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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¹Division of Dermatology, McGill University, Montréal, QC, Canada
²Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada

Conflict of interest: Monica K. Li is a consultant and speaker for Galderma Canada. Santina Conte has no relevant conflicts of interest.
Funding sources: None.

Abstract:
Acne vulgaris, caused by pathophysiological processes at the pilosebaceous unit, is among the most common chronic dermatological disorders. Acne sequelae, including scarring and dyspigmentation, are common, and are often more distressing to patients than active acne lesions, reinforcing the importance of prevention and effective treatment. Trifarotene, a novel fourth generation retinoid selective for retinoid acid receptor gamma, is approved for the management of moderate-to-severe facial and truncal acne, with recent data supporting its efficacy in acne-induced hyperpigmentation. The purpose of this paper is to review treatment modalities for post-inflammatory hyperpigmentation and present trifarotene as a novel, evidence-based topical option.

Keywords: acne, retinoid, trifarotene, hyperpigmentation

Introduction

Acne vulgaris (AV) is one of the most common dermatological disorders, triggered by chronic inflammation of the sebaceous gland in the hair follicle.¹ In addition to being notably common worldwide, with an estimated global prevalence of 9.38%, it occurs most frequently among adolescents, with 35-100% having acne at some point during their lives.² In Canada, it is estimated that 9 in 10 adolescents struggle with the disease, with AV commonly persisting into adulthood.^3,4 Acne-induced scarring and acne-induced dyspigmentation may persist long after the resolution of the primary lesions.⁵ The longer a patient with acne waits before starting an effective treatment, the greater the risk of sequelae development.⁵ Because acne is a common and chronic inflammatory condition that is frequently difficult to effectively manage, prevention of sequelae requires an assertive and sustainable treatment plan.⁶

AV and its sequelae play an important role on short-term and long-term self-perception and mental health, with psychosocial phenomena observed in affected individuals, including depression, suicidal ideation, anxiety, psychosomatic symptoms, pain, discomfort, embarrassment and social inhibition, which limit participation in daily and social activities and interpersonal relationships.^7,8 However, effective treatment of AV has been shown to reduce and prevent the development of acne sequelae as well as improve patients’ self-esteem, obsessive-compulsiveness, shame, embarrassment, body image, social assertiveness and self-confidence, reinforcing the importance of targeted management.^5,7

Acne-induced dyspigmentation is an impactful adverse sequela of AV in all skin phototypes, but is most frequent in skin of color. The chronic inflammation associated with AV may result in excess melanogenesis and abnormal melanin deposition, resulting in post-inflammatory hyperpigmentation (PIH) and post-inflammatory erythema (PIE) in all skin tones, with PIH more prevalent amongst patients with skin of color and PIE more common in lighter skin phototypes.^9,10 Acne-induced hyperpigmentation (AIH) is often long-lasting with negative impacts on patients’ quality of life, frequently causing more distress than active acne lesions,^9,11 and underlies their motivation to seek medical attention. In patients with active acne, the “post-inflammatory” in the term “PIH” may be misleading, as ongoing inflammation and new acne lesions present an additional challenge to treatment. Thus, in patients with active acne, it may be more accurate to refer to such pigmentary changes as AIH. For these patients, the most important goal in managing their AIH is ultimately optimal control and eventual resolution of their acne.

Currently, treatment options for acne-induced PIH can be grouped into four main classes: keratolytics, retinoids, corticosteroids, and depigmenting agents.¹² Topical therapy with hydroquinone is considered to be the gold standard treatment for hyperpigmentation, but usage may be limited due to adverse effects such as exogenous ochronosis.^13,14 The current therapeutic approach for PIH secondary to melasma specifically includes triple topical combination therapy with hydroquinone, a retinoid and a corticosteroid, but outcomes are often suboptimal due to adverse effects, limited efficacy and post-treatment relapses.¹⁵ Recently, a phase 4 doubleblind, placebo-controlled study by Alexis et al. demonstrated that trifarotene, a selective fourth generation retinoid, led to rapid improvement in overall disease severity, improvement in post-AV hyperpigmentation index, high patient satisfaction, and favorable treatment compliance, supporting the use of this topical retinoid in the management of AV-induced PIH.¹⁶

Background

Trifarotene is a new fourth generation topical retinoid approved by Health Canada and the United States Food and Drug Administration for the treatment of AV in patients over the ages of 12 years in Canada and 9 years in the United States.^17,18 In Canada, the indication is for topical treatment of AV of the face and/or trunk.¹⁷ It is sold as a 0.005% or 50 μg/g cream (Aklief® cream) in 75 g pumps, and is to be applied to affected areas once daily.¹⁹ Relevant ingredients include allantoin, copolymer of acrylamide and sodium acryloyldimethyltaurate with isohexadecane, polysorbate 80, sorbitan oleate, cyclomethicone 5, ethanol, phenoxyethanol, propylene glycol, purified water and medium-chain triglycerides, which have been noted to promote the proliferation of healthy tissue, wound healing, emulsification, improved moisturization and enhanced epithelial keratinocyte turnover, resulting in short-term thinning of the stratum corneum and resolution/prevention of comedones, as well as long-term thickening of the epithelium.^17,20-22

Retinoid acid receptor gamma (RAR-γ) is the principal receptor subtype found in the epidermis and is targeted by trifarotene.^23,24 Notably, acne-induced PIH occurs primarily in the epidermis.²⁵ Trifarotene, similar to retinoids from previous generations, normalizes follicular keratinization and has anti-inflammatory effects by modifying the expression of retinoic acid receptorregulated genes.²⁶ Moreover, a recent mouse study comparing the activity of several retinoids found that trifarotene demonstrated superior depigmenting and anti-pigmenting properties on mouse tail skin with and without ultraviolet (UV) exposure, reinforcing its favorability in the management of AV-induced PIH.²⁷

Supporting Evidence from Clinical Trials

Results from a Phase 4 Study

In a phase 4, double-blind, parallel-group study of patients (n=123) aged 13 to 35 years with moderate AV and AV-induced hyperpigmentation, the efficacy and safety of trifarotene 50 mcg/g applied once daily in conjunction with a skin care regimen (Cetaphil® Moisturizing Lotion, Cetaphil® Gentle Skin Cleanser and Cetaphil® PRO DermaControl Oil Control Moisturizer SPF30 sunscreen) over the course of 24 weeks was assessed.¹⁶ Notably, patients in the vehicle arm also used daily sun protection. Trifarotene’s efficacy in the management of AV-induced pigmentation was determined through overall disease severity scores (ODS) and post-AV hyperpigmentation indices (PAHPI). Moderate AV was defined as an Investigator Global Assessment (IGA) score of 3 on the face, ≥20 inflammatory lesions, and ≥25 non-inflammatory lesions (excluding the nose). Moderate to marked acne-induced hyperpigmentation (AIH) was qualified using an overall disease severity hyperpigmentation scale, with included patients having a score between 4-6. Patients with greater than one AV nodule or any number of cysts were excluded from the study, as well as female patients who were pregnant, lactating or using oral contraceptives approved for AV treatment. The primary endpoint was absolute change from baseline in ODS at 24 weeks of treatment. Additionally, percent change of AIH from baseline to week 24, absolute/percent change in AIH overall disease severity scores at weeks 12, 16 and 20, average AIH lesion size, post-AV hyperpigmentation index scores and intensity were assessed as secondary AIH variables. AV-related outcomes evaluated included absolute and percent change in total, inflammatory and non-inflammatory lesions, in addition to the proportion of patients achieving IGA success at 12 and 24 weeks. Subjective outcomes were assessed by means of qualitative exit interviews and a treatment satisfaction questionnaire.

