dose dependent. The results may be compared and contrasted with TCS use, which has a well-known dose dependent effect (e.g., anti-inflammatory effects at lower doses, immunosuppressive activity at higher doses) as well as dose dependent adverse effects (e.g., ecchymosis, parchment-like skin, and sleep disturbances).³⁶

Long-term topical treatment is often required for the management of a chronic inflammatory skin conditions like AD. Crisaborole’s long-term safety was evaluated in an open-label extension study of 517 patients with mild-to-moderate AD who used crisaborole for 48 additional weeks after the 28-day phase 3 study. The most frequently reported treatment related adverse effect (AE) were AD (3.1%), pain at the site of application (2.3%), and localized infection (1.2%).²⁷

The treatment options for patients under 2 years of age with AD are sparse. Pimecrolimus has recently been approved for infants as young as 3 months.³⁷ However, having a wider array of therapeutic strategies would be ideal for this demographic. A phase 4 multicenter, open-label, single arm investigation called the CrisADe CARE 1 study evaluated the safety, efficacy, and pharmacokinetics of crisaborole 2% ointment applied twice daily on 125 pediatric patients between 3-24 months of age.³⁸ These patients had extensive AD involving at least 5% of body surface area (BSA) except for the scalp. A total of 29.93% of patients reported non-serious AEs. The most common side effect was pyrexia (9.49%). The study found a total of 1 (0.73%) serious AE involving a febrile convulsion. The study did not comment on whether this AE was related to the use of crisaborole. No deaths occurred. This study is the first to evaluate the safety profile of crisaborole in children less than 24 months of age.

Crisaborole may have the potential of decreasing steroid use in patients with AD. Side effects of TCS can range from cutaneous atrophy to suppression of the hypothalamic-pituitary-axis.³⁹ Misunderstandings and steroid phobia can interfere with patient compliance, which in turn negatively affect disease control.⁴⁰ Currently, a proof-of-concept phase 4 clinical trial with 60 children between 2-18 years with mild-moderate AD is underway to determine whether crisaborole is an effective steroid reducing agent. The trial will be completed by November 2020.⁴¹ Similarly, a single-center observational prospective cohort study aimed to evaluate the efficacy and safety profile of crisaborole ointment 2% and a TCI versus crisaborole alone over 8 weeks. The study included participants aged 2-79 with mild-tomoderate AD and the projected completion was March 2020.⁴²

While high-quality phase 3 studies have demonstrated the efficacy of crisaborole compared to vehicle, head-to-head studies comparing crisaborole with TCS or TCI are needed to better define its role in the management of AD. A phase 4 multicenter, randomized, vehicle versus active (TCS and TCI) controlled study is being conducted on 600 patients with mild-to-moderate AD over 4 weeks to evaluate the safety and efficacy of crisaborole 2% ointment, crisaborole vehicle, TCS, and TCI applied BID in patients over 2 years of age.⁴³ Inclusion criteria include patients with AD involving at least 5% of BSA except for the scalp. The primary efficacy endpoint is change from the patient’s baseline in the EASI score by Day 29. The study will be completed by March 2021. This will be the first study to directly compare crisaborole to the current mainstay treatments of mild-to-moderate AD.

Conclusion

Crisaborole provides a novel and safe treatment option for mild-to-moderate AD. Crisaborole’s boron chemistry allows for formation of a low molecular weight molecule that penetrates human skin effectively but is inactivated and metabolized rapidly.³⁰ Crisaborole therapy has been shown to decrease pruritus, which disrupts the itch-scratch cycle that exacerbates signs of AD, improve quality of life, and decrease the risk of infection and scarring.⁴⁴ Adverse events related to crisaborole 2% are overall infrequent and range from mild-to-moderate in severity. Studies are currently underway to determine whether crisaborole can be used as long-term maintenance therapy for patients who respond to treatment. Furthermore, while crisaborole’s side effect profile is generally well tolerated, new head-to-head studies comparing crisaborole with TCS or TCI are underway to better define its role in the management of AD.

