An Oral Interleukin-23-Receptor Antagonist Peptide for Plaque Psoriasis.

BACKGROUND: The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production. METHODS: In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16. RESULTS: A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups. CONCLUSIONS: After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Spesolimab, A Novel Interleukin-36 Inhibitor for Generalized Pustular Psoriasis Flares in Adult Patients.

Generalized pustular psoriasis (GPP) is a rare, immune-mediated inflammatory disease with characteristic cutaneous and systemic manifestations. Mutations in the interleukin-36 receptor antagonist (IL36RN) gene have been implicated in its pathogenesis. Spesolimab is a novel systemic biologic therapy that selectively inhibits interleukin-36. It was recently approved by Health Canada and the US FDA for the treatment of GPP flares in adults. Results from phase 1 and 2 studies have been promising. Herein, we review the efficacy and safety of spesolimab for the treatment of GPP flares, as demonstrated in clinical trials.

Comparison of risankizumab and apremilast for the treatment of adults with moderate plaque psoriasis eligible for systemic therapy: results from a randomized, open-label, assessor-blinded phase IV study (IMMpulse).

BACKGROUND: Treatment of psoriasis with risankizumab has demonstrated superior efficacy to other treatments, such as adalimumab, ustekinumab and secukinumab. OBJECTIVES: This study compared the efficacy and safety of risankizumab and apremilast in adults with moderate plaque psoriasis eligible for systemic therapy. It also evaluated the efficacy and safety of switching to risankizumab vs. continuing apremilast in patients who did not achieve ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75 nonresponders) after 16 weeks of treatment with apremilast. METHODS: This 52-week, phase IV, multicentre, randomized, open-label, efficacy assessor-blinded study (NCT04908475) enrolled patients (aged ≥ 18 years) with a diagnosis of moderate chronic plaque psoriasis (≥ 6 months) and who were candidates for systemic therapy. The enrolled patients (randomized 1 : 2) received subcutaneous risankizumab (150 mg at weeks 0 and 4) or oral apremilast (30 mg twice daily). At week 16, all patients treated with apremilast were re-randomized (1 : 1) to risankizumab or apremilast, stratified by week-16 PASI 75 response. The co-primary outcomes in period A at week 16 were the achievement of ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) and static Physician's Global Assessment (sPGA) 0/1 with a two-grade or better improvement from baseline. At week 52, the primary endpoint in period B was the achievement of PASI 90 in PASI 75 nonresponders with apremilast at week 16. Safety was monitored throughout the study. All patients who received one dose of treatment were included in the efficacy and safety analysis. RESULTS: At baseline, 118 and 234 patients were assigned to receive risankizumab and apremilast, respectively. At week 16, PASI 90 was achieved by 55.9% [95% confidence interval (CI) 47.0-64.9] and 5.1% (95% CI 2.3-8.0), and sPGA 0/1 by 75.4% (95% CI 67.7-83.2) and 18.4% (95% CI 13.4-23.3), respectively. In period B, among PASI 75 nonresponders with apremilast at week 16, 83 switched to risankizumab and 78 continued apremilast. At week 52, 72.3% (95% CI 62.7-81.9) who switched to risankizumab achieved PASI 90 vs. 2.6% (95% CI 0.0-6.1) who continued apremilast. The most frequent adverse events (reported in ≥ 5%) in risankizumab-treated patients were COVID-19 infection and nasopharyngitis. Diarrhoea, nausea and headache were most frequent among apremilast-treated patients. CONCLUSIONS: For patients with moderate psoriasis, treatment with risankizumab demonstrated superior efficacy to those treated with apremilast, including those who did not benefit from prior treatment with apremilast. The safety profile of risankizumab was similar to prior studies, and no new safety signals were identified. These results show that, compared with apremilast, risankizumab treatment can significantly improve clinical outcomes in systemic-eligible patients with moderate psoriasis.

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway.

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial.