The PAHPI score, a secondary endpoint measured in this trial, represents a real-world reflection and should be considered by all clinicians as a quantifiable, reproducible way to measure disease-related concerns such as symptom severity and the impact of skin disease on patients’ quality of life.²⁸ More specifically, it is a composite scale and includes quantification of the number, size and intensity of acne lesions.¹⁶ With regards to ODS, there was a statistically significant reduction in pigmentation with trifarotene as compared to the control at 12 weeks, however significance was not achieved at weeks 16 and 24. Overall, ODS decreased by -45.4% in the trifarotene group and -44.9% in the vehicle group, while the decrease in the percentage of patients with marked AIH at 12 weeks was much more impressive in the trifarotene group as compared to the vehicle (trifarotene -26.3%, vehicle -2%). Both the treatment and vehicle groups showing improvement at 6 months may be reflective of the natural rate of pigment clearance from the skin. For PAHPI scoring, statistically significant reductions in size, intensity and number of hyperpigmented lesions were observed in patients treated with trifarotene as compared to the control group at weeks 20 and 24, while sub-scores assessing size, intensity and number of lesions showed higher absolute and percent change in the trifarotene group as compared to the vehicle-treated group. Overall, there were greater reductions in PAHPI total facial scores in the trifarotene group (-8.4% at 12 weeks, -18.9% at 24 weeks) than the control group (-4.5% at 12 weeks, -11.3% at 24 weeks), with PAHPI sub-scores in the treatment group being nearly double those of patients treated with the vehicle. When determining improvement in AIH, over 60% of patients were noted to have lighter or much lighter skin when treated with trifarotene over 24 weeks, while the number of patients with over 45 AIH lesions decreased more significantly amongst treated patients than those who received the vehicle formulation (trifarotene -14.7%, vehicle -1.3%). Both subjects (trifarotene 91.2%, vehicle 83%) and investigators (trifarotene 91.2%, vehicle 81.1%) noted slightly better improvements in AIH with trifarotene as compared to the vehicle, which was also appreciated upon review of patients’ photographs.

In addition to assessing trifarotene’s efficacy in the management of AV-induced hyperpigmentation, changes in AV lesions were also evaluated. Trifarotene was found to result in significantly greater reductions in total acne lesion counts than the vehicle (12 weeks: trifarotene -64.1%, vehicle -46.7%; 24 weeks: trifarotene -72.0%, vehicle -62.8%). IGA success was also more notable among patients treated with trifarotene, whereby 38.0% achieved IGA success by week 12 as compared to 20.8% of vehicle-treated patients, with continued improvement through to 24 weeks (trifarotene 61.1%, vehicle 39.4%).

To evaluate patients’ perspectives with regards to the efficacy of treatment, exit interviews were performed (n=30, mean age 24.8 years, 73.3% Fitzpatrick skin type IV-VI). Patients treated with trifarotene reported a greater reduction in AIH severity from baseline to week 24, with a higher proportion of individuals in the trifarotene group reporting an improvement in AIH (100%) compared to the vehicle group (83%). Moreover, the only patients to perceive a stagnation or worsening of their AIH were in the vehicle group. Furthermore, significantly more patients treated with trifarotene reported that their AIH was “much better” (83.3%) when compared to control patients (61.1%).

On safety, more adverse events were noted in vehicle-treated patients (n=19, 30.2%) than those treated with trifarotene (n=10, 16.7%), with differences thought to be secondary to infections, including COVID-19. Notably, the study was conducted during the height of the pandemic. Two vehicle-treated patients reported burning and dry skin at the application site, and all adverse events were mild or moderate in severity. Both treatments were shown to have good local tolerability, which could be due to the Cleanse, Treat, Moisturize, Protect (CTMP) regimen mandated on all patients in the clinical study.

This phase 4 study had multiple strengths. First, over two-thirds of all subjects included in the study were of Fitzpatrick phototypes IV to VI (67.5%), with 36.7% of patients treated with trifarotene of African American descent. Given that PIH is long-lasting, highly distressing and disproportionately affects individuals with skin phototypes III-VI, inclusion of patients with darker phototypes in clinical trials supports improved real-world translation.^29,30 Secondly, whereas traditional acne treatment clinical trials usually span 3 months, this trial assesses trifarotene’s efficacy over 6 months, providing greater insight into the drug’s ability to alleviate inflammatory changes in the skin and prevent and/or improve acne-induced pigmentary outcomes.

Short Summary of Results from Phase 4 Study

In essence, Alexis et al.’s clinical trial demonstrates that trifarotene is highly effective with good tolerability in the management of AV and AV-induced hyperpigmentation when used in conjunction with an appropriate skin care regimen that includes UV protection, yielding changes in overall disease severity and post-acne hyperpigmentation indices as early as 12 weeks. All parameters were noted to more significantly improve with trifarotene in comparison to vehicle therapy, including AIH lesion size, intensity and number, as well as total number of AV lesions, including both inflammatory and non-inflammatory lesions, utilizing assessments such as IGA, ODS score, post-AV hyperpigmentation index, exit interviews and photography.

Other Treatment Modalities for Post-Inflammatory Hyperpigmentation

There are currently several available treatment modalities for the management of AV-induced PIH. Regardless of the plethora of options, long-term strategies should include UV protection with sunscreen application of sun protection factor (SPF) 30 or above, a consistent skin care routine and where possible, the use of a topical retinoid proven to have depigmenting effects. Moreover, PIH has been shown to persist for greater than 1 year in nearly 50% of cases, and for over 5 years in 22.3% of patients affected by acne.³¹ Recognizing the need for prolonged treatment, consistent patient education is necessary to ensure long-term commitment and adherence to proposed treatment modalities, as well as to set patient expectations.³²

With management of PIH, treating the underlying, causative inflammatory process is the first step. In the case of AIH, trifarotene’s potent anti-inflammatory activity may contribute to its clinically demonstrated ability to limit the severity and duration of PIH.²⁴ Other safe and well-tolerated topicals with cutaneous anti-inflammatory properties include dapsone and clindamycin phosphate gels, which were also found to decrease acne severity and PIH.^33,34 Additionally, tyrosinase inhibitors, namely hydroquinone, are the mainstay of PIH therapy and work by suppressing melanin production.³² Cysteamine cream has also been proven to have comparable efficacy to topical hydroquinone. Should a less irritating agent be needed or desired, mequinol can be tried.¹³ Currently, PIH therapies have been best studied in melasma, with triple therapy preferred over unimodal therapy, such as combining hydroquinone 4%, tretinoin 0.05% and fluocinolone acetonide 0.01%.³² The hypothetical rationale of triple combination therapy is that the three molecules work synergistically to interfere with the production of melanin, slow the transfer of melanin to melanosomes, and accelerate the clearance of melanin from the epidermis by increasing keratinocyte turnover. Moreover, the retinoid counters the risk of steroid-induced skin atrophy, while the steroid component counters the irritation caused by the other two ingredients, which could lead to both patient discomfort and be counterproductive by inducing PIH. However, caution must be exercised, ensuring that patients understand the risks of exogenous ochronosis and steroid-induced cutaneous changes with prolonged and continuous hydroquinone and topical corticosteroid use, respectively. The usage of chemical peels, which work by removing the epidermal cells containing excess melanin, have been proven to be efficacious, with the most common peels using glycolic, salicylic and trichloroacetic acids.³² A comparative study previously demonstrated that serial glycolic acid peels with a modified Kligman formula (hydroquinone 2%, tretinoin 0.05% and hydrocortisone 1%) were efficacious and safe in the treatment of facial PIH in dark-skinned patients, while topical azelaic acid 15% gel was also found to successfully reduce acne and PIH in patients with skin of color.^35,36 Laser therapy has also proven to be successful in the management of PIH, including neodymium-doped yttrium aluminum garnet (Nd:YAG), picosecond (short, intense pulses) and ruby lasers.^12,32 However, as laser modalities deliver thermal energy, which may drive additional hyperpigmentation, usage should be reserved for experienced clinicians. Finally, regardless of the choice of therapy, any interventions must be well-tolerated and not add irritation or excess inflammation, given that the management of PIH is often lengthy and requires strict treatment adherence to optimize overall outcomes. Thus, user-friendly, well-tolerated and effective topical therapies, such as retinoids, are fundamental in the effective and sustainable management of acne-induced PIH.

