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

¹SKiN Centre for Dermatology Peterborough, ON, Canada
²Probity Medical Research, Peterborough, ON, Canada
³Queen’s University, Kingston, ON, Canada

Conflict of interest: MG has been an investigator, speaker and advisory board member for Arcutis.

Adapted from O’Toole A, Gooderham M. Topical Roflumilast for Plaque Psoriasis. Skin Therapy Lett. 2023 Sep;28(5):1-4. PMID: 37734074. Copyright 2023 by the Skincareguide.com Limited. Reprinted with permission.

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Case Presentations

Case #1

A 62-year-old female postal carrier presents with a 15-year history of plaque psoriasis which involves her elbows, dorsal hands, under the breasts and on the forehead and around the ears, total body surface area (BSA) of 3.5%. She has used numerous topical agents over the years, but most recently was prescribed hydrocortisone valerate 0.2% cream and clotrimazole for under the breasts, off-label tacrolimus 0.1% ointment for the face and ears and betamethasone valerate/calcipotriol foam for the elbows and hands. She reports using the topicals ‘when needed’ and presents with ongoing plaques in all described areas. She does admit she should probably be more consistent, but she has a busy life. Her past medical history is significant for obesity and hypertension. Her work uniform is uncomfortable and does not cover the visible areas of psoriasis making her very self-conscious. She books an appointment to discuss other options.

Case #2

A 38-year-old mechanic has a 10-year history of moderate-to-severe plaque psoriasis which requires systemic therapy. He has tried and failed methotrexate and acitretin in the past, and more recently has had success with an interleukin (IL)-23 inhibiting biologic agent started by his dermatologist. His body psoriasis cleared with the biologic, but he continues to have fissured plaques on his hands which is painful and interferes with his ability to work. He has been prescribed potent topical corticosteroid products in the past, including combination products, but he reports they are greasy, and he’s concerned about using steroids long-term. You see him in follow up, and he asks you for any other solutions.

Introduction

Plaque psoriasis is a chronic inflammatory skin condition with an estimated prevalence of 3%¹ and is characterized by scaly plaques which can be red to violaceous depending on the background skin tone. Psoriasis most commonly presents on the extensor surfaces but can involve anywhere on the body, including the scalp, face, and intertriginous areas (groin, under breasts or pannus, axillae). Most cases of plaque psoriasis are mild to moderate in severity, where half of patients have a BSA ≤3%.¹ Psoriasis significantly impacts quality of life, with the majority of patients reporting a “large impact” on their everyday life, even in those with limited BSA involvement.² Impact on quality of life is greater with special site involvement (i.e., face, groin, palms/soles) compared to no special site involvement.³ Itch is considered the most bothersome symptom in plaque psoriasis by almost half of patients.^3,4

The mainstay of treatment is topical including steroids, vitamin D analogs, retinoids, and calcineurin inhibitors (used off label), whether used as monotherapy in mild to moderate disease or as concomitant therapy with systemic agents in moderate to severe disease. Current topical therapies have limitations, however, including messy or greasy texture, complex or timeconsuming application, local side effects, or perceived inefficacy, which can all lead to lack of adherence to treatment and poor outcomes.⁵

Pathophysiology of Psoriasis and Role of Phosphodiesterase-4

Psoriasis is a chronic inflammatory disease influenced by environmental, genetic, and immunologic factors, characterized by rapid keratinocyte proliferation. The enzyme phosphodiesterase-4 (PDE4) plays a crucial role in immune cell regulation, with elevated activity in psoriatic skin promoting inflammation.⁶ PDE4 inhibitors, such as oral apremilast for moderate to severe psoriasis and crisaborole ointment for mild to moderate atopic dermatitis, are approved for use. Roflumilast, a potent PDE4 inhibitor, increases cyclic AMP, thereby reducing pro-inflammatory mediators like IL-17, IL-23, IFN-gamma, and TNF-alpha, thus normalizing immune response and keratinocyte differentiation.⁷ Roflumilast has greater affinity for PDE4 than the other currently available PDE4 inhibitors; depending on the comparator and isoform analyzed, it is approximately 25-300 times more potent than apremilast and crisaborole.^7-9

Topical Roflumilast Cream

Topical roflumilast 0.3% cream (Zoryve^TM) was approved for the treatment of plaque psoriasis including intertriginous psoriasis in adolescents (aged ≥12 years) and adults by the FDA in July 2022 and by Health Canada in April 2023; In October 2023, the FDA approved the expanded indication to include children 6-11 years of age as well. It is uniquely formulated as an emollient water-based cream designed to deliver the roflumilast molecule throughout the epidermis without disrupting the skin’s barrier function. A unique and patented emulsifier blend (Crodafos^TM CES) maintains the integrity of the lipid bilayer while facilitating delivery of roflumilast. The formulation does not contain sensitizing or irritating ingredients such as propylene glycol or fragrance, resulting in improved tolerability (compared to some other topicals currently available). Topical roflumilast 0.3% cream is also found in higher concentrations in the skin compared to that expected with oral dosing, with levels 62- to 126-fold higher in the skin compared to plasma.¹⁰ Its lipophilic and protein-affinity properties allow it to form a reservoir in the stratum corneum, enabling prolonged release. With a long half-life of 4 days, it allows for once-daily dosing, ensuring high efficacy and improved tolerability.¹⁰

Clinical Trials: Efficacy and Safety of Roflumilast

Phase 1 and 2 trials

A Phase 1/2a randomized controlled trial (NCT03392168) tested roflumilast cream 0.5%, 0.15% vs. vehicle for 28 days in patients with ≤5% BSA.¹¹ The primary endpoint was met with significant improvement in the Target Plaque Severity Score (TPSS) x target plaque area (TPA) with roflumilast 0.5% (P = .0007) and 0.15% cream (P = .0011) vs. vehicle; 66%-67% improvement from baseline to week 4 was noted with roflumilast vs. 38% for vehicle.¹¹

In a Phase 2b randomized controlled trial (NCT03638258), 331 adult patients were randomized to receive roflumilast cream 0.3%, 0.15%, or vehicle once daily for 12 weeks. The primary endpoint at 6 weeks of an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) was reached by 28% in the roflumilast 0.3% group (P < .001), 23% in the roflumilast 0.15% group (P = .004), and 8% in the vehicle group (Figure 1A). Important secondary endpoints included an intertriginous IGA (I-IGA) response (clear or almost clear and ≥2 grade improvement from baseline) in 73% of the roflumilast 0.3% group, 44% of the roflumilast 0.15% group, and 29% of the vehicle group in the subgroup of participants with at least mild IGA intertriginous involvement (~15% of trial population).¹² Itch and itch-related sleep loss were also improved in subjects receiving roflumilast. Subjects with a baseline worst itch numeric rating scale (WI-NRS) ≥6 treated with roflumilast 0.3% cream achieved ≥4-point improvement compared with vehicle, which was significant at all time points between week 2 and week 12 (all P < .05).¹³ The least squares mean improvement in itch-related sleep loss was statistically significant for both doses of roflumilast as early as week 6 and maintained through week 12.¹³

Phase 3 trials

Two identical pivotal Phase 3 trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389), enrolled patients older than 2 years of age, with 2% to 20% BSA and an IGA of at least 2 (mild).¹⁴ A total of 439 and 442 subjects were enrolled (DERMIS-1 and DERMIS-2, respectively) and randomized to receive roflumilast cream 0.3% or vehicle. The primary endpoint was achieving IGA success (clear or almost clear [0 or 1] with ≥2 grade improvement from baseline) at 8 weeks. IGA success was achieved by participants receiving roflumilast 0.3% cream vs. vehicle by 42.4% and 6.1% (DERMIS-1) and by 37.5% and 6.9% (DERMIS-2), respectively (P < .001 for both) as shown in Figure 1B. Important secondary endpoints included I-IGA success at week 8, 75% improvement in Psoriasis Area and Severity Index (PASI75) at week 8, and itch improvement as measured by WI-NRS at weeks 2, 4, and 8. In participants with an I-IGA score of at least 2 at baseline (approximately 20% of trial population), I-IGA success at week 8 was achieved by 71.2% vs. 13.8% (DERMIS-1) and 68.1% vs. 18.5% (DERMIS-2) in roflumilast 0.3% cream vs. vehicle, respectively.¹⁴ The majority of patients achieving I-IGA success also achieved an I-IGA score of clear (0) with 63.5% vs. 10.3% (DERMIS-1) and 57.4% vs. 7.4% (DERMIS-2) (P < .001) clearing intertriginous areas with roflumilast 0.3% vs. vehicle, respectively. PASI75 was reached with roflumilast 0.3% vs. vehicle in 41.6% vs. 7.6% (P <.001) and 39% vs. 5.3% (P < .001) in DERMIS-1 and DERMIS-2, respectively. Itch, the most bothersome symptom of psoriasis, also improved in patients with a baseline WI-NRS score of ≥4 at baseline. WI-NRS reduction of at least 4 points from baseline was achieved as early as week 2 in 34.9% vs. 22% (DERMIS-1, P = .12) and 41.9% vs. 21.1% (DERMIS-2, P = .003) and at week 8 in 67.5% vs. 26.8% (DERMIS-1, P < .001) and 69.4% vs. 35.6% (DERMIS-2, P < .001).¹⁴

Topical roflumilast was well tolerated with rates of treatment emergent adverse effects (TEAEs) similar in both groups: DERMIS-1 (roflumilast: 25.2% and vehicle: 23.5%) and DERMIS-2 (roflumilast: 25.9% and vehicle: 18.9%).¹⁴ Less than 1% of patients in any group experienced a serious adverse event. Rates of discontinuation due to TEAEs were low and similar between groups. The most commonly reported TEAEs were headache and diarrhea consistent with the effects of oral PDE4 inhibition, but present at much lower rates than seen with oral agents. Diarrhea was mild to moderate and reported in 3.5% and 2.8% of participants receiving roflumilast in DERMIS-1 and DERMIS-2, respectively, compared to none in the vehicle group. No patients interrupted therapy or discontinued due to diarrhea.¹⁴ Headache was reported in 1% and 3.8% in the roflumilast groups and 1.3% and 0.7% in the vehicle groups. The cream was well tolerated with low rates of application site pain: DERMIS-1 (roflumilast: 0.7% and vehicle: 0.7%) and DERMIS-2 (roflumilast: 1.4% and vehicle: 0%). Investigator-rated tolerability was consistent with patient-rated tolerability, with 98- 99% of roflumilast patients and 98% of vehicle patients showing no signs of irritation and 99% of patients reporting ‘no or mild’ sensation with application when assessed at both weeks 4 and 8.¹⁴