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¹Associate Professor, Department of Medicine, University of Toronto, Toronto, ON, Canada
²Clinical Assistant Professor, Department of Dermatology, University of British Columbia, Vancouver, BC, Canada
³Clinical Professor, Director of Pediatric Dermatology, University of Alberta, Edmonton, AB, Canada
⁴Professor, Western University, London, ON, Canada
⁵Assistant Professor, Department of Medicine, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
⁶Assistant Professor, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
⁷Division of Dermatology, Sainte-Justine University Medical Center; Clinical Professor in Pediatrics, University of Montreal, Montreal, QC, Canada
⁸Division of Dermatology, Sainte-Justine University Medical Center; Clinical Professor in Pediatrics, University of Montreal, Montreal, QC, Canada
⁹Clinical Associate Professor, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Funding:
This Supplement was developed using the Authors’ Expert Opinion, supported by an unrestricted Educational Grant from Pfizer Canada.
Use crisaborole ointment in off-label settings is left up to the discretion of the treating health care professional after careful clinical evaluation.

Abstract:
Background: Atopic dermatitis (AD) is associated with epidermal barrier dysfunction. The chronic skin condition presents clinically with pruritus and recurrent skin lesions. The psychosocial impact of the condition is severe for most patients and their families.
Crisaborole, a topical PDE4 inhibitor, has demonstrated efficacy in patients with mild-to-moderate AD.

Objectives: A diversity of cases are presented that reflect real-world clinical use of topical crisaborole ointment, as a mechanism to help optimize patient care.

Methods: Evidence from the literature coupled with the panels’ expert opinion, experiences and, key insights reflect the panels’ clinical use of topical crisaborole ointment for AD and irritant dermatitis (off-label use) and how patients can benefit from its use, i.e., “what experienced specialists are doing across Canada.”

Results: The panel treated and presented cases that report on crisaborole ointment used as monotherapy, combination therapy, sequential therapy, and maintenance therapy. The presented cases aim to illustrate the diversity of crisaborole use concerning age range, skin type/ethnicity, and body location. Each case presents a summary of the learning points.

Conclusions: The presented cases reflect the panels’ real-world clinical experience with crisaborole for the treated patients. The panel suggested that crisaborole ointment provides a good safe alternative to TCS and TCI. Treatment with the ointment should be avoided on severely flaring skin and for those that experience irritation, burning, or stinging while testing it on unaffected skin areas.

Key Words:
Atopic dermatitis, Real-world cases, Topical PDE-4 inhibitor

Introduction

Atopic dermatitis (AD) is a lifelong inflammatory skin condition associated with epidermal barrier dysfunction and altered immune function, presents clinically with recurrent episodes of pruritic erythematous papules and plaques.¹ AD usually starts in infancy, where it affects up to 20% of children in North America, and is also highly prevalent in adults.² Two-thirds of AD patients are reported to have mild disease, 26% moderate, and 7% severe AD disease.³ The majority of patients are treated by primary care physicians who primarily use topical anti-inflammatory therapy for their mild-to-moderate AD cases.^4-13

The psychosocial burden of AD on patients and their families is enormous.¹⁵ The inflammatory skin disease increases the risk of other immune-mediated inflammatory atopic disorders, such as asthma, allergic rhinitis and food allergies, as well as mental health disorders in some.^15,16

Patients with AD should use gentle cleansers and moisturizers that are balanced to the skin pH in addition to behavioural measures such as avoidance of irritants and triggers.