Conclusion

Trifarotene 0.005% cream has been proven to be effective and welltolerated in the management of moderate AV and acne-induced PIH, likely due to its capacity to reduce inflammation throughout the epidermis via interactions with specific receptor isotypes. Not only has trifarotene proven to reduce the number and severity of active AV lesions, it has also shown to play a role in the prevention and reduction of PIH, which is especially important in preventing the long-term sequelae of acne in individuals of skin of color. Given its safety and tolerability profiles, as well as its relative cost-effectiveness, trifarotene should be considered when treating both acne and hyperpigmentation. Further studies evaluating the combination effect of trifarotene with other mainstay therapies, including a CTMP framework, beyond 6 months will be valuable in enhancing our understanding of optimal multimodal management of acne-induced hyperpigmentation.

Acknowledgement: We thank JP York, PhD and Rajeev Chavda, MBBS, MD, DBM for their editorial review and support.

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¹Virginia Tech-Carilion School of Medicine, Roanoke, VA, USA
²Dermatology Section, Department of Internal Medicine, Virginia Tech-Carilion School of Medicine, Roanoke, VA, USA

Conflict of interest: Casey Engel has no relevant conflicts of interest. Zachary Holcomb is an investigator for AstraZeneca/Parexel. Funding sources: None.

Abstract:
Intravenous immune globulin (IVIG) is a manufactured blood product commonly used to treat immunodeficiency syndromes, inflammatory disorders, and autoimmune diseases of the skin. The use of IVIG in dermatology has evolved and expanded over time, serving as a useful therapeutic intervention for several inflammatory skin disorders. In addition to demonstrating efficacy in treating several cutaneous pathologies, IVIG also mitigates the need for steroids or other immunosuppressant medications in many dermatologic diseases. This review highlights the evidence for IVIG use across several dermatologic conditions, emphasizing the dosing regimens and safety considerations.

Keywords: intravenous immunoglobulin, IVIG, immunomodulation, autoimmune diseases, bullous dermatoses, dermatomyositis, Stevens-Johnson syndrome

Introduction and Mechanism of Action

Intravenous immune globulin (IVIG) is composed of polyclonal immunoglobulin G (IgG) derived from human plasma and has been used clinically for over 50 years. IVIG has historically been used to treat immunodeficiency syndromes, but more recently it has been employed in treating a wide variety of dermatologic conditions, including autoimmune bullous dermatoses, collagen vascular diseases, inflammatory myositides, systemic vasculitides, severe atopic dermatitis, chronic urticaria, graft-versus-host disease, and more. IVIG exerts its effects through modulation of the immune system and anti-inflammatory actions. Proposed mechanisms of action include Fc receptor blockade, complement inhibition, pathogen neutralization, dendritic cell downregulation, clearance of pathogenic IgG, alterations in regulatory T cells, and enhancement of sensitivity to corticosteroids.^1,2 IVIG is typically administered using a dosing regimen of 2 g/kg for most indications, excluding Kawasaki disease and toxic epidermal necrolysis, further detailed below. This dosing regimen is usually distributed evenly over 2-5 days. IVIG undergoes an extensive screening process involving virus inactivation and removal in addition to donor screening.^1,2 This review explores the dermatologic conditions where IVIG has demonstrated efficacy (see Table 1).

Dosing and Administration

There are several different formulations of IVIG available. It is important to be aware of the available formulations as they may vary regarding indication, half-life, storage, contraindications, and administration. If a patient is to receive multiple IVIG treatments, the same previously tolerated formulation should be used when possible to minimize adverse reactions. Immune globulin can also be administered subcutaneously and intramuscularly, though this review will focus on the use of intravenous immune globulin.

The standard dose for IVIG is 2 g/kg divided evenly over 2-5 daily infusions. It is recommended to calculate dosage using actual body weight, unless the patient’s BMI is greater than 30 kg/m² or if their actual weight is greater than 20% higher than ideal body weight, in which case dosing can be calculated using ideal body weight.^1,2

When used to treat immunodeficiencies, trough levels can be obtained to assist in calculating the interval between doses. However, when used for dermatologic conditions, the primary endpoint is often clinical improvement and thus IgG levels are not routinely measured. The half-life of IVIG ranges from 3-5 weeks; accordingly, infusions are typically administered in cycles every 4 weeks until the disease is adequately controlled.

IVIG is generally started at a slow infusion rate, usually 0.01 mL/kg per minute, to reduce the risk of infusion-related adverse effects. This rate may be increased based on patient tolerability and monitoring. The total dose is frequently given over 4-8 hours.

Adverse Effects and Contraindications

Adverse reactions occur in 5-15% of all IVIG infusions and are typically self-limited. They generally occur during or within several hours of the infusion and are often associated with the first infusion or with a new IVIG formulation. Common reactions include headache, chills, flushing, fatigue, abdominal pain, and myalgias. Other adverse effects include urticaria, anaphylactic shock, dyspnea, acute pulmonary edema, aseptic meningitis, hemolysis, transient neutropenia, hyponatremia, and infection. The risk of adverse effects is associated with the dose of IVIG and the rate of infusion. IVIG has a boxed warning for the risks of thrombosis, kidney dysfunction, and acute kidney injury. Subcutaneous immune globulin has a lower rate of adverse effects and may be preferred in patients with contraindications or adverse reactions to IVIG. Risk factors and relative contraindications to IVIG include hyperviscosity states, underlying organ dysfunction, or prothrombotic stimuli. Patients with cardiac or renal disease should be monitored for fluid overload. While most patients with low or absent IgA are able to tolerate IVIG, patients who experience anaphylaxis who have low or undetectable IgA levels and/or IgE anti-IgA antibodies should receive pre-medication and a product with low IgA or subcutaneous immune globulin. Mitigation of adverse effects can be achieved by slowing the infusion rate, providing additional intravenous hydration prior to the infusion, and providing pre-medications as outlined below.

Pretreatment Testing, Pre-medication and Monitoring

To rule out infection and risk for complications, it is recommended to obtain a complete blood count, hepatic function panel, metabolic panel, and urinalysis prior to initiating IVIG. This pretreatment testing can be repeated at 6-month or yearly intervals on a case-by-case basis. Some clinicians may also choose to assess coagulation parameters, viral serologies, cryoglobulins, immunoglobulin levels (including screening for IgA deficiency), and rheumatoid factor prior to initiation of IVIG, although this testing is not routinely performed.