Long-term Use of Topical Roflumilast

Long-term use of roflumilast was investigated in a 52-week open-label extension (OLE) of the Phase 2b study.¹⁵ There were two cohorts in the OLE: cohort 1 (n=230) was comprised of patients who completed the initial 12-week phase of the Phase 2b study (for a total of 64 weeks of therapy), and cohort 2 (n=102) had naïve patients with a diagnosis of at least mild psoriasis for a minimum of 6 months. The completion rate after 52 weeks was 73.5%, with low rates of discontinuation due to TEAEs or inefficacy, and the majority of discontinuations were due to withdrawal or loss of follow-up considering these trials were conducted during the COVID pandemic. The proportion of patients achieving IGA success was consistent over time, with 34.8% of cohort 1 patients and 39.5% of cohort 2 patients achieving IGA success with 64 weeks and 52 weeks of as-needed therapy, respectively. I-IGA success was achieved by 60% at week 12 and maintained by 66.7% of cohort 2 patients by week 52 but was not recorded in cohort 1 patients. Of the patients who achieved clear or almost clear skin during the open label portion, the mean durability of maintaining their response was 10 months.¹⁶ Topical roflumilast was well tolerated in the OLE, with the majority of TEAEs rated mild or moderate, 97% considered unrelated to treatment, and ≥97% showed no signs of irritation on physician assessment.¹⁵

Discussion

PDE4 inhibition with topical roflumilast is a promising nonsteroidal option for patients with plaque psoriasis of varying severities. Key data from the pivotal trials, DERMIS-1 and DERMIS-2, report IGA success in approximately 40% of study participants with psoriasis ranging from mild to severe. Results are supported by earlier phase studies measured at earlier time points. IGA success was noted as early as week 4, and responses were maintained to week 64 with as-needed use, suggesting that once a response is obtained, it can likely be sustained over time. Itch, the most bothersome symptom of plaque psoriasis, improved by 2 weeks (the first assessed time point) in all studies and itch improvement maintained over time. Itch-related sleep loss also improved compared to vehicle. Early responses such as itch and sleep improvement can encourage adherence to therapy and improve outcomes.

Given the spectrum of obstacles in the treatment of plaque psoriasis, including patient adherence and tolerance with topical therapies, as well as the management of itch and special sites (e.g., face and intertriginous areas), topical roflumilast appears to address these challenges. Individuals with psoriasis are often prescribed multiple topical medications to treat different skin areas, which contributes to a complicated treatment regimen and patient non-adherence. Topical roflumilast addresses this significant unmet need with its once-daily, non-steroidal and carefully designed vehicle that is appropriate for use on most body areas, avoiding the need for multiple prescriptions and simplifying the treatment regimen. A foam formulation is also being developed for use on the body and scalp.

The PASI75 responses noted with topical roflumilast were also comparable with a recent trial of oral apremilast for patients with mild to moderate psoriasis (ADVANCE trial, NCT03721172).¹⁷ With similar baseline characteristics (PASI 6-7, BSA 6-7% and the majority of patients with IGA 3 or moderate severity) in DERMIS-1/ DERMIS-2 and the ADVANCE trial, the proportion of patients achieving PASI75 were similar or better with roflumilast compared to oral apremilast. The comparability of a topical therapy demonstrating efficacy that is similar to or better than an oral PDE4 agent such as apremilast, can be explained by the properties of topical roflumilast, which include the lipophilicity and reservoir in the stratum corneum combined with the higher affinity of roflumilast for PDE4. In patients with mild to moderate psoriasis, topical roflumilast may potentially delay or even avoid the need for oral therapy by providing similar efficacy. The limitation will be patients with higher BSA where the risk of TEAEs, such as diarrhea, may be higher or those with psoriatic arthritis where a systemic therapy may be preferred.

Case Follow Up

Case #1 continued

After further discussion of options, this 62-year-old woman does not wish to start a systemic medication and would like to continue with topical therapy. For more effective control, she requires a more simplified treatment regimen and more education on how to use topical therapies effectively. Reducing the number of prescriptions and applications per day can simplify her busy life, so topical roflumilast 0.3% cream is one product that she can use on all areas of psoriasis once a day, making this convenient and easy for her. Alternatively, she could reduce her current regimen and use off-label tacrolimus 0.1% ointment twice daily on the face, ears, and body folds and the betamethasone dipropionate/calcipotriol foam once daily on the hands and elbows. Education on optimal use of these products is required to inform that they need to be continued until the skin is clear and then used as needed.

Case #2 continued

The 38-year-old male is looking for optimization of his current biologic therapy to improve the residual psoriasis on his hands and his preference is to not use steroids. Current options include: adding a non-steroidal, non-greasy, once-daily topical, such as roflumilast 0.3% cream; adding back an oral systemic medication such as acitretin in addition to his biologic; or increasing the frequency of his biologic injection. His preference is to try a new topical agent to avoid taking more systemic medication. After 4 months of follow up of using roflumilast 0.3% cream, his fissures have healed and his hands are almost clear. Not only does he feel better at work, but he has been able to re-join his softball league this year.

Conclusion

Targeting PDE4 with a highly selective inhibitor such as roflumilast is a proven effective strategy for the treatment of plaque psoriasis. Topical roflumilast cream 0.3%, already approved by Health Canada and the FDA for use in adolescents and adults, has demonstrated efficacy and tolerability. It is nonsteroidal, administered once daily, and highly potent, yet delivered in a cosmetically elegant formulation that is well tolerated by patients. It can be used on most body areas, including the sensitive intertriginous regions and face, making one product suitable for treating all areas of involvement. Topical roflumilast will offer patients and their health care providers a simple, convenient, safe, effective, and durable therapeutic option for the management of psoriasis.

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

Conflict of interest: The authors have no conflicts of interest to declare. Funding: None.

Abstract:
The pathogenesis of psoriasis has been linked to autoimmune and autoinflammatory traits that result in atypical cytokine and keratinocyte activation and proliferation. Many cytokine pathways are involved in the development of inflammation with interleukin-23 (IL-23) playing a significant role in plaque-type psoriasis. Biologic agents that target specific cytokines have shown to be effective therapies in the treatment of plaque-type psoriasis over other conventional treatments such as systemic retinoids. Tildrakizumab is an immunoglobulin G1-kappa monoclonal antibody that inhibits the IL-23/IL-17 pathway and has demonstrated through two three-part randomized Phase 3 clinical trials (reSURFACE 1 and reSURFACE 2) and their extension trials to be an efficacious and safe therapy for the targeted treatment of moderate-to-severe plaque-type psoriasis.

Keywords: psoriasis, tildrakizumab, IL-23/IL-17 pathway, targeted therapy, re-SURFACE trials, Ilumya®

Introduction

Psoriasis is a chronic inflammatory skin disease that affects 2% of the population. The pathogenesis of psoriasis is multifactorial and associated with a polygenic genetic predisposition and various triggers, leading to an abnormal type 1 immune response stimulating abnormal keratinocyte proliferation and differentiation.^1-3 Among the various cytokines implicated in the development of psoriasis, interleukin-23 (IL-23) has shown to play a significant role via induction of IL-17 and regulation of T memory cells and activation of macrophages that contribute to chronic inflammation (Figure 1).² The development of co-morbidities such as joint and vascular inflammation, and an increased risk of cardiometabolic, gastrointestinal, and chronic kidney diseases, can lead to psychological and quality of life impairments for many patients.¹ A systematic review and meta-analysis showed that the risk of developing depression is greater in patients with psoriasis, which may result from factors such as stigma and social isolation, physical pain from pruritus and bleeding, and co-morbidities, as well as associations with pro-inflammatory biomarkers.⁴ An increased prevalence of depression, anxiety and suicide ideation amongst the psoriatic population reveals a high burden of disease.¹

While phototherapy continues to be used in the sphere of psoriasis, other therapies such as immunosuppressive and immunomodulatory treatments, including methotrexate, carry long-term risk of adverse effects.⁵ With an improved safety and efficacy profile over conventional treatments, biologics are increasingly emerging as standard of therapy for the management of psoriasis.

Novel Therapy

In March 2018, tildrakizumab, a high-affinity, humanized immunoglobulin G1-kappa (IgG1/k) monoclonal antibody targeting the p19 unit of IL-23, was approved by the US FDA for the treatment of patients with moderate-to-severe chronic plaque psoriasis.⁶ Health Canada approval followed in May 2021. Data from two randomized Phase 3 trials (reSURFACE 1 and reSURFACE 2, n=772 and n=1090) and their extension trials showed favorable efficacy and tolerability of tildrakizumab.^7,8

Mechanism of Action

Tildrakizumab binds to the p19 subunit on IL-23 and inhibits the binding of IL-23 with the IL-23 receptor (IL-23R) on Th-17 cells.⁶ When the IL-23p19 subunit binds to the IL-23 receptor, it results in tyrosine phosphorylation of JAK2 within Th-17 cells, thereby inducing phosphorylation of STAT3 and TYK2 and gene expression of RORγt, leading to Th17 cell differentiation. Th17 cell differentiation releases proinflammatory cytokines (IL-17A/F) that in turn induce keratinocyte activation and proliferation.^9-11 By blocking the binding of IL-23p19 to IL-23R, the release of IL-17A/F cytokines is inhibited.

Clinical Trials

The efficacy and safety of tildrakizumab was assessed in two three-part randomized Phase 3 trials (reSURFACE 1 and reSURFACE 2).⁷ The two trials spanned 250 sites globally and included sites in Australia, Canada, the UK, the US, Europe, Israel, and Japan. Enrolled participants were aged 18 years or older with moderate-to-severe chronic plaque psoriasis as defined by body surface area ≥10%, Physician’s Global Assessment (PGA) score ≥3 and Psoriasis Area and Severity Index (PASI) score ≥12. Baseline characteristics were similar across all groups and included a higher percentage of male (65%-73%) and White (65%-92%) participants with average PASI scores of 19.3-20.7. Two co-primary endpoints were evaluated in the trials and included: achieving PASI 75 and PGA response (score of 0 (“clear”) or 1 (“minimal”) with ≥2 grade score reduction from baseline) at week 12. Secondary endpoints were PASI 90 and PASI 100 at week 12 in both studies. In reSURFACE 2, PASI 75 and PGA response at week 28 were also secondary endpoints. In reSURFACE 1, 772 subjects were randomized to receive 200 mg (n=308), 100 mg (n=309), or placebo (n=155). In reSURFACE 2, 1090 subjects were randomized to receive 200 mg (n=314), 100 mg (n=307), placebo (n=156), or etanercept (n=313). Tildrakizumab was administered at week 0 and 4 during part 1 and at week 16 during part 2. Etanercept was administered twice weekly in part 1 and once weekly during part 2 of the reSURFACE 2 trial.

At week 12, subjects assigned to 100 mg or 200 mg of tildrakizumab groups showed significant clinical improvement in both re-SURFACE 1 and 2 trials compared to vehicle controls. Table 1 shows efficacy results for the two co-primary efficacy endpoints and the two secondary endpoints (p<0.0001 for comparisons of both tildrakizumab groups vs. placebo in both trials).