AD is a chronic relapsing disorder with periods of quiescence punctuated by intermittent flares. When AD flares then treatments such as topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), and more recently, phosphodiesterase-4 (PDE4) inhibitors should be considered, while continuing skincare and measures to avoiding triggers of AD. TCS and TCI treatments are widely used as monotherapy in cases of mild-to-moderate AD or in combination with systemic treatments for more severe AD involvement. These treatment regimens are supported by clinical guidelines and clinical pathways worldwide and have an established safety record.^4-13 Crisaborole ointment (Eucrisa, Pfizer), a unique topical prescription option for AD, is a PDE4 inhibitor with demonstrated efficacy in patients aged two and older with mild to moderate AD.¹⁶

The presented real-world case-based approach explores the role topical crisaborole can play in the prevention, treatment and maintenance of AD and other inflammatory skin conditions, in clinical practice. The selected patient cases aim to outline a diversity of cases that reflect real-world use of topical crisaborole ointment for patients with AD and other skin conditions, either as monotherapy or in combination with other treatments. Any discussion concerning off-label use is considered an expert opinion only.

Methods

Aim of the Project

This current real-world case project was conceived as a mechanism to help optimize patient care by recognizing the role crisaborole ointment can play in the prevention, treatment and maintenance of AD. Additionally, the project explores where this therapeutic agent could be used in managing AD in patients who require a combination of therapies. The cases intend to illustrate the authors’ real-world clinical experience rather than reflect controlled clinical trial data. Evidence coupled with the expert opinion, experiences, key insights and recommendations is presented and discussed. Recommendations given by the panel reflect the use of topical crisaborole ointment for AD and how patients can potentially benefit from its use, i.e. “what experienced specialists are doing across Canada”. Any discussion concerning off-label use is considered an expert opinion only.

The target audience for this publication is physicians and other health-care professionals who treat patients with AD.

Steps in the Process

The five-step procedure included a) project definition and panel selection, b) collection of information and preparation of cases, c) meeting to select cases for the publication, d) literature review to support the cases, and e) creation, review, and finalization of the manuscript.¹⁷

Role of the Panel

An expert panel of eight dermatologists and pediatric dermatologists, selected to represent the diverse geographical regions within Canada, who commonly treat patients with AD, was convened on November 9, 2019, in Toronto, as part of the semiannual Dermatology Update conference. The panel members reported clinical cases of pediatric and adult patients who were suitable candidates for crisaborole ointment treatment.

The panel members discussed the cases in the light of the supporting literature, then decided which cases would be included in the publication. The publication was prepared and reviewed by the panel members.

Topical Treatment for Mild-To-Moderate AD

Avoidance of triggers of AD flares and education are the first steps in the prevention, treatment, and maintenance of AD.6

Skincare Using Gentle Cleansers and Moisturizers

Skincare using gentle cleansers and moisturizers remains the cornerstone of treatment for all severities of AD. Daily use of this skincare regimen is supported by established guidelines and clinical pathways.^4-13 Moisturizers play an important role in combating and controlling xerosis, decreasing epidermal water loss, and restoring epidermal barrier function.^6,10 Moisturizers should be liberally and frequently applied and can be used alone for mild disease or in combination with other therapies regardless of the severity of their AD. ^6,10

TCS and TCI

If avoidance of triggers and the use of a daily skincare regimen with gentle cleansers and moisturizers are not effective, topical anti-inflammatory agents, such as corticosteroids (TCSs) or calcineurin inhibitors (TCIs) are used twice a day until the lesions have cleared.^3-13 TCS is the first-line anti-inflammatory option, available in a variety of strengths from mild to potent and very potent.^6,11 Side effects such as skin atrophy, purpura, telangiectasia, striae, focal hypertrichosis, impaired wound healing, allergic contact dermatitis, and acneiform or rosacea-like eruptions on the face are very uncommon when TCS is used appropriately.⁶ Both patients’ and parents’ fear of TCS and steroid phobia should be discussed to improve adherence and avoid under-treatment.⁶

TCI’s are another safe and effective treatment option, however short-term side effects such as skin burning, and pruritus, especially when applied to acutely inflamed skin and cutaneous viral infections, may occur.⁶ Patients and parents should be informed about these potential side effects to avoid premature discontinuation of treatment.⁶ TCIs are therapeutic agents often used for mild AD on the face, neck, and folds, and used in prevention and TCS reduction elsewhere on the body.