Some patients do not require pre-medication for IVIG, but a standard pre-medication protocol includes acetaminophen or a nonsteroidal anti-inflammatory drug to prevent inflammatory and anaphylactoid symptoms. H1-antihistamines (such as diphenhydramine) are also frequently administered at the beginning of the infusion. Finally, glucocorticoids can be given to patients who experience an adverse reaction, such as headache, with their first infusion. Patients should be well-hydrated before and during their IVIG infusion, particularly those with risk factors for thrombosis or renal complications. This can be accomplished through oral fluid intake and/or administration of intravenous fluids with the infusion. Throughout the infusion, patients should be monitored for symptoms or alterations in vital signs.³

Autoimmune Bullous Dermatoses

IVIG has emerged as a valuable second-line or adjunctive treatment in pemphigus vulgaris, pemphigus foliaceus, epidermolysis bullosa acquisita, and bullous pemphigoid. Two randomized controlled trials demonstrated efficacy in treating pemphigus and bullous pemphigoid with IVIG at 4-week intervals in combination with conventional therapies of systemic steroids and immunosuppressants.^4,5 IVIG causes a selective and rapid decline in autoantibodies implicated in the bullous dermatoses, with the proposed mechanism of increasing the catabolism of abnormal serum IgG antibodies.⁶ A consensus statement on the use of IVIG in patients with autoimmune mucocutaneous blistering diseases reinforces its use in cases of treatment failure, significant adverse effects from conventional therapy, contraindications to systemic therapy (such as aseptic bone necrosis, diabetes mellitus, severe osteoporosis), progressive disease despite conventional therapy, uncontrolled and debilitating disease, and rapidly progressive epidermolysis bullosa acquisita with generalized cutaneous involvement.⁷ IVIG can be used as monotherapy or in combination with rituximab or corticosteroids in patients with recalcitrant disease, and a multidrug approach may confer a lower relapse rate.⁸ IVIG has also demonstrated utility in treating mucous membrane pemphigoid, linear IgA dermatosis, IgA pemphigus, paraneoplastic pemphigus, and pemphigoid gestationis. Administered at the standard dosage of 2 g/kg over 2-5 consecutive days every 4 weeks for a duration of 3-6 months, IVIG has been used to treat severe, treatment-resistant bullous dermatoses for decades. Treatment response is assessed by monitoring for the absence of new lesions, epithelialization of existing lesions, and a decrease in autoantibody titers (autoantibody titers typically decrease over 6 or more months of therapy). Once disease control is achieved, the interval between IVIG infusions may be progressively increased until discontinuation (once the interval is >2 months in between infusions cycles). This approach underlines the evolving and nuanced role of IVIG in the management of autoimmune bullous dermatoses, providing an effective alternative for patients with specific clinical considerations and treatment challenges. Of note, IVIG is typically used as adjunctive therapy in these bullous disease processes due to the possibility of symptom rebound upon weaning or discontinuation (in the absence of another concomitant immunomodulatory therapy).

Dermatomyositis

Several clinical trials have demonstrated the efficacy and tolerability of IVIG in treating dermatomyositis, resulting in US FDA approval for this indication in 2021.⁹ IVIG has been identified as a first-line treatment in patients with dermatomyositis exhibiting severe muscular involvement, those with malignancy, and cases where nutritional intake is compromised due to pharyngeal muscle involvement. It serves as a valuable second-line and adjunctive option in juvenile dermatomyositis and paraneoplastic dermatomyositis. Notably, controlled studies have demonstrated favorable outcomes with the use of IVIG in dermatomyositis including improvement of refractory cutaneous dermatomyositis as well as decrease or discontinuation of immunosuppressive medications in the majority of patients.¹⁰ A recent meta-analysis demonstrated that in patients with refractory dermatomyositis, IVIG significantly improved muscle strength and decreased serum creatine kinase level in addition to improving cutaneous manifestations.¹¹ For this indication, IVIG is administered at the standard dose of 2 g/kg body weight given in divided doses over 2-5 consecutive days. The maximal response to IVIG treatment typically occurs at around 4 months, necessitating ongoing therapy for at least 3-6 months in conjunction with conventional treatments at lower doses for sustained benefits in most patients.¹² These developments underscore the growing importance of IVIG in the comprehensive management of dermatomyositis, as it provides an efficacious and non-immunosuppressive treatment option for this patient population.

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

The efficacy of inpatient treatment with corticosteroids and immunosuppressive agents in SJS/TEN continues to be controversial. While supportive care and causative drug discontinuation remain the mainstay of treatment, the high mortality of this severe drug reaction merits continued exploration of other treatment options. The administration of IVIG at doses exceeding 2-3 g/kg, initiated promptly upon diagnosis, has been shown to arrest disease progression, reduce mortality, and improve overall outcomes in some patients.^13-15 For TEN, higher doses of 3 g/kg distributed over 3 consecutive days are recommended. Assessment of treatment response is typically based on the absence of epidermal detachment and re-epithelization of affected areas. It is worth noting that while some studies have reported improvement in TEN with the use of IVIG, other studies have found that IVIG does not yield survival benefits in TEN and SJS/TEN overlap, necessitating further exploration through randomized controlled trials.^16,17

Scleromyxedema

While scleromyxedema remains a challenging cutaneous mucinosis that does not always respond well to immunosuppressive agents, several case reports and case series have demonstrated encouraging outcomes with the use of IVIG. More recently, the first prospective trial exploring the use of IVIG for scleromyxedema reported a significant objective clinical improvement with IVIG, further demonstrating its utility as a first-line treatment.¹⁸ IVIG can be used alone or in combination with corticosteroids or other therapies.^19,20 Treatment is administered at the standard dose of 2 g/kg over 2-5 days every 4 weeks for 6 months or longer for maintenance. If patients have not achieved an adequate response after six cycles of IVIG, it is recommended to transition them to another therapy.

Kawasaki Disease

In conjunction with acetylsalicylic acid, IVIG is the gold standard FDA-approved treatment for Kawasaki disease, a vasculitis that most frequently affects pediatric patients. In this context, IVIG should be administered within 10 days of symptom onset at a dose of 2 g/kg as a single infusion given over 10-12 hours, alongside acetylsalicylic acid 50 mg/kg.²¹ If this standard treatment fails, a second dose of IVIG can be administered. Appropriate treatment is instrumental in reducing the risk of severe disease sequelae such as myocardial, coronary, and neurologic abnormalities, and meta-analyses have shown that the use of IVIG is associated with a significant decrease in new coronary artery abnormalities with a dose-dependent effect.²¹ The use of IVIG in Kawasaki disease exemplifies the vital role of immunoglobulin therapy in modulating inflammatory responses and preventing long-term complications, particularly in the pediatric population.

Systemic Lupus Erythematosus (SLE)

While not a conventional therapy for SLE, IVIG has demonstrated efficacy in severe forms of SLE such as refractory lupus nephritis and SLE-associated immune thrombocytopenia.²² IVIG has shown some response in cutaneous lupus erythematosus resistant to conventional therapies. A meta-analysis found that IVIG led to a significant reduction in SLE disease activity as well as improvement in complement levels.²³ There is also a role for IVIG in the treatment of pregnant patients with SLE due to its safety profile, where it has been shown to reduce lupus activity scores and pregnancy loss.²⁴ Other SLE variants in which IVIG treatment should be considered include neuropsychiatric lupus, Guillan-Barré syndrome associated with SLE, refractory lupus nephritis, and lupus-associated immune thrombocytopenia.²² For SLE, IVIG is typically administered at the standard dose of 2 g/kg over 2-5 days every 4 weeks. Given the recent advances and emerging therapeutic options for cutaneous lupus erythematosus, IVIG is generally reserved for patients who need to avoid immunosuppression.

Other Uses

Several case studies have explored the use of IVIG in antineutrophilic cytoplasmic antibody (ANCA)-associated small vessel vasculitides, Behcet disease, pretibial myxedema, systemic sclerosis, livedoid vasculopathy, pyoderma gangrenosum, severe atopic dermatitis, chronic urticaria, graft-versus-host disease, herpes gestationis, erythema multiforme, and Kaposi sarcoma. Further trials are needed to explore the overall efficacy and tolerability of IVIG in these conditions.

Conclusion

In conclusion, this review explores the multifaceted use and significance of IVIG in dermatology. From more common autoimmune bullous dermatoses to relatively rare conditions such as scleromyxedema, IVIG is a versatile, effective, and generally safe therapeutic option. Though often used off-label, the list of indications for IVIG in dermatology continues to grow, reflecting the dynamic landscape of dermatologic treatments. While further randomized controlled trials are needed to fully understand the efficacy of IVIG in treating many dermatologic conditions, this review aims to enhance patient care and promote evidence-based decision-making based on available data.