Two extension studies of the reSURFACE 1 and 2 Phase 3 trials were conducted up until 148 weeks (2 years) and 244 weeks (5 years). In the 148-week extension, efficacy was assessed for responders (PASI 75) to 100 mg and 200 mg tildrakizumab, partial responders (PASI 50-75) to 100 mg and 200 mg tildrakizumab, and partial/non-responders (PASI 50-75/PASI 0-50) to etanercept at week 28. Tildrakizumab responders (100 mg, n=329; 200 mg, n=227) and partial responders (100 mg, n=40; 200 mg, n=201) were maintained on the same dose and partial/non-responders to etanercept 50 mg were switched to tildrakizumab 200 mg dosing (n=121), administered every 12 weeks, until week 148.⁸ In the 244-week extension study, the tildrakizumab 100 mg and 200 mg week 28 responders (100 mg, n=302; 200 mg, n=213) and partial/non-responders to etanercept who were switched to tildrakizumab 200 mg at week 28 (n=107) were maintained on the same dose, administered every 12 weeks, until week 244.¹² The efficacy results for both extension studies are shown in Table 2.

Overall, the reSURFACE trials 2-year extension study demonstrated that 80% of patients who initially responded to tildrakizumab maintained PASI 75 efficacy up to week 148 with continued tildrakizumab treatment.⁸ The 5-year extension study showed improved PASI 75, 90, and 100 responses from week 128 to week 244 across tildrakizumab responders and etanercept partial/nonresponders groups, demonstrating sustained psoriasis control with tildrakizumab treatment in moderate-to-severe psoriasis patients.¹²

Safety Profile

Phase 3 trials of tildrakizumab showed an overall safety profile similar to vehicle. The most common adverse event in these investigations was nasopharyngitis (200 mg 6%, 100 mg 8%, and vehicle 5% in reSURFACE 1; 200 mg 11%, 100 mg 13%, and vehicle 8% in reSURFACE 2) and upper respiratory tract infection (200 mg 5%, 100 mg 3%, and vehicle 6% in reSURFACE 1). The proportion of patients with serious adverse events or who discontinued were low across both reSURFACE 1 and 2 trials (2%, 1% in the 200 mg tildrakizumab group; 0%, 1% in the 100 mg tildrakizumab group; 1%, 1% in the placebo group for reSURFACE 1 and reSURFACE 2, respectively). Notably, many side effects associated with other psoriasis medications, such as Candida infections, commonly seen in anti-IL 17A antibodies medications, were infrequent in reSURFACE trials. No new cases of inflammatory bowel disease or exacerbation of pre-existing disorders was reported in these studies. Suicidal ideation and behavior that have been observed with brodalumab, an IL-17A antibody, were not reported in any of the reSURFACE trials. Only one major adverse cardiovascular (CV) event, a side effect that has been linked to briakinumab, an IL-12 and IL-23p40 antibody, was reported in the trials.⁷

In the 2-year and 5-year extension study, there were no apparent dose-dependent safety signals or unexpected adverse events. Nasopharyngitis remained the most common treatment-emergent adverse event. The safety profile for 2- and 5-year extension trials for adverse events occurring in greater than 5% of patients is shown in Table 3.⁸

In the 5-year extension study, the cumulative incidence for major adverse CV events (0.5, 0.7 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively), malignancy excluding non-melanoma skin cancer (0.7, 0.6 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively), and severe infections (1.2, 1.3 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively) were generally comparable with Psoriasis Longitudinal Assessment and Registry (0.22, 0.55, 1.45 per 100 PYs). No dosage-related differences in frequency of severe infections or malignancies were noted.¹²

An additional pooled analysis of the 5-year extension study data compared the safety profile of tildrakizumab in younger (<65 years: 100 mg, n=303; 200 mg, n=211) and older (≥65 years: 100 mg, n=26; 200 mg, n=16) patients with psoriasis. Both age groups showed similar profiles, with nasopharyngitis and upper respiratory tract infections being the most common treatment-emergent adverse events. While older patients showed higher incidence than younger patients of CV events (100 mg/200 mg 14/21 per 100 PYs vs. 1/3 per 100 PYs), nonmelanoma skin cancer (6/10 vs. 8/6), and other malignancies (17/11 vs. 4/6), these increases were likely attributable to aging and longer psoriatic disease duration, and not as a result of psoriasis treatment. Overall, tildrakizumab demonstrated similar efficacy across both age groups, with comparable improvements in quality of life, and without major safety issues.¹³ These results further support the favorable safety profile of tildrakizumab.

Conclusion

Tildrakizumab is a promising target therapy to treat moderate-to-severe plaque psoriasis. Evidence from the Phase 3 clinical investigations and their extension trials has demonstrated that tildrakizumab is efficacious and well-tolerated by patients and maintains a reassuring safety profile. The most common side effects from the trials (up to 5 years), were nasopharyngitis and upper respiratory tract infection. Adverse effects that have been linked to other biologic agents, such as Candida infections, CV events, and suicide ideation, were not identified or were uncommon in the 5-year trials. While the reSURFACE 1 and 2 trials and their extensions have provided evidence of the longer-term safety profile of tildrakizumab, pharmacovigilance remains important through real-world and/or prolonged experience.

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¹SKiN Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Queen’s University, Kingston, ON, Canada

Conflict of interest: A. O’Toole has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis Biotherapeutics, ASLAN Pharmaceuticals, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Sun Pharma, UCB and Ventyx. M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Aristea, ASLAN Pharmaceuticals, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, UCB and Ventyx.
Funding: None.

Abstract:
Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health Canada for use in adolescents and adults, has proven efficacy and tolerability. It is non-steroidal, administered once-daily, and highly potent, with a unique delivery formulation. It can be used on most body areas, including the sensitive intertriginous regions and face. Herein, we review the safety and efficacy of roflumilast 0.3% cream, as demonstrated in clinical trials.

Keywords: roflumilast, PDE4 inhibitor, topical therapy, plaque psoriasis, intertriginous psoriasis, inverse psoriasis

Introduction

Plaque psoriasis is a chronic inflammatory skin condition with an estimated prevalence of 3%¹ and is characterized by scaly plaques which can be red to violaceous depending on the background color of skin. Psoriasis most commonly presents on the extensor surfaces but can involve anywhere on the body, including the scalp, face, and intertriginous areas. Most cases of plaque psoriasis are mild to moderate in severity, where half of patients have a body surface area (BSA) ≤3% and three-quarters have a BSA ≤10%.¹ Psoriasis significantly impacts quality of life, with the majority of patients reporting a “large impact” on their everyday life, even in those with limited BSA involvement.² Impact on quality of life is greater with special site involvement (i.e., face, groin, palms/soles) compared to no special site involvement.³ Itch is considered the most bothersome symptom in plaque psoriasis by almost half of patients.^3,4

The mainstay of treatment is topical including steroids, vitamin D analogs, retinoids, and calcineurin inhibitors (used off label), whether used as monotherapy in mild to moderate disease or as concomitant therapy with systemic agents in moderate to severe disease. Current topical therapies have limitations, however, including messy or greasy texture, complex or time-consuming application, local side effects, or perceived inefficacy, which can all lead to lack of adherence to treatment and poor outcomes.⁵ Indeed, almost 80% of patients with a BSA of ≤10% were very dissatisfied with their treatment in one US survey.²

Pathophysiology of Psoriasis and Role of Phosphodiesterase-4

Environmental, genetic, and immunologic factors play a role in this complex, chronic, multifactorial inflammatory disease that involves hyperproliferation of the keratinocytes with an increase in epidermal cell turnover rate. Phosphodiesterase-4 (PDE4) is a key enzyme involved in immune cell homeostasis. Elevated PDE4 activity in psoriatic skin leads to an increase in pro-inflammatory pathogenic mediators underlying plaque psoriasis,⁶ making PDE4 a suitable target in disease management. PDE4 inhibitors have been approved for use in dermatology, including oral apremilast for moderate to severe plaque psoriasis (and psoriatic arthritis) and crisaborole ointment for mild to moderate atopic dermatitis. Roflumilast is a selective and highly potent inhibitor of PDE4,⁷ resulting in an increase in cyclic 3′,5′-adenosine monophosphate (cAMP) activity and subsequent decrease in the expression levels of key pro-inflammatory mediators of psoriasis including interleukin (IL)-17, IL-23, interferon‐gamma and tumor necrosis factor-alpha.⁶ Reducing pro-inflammatory mediators helps balance the immune response and normalizes keratinocyte differentiation.⁶ Roflumilast has greater affinity for PDE4 than the other currently available PDE4 inhibitors used to treat skin disease; depending on the comparator and isoform analyzed, it is approximately 25-300 times more potent than apremilast and crisaborole.^7-9

Topical Roflumilast

Topical roflumilast 0.3% cream (Zoryve^TM) was approved by the US FDA for the treatment of plaque psoriasis including intertriginous psoriasis in adolescents (aged ≥12 years) and adults in July 2022, with Health Canada approval gained in April 2023. It is uniquely formulated as an emollient water-based cream designed to deliver the roflumilast molecule throughout the epidermis without disrupting the skin’s barrier function or extracting lipids from the epidermis. A unique and patented emulsifier blend (Crodafos^TM CES) maintains the integrity of the lipid bilayer while facilitating delivery of roflumilast. The composition of Crodafos^TM CES includes cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate which allows roflumilast to diffuse through the epidermis by saturating the stratum corneum and subsequently entering the dermis via the intracellular space. The formulation does not contain ingredients such as propylene glycol or fragrance, resulting in improved tolerability (compared to some other topicals currently available). Topical roflumilast 0.3% cream is also found in higher concentrations in the skin compared to that expected with oral dosing, with levels 61.8- to 126-fold higher in the skin compared to plasma.¹⁰ The lipophilic, protein-affinity and water-insoluble properties of topical roflumilast leads to reservoir formation in the stratum corneum and prolonged release into the skin and systemic circulation. In fact, topical roflumilast has a long half-life of 4 days,¹⁰ affording the ability for once-daily dosing, high efficacy and improved tolerability. The tolerability and low rate of adverse effects are attributable to reduced bioavailability in the topical form compared to the oral form of roflumilast.¹⁰

Clinical Trials: Efficacy and Safety of Roflumilast

Topical roflumilast has proven efficacy and safety in multiple clinical trials. A Phase 1/2a randomized controlled trial (NCT03392168) tested roflumilast cream 0.5%, 0.15% vs. vehicle for 28 days in patients with ≤5% BSA.¹¹ The primary endpoint was met with significant improvement in the Target Plaque Severity Score (TPSS) x target plaque area (TPA) with roflumilast 0.5% (P = .0007) and 0.15% cream (P = .0011) vs. vehicle; 66%-67% improvement from baseline to week 4 was noted with roflumilast vs. 38% for vehicle.¹¹