Systemic Therapy

For patients affected by more severe AD, agents that target immune responses and inhibit T cells by targeting Th1, Th2, Th22, phosphodiesterase-4 (PDE4), IL-4, and IL-31 are available.¹⁸ Phototherapy and traditional systemic therapies, including methotrexate, cyclosporine, and mycophenolate mofetil, can also be used off-label in severe AD.

Crisaborole Ointment

Crisaborole (Eucrisa, Pfizer), a topical prescription option for AD, is a PDE4 inhibitor with demonstrated efficacy in patients aged two and older with mild to moderate AD.16 Two, multicenter phase III trials, demonstrated early sustained control of mild-to-moderate AD in patients aged over two years with crisaborole ointment use over twenty-eight days.¹⁶ When compared to the vehicle, treatment with the 2% crisaborole ointment showed reduced pruritus, AD severity, and other signs of AD (erythema, exudation, excoriation, induration/papulation, and lichenification), although clinicians have expressed concerns about stinging and burning on at application sites.^16,19

A multicenter extension study indicated that crisaborole ointment for up to fifty-two weeks is safe.¹⁷ The extension study reported an overall 10.2% rate of crisaborole treatment-related adverse events such as dermatitis (3.1%), application site pain, stinging, burning (2.3%), and application site infection (1.2%).³ These events were considered mild, and no one withdrew from the study due to these adverse events.

Less common potential side effects included skin irritation and hives or welts, which may be due to underlying atopy. Given the good tolerability and safety profile, crisaborole ointment makes for an alternative steroid-sparing topical option to TCS and TCI.¹⁶

Data Gathering of Real-World Cases on Crisaborole Ointment Use

The panel members used a template for their case studies, which asked the following questions:

• What are the cases and the impact of the condition?
• What are the treatment options, and what treatment(s) were previously used for this case
• Why might crisaborole ointment work in this case, where does it fit and what were the results of the treatment?
• Did any adverse events occur? If yes, describe.
• What (if any) are the special circumstances related to this particular case, and which lessons are learned?

Patient evaluations were at baseline (start) and at eight weeks (+/- 5 days) using physician reported skin condition (SCORing Atopic Dermatitis Clinical assessment [SCORAD] score.²¹ SCORAD recorded AD location and percentage area (A), Intensity (B): Redness, swelling, oozing/crusting, scratch marks, skin thickening, dryness [the intensity of each of the following signs is scored as none (0), mild (1), moderate (2) or severe (3)] and subjective symptoms (C) [Sleeplessness: 0 = no sleeplessness and 10 = the worst imaginable sleeplessness, Itch: 0 = no itch and 10 = the worst imaginable itch]). Total SCORAD is the sum of A, B, and C, minimum score = 0, maximum score = 103.21 The impact of the skin condition after treatment regime use and adverse events were recorded at baseline (start) and week 8 (+/- 5 days) (end).

Some of the physicians used quality of life for the participants 15 years or younger as assessed by Children’s Dermatology Life Quality Index (CDLQI). The minimum score is 0, and the maximum score is 30, the latter corresponds with the most severe impairment of quality of life. Other scores used were severity of itching as assessed by the Pruritus score determined using the Numerical Rating Scale (Minimum score is 0. The maximum score is 10, the latter corresponding to the most severe itching imaginable by the patient).

Selected Real-World Cases

The panel selected a total of eleven cases that reported on realworld use of crisaborole ointment as monotherapy, combination therapy, sequential therapy, maintenance therapy, preventive therapy, and its application in dermatitis beyond AD. (Table 1). The presented cases aim to illustrate the diversity of crisaborole use concerning age range, skin type/ethnicity, body location, the severity of AD, and reports of off-label use.