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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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¹Beacon Dermatology, Calgary, AB, Canada
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Dermatologie Clinic, Drummondville, QC, Canada
⁴Bausch Health Canada Inc, Laval, QC, Canada
⁵SKiN Centre for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
Isabelle Delorme has been a member of advisory boards for AbbVie, Bausch Health, Eli-Lilly, Janssen, Novartis, Sanofi-Genzyme. She has been a part of clinical trials for AbbVie, Amgen, Anaptys Bio, Arcutis, Bausch Health, BMS, Celgene, Dermira, Devonian, Eli-Lilly, Galderma, Glenmark Pharmaceutical, Innovaderm Research, Janssen, Leo Pharma, Novartis, Regeneron. She has recieved honoraria from AbbVie, Amgen, Avene, Celgene, Eli-Lilly, Janssen, Novartis, UCB Pharma. She has been part of speaker’s bureaus for AbbVie, Celgene, Bausch Health, Eli-Lilly, Janssen, Medexus Inc., Novartis, Sanofi Genzyme. Melinda Gooderham has been an investigator, speaker and/or advisor for – AbbVie, Amgen, Akros, Arcutis, Aslan, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Andrei Metelitsa has been a consultant for Bausch Health, Galderma, Leo Pharma and Pfizer.
Daniel O’Sullivan, Rami Zeinab and Mark Legault are employees of Bausch Health Canada.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Dermatological diseases such as atopic dermatitis, acne, and psoriasis result in significant morbidity and decreased quality of life. The first line of treatment for such diseases is often topical medications. While topical delivery allows active drug to be delivered directly to the target site, the skin is a virtually impermeable barrier that impedes delivery of large molecules. Thus, the formulation and delivery system are integral elements of topical medications. Patients also have preferences for the properties of topical formulations and these preferences can positively or negatively impact adherence. Therefore, the choice of topical formulation is a key consideration. Recent developments in drug delivery systems have produced enhanced topical treatments that improve efficacy, safety, and patient acceptability. Awareness of the delivery system in which drugs are formulated is critical as this can have profound implications on treatment success. This paper provides an overview and clinical commentary on advances in topical delivery systems and their impact on dermatological practice.

Keywords: acne, corticosteroid, dermatitis, dermatology, halobetasol, psoriasis, retinoid, tazarotene, topical, vehicle, Duobrii, Arazlo, Bryhali

Introduction

Topical therapies are often the first line of treatment for common skin diseases such as atopic dermatitis (AD), acne vulgaris (AV), and psoriasis (PsO).¹ Prescribing effective therapy is crucial for optimal treatment outcomes.² However, the composition of topical treatments is complex and should be taken into consideration when choosing a topical treatment in terms of both “formulation” and “drug delivery system” wherein the formulation includes the active drug and vehicle while the delivery system refers to technologies affecting the therapeutic action of the drug (including potency, stability, dispersion, and penetration). Both formulation and delivery system should be considered for each patient on the basis of the potency of the active molecule, patient preference, skin type, skin condition, and affected site.³ Several recent reviews have discussed topical vehicles, ingredients, and their effects on the skin,^4-10 however, there is a gap in reviewing advanced delivery systems currently in clinical use. This paper provides an up-to-date review of advances in topical delivery systems with a focus on those in clinical use for the treatment of AD, AV, and PsO.

Atopic Dermatitis, Acne Vulgaris and Psoriasis

Skin conditions are a common cause of disease globally,¹¹ with AD, AV, and PsO amongst those with the highest disease burden on patients¹². These conditions disrupt the normal skin function,¹³ trigger abnormal inflammatory responses, alter skin microbiome, and increase susceptibility to irritants/allergens.^5-7 AD is a chronic, relapsing disease, presenting as inflamed skin with intense itching.^14,15 AV is due to inflammation of the sebaceous follicles, resulting in increased sebum production and a favorable environment for bacterial growth.¹⁶ PsO is a chronic disease that presents with characteristic scaling, redness, and thickening of the skin. All of these skin diseases can have important detrimental effects on short and long-term psychosocial and physical health, with substantial morbidity and reduced quality of life.^15,17,18 As such, early treatment with the most efficacious therapies available is critical.

Factors to Consider with Topical Drug Delivery Systems

Applying treatment topically provides several advantages for managing skin diseases. It enables delivery of drug directly to the target site, minimizing systemic exposure.¹⁹ The skin provides for a regulated, constant delivery rate and circumvents first-pass metabolism.²⁰ However, delivering drugs to targets beneath the epidermis can be challenging.²¹ The skin is a multi-layered defense barrier constructed to withstand the penetration of external compounds.²² The stratum corneum is very effective in performing this role and minimizes the ingress and egress of molecules/ chemicals.²³ As a result, the skin is impermeable to almost all compounds with a molecular weight greater than 500 Daltons.^22,23 As diffusion is the principal mechanism by which a drug penetrates the skin,²² formulations must be optimized to maintain solubility, stability, dispersion, and penetration of the active ingredient(s) while ensuring they are sustained at the target site for sufficient time, as well as limit systemic exposure³.

The effectiveness of a topical medication depends not only on pharmacodynamic factors but also on patient preferences, adherence, and the location of disease.^2,24 Patient preferences are related to the formulation and drug delivery system whose attributes include moisturization, absorption, greasiness, stickiness, as well as ease and frequency of use.²⁵ These attributes influence adherence to the therapeutic regimen which is a major determinant of treatment success.²⁵ Teixeira et al.²⁶ reported that adherence was impacted not only by patient preferences, but also the body area affected. For example, adherence was higher for patients using gel/cream vs. ointment formulations when the body area affected was large. However, this was reversed with smaller areas. As such, delivery systems are no longer only considered ‘carriers’ of active ingredients, but also integral to the formulation. Hence, drug delivery system research and development have been the main drivers of recent advancements in topical formulations.

Advanced Topical Drug Delivery Systems

Over the years, advanced drug delivery systems have been developed to enhance effectiveness, tolerability, safety, and patient acceptability of topical formulations. Some of these advanced delivery systems are integrated into approved products utilized in clinical practice in Canada (Figures 1 & 2). As such, it is important for healthcare providers to be aware of these systems and their profound implications on treatment outcomes. The following summary provides an overview of some recent advances in drug delivery systems and their clinical application (Table 1).

Table 1. Advanced topical drug delivery systems in clinical use

Microencapsulation

Description of Delivery System

Microencapsulation is a technique that involves entrapping active ingredient(s) in a microcapsule, creating a barrier between the ingredients and the skin.²⁷ Once applied, microcapsules allow controlled release of active ingredients over time.²⁸ This offers advantages for topical delivery of agents (Table 1) where active ingredients are protected against degradation and maintained at the target site for an extended time while limiting local adverse reactions.^28,29

Clinical Application Highlights

Encapsulation is the technology behind two topical treatments approved for treatment of moderate to severe AV in the US. The first formulation is a foam-based delivery system that optimizes the topical delivery of minocycline (minocycline topical foam 4%, Amzeeq®).³⁰ Minocycline was previously not available topically due to its instability and systemic side effects.³¹ Such limitations were mitigated with microencapsulation. In phase 2^32,33 and 3³⁴ clinical trials, microencapsulated minocycline significantly reduced AV lesions and severity compared to placebo; with minimal adverse effects. The second is a cream-based formulation combining tretinoin 0.1% and benzoyl peroxide (BPO) 3% (Twyneo®).³⁵ Tretinoin and BPO are individually entrapped within silica-based microcapsules preventing the degradation of tretinoin by BPO.²⁸ The active ingredients are released over time, providing a consistent drug concentration at the affected site.³⁶ Results from clinical trials show that patients who received this encapsulated combination therapy had improved treatment outcomes compared with patients who received vehicle only. The treatment was well tolerated.³⁶