In a Phase 2b randomized double-blinded controlled trial (NCT03638258), 331 adult patients were randomized 1:1:1 to receive roflumilast cream 0.3%, 0.15%, or vehicle once daily for 12 weeks. The primary endpoint at 6 weeks of an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) was reached by 28% in the roflumilast 0.3% group (P < .001), 23% in the roflumilast 0.15% group (P = .004), and 8% in the vehicle group (Figure 1A). The mean change in Psoriasis Area and Severity Index (PASI) from baseline at week 6 was -50.0%, -49.0%, and -17.8%, in roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively. Important secondary endpoints included an intertriginous IGA (I-IGA) response (clear or almost clear and ≥2 grade improvement from baseline) in 73% of the roflumilast 0.3% group, 44% of the roflumilast 0.15% group, and 29% of the vehicle group in the subgroup of participants with at least mild IGA intertriginous involvement (~15% of trial population).¹² Itch and itch-related sleep loss were also improved in subjects receiving roflumilast. Subjects with a baseline worst itch numeric rating scale (WI-NRS) ≥6 treated with roflumilast 0.3% cream achieved ≥4-point improvement compared with vehicle, which was significant at all time points between week 2 and week 12 (all P < .05).¹³ The least squares mean improvement in itch-related sleep loss was statistically significant for both doses of roflumilast as early as week 6 and maintained through week 12.¹³

Two identical pivotal Phase 3 trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389), enrolled patients older than 2 years of age, with 2% to 20% BSA and an IGA of at least 2 (mild).¹⁴ A total of 439 and 442 subjects were enrolled (DERMIS-1 and DERMIS-2, respectively) and randomized 2:1 to receive roflumilast cream 0.3% or vehicle. The primary endpoint was achieving IGA success (clear or almost clear [0 or 1] with ≥2 grade improvement from baseline) at 8 weeks. IGA success was achieved by participants receiving roflumilast 0.3% cream vs. vehicle by 42.4% and 6.1% (DERMIS-1) and by 37.5% and 6.9% (DERMIS-2), respectively (P < .001 for both) as shown in Figure 1B. Important secondary endpoints included I-IGA success at week 8, 75% improvement in PASI (PASI75) at week 8, and itch improvement as measured by WI-NRS at weeks 2, 4, and 8. In participants with an I-IGA score of at least 2 at baseline (approximately 20% of trial population), I-IGA success at week 8 was achieved by 71.2% vs. 13.8% (DERMIS-1) and 68.1% vs. 18.5% (DERMIS-2) in roflumilast 0.3% cream vs. vehicle, respectively.¹⁴ The majority of patients achieving I-IGA success also achieved an I-IGA score of clear (0) with 63.5% vs. 10.3% (DERMIS-1) and 57.4% vs. 7.4% (DERMIS-2) (P < .001) clearing intertriginous areas with roflumilast 0.3% vs. vehicle, respectively. PASI75 was reached with roflumilast 0.3% vs. vehicle in 41.6% vs. 7.6% (P < .001) and 39% vs. 5.3% (P < .001) in DERMIS-1 and DERMIS-2, respectively. Itch, the most bothersome symptom of psoriasis, also improved in patients with a baseline WI-NRS score of ≥4 at baseline. WI-NRS reduction of at least 4 points from baseline was achieved as early as week 2 in 34.9% vs. 22% (DERMIS-1, P = .12) and 41.9% vs. 21.1% (DERMIS-2, P = .003) and at week 8 in 67.5% vs. 26.8% (DERMIS-1, P < .001) and 69.4% vs. 35.6% (DERMIS-2, P < .001).¹⁴

Topical roflumilast was well tolerated with rates of treatment emergent adverse effects (TEAEs) similar in both groups: DERMIS-1 (roflumilast: 25.2% and vehicle: 23.5%) and DERMIS-2 (roflumilast: 25.9% and vehicle: 18.9%).¹⁴ Less than 1% of patients in any group experienced a serious adverse event. Rates of discontinuation due to TEAEs were low and similar between groups. The most commonly reported TEAEs were headache and diarrhea consistent with the effects of oral PDE4 inhibition, but present at much lower rates than seen with oral agents. Diarrhea was mild to moderate and reported in 3.5% and 2.8% of participants receiving roflumilast in DERMIS-1 and DERMIS-2, respectively, compared to none in the vehicle group. No patients interrupted therapy or discontinued due to diarrhea.¹⁴ Headache was reported in 1% and 3.8% in the roflumilast group and 1.3% and 0.7% in the vehicle group. The cream was well tolerated with low rates of application site pain: DERMIS-1 (roflumilast: 0.7% and vehicle: 0.7%) and DERMIS-2 (roflumilast: 1.4% and vehicle: 0%). Investigator-rated tolerability was consistent with patient-rated tolerability, with 98- 99% of roflumilast patients and 98% of vehicle patients showing no signs of irritation and 99% of patients reporting ‘no or mild’ sensation with application when assessed at both weeks 4 and 8.¹⁴

Long-term Use of Topical Roflumilast

Long-term use of roflumilast was investigated in a 52-week openlabel extension (OLE) of the Phase 2b study.¹⁵ There were two cohorts in the OLE: cohort 1 (n=230) was comprised of patients who completed the initial 12-week phase of the Phase 2b study (for a total of 64 weeks of therapy), and cohort 2 (n=102) had naïve patients with a diagnosis of at least mild psoriasis for a minimum of 6 months. The completion rate after 52 weeks was 73.5%, with low rates of discontinuation due to TEAEs or inefficacy, and the majority of discontinuations were due to withdrawal or loss of follow-up. The proportion of patients achieving IGA success was consistent over time, with 34.8% of cohort 1 patients and 39.5% of cohort 2 patients achieving IGA success with 64 weeks and 52 weeks of as-needed therapy, respectively. I-IGA success was achieved by 60% at week 12 and maintained by 66.7% of cohort 2 patients by week 52 but was not recorded in cohort 1 patients. Of the patients who achieved clear or almost clear skin during the open label portion, the mean durability of maintaining their response was 10 months.¹⁶ Topical roflumilast was well tolerated in the OLE, with the majority of TEAEs rated mild or moderate, 97% considered unrelated to treatment, and ≥97% showed no signs of irritation on physician assessment.¹⁵

Discussion

PDE4 inhibition with topical roflumilast is a promising non-steroidal option for patients with plaque psoriasis of varying severities. Key data from the pivotal trials, DERMIS-1 and DERMIS-2, report IGA success in approximately 40% of study participants with psoriasis ranging from mild to severe. Results are supported by earlier phase studies measured at earlier time points. IGA success was noted as early as week 4, and responses were maintained to week 64 with as-needed use, suggesting that once a response is obtained, it can likely be sustained over time. Itch, the most bothersome symptom of plaque psoriasis, improved by 2 weeks (the first assessed time point) in all studies and itch improvement maintained over time. Itch-related sleep loss also improved compared to vehicle. Early responses such as itch and sleep improvement can encourage adherence to therapy and improve outcomes.

Given the spectrum of obstacles in the treatment of plaque psoriasis, including patient adherence and tolerance with topical therapies, as well as the management of itch and special sites (e.g., scalp and intertriginous areas), topical roflumilast appears to address these challenges. Individuals with psoriasis are often prescribed multiple topical medications to treat different skin areas, which contributes to a complicated treatment regimen and patient non-adherence. Topical roflumilast addresses this significant unmet need with its once-daily, non-steroidal and carefully designed vehicle that is appropriate for use on most body areas, avoiding the need for multiple prescriptions and simplifying the treatment regimen. A foam formulation is also being developed for use on the body and scalp.

The PASI75 responses noted with topical roflumilast were also comparable with a recent trial of oral apremilast for patients with mild to moderate psoriasis (ADVANCE trial, NCT03721172).17 With similar baseline characteristics (PASI 6-7, BSA 6-7% and the majority of patients with IGA 3 or moderate severity) in DERMIS-1/ DERMIS-2 and the ADVANCE trial, the proportion of patients achieving PASI75 were similar or better with roflumilast compared to oral apremilast. In ADVANCE, 21.6% of those receiving oral apremilast 30 mg twice daily achieved PASI75 compared to 4.1% receiving placebo at 16 weeks. In DERMIS-1 and DERMIS-2, after 8 weeks of therapy, 41.6% and 39% of roflumilast patients achieved PASI75 compared to 7.6% and 5.3% of vehicle patients, respectively. The comparability of a topical therapy demonstrating efficacy that is similar to or better than an oral PDE4 agent such as apremilast, can be explained by the properties of topical roflumilast, which include the lipophilicity and reservoir in the stratum corneum combined with the higher affinity of roflumilast for PDE4. In patients with mild to moderate psoriasis, topical roflumilast may potentially delay or even avoid the need for oral therapy by providing similar efficacy. The limitation will be patients with higher BSA where the risk of TEAEs, such as diarrhea, may be higher or those with psoriatic arthritis where a systemic therapy may be preferred.

Conclusion

Targeting PDE4 with a highly selective inhibitor such as roflumilast is a proven effective strategy for the treatment of plaque psoriasis. Topical roflumilast cream 0.3%, already approved by Health Canada and the FDA for use in adolescents and adults, has demonstrated efficacy and tolerability. It is non-steroidal, administered oncedaily, and highly potent, yet delivered in a cosmetically elegant formulation that is well tolerated by patients. It can be used on most body areas, including the sensitive intertriginous regions and face, making one product suitable for treating all areas of involvement. Topical roflumilast will offer patients and their health care providers a simple, convenient, safe, effective, and durable therapeutic option for the management of psoriasis.

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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.

¹Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada;
³Skin Investigation Network of Canada (SkIN Canada), Toronto, ON, Canada; ⁴Dalhousie University, Halifax, NS, Canada; ⁵Probity Medical Research, Waterloo, ON, Canada

Conflict of interest: Nadia Kashetsky reports no conflicts of interest. Irina Turchin was a consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Novartis, Pfizer, Sanofi, UCB.

Abstract:
As systemic administration of Janus kinase-inhibitors is associated with safety concerns, local alternatives, such as topical ruxolitinib, have been developed. This review summarizes utilization of topical ruxolitinib in dermatology. A literature search was performed of studies reporting topical use of ruxolitinib in dermatologic conditions. Twenty-four articles were included, representing 2618 patients. Results show improvement with topical ruxolitinib formulations in atopic dermatitis, vitiligo, psoriasis, and lichen planus. Results are conflicting in alopecia areata. Minimal bioavailability and low rates of mild-to-moderate treatment-related adverse events support a favorable safety profile and higher tolerability of topical ruxolitinib compared to oral Janus kinase-inhibitors.