Case 1: A 4½-year old girl with AD since the first months of life, which had recently increased in severity. The moderate-tosevere condition involved multiple sites, including hands and feet. Previous treatment with various TCS formulations was unsuccessful. When crisaborole started, mometasone ointment was continued as needed on the lesions on her body. The rationale for starting topical 2% crisaborole ointment was the failure of previous treatments and a specific interest in improving the skin condition of her hands and feet. Her skin condition markedly improved over the eight week treatment period (Figure 1A-1J). No adverse events occurred, and the ointment was well tolerated even on the face.

Learning point: Crisaborole is a well-tolerated (even on the face) alternative for TCS and is effective on hands and feet.

Figure 1A – 1D

Figure 1E and 1F

Figure 1G and 1H

Figure 1I and 1G

Case 2: For four months, a 4-year-old boy had suffered from AD, primarily on the face, antecubital, and popliteal fossa. He had almost constant pruritus and open, erythematous skin. His interaction with other children was poor, and both the patient and parents had difficulty sleeping. Previous long-term TCS treatments lacked success. Moreover, his mother was concerned about prolonged steroid use and requested trying crisaborole ointment. After eight weeks of crisaborole ointment application, his skin condition had greatly improved (Figure 2A and 2B). Although at first, the ointment caused skin irritation, this was easily alleviated with the use of a moisturizer.

Learning point: Crisaborole seems to induce irritation, burning, and stinging more frequently in clinical practice than reported in clinical trials. The patient experienced irritation, burning, and stinging in the areas where crisaborole was used. Information and education on measures to prevent or to treat these side-effects were effective. The advice given included the use of a refrigerated moisturizer, frequently applied before and after application of the ointment to optimize crisaborole results and decrease irritation. The mother was encouraged to continue treatment after the physician discussed the expected outcomes of the therapy. The irritation was alleviated with the use of a moisturizer as instructed.

Figure 2A and 2B

Case 3: A 29-year-old neonatal intensive care unit (NICU) nurse developed hand dermatitis one year ago. During work, she frequently used a hand sanitizer causing pruritus and painful fissures. She had a negative history for AD, and other atopic disorders and Patch tests were negative. The eruptions cleared when she was on holiday. After consultation with the occupational health department for help and guidance, she received a special hand sanitizer. She refused TCS as she was concerned about developing skin thinning. Within eight weeks of starting crisaborole ointment, the condition had resolved. The ointment was well tolerated, and she resumed her work as a NICU nurse (Figure 3A and 3B).

Learning point: The patient with occupational irritant hand dermatitis did not want to use TCS. The alternative treatment with crisaborole ointment was successful for this patient. Use of crisaborole in the treatment of irritant contact hand dermatitis is off-label.

Figure 3A and 3B

Case 4: A 68-year-old woman with a history of rosacea also had recurrent facial eruptions. Patch testing was positive to Kathon CG, which was found in her laundry product which she had since avoided. Since TCS were unsuccessful, treatment with crisaborole ointment was started, used in combination with ceramides containing cream as needed. Her skin condition markedly improved within two weeks (Figure 4A – 4D).

Learning point: The ointment may be a useful alternative for TCS for facial areas in patients with concomitant facial inflammatory skin conditions. Although crisaborole may induce irritation, burning, and stinging, in this patient with underlying rosacea, the product was well tolerated. Topical steroids can induce a rosacealike eruption. Crisaborole did not aggravate this patient’s rosacea. Patch testing was useful in identifying the causative allergen. The use of crisaborole in allergic contact dermatitis is off-label.

Figure 4A and 4D

Case 5: An 11-month-old baby-boy had facial AD from the age of nine months. He had coincident acute myelogenous leukemia (AML) and was recovering from chemotherapy. His parents were concerned about TCS and TCI being immunosuppressive agents and due to his ongoing AML treatment refused them. Crisaborole ointment seemed a good alternative option. His skin condition improved within an eight week observation period, and no adverse events occurred (Figure 5A – 5D).