Microsponges

Description of Delivery System

Microsponges are microscopic, uniform, spherical, porous delivery systems.³⁷ Some features of micropsonges are summarized in Table 1. Their large surface area allows a range of substances to be incorporated into gels, creams, liquids, or powders.³⁸ They can absorb skin secretions, therefore reducing the oiliness of the skin.^38,39 When applied, the release of drug is controlled through diffusion, rubbing, moisture, pH, friction, or ambient skin temperature, producing a controlled release and reducing side effects.⁴⁰ Microsponge polymers possess the ability to load a spectrum of active ingredients and provide the benefits of enhanced effectiveness, mildness, and tolerability to a wide range of skin therapies.⁴¹ The microsponge system is stable over a range of pH and temperatures, compatible with most vehicles and ingredients, self-sterilizing as average pore size prevents bacterial penetration, and has a higher payload⁴² (50-60%) vs. conventional topical drugs and microencapsulation. However, due to their size (5-300 μm), passage through the stratum corneum is limited.³⁹

Clinical Application Highlights

Early topical formulations of tretinoin had high concentrations of active ingredients in alcohol-based solutions leading to skin dryness and irritation.^43,44 The innovation of microsponges led to the first alcohol-free, topical retinoid delivery system (tretinoin gel, Retin-A Micro^®).⁴⁵ This microsponge gel contains tretinoin in concentrations of 0.04%, 0.06%, 0.08%, and 0.1%. Tretinoin is entrapped in patented methyl methacrylate/glycol dimethacrylate copolymer porous microspheres (Microsponges^® system), within a carbomer-based gel. In the vehicle-controlled clinical trials, tretinoin gel was significantly more effective than vehicle in reducing the severity of acne lesions; and significantly superior to vehicle in the investigator’s global evaluation of the clinical response.^46-48 Microsponge delivery of tretinoin has also been associated with decreased irritation compared to earlier alcoholbased cream (Retin-A® cream, 0.1%).⁴⁹

Polymeric Emulsion Technology

Description of Delivery System

In polymeric emulsion technology (PET), active ingredients are encapsulated within oil droplets, together with moisturizing/ hydrating ingredients (light mineral oil, diethyl sebacate).⁵⁰ The oil droplets are uniformly dispersed within an oil-in-water emulsion and separated by a three-dimensional mesh matrix.⁵¹ Recently, PET has been combined with optimized selection of excipients and emollients to produce a patented delivery system called Prismatrex™. This novel technology allows simultaneous and uniform dispersion of active ingredients onto the skin at lower doses than conventional formulations to achieve comparable therapeutic effect, while providing enhanced hydration and moisturization.⁵² Also, the technology allows many attributes of patient preferences to be met. By combining water-soluble moisturizing components within the matrix, a lotion can have a pleasant feel; the use of moisturizers over alcohol-based components creates a lowirritancy/ low-drying formulation; and the mesh network breaking down upon contact with the salts on the skin surface results in quick release and absorption, leaving behind minimal greasy or sticky residue.^50,51

Clinical Application Highlights

Prismatrex™ is used in recent formulations containing retinoids, corticosteroids, or combination of both. Topical corticosteroids are a mainstay in the treatment of AD and PsO. Due to the defective skin barrier in AD and PsO, formulations with moisturizing effects in a patient-preferred format offer additional therapeutic advantages over previous formulations.⁵³ Halobetasol propionate (HP) 0.01% lotion (Bryhali^®), formulated with Prismatrex™, provides several improvements compared to the older 0.05% cream formulation. For example, a reduced concentration of drug while maintaining comparable efficacy to the cream formulation, and a safety profile that allows extended use up to 8 weeks.⁵⁴ Furthermore, the formulation is non-greasy and aesthetically pleasing, providing a patient preferred treatment option.⁵⁵

Topical retinoids are a cornerstone in the treatment of AV. However, dryness, erythema, and peeling are important side effects that can impact treatment adherence.⁵⁶ Prismatrex™ has been used to formulate the third-generation retinoid, tazarotene (TAZ) 0.045% lotion (Arazlo®). The small particle size with this formulation allows better access to the pilosebaceous unit.⁵⁷ Also, this novel technology allows for uniform distribution of TAZ on the skin along with moisturizing ingredients and emollients, therefore, TAZ may be delivered at a lower and potentially less irritating concentration than the previous 0.1% cream formulation.⁵⁸ Two identical phase 3, vehicle-controlled studies demonstrated statistically superior efficacy for TAZ 0.045% lotion vs. placebo in once-daily treatment of moderate to severe AV.⁵⁹

A fixed-combination lotion containing both HP 0.01% and TAZ 0.045% (Duobrii®, HP/TAZ) is formulated using Prismatrex™ technology and indicated for PsO treatment. Higher tissue permeation efficiency of both HP (vs. HP 0.05% cream) and TAZ (vs. TAZ 0.1% cream, Tazorac®) has been achieved with the combination using Prismatrex™ technology.⁵⁰ The delivery of both active ingredients with anti-inflammatory and anti-proliferative properties into a lotion confers a synergistic effect.^50,52 Also, it has demonstrated improved efficacy, tolerability, and maintenance of therapeutic effect compared with monotherapy with either of the active ingredients.^50,52,60-62 HP/TAZ’s acute and long-term efficacy (including maintenance of efficacy after cessation of treatment), tolerability, and safety have been demonstrated in phase 2 and 3 vehicle-controlled trials and an open-label extension study.⁶³ Importantly, HP/TAZ is associated with low incidences of adverse events that may be of concern with corticosteroid and retinoid monotherapy.⁶⁴ Skin atrophy occurs in up to 5% of patients treated with topical corticosteroids.⁶⁴ In HP/TAZ clinical trials, incidences of skin atrophy were rare and generally resolved by the end of the study despite 8 weeks of daily application.^63-64 This may be because TAZ increases the number and activity of dermal fibroblasts and stimulates collagen and elastin production.⁶⁵ Irritation, pain, and retinoid dermatitis may be a challenge with retinoid monotherapy. Incidences of these AEs were lower with HP/TAZ, than with TAZ monotherapy, potentially due to the anti-inflammatory properties of HP.⁶⁴ Clinical trials have also shown that the majority of participants who achieve clear skin with HP/TAZ, experience prolonged maintenance of therapeutic effect after treatment cessation.⁶⁰ Taken together, HP/TAZ provides a treatment option for PsO that is efficacious, safe, combines the beneficial effects of corticosteroids and retinoids, delivers moisturizing and hydrating ingredients, yields longer remission, and is acceptable to patients.

Real World Clinical Commentary

A challenge frequently encountered by dermatologists when managing AD, AV, and PsO is balancing sustained disease suppression with the avoidance of local/systemic side effects. To address this concern, advanced drug delivery systems, such as Primsmatrex™, allow for more efficient delivery of lower doses of active ingredients without compromising efficacy. However, this must also be balanced with overall patient acceptance. Patients consistently cite the following preferences for treatment options: non-greasy applications, reduced skin irritation, spreadable and easily absorbed,³⁶ easily applied in certain body sites (e.g., scalp); easy to wash off with minimal residue, and fast skin responses.⁶⁶ Novel delivery systems often enhance utilization of existing ingredients making them more acceptable to patients, resulting in therapeutic advances. For example, in acne, the innovative drug delivery systems used in Retin-A Micro®, Arazlo® and Twyneo® have significantly improved tolerability of existing topical retinoid ingredients without sacrificing the overall efficacy of these molecules. While patients are advised to maintain a dosing schedule of every second day during the initial phases of treatment to avoid potential irritation, these agents are well tolerated given the nature of the formulations.