Keywords: ruxolitinib, topical, Opzelura™, Janus kinase-inhibitors, JAK-inhibitors, vitiligo, atopic dermatitis, eczema, psoriasis, alopecia areata, lichen planus

Introduction

Immune-mediated skin conditions are common and cause significant morbidity and healthcare utilization.^1,2 Treatment of these conditions was previously focused on symptom management and nonspecific immunosuppression, however, recent advances in understanding the pathogenesis of immunologic disease has led to novel therapeutic targets.^2,3

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, shown to be vital in downstream signaling of inflammatory cytokines, is amongst these novel therapeutic targets, for which JAK-inhibitors have been developed.^4-6 JAK-dependent cytokines are important in the immunopathology of diverse immune-mediated skin diseases, leading to the utilization of JAK-inhibitors in dermatology.^4,6 However, as systemic administration of JAK-inhibitors are associated with safety concerns, local alternatives, such as topical ruxolitinib (RUX), have been developed.^7,8 Topical 1.5% RUX cream was US FDA approved for AD in September 2021 and nonsegmental vitiligo in July 2022.⁹

Although several systematic reviews have described the utilization of JAK-inhibitors in dermatology, a summary of topical RUX in dermatology is lacking.^10-12 Accordingly, this review comprehensively summarizes the available data on efficacy and safety outcomes of topical RUX in dermatological conditions.

Methods

A literature search was performed of studies reporting topical RUX utilization in dermatologic conditions (Figure 1).

Results

Twenty-five articles were included in this review, representing 2618 patients (Table 1). Articles reported data on topical RUX use in atopic dermatitis (AD, n=8), vitiligo (n=6), alopecia areata (AA, n=5), psoriasis (n=2), and lichen planus (LP), necrobiosis lipoidica, discoid lupus erythematosus, and seborrheic dermatitis (n=1 each).

Efficacy

Atopic Dermatitis

A 4-week, phase I, open-label, maximum-use trial investigated efficacy of RUX cream in patients with AD, aged 12-65 years, disease duration ≥2 years, Investigator’s Global Assessment (IGA) score ≥2, and ≥25% body surface area (BSA) involvement (n=41).^13,14 Patients applied 1.5% RUX cream twice-daily (BID) for 4 weeks. An extension period to week 8 was completed by 37 patients. IGA treatment success (an IGA score of 0/1 with a ≥2-grade improvement from baseline) was reported in 20% of patients at day 15, 35.9% of patients at day 28, and 56.8% of patients at day 56. Mean standard deviation (SD) BSA decreased from 38.1% (16.3%) at baseline to 6.5% (8.2%) at day 28 and 3.1% (5.4%) at day 56; 79.5% and 94.6% of patients achieved ≥75% improvement in Eczema Area and Severity Index (EASI-75) at day 28 and day 56; and 82.6% and 90.5% of patients achieved ≥4-point improvement in the itch Numerical Rating Scale (NRS) at days 28 and 56, respectively. The mean daily application amount of RUX cream over the first 4 weeks was 20.2 g compared to 5.4 g in the phase III studies.^13,14

An 8-week, phase II, randomized study with vehicle control and active control (0.1% triamcinolone acetonide cream) investigated efficacy of RUX cream in patients with AD, aged 18-70 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=307).¹⁵ Patients were randomly assigned to 1.5% RUX cream BID (n=50), 1.5% daily (n=52), 0.5% daily (n=51), 0.15% daily (n=51), 0.1% triamcinolone BID for 4 weeks then vehicle for 4 weeks (n=51), or vehicle BID (n=52). Mean percentage change in EASI score from baseline at week 4 was 71.6% versus 15.5% for 1.5% RUX cream BID versus vehicle (P<0.0001). At week 4, IGA response defined as a patient achieving an IGA score of 0 to 1, with 2 or more points improvement from baseline was achieved by 38% of patients in the RUX 1.5% arm compared to 25.5% of patients in the 0.1% triamcinolone arm.

Within 36 hours after the first 1.5% RUX cream application BID, itch NRS was significantly reduced compared to vehicle (-1.8 versus -0.2, P<0.0001), and significantly more patients achieved minimally clinically important difference (42.5% versus 13.6%, P<0.01).¹⁶ Within 2 weeks, all RUX cream regimens decreased itch NRS and achieved significant improvements in quality of life as measured by Skindex-16.¹⁶

Two, 8-week, phase III, randomized, double-blind, vehicle-controlled studies of identical study design, investigated efficacy of RUX cream in patients with AD, aged ≥12 years, disease duration ≥2 years, IGA score 2-3, and 3%-20% BSA (n=631/n=618 in Study 1/2).^17,18 Patients were randomized to apply 1.5% RUX cream BID (n=253/n=246), 0.75% BID (n=252/n=248), or vehicle cream BID (n=126/n=124). IGA treatment success at week 8 was achieved by significantly more patients in both Study 1 and Study 2 with 1.5% RUX cream (53.8%/51.3%) and 0.75% RUX cream (50.0%/39.0%) compared to vehicle (15.1%/7.6%, all P<0.0001).

Pooled data demonstrated significant rapid itch reduction within 12 hours of 1.5%/0.75% RUX cream application (-0.5/-0.4, versus -0.1 for vehicle; both P<0.02).¹⁹ At 36 hours, a ≥4-point itch NRS improvement was achieved by significantly more patients with 1.5%/0.75% RUX cream (11.2%/8.9%, versus 2.1% for vehicle; both P<0.005),¹⁹ and significantly more patients achieved an itch free state versus vehicle.²⁰

At week 8, significant impact on work productivity and activity impairment were achieved.²¹ Estimated incremental annual indirect cost savings for patients were US$5302/US$4228 for 1.5%/0.75% RUX cream.²¹

Long-term safety and efficacy of 1.5% and 0.75% RUX cream was further investigated in the long-term extension of the phase III studies.²² Patients initially randomized to twice-daily 0.75%/1.5% cream were maintained in their assigned arms for 44 weeks, and patients randomized to vehicle were re-assigned at week 8 to either RUX cream strength. At week 52 of as-needed treatment, 74.1%-77.8% of patients had IGA0/1, and a mean affected BSA was low (1.4%-1.8%).

Vitiligo

A 20-week, phase II, open-label proof-of-concept study investigated efficacy of RUX cream in patients with vitiligo, ≥18 years, with ≥1% BSA (n=11).²³ Patients applied 1.5% RUX cream BID for 20 weeks.²³ Mean improvement in Vitiligo Area Scoring Index (VASI) at week 20 was significant (23%, P=0.02). An extension of this study included 8 patients without previous response, and showed significant overall mean improvement from baseline at 52 weeks (37.6%, P=0.011).²⁴

A 52-week, phase II, randomized, double-blind, dose-ranging study investigated the efficacy of RUX cream in patients with vitiligo, aged 18-75 years, 0.5% facial BSA, and ≥3% non-facial BSA (n=157).^25,26 Patients were randomly assigned to 1.5% RUX cream BID (n=33), 1.5% daily (n=30), 0.5% daily (n=31), 0.15% daily (n=31), or vehicle cream BID (n=32). A ≥50% improvement in facial Vitiligo Area Scoring Index (F-VASI50) at week 24, was achieved by 50%/45% of patients with 1.5% RUX daily/BID versus 3% with vehicle (P<0.001/P=0.001). In patients who received 1.5% RUX cream BID in this trial, a sub-analysis indicated a larger proportion of F-VASI50 responders were aged ≤50 years, women, had baseline ≤1.5% facial BSA, disease duration >20 years, and received previous phototherapy.²⁷ All body areas had repigmentation, including difficult to treat acral areas.²⁷

Following the double-blind period of this phase II study, an open-label phase assessed the efficacy of RUX cream with narrowband ultraviolet B (NB-UVB) (n=19).²⁸ At week 104, overall mean improvement was 50.1% for F-VASI and 29.5% for total body VASI (T-VASI) versus the last visit before adding NB-UVB.

Two 24-week, phase III, double-blind, vehicle-controlled trials of identical study design investigated the efficacy of RUX cream in patients with vitiligo, aged ≥12 years, ≤10% BSA, ≥0.5% facial BSA, and ≥3% non-facial BSA (n=330/n=344 in Study 1/2).^29,30 Patients were randomized to apply 1.5% RUX cream BID (n=221/n=229) or vehicle cream BID (n=109/n=115) for 24 weeks. At week 24, F-VASI75 was achieved by 29.8%/30.9% of patients in the RUX cream arms compared to vehicle (7.4%/11.4%, P<0.001).

Alopecia Areata

A 28-week, phase I, prospective, double-blind, placebo controlled, pilot study investigated the efficacy of 1% RUX ointment, 2% tofacitinib ointment, 0.05% clobetasol dipropionate ointment, and vehicle in patients with alopecia areata (AA) (n=16).³¹ All 4 ointments were applied to designated areas BID. Partial regrowth was achieved in 5/6/10/2 patients treated with 1% RUX/2% tofacitinib/0.05% clobetasol dipropionate/vehicle.

A phase II, 2-part, double-blind, randomized, vehicle-controlled study, investigated the efficacy of RUX cream in patients with AA, aged 18-70 years, Severity of Alopecia Tool (SALT) score 25%-99% (Part A: n=12; Part B: n=78).³² In Part A patients applied 1.5% RUX cream BID for 24 weeks. A ≥50% improvement in SALT (SALT50) was achieved by 50% of patients at week 24. In Part B patients were randomized to 1.5% RUX cream BID (n=39) or vehicle BID (n=39) for 24 weeks. Percentage of patients achieving SALT50 between RUX cream and vehicle at week 24 was not significant (12.8% versus 12.8%, P=0.99).

Moreover, 4 case reports utilizing RUX cream in patients with AA demonstrate conflicting results. A teenaged female had marked improvement with 0.6% RUX cream BID for 12 weeks,³³ whereas a 66-year-old female who exhibited lack of improvement with 0.6% RUX cream daily for 8 weeks, increased to BID for 6 weeks.³⁴ Finally, 2 patients, a 17-year-old female, and 4-year-old male, showed partial and no regrowth, with 1% RUX in a liposomal base BID for 18 months, and 2% RUX in a liposomal base BID then 1% tofacitinib liposomal base BID for 3 months, respectively.³⁵

Psoriasis

A 4-week, phase II, double-blind, vehicle or active comparator study assessed efficacy of RUX cream in patients with stable and active plaque psoriasis, aged 18-75 years, <20% BSA (n=29).³⁶ Patients were randomized to 0.5% or 1.0% RUX cream daily, 1.5% RUX BID, vehicle daily or BID, 0.005% calcipotriene cream BID, or 0.05% betamethasone dipropionate cream BID for 4 weeks. At 4 weeks, mean total lesion score decreased by 53%/54% for 1.0% RUX daily/1.5% RUX BID versus vehicle (32%, P=0.033/P=0.056).