Learning point: In immunosuppressed or otherwise vulnerable patients, crisaborole ointment is an effective alternative to TCS to treat AD even on the face. Parental wishes to not use TCS or TCI were granted because crisaborole’s mechanism is not immunosuppressive. Although crisaborole is approved for use in individuals 2 years of age and older, it was safely and effectively used in this infant.

Figure 5A and 5D

Case 6: A 2-month-old baby boy presented with diffuse xerosis and AD present since three days of age. His condition impacted the entire family. His mother had applied Vaseline six times a day and TCS twice a day. He had not responded to treatment with several different types of TCS. The physician was concerned about absorption and possible adrenal axis suppression. After eight weeks of crisaborole ointment use, pruritus had subsided and both the baby and his family were able to sleep through the night (Figure 6A and 6B). Before starting treatment with crisaborole ointment, he had regularly had skin infections with MRSA, which did not reoccur since the start of the crisaborole ointment.

Learning point: Crisaborole proved to be a useful alternative for TCS where absorption and possible adrenal axis suppression were a major concern. Of interest is the resolved recurrent infection since the use of crisaborole, which may be attributed to the improved skin condition. Crisaborole is approved for use in individuals with AD two years of age and older.

Figure 6A and 6B

Case 7: A 15-year-old male had recurrent resistant atopic dermatitis and dyspigmentation from chronic TCS use. Treatment of the generalized flares and superinfection consisted of intravenous antibiotics and oral cyclosporine, to which he had a good initial response. To address his concern about TCS use and the desire for a simpler regimen, twice daily application with crisaborole ointment was started while continuing the cyclosporine. After eight weeks of use, he had an excellent response, with marked improvement in his quality of life. Whenever the patient stops topical crisaborole, some AD returns (Figure 7A and 7B).

Learning point: The use of crisaborole ointment in combination with systemic therapy was effective for this patient. The ointment is to be applied at the first sign of a flare before lesions develop and avoided the need to increase systemic therapy. As a result, he gained confidence in controlling his skin condition and improving his outlook on his situation.

Figure 7A and 7B

Case 8: A 5½-year-old boy had mild-to-moderate AD since the age of three and recently developed symptomatic hand and feet involvement. The rationale for crisaborole use on his hands and feet was the suboptimal response to previous TCS/TCI therapy. Concomitant use of TCS and TCI was continued together with crisaborole. His skin had almost cleared after eight weeks of crisaborole ointment use (Figure 8A – 8D).

Learning point: An incremental benefit of adding crisaborole as part of a combination regimen with TCS and TCI TCI introduces new possibilities for patients with AD on their hands and feet.

Figure 8A and 8D

Case 9: Since the first months of life, a 5-year-old male has had moderate-to-severe AD with symptomatic painful involvement of his hands, impacting daily activities. He had difficulty handling toys and interacting with other children and their parents. TCS and TCI treatments were not successful. With crisaborale, his hand palms and wrists’ involvement almost completely cleared. (Figure 9A – 9E).

Learning point: Effective penetration of crisaborole on thicker skin such as hand-palms and foot-soles may facilitate improvement in these special sites.

Figure 9A and 9B

Figure 9C and 9E

Case 10: A 4-year-old girl had AD. TCS therapy was started for her flaring disease. Her mother was concerned about vaccines and TCS use. Crisaborole ointment treatment was started to address the mother’s concerns. At eight weeks of ointment application, there was an 80% clinical improvement; however, some moderate AD persisted at some sites which required strong TCS.

Learning point: Although the crisaborole ointment did not completely resolve the disease, the mother preferred it to TCS for milder lesions and wished to reserve TCS for more resistant lesions.