The microencapsulation of minocycline foam allows delivery in a topical formulation as opposed to an oral format, which significantly enhances the safety profile. In psoriasis, where availability of topical agents is quite limited, the Prismatrex™ technology in HP/TAZ provides an excellent new treatment option which combines two effective drugs and is a welcome addition to our therapeutic algorithm. In clinical practice, this formulation is effective, can be less irritating to the skin than TAZ alone and is less likely to induce steroid-induced atrophy as compared to HP alone. Another advantage to these advanced topicals is that they result in improved adherence and therefore better treatment outcomes in the long run. Overall, when choosing the optimal therapeutic agent for treatment of AD, AV, or PsO the dermatologist now has the option to select a formulation that uses an advanced drug delivery system to maximize the chances of achieving successful treatment outcomes. Research in advanced delivery systems is vast, with a wide range of technologies showing promise for future clinical use, such as nanoparticles⁶⁷, ethosomes⁶⁸, niosomes⁶⁹, and liposomes⁷⁰.

Conclusion

Topical treatment is a cornerstone in managing AD, AV, and PsO;¹⁹ however, the delivery of active drugs through the dermal barrier remains a challenge. Furthermore, patient acceptability is a major contributing factor to the effectiveness and adherence to topical treatments. Advances in topical drug formulations and delivery systems address many limitations seen with older formulations. These advances allow for efficient and uniform delivery of active ingredients to target sites, greater patient acceptability, and enhanced treatment outcomes.

Acknowledgements

Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada, funded by Bausch Health Canada.

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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.

¹Division of Dermatology, University of Alberta, Edmonton, AB, Canada
²Recordati Rare Diseases Canada Inc., Toronto, ON, Canada

Conflict of interest: Robert Gniadecki reports carrying out clinical trials for Bausch Health, Sanofi, AbbVie and Janssen and has received honoraria as a consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallinckrodt, Novartis, Kyowa Kirin, Recordati, Sun Pharma and Sanofi. Emilia Paron is an employee of Recordati Rare Diseases Canada Inc.

Funding sources: None.

Abstract:
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), representing almost 50% of all lymphomas arising in the skin. There is an unmet need in the treatment of MF in Canada, as current available therapies for early-stage MF are limited, without topical agents previously indicated. Chlormethine gel is a topical antineoplastic agent with phase II clinical trial and real-world data demonstrating safety and efficacy as a treatment option for adults with MF. Skin-related side effects such as dermatitis can be managed through appropriate strategies. The use of chlormethine gel can be considered for patients with stage IA and IB MF-CTCL as it provides an easily administered, skin-directed treatment option that fills an unmet need in Canada.

Keywords: mycosis fungoides (MF) cutaneous T-cell lymphoma, chlormethine gel, topical treatment, alkylating agent, Ledaga™

Introduction

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL), which primarily manifests in the skin.^1-5 The prognosis of MF depends on the type and extent of skin lesions and extracutaneous disease.⁶ In early stages (IA-IIA), the lesions comprise red, scaly patches or plaques and as disease progresses to late stages (≥IIB), the patients develop skin tumors, often with ulcerations.⁶ Diagnosis is often delayed as patients can experience several years of nonspecific skin changes that may resemble psoriasis or eczema.^5,7

MF typically affects adults with a median age at diagnosis of 55-60 years, and a male-to-female ratio of 1.6-2:1.⁸ In Canada, the annual national incidence of MF is estimated at 4 cases per million individuals per year, with a mortality rate of approximately 0.4 deaths per million annually observed from 1992 to 2010.⁹

Early-stage MF patients represent approximately 70% of cases and most achieve normal life expectancy, with treatment aiming to prevent evolution to more severe disease and relieve burden on quality of life. Approximately 30% of patients progress to advanced disease (stage IIB or higher), and the 5-year survival rate is unfavorable: only 47% (stage IIB) to 18% (stage IVB). Many patients with MF experience comorbidities impacting their functional, emotional, and social well-being, such as cardiovascular events and secondary cancers.^10-14 Currently, apart from allogeneic stem cell transplantation, there is no cure for MF, and treatment approaches focus on patients’ health-related quality of life (HRQOL).¹⁰ In Canada, there remains an unmet need for novel MF therapies to address treatment gaps.

Chlormethine gel is a Health Canada approved topical antineoplastic agent for the treatment of stage IA and IB MF-CTCL in adult patients who have received prior skin‐directed therapy.¹⁵ Regulatory approval for MF-CTCL has also been granted by the US FDA and European Medicines Agency. Evidence from a phase II clinical trial and real-world experience with chlormethine for over 30 years demonstrates chlormethine gel as a convenient topical agent with an efficacious and well-tolerated safety profile for adults.^16-22

Diagnosis, Pathogenesis and Treatments of MF

Diagnosis of MF is often performed by a multi-disciplinary team of specialists, including dermatologists, hematologists, dermatoand hematopathologists.^23,24 For histopathological confirmation, multiple skin biopsies are often required, and molecular studies (T-cell receptor clonality analysis) and immunostainings are needed. Full staging is usually not required in the early stage (IA) because the disease is confined to the skin, but imaging and peripheral blood flow cytometry should be considered in stages IB and higher. The diagnosis can be delayed for years due to the likeness of MF to benign conditions that lack specific diagnostic tests.^24,25 As such, guidelines have been prepared for recommendations of diagnosis, initial staging, and diagnostic algorithms for treatment (Table 1).^26,27

In early stages of MF, malignant T-cells accumulate in the papillary dermis and epidermis and are accompanied by an abundant inflammatory infiltrate. With disease progression, malignant T-cells become polarized into the T helper 2 (Th2) pattern and secrete cytokines impairing local and systemic immunity and promoting inflammation.²⁸ Recent evidence suggests that hematogenous spread of malignant cells between different areas of the skin is responsible for disease progression.²⁹ Secondary infections with Staphylococcus aureus are common and may further exacerbate the disease.^30,31 Extracutaneous involvement comprises most commonly in the peripheral blood and the lymph nodes, with occasional metastases to parenchymatous organs such as the spleen, brain, lung, kidney or liver.^30,31

At all stages, the aim of treatment is to decrease malignant cell burden and identify and control comorbidities.^23,32 As MF is a rare disease, randomized clinical studies are lacking and treatment nationally is based mainly on international guidelines and clinical experience. Given the limited evidence base for many treatments, there have been no topical pharmacotherapies specifically approved for MF in Canada until chlormethine gel was approved in 2021.¹⁵ In all stages, skin directed therapies (SDT) remain the mainstay of treatment and are combined with systemic therapies when needed.^8,24,26,27 SDT for early-stage MF may consist of one or more of the following: topical corticosteroids, topical retinoids (including tazarotene indicated for the topical treatment of acne vulgaris),³³ topical imiquimod, topical carmustine, psoralen plus ultraviolet A (PUVA), narrowband ultraviolet B (UVB), radiation therapy and total skin electron beam therapy (TSEBT).²⁷

Topical steroids are typically used for patients as background treatment to manage the symptoms of MF, such as pruritus, rather than to treat the disease.²³ Data supporting the use of imiquimod and carmustine are limited to case series.^34-36 Phototherapies (PUVA, narrowband UVB) are the most frequently used treatments for early-stage disease,^8,23,27 however many patients in Canada have limited access.