A 4-week, phase II, open-label, multicenter, cohort, doseescalation study evaluated efficacy of RUX cream in patients with stable and active psoriasis, aged 12-65 years (n=25).³⁷ Patients applied 1.0% or 1.5% RUX cream daily or BID for 4 weeks to 2%-20% BSA. In all cohorts, at 4 weeks, mean total lesion scores decreased and PGA scores improved.

Other

An 8-week, phase II, single-arm, open-label trial investigated the efficacy of RUX cream in patients with biopsy proven lichen planus (LP), aged ≥18 years, ≤20% BSA and ≥4 lesions (n=12).³⁸ Patients applied 1.5% RUX cream BID for 8 weeks. At week 4, lesion count significantly decreased by a median of 50 lesions (P<0.001); and mean modified Composite Assessment of Index Lesion Severity of index versus control lesions decreased significantly by a mean of 7.6 points (P=0.016).

A 19-year-old female with refractory necrobiosis lipoidica showed marked improvement with 1.5% RUX cream BID for 3 months.³⁹ A 28-year-old female with discoid lupus erythematosus exhibited improvement of scalp lesions with 1.5% RUX cream daily for 2 months.⁴⁰ A 74-year-old male with seborrheic dermatitis and rosacea showed complete and partial response, respectively, with 1.5% RUX cream BID for 2 weeks.⁴¹

Safety and Tolerability

Bioavailability of RUX cream was limited.^{13,14,25,36,37,42,43} The highest strength average steady-state trough plasma concentrations were well below clinically relevant systemic pharmacological activity, remaining below the half-maximal inhibitory concentration of JAK-mediated myelosuppression.^{13,14,25,36,37,42,43}

No serious treatment related adverse events (TRAE) were reported across all topical RUX data. Mild-to-moderate TRAE were reported in minority of patients, most commonly including application-site pain, pruritus, acne, erythema, and hyperpigmentation. Rare treatment-emergent adverse events included increase in aspartate aminotransferase and alanine aminotransferase, leukopenia, hemoglobin decrease, mild reticulocytosis, dyspnea, abnormal taste, and transient hypoaesthesia of the fingertips.

Discussion

This review summarizes the utilization of topical RUX in dermatological conditions. Results show improvement with topical RUX formulations in AD, vitiligo, psoriasis, and LP. Results are conflicting in AA. Minimal bioavailability and low rates of mild-to-moderate TRAEs support higher tolerability of topical RUX as compared to oral JAK-inhibitors.

RUX is a targeted inhibitor of JAK1/2, selectively interrupting effects of the cytokines which signal through JAK1/2 proteins.⁴⁴ AD pathogenesis involves JAK1/2 mediated cytokines interleukin (IL)-4, IL-13, IL-31, and IL-33.^6,45 Vitiligo and AA, both involve JAK1/2 mediated interferon (IFN)-gamma and IL-15 in their pathogenesis.⁶ IFN-gamma is also important in the pathogenesis of LP and psoriasis.^4,6,38 Psoriasis pathogenesis also has shown involvement of other JAK1/2 mediated cytokines including IL-6, IL-21, IL-22, and IL-23.^4,6

Conclusion

Available clinical trial data support the efficacy of topical RUX in AD, vitiligo, psoriasis, and LP with a favorable safety profile and tolerability compared to oral JAK-inhibitors suggesting that topical RUX is a promising new therapy in dermatology.

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¹Clinical Professor, Laval University, Quebec University Hospital Center, Hotel-Dieu of Quebec, Quebec, QC, Canada
²Dermatology resident, McGill University, Montreal, QC, Canada
³Medical Director and Principal Investigator, Dermatological Research Center of Metropolitan Quebec (CRDQ), Quebec, QC, Canada

Abstract

Drs. Joël Claveau & Julien Ringuet, two Canadian dermatologists with prominent clinical and research practices, attended the Les Journées Dermatologiques de Paris conference in Nov-Dec 2022, with a focus on presentations and posters about psoriasis. This article reviews key insights they obtained at the meeting. In brief:

• Psoriasis has a profound and multifaceted impact, but remains undertreated
• Progression to psoriatic arthritis is common; dermatologists can facilitate earlier detection
• The presence of comorbidities may inform the choice of biologic treatment
• New topical and systemic options enable treatment optimization for various subgroups
• Adverse effects of cancer immunotherapy include psoriasis, which requires treatment

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Psoriasis is a chronic inflammatory skin disease that affects an estimated 2% of people worldwide, with higher rates in Caucasian than Asian populations.¹ Plaque psoriasis is by far the most common form of the disease, accounting for about 90% of cases.¹ A relapsing condition with a wide range of severity, psoriasis often requires long-term therapy.¹

High Impact & Complex Comorbidities

The impact of psoriasis extends across all dimensions of life. The skin manifestations alone, which typically include thick, scaly and sometimes pruritic plaques, can significantly impact psychosocial well-being. Research has found that about 80% of patients feel embarrassment and shame, while 75% see themselves as unattractive and sexually undesirable.² A 2020 French study found that psoriasis also affected the quality of life and sexuality of patients’ life partners.³ In patients who develop psoriatic arthritis, inflamed joints, pain and fatigue can significantly impair mobility and occupational functioning.²

Now recognized as an immune-mediated inflammatory disorder, psoriasis extends to several other body systems.¹ Characteristic comorbidities are listed in Table 1.

Table 1: Comorbidities associated with psoriasis^4,5

Psoriatic arthritis, the most prevalent comorbidity of psoriasis, develops in about 30% of patients and appears about 10 years after the onset of psoriasis, on average.⁶ A heterogeneous disease, psoriatic arthritis may affect a few or many hand and foot joints (peripheral disease) and/or may involve the spine and sacroiliac joints (axial disease). Depending on how it is defined, axial involvement occurs in 25% to 70% of people with psoriatic arthritis.⁷

Presenters at the meeting emphasized that psoriatic arthritis develops along a “pathological continuum” that is often undetected. Indeed, about 15% of psoriasis patients followed by dermatologists have undiagnosed psoriatic arthritis.⁴ Dermatologists are in a unique position to identify early psoriatic arthritis. They should question their psoriasis patients about joint pain, stiffness, and search for signs of dactylitis and enthesitis. They could also consider referring patients for imaging and rheumatologic evaluation when deemed appropriate.^6,8

Treatment Trends & Unmet Needs

New advances in psoriasis treatment have raised the expectations and goals of treatment. Ninety-percent improvement in the Psoriasis Area Severity Index (PASI 90), or even PASI 100, has become a realistic treatment goal.⁹ The focus has also shifted toward absolute outcomes (e.g. PGA clear or almost clear).⁹ Efficacious treatments improve not only psoriasis symptoms, but also quality of life.² Treatment should be initiated early, especially when psoriatic arthritis is involved, to prevent disabling joint damage.⁸

Current medical treatment classes include topical agents (e.g. corticosteroids, vitamin A and D derivatives), traditional systemic agents (e.g. methotrexate, cyclosporine, acitretin), the oral phosphodiesterase-4 (PDE-4) inhibitor apremilast, and an expanding array of biologic agents (Table 2), sometimes recommended as first-line agents for moderate-to-severe plaque psoriasis.¹⁰ Historically, phototherapy (UVB and PUVA) was widely used to treat moderate to severe psoriasis, and narrow-band UVB phototherapy continues to be a good option for some patients.¹⁰

Table 2: Biologic agents used to treat psoriasis^11,12

Several presentations at the meeting focused on biologics that inhibit the IL-17 and IL-23 cytokine pathways. In patients with moderate-to-severe arthritis, high levels of these cytokines are associated with an increased risk of comorbidities.¹³ IL-17 and IL-23 inhibitors, which target psoriasis immunopathology and show an overall superior skin efficacy, have been gradually displacing anti-TNF agents and IL-12/23 inhibitors as first-line biologic options.^9,13 A meta-analysis of 44 studies established the overall safety and tolerability of IL-17 and IL-23 inhibitors.¹⁴ Common adverse events with these classes include infections, nasopharyngitis, and headaches,¹⁴ although the causality of these effects remains uncertain.

Despite the effectiveness of current treatments, psoriasis remains undertreated. In a 2019 online survey conducted in Germany, 59% of patients who received medical care for psoriasis were only moderately or less satisfied with their treatment.¹⁵ In the US, a study of registry patients found that, while most showed an “acceptable” treatment response after 6 and 12 months of systemic therapy, fewer than half reached their treatment targets.¹⁶ Clinicians are advised to optimize treatment in such patients. Effective strategies include increasing the dose, reducing the interval between treatments, or switching to another agent.⁹

Considerations in the Choice of Biologic Treatment

While both IL-17 and IL-23 are involved in the pathogenesis of psoriatic arthritis, IL-17-mediated inflammation may play a greater role in the development of axial disease and cardiometabolic comorbidities, while IL-23 may have greater involvement in the development of IBD.¹³ These distinctions can inform the choice between the two classes (Table 3).

Table 3: Choosing a biologic class based on comorbid PsA or IBD^8,11

Axial psoriatic arthritis: If patients require biologic therapy, anti-TNF agents are often used first-line, but IL-17 inhibitors are preferred if skin involvement is significant.⁷ In the MAXIMIZE study, over 60% of patients receiving the IL-17 inhibitor secukinumab showed an ASAS20 response at week 12, compared to 31% in the placebo group, and response was maintained through week 52.⁷ Drugs targeting the IL-12/23 pathway are not currently recommended due to a lack of studies showing clear efficacy⁷ as well as negative studies for ankylosing spondylitis.

Peripheral psoriatic arthritis: Evidence exists for all classes of biologics used to treat psoriasis, as well as for the PDE-4 inhibitor apremilast.⁸ The JAK inhibitors tofacitinib and upadacitinib have also shown efficacy and are approved for this indication.

Inflammatory bowel disease: For psoriasis with comorbid IBD, positive data exist for the use of anti-TNF inhibitors, the IL-12/23 inhibitor ustekinumab, and IL-23 inhibitors.¹¹ Of note, Health Canada approved the IL-23 inhibitor risankizumab for Crohn’s disease in late 2022. On the other hand, the IL-17 inhibitors secukinumab and brodalumab have failed studies in Crohn’s disease.¹¹ Cases of new-onset IBD have been observed in psoriasis patients treated with IL-17 inhibitors, though the signal is low and these cases may arise from the disease process itself, rather than as an outcome of IL-17 inhibition.¹¹

Speed of onset of action has become an important differentiator among systemic treatments, as patients place high value on rapid clearance.⁹ Dosing regimen also comes into play, with many patients showing a preference for less frequent administration.