Figure 10A and 10G

Case 11: A 12-year-old male with AD since infancy had involvement of the hands and limbs. His condition failed to show improvement from intermittent TCS. The rationale for starting crisaborole ointment was the family’s frustration with the lack of results and a possible penetration advantage of the ointment on the hands. A left/right assessment of clobetasol versus crisaborole ointment was conducted. His mothers’ perceptions were that his hands both improved, but the crisaborole ointment was more effective than clobetasol. On the arms and legs, both treatments were successful, but clobetasol outperformed crisaborole ointment. The therapy was continued after the eight weeks study period as the family was happy with the treatment response. No adverse events occurred. Subsequently, mom used crisaborole alone on his hands and had ongoing good maintenance and prevention of flares. (Figure 10A – 10G). Follow up results are shown in Figure 11A – 11E.

Learning point: The crisaborole ointment performed better on the hands than clobetasol, however when used on the arms and legs, the reverse was the case, indicating that the ointment may be particularly useful on thicker skin areas.

Figure 11A and 11E

Discussion

For each case, the age, skin type, underlying skin condition, rationale for using crisaborole, and in some cases, treatment duration were highlighted as well as its role as part of a maintenance/prevention and treatment regimen. The cases presented a spectrum of clinical responses to crisaborole, including instances of poor response, such as in case 10, where AD persisted, and TCS was further needed. The panel discussed challenges of recognizing and managing AD in darker skin which may be addressed using crisaborole ointment, although studies are needed to confirm possible benefits. Most of the cases were atopic dermatitis, the approved indication. Two other types of dermatitis (hand dermatitis, allergic contact dermatitis) were included although they have not approved indications since these conditions are often difficult to treat and do not always respond to topical steroids. In addition, on the face, topical steroids may be associated with a greater potential for adverse events.

Steroid Phobia

Steroid phobia refers to the negative feelings and beliefs related to TCSs experienced by patients and patients’ caregivers. The panel expressed concerns that this phenomenon may be a contributing factor in treatment failure in AD patients. A systematic review²² found that TCS phobia is present across all cultures and that adequate information for patients and parents is lacking. The authors of the systematic review propose that the sources from which patients are receiving information about TCS may be targetable for intervention to increase adherence to TCS treatment regimens.²²

Crisaborole can be an effective alternative for TCS and TCI, especially in patients with conditions requiring long-term TCS or TCI use.

In case of safety concerns (even when subjective) with TCS and TCI use in young patients or concerns about steroid absorption in all groups, patients can safely use crisaborole ointment. Moreover, preservatives in crisaborole pose no safety issues. The panel agreed that crisaborole ointment provides a good safe alternative to TCS and TCI in such cases, enhancing treatment adherence and thus outcomes.

Irritation, Burning and Stinging

Crisaborole seems to induce irritation, burning, and stinging more frequently in clinical practice than reported in clinical trials.^3,6,19 This side effect was also reported for two of the presented cases (case 2 and 4). The panel suggested that in their experience, irritation, burning, and stinging are more quickly resolved than in the case of TCI use, where similar side effects are also observed. If TCI related stinging occurs most clinicians will apply steroids temporarily and then subsequently TCIs are usually tolerated.

The panel recommended providing information on this issue and education on measures to prevent or to treat it before the start of the treatment with crisaborole. The panel recommended frequent use of a refrigerated moisturizer before and after application of the ointment, and the use of an anti-itch lotion as needed throughout the day. The panel further suggested that it may be helpful to have patients testing crisaborole on healthy skin. Modify or discontinue the treatment if the formulation triggers burning or stinging even on healthy skin with concomitant use of a refrigerated moisturizer. The panel discussed avoiding crisaborole ointment use on severely flaring skin and starting with TCS until the flare is controlled, followed by crisaborole ointment.

Antibiotic Resistance

Antibiotics are commonly used as part of the management of AD. However, only a minority of patients with AD have clinically significant S. aureus infection. Moreover, data is lacking for highly beneficial outcomes with exclusive use of antibiotics in the management of AD.²³ Case 6 shows an example of the possible use of crisaborole as a steroid-sparing and antibiotic-sparing agent. Because of antibiotic resistance, the use of the crisaborole ointment may be of interest and aligns with current emphasis on antibiotic stewardship in AD. Anti-inflammatory agents control eczema, which leads to less frequent infections and less antibiotic use.