Thus, the scarcity of robust, comparative data informing treatment guidelines underscores the unmet need for accessible SDT in MF.³⁷

Chlormethine Gel: Mechanism of Action, Completed and Ongoing Studies

Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells. Chlormethine binds to N7 positions in guanines via reactive chloroethyl moieties and potentially also binding to N3 positions in adenines in DNA. The bifunctional nature of chlormethine along with its small molecular size allows it to form interstrand cross-links within DNA, making it a more effective tumor chemotherapeutic agent than monofunctional analogues. Unrepaired cross-links prevent transcription, replication, and segregation of DNA, ultimately causing cell death.¹⁵ Indeed, a recent in vitro study by Chang YT et al. demonstrated that chlormethine, as an alkylating agent, is able to inhibit predominantly rapidly proliferating malignant skin T-cells, through the induction of DNA breaks, the impairment of the DNA repair machinery and by increasing the expression of apoptotic gene (CASP3).³⁸ The formulation of chlormethine gel was designed to maximize efficacy and tolerability. The non-aqueous nature of chlormethine gel imparts high stability, and the solvent, diethylene glycol monoethyl ether (DEGEE), promotes delivery of the drug to the epidermis,³⁹ with no evidence of systemic absorption of chlormethine following gel application.⁴⁰ DEGEE has shown to be non-skin irritating even after prolonged and repeated contact.⁴¹ No risk to patients with suppressed bone marrow or COVID-19 has currently been identified in the literature with chlormethine gel.

The pivotal phase II study (201) evaluated 0.02% chlormethine gel (n=130) vs. 0.02% chlormethine ointment (n=130) for the treatment of patients with persistent or recurrent stage I or IIA disease. Diagnosis was confirmed with a skin biopsy of a representative lesion, obtained in the 90 days prior to study initiation and after a 4-week treatment washout period of treatments directed at the disease.⁴² Patients were not taking concomitant corticosteroids during the study. Chlormethine gel was applied once-daily to specific lesions (stage IA) or to the total skin surface (stage IB/IIA) for up to 12 months. Study 201 comprised a pre-study visit (screening), a baseline (Day 1) visit, and monthly visits for 6 months and then visits every 2 months up to month 12.⁴³

Response rates (RR) for chlormethine gel were consistently higher than those for chlormethine ointment for the primary endpoint of Composite Assessment of Index Lesion Severity (CAILS). In the intention-to-treat (ITT) population, the confirmed RR was higher for the gel than ointment (59% vs. 48%) and the criterion for non-inferiority was met.⁴² Similar efficacy results were seen between stratum 1 (stage IA) and stratum 2 (stages IB/IIA) patients. In the efficacy evaluable (EE) population, 77% of patients receiving gel vs. 59% of patients receiving ointment achieved a confirmed CAILS response (Figure 1). In study 201, time to CAILS response was defined as the time from baseline to the first confirmed CAILS response [complete response (CR), defined as 100% improvement, with a score of 0, or partial response (PR), defined as a 50% to 100% reduction from baseline score]⁴³ and was achieved in the gel arm at 26 weeks and 42 weeks in the ointment arm. Therefore, patients in the gel arm attained a 50% RR approximately 16 weeks sooner than patients in the ointment arm.

In addition, the RR improved the longer patients were treated with chlormethine gel. Approximately 46% of patients treated with gel achieved a confirmed response at 24 weeks and 76% achieved a confirmed response at 52 weeks. Continued treatment and monitoring is recommended to ensure optimal patient response as the maximum response to chlormethine gel treatment was observed between 8 and 10 months in the pivotal study,^42,43 and a by-time reanalysis of study 201 demonstrated early, late and intermittent response patterns.⁴⁴

Duration of response (DOR) based on CAILS score in the ITT population was analyzed and 86% patients in the gel arm and 82% patients in the ointment arm maintained their response through the end of the trial (12 months). It is estimated that at least 90% of responses will be maintained for ≥10 months, the maximum follow-up in the trial.^42,43

In study 201, 61.7% of patients who received gel and 50.4% of patients who received ointment reported at least one adverse event (AE) that was considered related to the study drug.⁴² Dermatitis (54.7%) was most common,¹⁵ although this was managed with treatment adjustments, such as suspension or reduction of chlormethine treatment and the use of emollients or oral antihistamines.⁴² In study 201, the following guidance was implemented in the protocol to manage dermatitis: treatment should be stopped for any grade of skin ulceration or blistering, or moderately severe or severe dermatitis. Upon improvement, treatment can be restarted at a reduced frequency (once every 3 days), and if treatment is tolerated for at least 1 week, the frequency of application can be increased to every other day for at least 1 week and then to once-daily application if further tolerated.¹⁵ No treatment-related serious AEs were reported, and no statistically significant differences were observed in the overall incidence of AEs or any other subcategory between the gel and the ointment arms.⁴² The safety data from study 201 was consistent with the lack of systemic exposure to chlormethine or its degradation product.⁴² In real-world practice, irritant contact dermatitis has been observed most frequently.⁴⁵ Results from the Mechlorethamine Induced Contact Dermatitis Avoidance Study (MIDAS) study suggest that patients who develop allergic contact dermatitis in response to chlormethine gel treatment may have an allergic-type phenotype that predisposes to cutaneous reactions to common allergens, unrelated to chlormethine treatment.⁴⁶ Chlormethine gel is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.¹⁵

Real-world evidence has shown further efficacy and safety of chlormethine gel in the treatment of MF as demonstrated in the prospective, observational, non-interventional US-based PROVe trial over a 2-year period.⁴⁷ Patients were enrolled if they were diagnosed with any stage of MF and were being treated with chlormethine gel in combination with other MF therapies. The proportion of stage IA and IB responders [defined as ≥50% reduction from baseline in body surface area (BSA) involvement] was 44% in patients who received chlormethine gel plus topical corticosteroids plus other treatment and 45% in patients who receive chlormethine and other treatment at 12-month evaluation. Peak response occurred at 18 months for stage IA and IB patients in the chlormethine gel plus other treatment group (67%). In this study, HRQOL was assessed with the Skindex-29 questionnaire. Post-baseline weighted mean subscale scores for responders showed a better HRQOL than for non-responders. The differences between responders and non-responders were statistically significant (p<0.001 for each subscale) indicating that chlormethine gel improved HRQOL in patients responding to treatment. Treatment-related AEs were experienced in 28% of patients; most commonly dermatitis (12%), pruritus (7%), skin irritation (7%) and erythema (4%).⁴⁷

Chlormethine gel has demonstrated efficacy and safety in the treatment of patients with MF globally, and experience from clinical practice has shown chlormethine gel used both as monotherapy in early-stage MF and in combination with other therapies in advanced-stage disease. Emergent cutaneous reactions can be managed if appropriate protocols are followed. Application frequency modifications such as gradual initiation of chlormethine gel 1-4 times a week and increasing to once daily application upon toleration, with most centers using topical steroids to manage skin-related AEs.^45,48,49

The incidence and severity of contact dermatitis following treatment with chlormethine gel alone or in combination with triamcinolone ointment in patients with MF has been evaluated in the MIDAS study⁵⁰ and the ongoing REACH trial (Study to Determine the Aetiology of Chlormethine Gel Induced-skin Drug Reaction in Early-Stage Mycosis Fungoides Cutaneous T cell Lymphoma) (NCT04218825), may provide further information on how to manage dermatitis for patients treated with chlormethine gel.

Conclusion

Major international guidelines recommend the use of chlormethine gel as a first-line treatment in adult patients with early-stage MF^{8,23,26,27,51} and chlormethine gel is approved for the treatment of stage IA and IB MF-CTCL in adults who have received prior skin‐directed therapy in Canada.¹⁵ Chlormethine gel demonstrates improvements in CAILS, mSWAT and BSA during a phase II clinical trial with patients treated with chlormethine gel achieving response faster and maintaining response for a longer period of time.⁴² Real-world evidence demonstrates improvements in HRQOL for patients on treatment.⁴⁷ AEs related to chlormethine gel use are overall consistent with the lack of systemic exposure to chlormethine and its degradation product, and the occurrence of skin-related events such as dermatitis can be managed through frequency of application reduction and appropriate strategies.^45,48,49 Overall, chlormethine gel provides a valuable role in the management of MF.

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