Oral candidiasis, a rare side effect related to the mechanism of action of IL-17 inhibition, generally responds to treatment and is not a reason for discontinuing the biologic.¹¹ Reported cases of suicidality with brodalumab have led to further investigations; to date, a causal relationship has not been established.¹¹

New Molecules

Several new practice-changing molecules were introduced at the meeting. Topical tapinarof, a hydrocarbon receptor-modulating agent, has been investigated for both psoriasis and atopic dermatitis and is expected to enter the Canadian market soon. In two Phase 3 PSOARING trials, a Physician Global Assessment (PGA) response occurred at week 12 in 35.4% and 40.2% of patients treated with tapinarof, respectively, compared to 6.0% and 6.3% in the vehicle groups.¹⁷ Of note, 58% of the patients who did not achieve PGA-0 or PGA-1 at week 12 reached this outcome at week 52 in the open-label extension study.¹⁸ In patients who reached PGA-0, the median duration of remission after discontinuation of treatment was 130 days.¹⁸ A second new topical agent, a potent PDE-4 inhibitor called roflumilast, showed similar results in the DERMIS 1 and 2 trials: at week 8, 42.4% and 37.5% reached the Investigator Global Assessment (IGA) endpoint in the active treatment groups, respectively, versus 6.1% and 6.9% in the control arms.¹⁹ A distinctive feature of this agent is its efficacy and tolerability in special sites such as facial, genital and intertriginous areas.

Deucravacitinib is a new oral JAK inhibitor that specifically targets the TYK2 receptor, which differentiates it from less targeted JAK inhibitors. As shown in the Phase 3 POETYK-1 and -2 trials, the molecule is potent enough to treat moderate-to-severe psoriasis. In the trials, 53-58% of patients in the treatment arms reached the co-primary endpoint of PASI 75, compared to 35-40% in comparator apremalist arms and 9-12% in the control arms.²⁰ Corresponding results for the other co-primary endpoint (IGA 0-1) were 50-53% for deucravacitinib, 32-34% for apremilast, and 7-8% for placebo.²⁰ Longer-term data showed that efficacy was maintained for up to 52 weeks. These results led Health Canada to approve this agent in late 2022.

Deucravacitinib has also been investigated for psoriatic arthritis in a recently published Phase 2 study.²¹ Patients were randomized to receive placebo or one of two doses (6 mg and 12 mg daily) of deucravacitinib, with ACR-20 response at week 16 as the primary endpoint. Response was significantly higher with deucravacitinib 6 mg (52.9%) and 12 mg (62.7%) than with placebo (31.8%),²¹ suggesting this oral agent may play a role in the treatment of psoriatic arthritis. Phase 3 studies are ongoing.

A first-in-class biologic called spesolimab, which targets the IL-36 receptor, has recently been approved by the FDA for the treatment of generalized pustular psoriasis (GPP), a severe form of psoriasis that causes pustules on an erythematous base often associated with systemic symptoms. In the Phase 2 trial of patients with severe GPP, spesolimab 900mg IV demonstrated clear superiority over placebo (54% vs. 6%) for the main outcome measure of GPPGA-0.²² [GPPGA = Generalized Pustular Psoriasis Physician Global Assessment.] Serious adverse events were reported in 6% of patients on spesolimab versus 0% on placebo, and a signal of infectious risk also emerged in the spesolimab group. The ongoing Effisayil 2 trial is evaluating spesolimab as maintenance treatment for GPP.²³

Cancer Immunotherapy and Psoriasis

The meeting helped raise awareness of an increasing challenge in dermatology: the management of adverse events induced by cancer immunotherapy. Immune checkpoint inhibitors (ICIs) represent a significant leap in cancer treatment, but they come at the cost of various immune-related adverse events, including dermatologic adverse events in about 40% of cases.²⁴ In a multi-centre study of patients on ICI therapy, psoriasis accounted for 23% of skin-related side effects.²⁵ While most ICI-induced psoriasis is the plaque subtype, all other subtypes have been reported.²⁴ Other common dermatologic sequelae of ICI treatment include lichenoid and eczematous eruptions, pruritus, and vitiligo.

Figure 1: Checkpoint inhibitor-induced psoriasis

ICI treatment can induce psoriasis de novo or cause preexisting psoriasis to flare up.²⁴ This can complicate treatment decisions and underscores the need for oncologists to consult dermatologists when treating patients with a history of psoriasis or psoriatic arthritis, including during flareups.

On a positive note, the presence of skin toxicities may signal that ICI treatment is working. In a population-level cohort study that reviewed a database of over 200 European and US patients treated with ICI, the development of cutaneous adverse events was strongly associated with therapeutic response and patient survival.²⁶ If more severe ICI-induced skin toxicities are not managed, however, they may compromise the therapeutic outcome of cancer treatment.²⁵

For moderate cases of CI-induced psoriasis, acitretin, methotrexate, and/or apremilast are deemed suitable options.²⁴ For more severe presentations, the EADV task force “Dermatology for Cancer Patients” recommends reinforcing therapy for moderate disease (including dose optimization) and consideration of anti-TNF and IL-23-targeting biologics in non-responders.²⁴ The paper also advises avoiding IL-17-targeting agents due to their gastrointestinal effects,²⁴ though this is still a subject of debate. Ideally, ICI treatment should be discontinued until the psoriasis improves to grade 0 or 1.²⁴

Overall, the management of ICI-induced dermatologic adverse events requires a balance between reducing troubling skin toxicities that compromise patients’ quality of life and preserving the benefits of cancer treatment.

Conclusions

The global medical community has come to understand psoriasis as a systemic disease with a profound impact. The optimal treatment choice depends not only on the disease subtype and severity, but on a patient’s comorbidity profile. While both systemic and topical treatments continue to improve, many patients remain undertreated. Dermatologists can play a significant role in detecting emergent psoriatic arthritis and in managing psoriasis induced by cancer treatment.

Test Your Knowledge

Question 1: Which class of biologic is not suitable for psoriasis patients with comorbid inflammatory bowel disease, and why?

Question 2: If patients on cancer immunotherapy develop psoriasis, should they be switched to a different cancer treatment?

Melinda J. Gooderham, MSc, MD, FRCPC^1,2; H. Chih-ho Hong, MD, FRCPC^2,3; Ivan V. Litvinov, MD, PhD, FRCPC⁴

¹Skin Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁴Division of Dermatology, Department of Medicine, McGill University, Montreal, QC, Canada

Conflict of interest:
M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Arena Pharmaceuticals, Asana BioSciences, ASLAN Pharmaceuticals, Bausch Health/Valeant, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, and UCB. H. C. Hong has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli-Lilly, Galderma, GSK, ICPDHM, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, and UCB. I. Litvinov has received a grant or an honorarium from AbbVie, Actelion, Bausch Health, Bristol-Myers Squibb, Galderma, ICPDHM, Janssen, Johnson & Johnson, Merck, Novartis, Pfizer, and Sun Pharmaceuticals.

Funding for this manuscript was provided in the form of an educational grant from Bristol Myers Squibb Canada Co.

Abstract:
Moderate to severe chronic plaque psoriasis may be difficult to control using current therapies, which has led to development of a novel class of therapy, selective tyrosine kinase 2 (TYK2) inhibitors, to address this unmet need. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, which has shown efficacy in moderate to severe chronic plaque psoriasis from two phase III pivotal trials (POETYK PSO-1 and PSO-2), whereby response rates were significantly higher with deucravacitinib vs. placebo or apremilast for Psoriasis Area Severity Index (PASI) 75 and static Physician’s Global Assessment (sPGA) 0/1. Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast. Although deucravacitinib is a type of Janus kinase (JAK) inhibitor, it only blocks specific cytokine-driven responses, potentially reducing off-target effects more commonly associated with other JAK inhibitors on the market. Incidence rates of serious adverse events, such as serious infections, malignancies, thrombosis, cardiovascular events, creatinine kinase elevation, hematologic changes, and lipid profile abnormalities were absent or low.

Key Words:
plaque psoriasis, TYK2 inhibitor, deucravacitinib, apremilast, clinical trial, efficacy, safety, PASI, sPGA

Introduction

Psoriasis is a common, chronic, immune-mediated inflammatory disease, estimated to affect 1 million people in Canada.^1,2 The most common type is chronic plaque psoriasis, which affects 90% of this patient population.¹

Moderate chronic plaque psoriasis is typically defined as involving ≥3-10% body surface area (BSA), with severe disease involving more than 10% BSA.³ When inadequately treated, this can cause severe psychosocial impact and impair patients’ quality of life (QoL).³

Currently, various oral systemic agents, biologic agents, and phototherapy have Health Canada-approved indications for management of moderate to severe chronic plaque psoriasis. Despite numerous treatment options, unmet needs still exist. An emerging class of therapy in development are selective tyrosine kinase 2 (TYK2) inhibitors, which may meet those needs. Oral deucravacitinib is a first-in-class selective TYK2 inhibitor, recently US FDA approved and currently under review by Health Canada. Other oral selective TYK2 inhibitors for treatment of moderate to severe plaque psoriasis in various stages of development include GLPG3667 and NDI-034858.^4,5

Pathogenesis of Plaque Psoriasis

The pathogenesis of chronic plaque psoriasis starts with environmental, immunologic, and/or genetic triggers that can lead to release of cytokines from innate immune cells, activating myeloid dendritic cells.^6,7 Activated myeloid dendritic cells present antigens to T cells and release cytokines, including interleukin (IL)-23 and IL-12;^6-8 both IL-23 and IL-12 signal through TYK2-mediated pathways. IL-12 contributes to T helper (Th)1-cell differentiation and IL-23 activates keratinocytes via pro-inflammatory Th17 cells;⁶ both processes lead to tumor necrosis factor (TNF)-α and interferon (IFN)-γ production. Cytokines secreted by Th17 and Th1 cells activate keratinocytes;⁹ this is one of the first steps in the development of psoriatic lesions. A positive feedback loop recruits other immune cells, further potentiating the inflammatory process.⁶

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

TYK2 is a Janus kinase (JAK) enzyme that is coded by the TYK2 gene and constitutively expressed in immune cells.¹⁰ Mutations and polymorphisms in TYK2 impact IL-23, IFN-α/β, and IL-12 immune-mediated signalling, and are associated with an altered risk for psoriasis; for example, loss of function mutations in TYK2 have been found to be protective against autoimmunity, including psoriasis.¹⁰ Selective TYK2 inhibition blocks IL-23, IL-12, and type I IFN-driven responses, but not those driven by other JAKs (Figure 1).^11-13

Deucravacitinib: Mechanism of Action

Deucravacitinib is a specific, oral, intracellular TYK2 inhibitor that targets immune responses driven by type 1 IFN and IL-23 that contribute to psoriasis pathogenesis, including IL-17 production and Th1/Th17 polarization.^12-14 It binds with high specificity to the TYK2 regulatory domain, blocking kinase activity and conferring selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis (Figure 2).^12-14

Deucravacitinib uniquely binds to the regulatory domain of TYK2 and only blocks specific cytokine-driven responses, leading to a broad therapeutic range while reducing off-target effects.^11-13 In contrast, JAK 1–3 inhibitors bind to the active domain adenosine triphosphate (ATP) binding site common to all JAK molecules (including TYK2) to mediate both immune responses and broader systemic processes (e.g., myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, lipid metabolism, etc.), some of which are necessary for normal physiologic functioning, resulting in a narrower therapeutic range.¹³

Efficacy of Deucravacitinib: Key Evidence from Pivotal Phase III Clinical Trials

In a phase II trial of patients with psoriasis, deucravacitinib demonstrated superior efficacy vs. placebo based on ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) over 12 weeks.¹⁴ Efficacy results from two phase III pivotal trials of deucravacitinib were recently reported and confirmed results from the phase II trial.