Combination Treatment

Combining or alternating crisaborole with TCS or TCI may be successful for more severe disease. The ointment was safely used in time-intervals between the application of a moisturizer, TCS, or in combination with systemic therapy. Several cases showed a marked improvement in the skin condition of the treated patients and no adverse events.

Specific Body Locations

Case 4 shows an example of the safety and tolerability of crisaborole when used on specific sites (e.g., face and lips). An incremental benefit of crisaborole use as part of a combination regimen was shown in a patient (case 8) who recently had AD involvement of his feet, with hyperkeratosis and desquamation.

The rationale for crisaborole use, in this case, was good absorption of the ointment due to the relatively small size of the molecule allowing better penetration.

Case 11 showed beneficial crisaborole use on the hands, which did not improve with intermittent TCS application. This patient conducted a real-time comparative test using clobetasol on one side of the body and crisaborole on the other. Crisaborole worked better on the hands while clobetasol showed better results on his arms and legs.

The use of crisaborole for non-AD (case 3) was shown in a patient with occupational HD, which resulted in complete response. Advisors recommended further studies of crisaborole on the hands and feet (e.g., the study of occupational hand dermatitis and penetration study) to support the use of the ointment for these complex areas.

Table 1: Summary of the eleven cases studies
Case 1: TCS^a: Betametasone dipropionate 0.1% ointment, Mometasone ointment, TCI^b. Tacrolimus 0.1% ointment, Skincarec: Hydratation-Eucerin, Aquaphor, Aderma cleanser and hydrating agent.
Case 2: TCS^d: Desonide cream BID x 1 year, Hydrocortisone 17 valerate UNG BID x 1 year.
Case 3: TCS^e: Hydrocortisone cream
Case 4: TCS^f: 1% hydrocortisone cream
Case 6: TCS^g: Hydrocortisone 2.5%g then switched to desonide for body, Dermasmoothe FS for scalp and face. Then switched to hydroval 0.2% ointment to entire body.
Case 8: TCS^h: 0.1% betametasone valerate ointment (body), 0.1% protopic ointment (face).
Case 9: TCSⁱ and TCI: Betametasone dipropionate 0.1% ointment, Mometasone ointment, Tacrolimus 0.1% ointment.
Case 10: TCS^j: Begin with strong corticosteroids, Desonide ointment for the face, Betamethasone valerate 0,1% ointment for the hands and feet.
Case 11 : TCS^k : Clobetasol.

Atopic dermatitis (AD), Twice daily (BID), Crisaborole ointment (CO), Adverse events (AEs), Neonatal intensive care unit (NICU), Hand Dermatitis (HD), Medical history (Hx), Acute Myelogenous Leukemia (AML), Intravenous (IV) Oral (PO).

Maintenance Therapy

The panel discussed the spectrum of clinical response of crisaborole used in adjunction to a moisturizer as maintenance therapy and suggested that crisaborole ointment should start at the first sign of a new flare before the development of lesions. TCS should be added if it is not successful. Currently, data on the use of crisaborole ointment for long term maintenance therapy is lacking; however, the panel suggested further studies of crisaborole as maintenance therapy.

Conclusion

The discussed cases reflect the panels’ real-world clinical experience with crisaborole for the treatment of patients with AD and the off-label treatment of irritant dermatitis. The panel suggested that crisaborole ointment provides a good safe alternative to TCS and TCI. Use of crisaborole should be avoided on severely flaring skin and for those that experience irritation while testing it on unaffected skin areas.

Acknowledgement

The authors acknowledge and thank Anneke Andriessen, PhD, for her invaluable assistance with preparing this manuscript.

Limitations

The cases are intended to illustrate the real-world experience rather than reflect a controlled clinical trial data environment, nor do they presented cases mirror statistical outcomes. Use crisaborole ointment in off-label settings is left up to the discretion of the treating health care professional after careful clinical evaluation.

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