In the 52-week, double-blinded, phase III POETYK PSO-1 trial, participants with moderate to severe chronic plaque psoriasis were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=332), placebo (n=166), or apremilast 30 mg twice daily (n=168).¹⁵ Similarly, participants in the 52-week, doubleblinded, phase III POETYK PSO-2 trial were randomized 2:1:1 to deucravacitinib 6 mg once daily (n=511), placebo (n=255), or apremilast 30 mg twice daily (n=254).¹⁶

The coprimary endpoints of both trials were response rates for PASI 75 and static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib vs. placebo at week 16.^15,16 Key secondary endpoints included the scalp-specific Physician’s Global Assessment (ss-PGA) and patient-reported symptoms and signs of psoriasis (evaluated using the Psoriasis Symptoms and Signs Diary [PSSD]) and QoL (evaluated using the Dermatology Life Quality Index [DLQI]).¹⁵

In both PSO-1 and PSO-2 trials, PASI 75 response rates at week 16 were significantly higher with deucravacitinib (58.4% and 53.0%) vs. placebo (12.7% and 9.4%) or apremilast (35.1% and 39.8%). Response rates for sPGA 0/1 were also significantly higher with deucravacitinib (53.6% and 50.3%) vs. placebo (7.2% and 8.6%) or apremilast (32.1% and 34.3%) (Table 1).^15,16 Deucravacitinib responses improved beyond week 16 and were maintained through week 52.¹⁵ Furthermore, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 comparable to those observed in patients who received continuous deucravacitinib treatment from day 1.¹⁵

Regarding key secondary endpoints, significantly greater proportions of patients in the deucravacitinib vs. placebo and apremilast arms achieved ss-PGA 0/1 and DLQI 0/1 responses, as well as greater reduction from baseline in PSSD symptom scores at week 16 and week 24 (Table 1).^15,16

Table 1. POETYK PSO-1 and PSO-2 efficacy results

Pooled PSO-1 and PSO-2 data showed that significantly greater proportions of patients receiving deucravacitinib achieved absolute PASI ≤1, ≤2, and ≤5 vs. patients receiving placebo (week 16) or apremilast (weeks 16 and 24), and proportions of patients achieving different PASI thresholds with deucravacitinib increased from week 16 to week 24.¹⁷

In an analysis of PSO-1 and PSO-2 that compared efficacy of deucravacitinib vs. placebo and apremilast in individual scoring components (erythema, induration, desquamation) and body regions of PASI (head/neck, upper extremities, trunk, lower extremities), deucravacitinib was associated with numerically greater percent reductions from baseline in each PASI body region and component scores at week 16 than placebo and apremilast.¹⁸ Higher proportions of patients in the deucravacitinib vs. placebo and apremilast groups achieved ≥75% reduction at week 16 in each PASI body region and PASI scoring; differences in efficacy when compared to apremilast were maintained at week 24.¹⁸ For patients in the deucravacitinib group, improvements occurred as early as week 1 and increased over time on treatment.¹⁸

In a long-term extension study of PSO trials, investigators analyzed the efficacy of deucravacitinib in patients who did not respond adequately to treatment with apremilast by week 24. Patients initially randomized to apremilast who failed to achieve a PASI 50 in PSO-1 (n=54) or PASI 75 in PSO-2 (n=111) were switched to deucravacitinib through week 52. After switching from apremilast to deucravacitinib, 46.3% of PASI 50 nonresponders and 42.3% of PASI 75 non-responders achieved PASI 75 by week 52.¹⁹ Improvements were also seen for sPGA 0/1, DLQI 0/1, and mean change from baseline PSSD symptom score.¹⁹

Two-year data from a long-term extension of both PSO trials showed that deucravacitinib had durable clinical efficacy, including mean response rates of 79.8% for PASI 75 and 60.7% for sPGA 0/1 at week 60, regardless of which treatment was initiated at week 16 (when patients in the placebo group could switch to deucravacitinib) or at week 24 (when apremilast nonresponders could switch to deucravacitinib) in the parent study.²⁰

Deucravacitinib: Safety and Tolerability Profile

During weeks 0–16 and weeks 0–52 assessment periods in both PSO trials, overall adverse event (AE) rates were similar across all 3 treatment groups (deucravacitinib, placebo, and apremilast).^15,16,21 The most frequent AEs in patients treated with deucravacitinib were nasopharyngitis (9.0%) and upper respiratory tract infection (5.5%). The most frequent AEs in apremilast-treated patients were diarrhea (11.8%), headache (10.7%), nausea (10.0%), and nasopharyngitis (8.8%); placebotreated patients most frequently experienced nasopharyngitis (8.6%) and diarrhea (6.0%).16,21 Incidence rates for AEs of interest, including skin events (e.g., acne and folliculitis), herpes zoster, serious infections, malignancies, thrombotic events, cardiovascular events, creatinine kinase elevation, changes in complete blood count, and changes in lipid profile were absent or low in the deucravacitinib group.¹⁵

The frequency of serious adverse events (SAEs) reported in weeks 0–16 were low across all groups (1.8% in deucravacitinib treated patients vs. 2.9% with placebo and 1.2% with apremilast).^16,21 Discontinuation rates due to AEs were lowest in the deucravacitinib group (2.4%) vs. placebo (3.8%) and apremilast (5.2%).^16,21

A pooled analysis of PSO-1 and PSO-2 trials confirmed that deucravacitinib was well tolerated for up to 52 weeks across patient subgroups based on baseline characteristics of age, sex, race, and body weight. The frequency and type of AEs and SAEs in each subgroup were consistent with the overall patient population, with similar trends for overall AEs and AE classes in the placebo and apremilast groups across subgroups.²¹

In the long-term extension trial, safety results were consistent with those reported in PSO-1 and PSO-2 trials. SAEs remained low, including those that led to discontinuation. There were no new safety signals or clinically meaningful changes in laboratory values.²⁰ The most common AEs included nasopharyngitis (16.8% at 1 year; 17.8% at 2 years), upper respiratory tract infection (9.1% at 1 year; 9.9% at 2 years), headache (5.9% at 1 year; 6.5% at 2 years), diarrhea (5.1% at 1 year; 5.5% at 2 years), and arthralgia (4.0% at 1 year; 5.6% at 2 years).²⁰ An increase in serious infections was observed, which the authors concluded was attributable to COVID-19 infections due to the ongoing pandemic (studies were conducted during the pandemic through the cut-off date of October 1, 2021, prior to widespread availability of vaccines).

These safety results have not as of yet uncovered treatmentemergent SAEs that are more commonly associated with JAK inhibitors, such as herpes zoster, malignancies, thrombosis, major adverse cardiovascular events (MACE), creatinine kinase elevation, hematologic changes, lipid profile abnormalities, and renal and hepatic abnormalities.^20-24

Discussion

Selective TYK2 inhibition is a promising novel target for the treatment of moderate to severe chronic plaque psoriasis. Molecules that confer selective inhibition of TYK2-mediated pathways that contribute to psoriasis pathogenesis, without involvement of other JAKs, can lead to a broad therapeutic range while reducing off-target effects such as serious infections, malignancies, thrombosis, and MACE.

Key data from the pivotal phase III POETYK PSO-1 and PSO-2 clinical trials showed that patients with moderate to severe chronic plaque psoriasis treated with the first-in-class, oral, selective TYK2 inhibitor deucravacitinib achieved statistically significant PASI 75 and sPGA 0/1 outcomes that were superior to placebo and apremilast at week 16.^15,16 Additionally, significantly greater proportions of patients achieved absolute PASI ≤1, ≤2, and ≤5 with deucravacitinib vs. placebo or apremilast.¹⁷ Body region-specific data showed that deucravacitinib had numerically larger percentage improvements at weeks 16 and 24 from baseline vs. apremilast and placebo, across all components of scoring and with onset of action as early as week 1.¹⁸

Deucravacitinib was efficacious at week 52 in patients who had inadequate responses to apremilast at week 24 and subsequently switched to deucravacitinib, which was demonstrated in physician-assessed endpoints (PASI 75/90, percentage change from baseline in PASI, and sPGA 0/1) and in patient-reported outcomes (DLQI 0/1 and change from baseline in PSSD symptom score).¹⁹

Deucravacitinib was generally well tolerated and safe compared to placebo and apremilast, with overall AE rates similar across all 3 treatment groups.^15,21 The most common AEs in patients treated with deucravacitinib were nasopharyngitis and upper respiratory tract infection, while incidence rates of SAEs and AEs of interest were low.^15,21

1. What are the off-target serious adverse effects associated with JAK inhibitors?
2. In the PSO-1 and PSO-2 clinical trials, what were the outcomes of apremilast non-responders who were switched to deucravacitinib at week 24?

Conclusion

Selective TYK2 inhibition is a novel target in the treatment of moderate to severe plaque psoriasis. The first-in-class oral TYK2 inhibitor deucravacitinib, already approved by the FDA in the US, has been shown to be efficacious, safe, and tolerable for up to 2 years of use. It is expected that deucravacitinib, and potentially other oral TYK2 inhibitors in development, will offer dermatologists and their patients with a convenient, effective, and safe alternative to other currently available oral systemic agents biologic agents, and phototherapy for the management of moderate to severe chronic plaque psoriasis.

Acknowledgements

The authors wish to thank Teri Morrison and Athena Kalyvas from the International Centre for Professional Development in Health and Medicine (ICPDHM) for editorial support.

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IL-23s: Psoriasis therapy overview

People with moderate-to-severe psoriasis can benefit from tildrakizumab (Ilumya), a biologic treatment that belongs to a class of drugs called interleukin-23 (IL-23) inhibitors. Biologics are protein-based medications that target specific parts of the immune system. IL-23 inhibitor specifically targets a type of cytokine called IL-23 and blocks cellular activity, which results in reduced inflammation that causes psoriasis.

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Tildrakizumab (Ilumya) is a brand-name biologic medication that’s used to treat moderate to severe plaque psoriasis. This drug is an interleukin (IL-23) inhibitor that’s very effective and works long-term to control the symptoms of psoriasis. Tildrakizumab can help a wide range of psoriasis patients (even those with inflammatory bowel disease, IBD), including those with other health complications. A dermatologist can prescribe the medication, which is injected under your skin (subcutaneous injection) once every 12 weeks.

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