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. This study investigated the efficacy and safety of bimekizumab in patients with moderate to severe plaque psoriasis, the effects of treatment withdrawal, and two maintenance dosing schedules over 56 weeks. METHODS: BE READY was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial done at 77 sites (hospitals, clinics, private doctor's practices, and dedicated clinical research centres) in nine countries across Asia, Australia, Europe, and North America. Adult patients aged 18 years or older with moderate to severe plaque psoriasis were stratified by region and previous biologic exposure, and randomly assigned (4:1) to receive bimekizumab 320 mg every 4 weeks or placebo every 4 weeks by use of interactive response technology. Coprimary endpoints were the proportion of patients achieving 90% or greater improvement from baseline in the Psoriasis Area Severity Index (PASI90) and the proportion of patients achieving a score of 0 (clear) or 1 (almost clear) on the five-point Investigator's Global Assessment (IGA) scale at week 16 (non-responder imputation). Bimekizumab-treated patients achieving PASI90 at week 16 were re-allocated (1:1:1) to receive bimekizumab 320 mg every 4 weeks, every 8 weeks, or placebo for weeks 16-56. Efficacy analyses were done in the intention-to-treat population; the safety analysis set comprised all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT03410992), and is now completed. FINDINGS: Between Feb 5, 2018, and Jan 7, 2020, 435 patients were randomly assigned to receive either bimekizumab 320 mg every 4 weeks (n=349) or placebo every 4 weeks (n=86). Coprimary endpoints were met: at week 16, 317 (91%) of 349 patients receiving bimekizumab 320 mg every 4 weeks achieved PASI90, compared with one (1%) of 86 patients receiving placebo (risk difference 89·8 [95% CI 86·1-93·4]; p<0·0001); and 323 (93%) of 349 patients receiving bimekizumab 320 mg every 4 weeks achieved an IGA score of 0 or 1 versus one (1%) of 86 patients receiving placebo (risk difference 91·5 [95% CI 88·0-94·9]; p<0·0001). Responses were maintained through to week 56 with bimekizumab 320 mg every 8 weeks and every 4 weeks. Treatment-emergent adverse events in the initial treatment period (up to week 16) were reported in 213 (61%) of 349 patients receiving bimekizumab 320 mg every 4 weeks and 35 (41%) of 86 patients receiving placebo every 4 weeks. From week 16 to week 56, treatment-emergent adverse events were reported in 78 (74%) of 106 patients receiving bimekizumab 320 mg every 4 weeks, 77 (77%) of 100 patients receiving bimekizumab 320 mg every 8 weeks, and 72 (69%) of 105 patients receiving placebo. INTERPRETATION: Bimekizumab showed high levels of response, which were durable over 56 weeks, with both maintenance dosing schedules (every 4 weeks and every 8 weeks). Moreover, bimekizumab was well tolerated, with no unexpected safety findings. Data presented here further support the therapeutic value of bimekizumab and inhibition of IL-17F in addition to IL-17A for patients with moderate to severe plaque psoriasis. FUNDING: UCB Pharma.

Sustained Resolution of Nail Psoriasis Through 5 Years with Ixekizumab: A Post-Hoc analysis from UNCOVER-3.

Nail psoriasis is a chronic, difficult-to-treat condition affecting almost half of patients with psoriasis. It is associated with considerable social stigma and impairment of patients' quality of life. The aim of this study was to assess improvements in objective measures of nail psoriasis among patients from the long-term extension of the UNCOVER-3 study who received the interleukin-17A inhibitor ixekizumab and had either any degree of nail psoriasis (Nail Psoriasis Severity Index (NAPSI) >=1) or significant nail psoriasis (fingernail NAPSI ≥ 16 and ≥ 4 fingernails involved) at baseline. Efficacy outcomes reported through week 264 included the mean percentage improvements from baseline in NAPSI score and the proportion of patients achieving nail psoriasis resolution (NAPSI=0). In UNCOVER-3, 56.9% (219/385) of patients had nail psoriasis at baseline; of those, 61.2% (134/219) had significant nail psoriasis. At week 60, a total of 66.9% and 59.1% of patients with baseline nail psoriasis and significant baseline nail psoriasis, respectively, reported complete clearance of nail psoriasis, an effect which was sustained through week 264. This analysis demonstrates that continuous treatment with ixekizumab in adult patients with moderate-to-severe-psoriasis through 264 weeks was associated with improvements and clearance of fingernail psoriasis, irrespective of the severity of nail psoriasis at baseline.

Certolizumab Pegol Use in the Treatment of Moderate-to-Severe Psoriasis: Real-World Data From Two Canadian Centers.

BACKGROUND: Certolizumab pegol (CZP) is a TNF-ɑ inhibitor used to treat moderate-to-severe plaque psoriasis (PsO) in adult patients, including women of childbearing potential (WOCBP) and patients with psoriatic arthritis (PsA). There are currently limited real-world data on CZP for treatment of PsO. OBJECTIVES: To examine the use of CZP for treatment of PsO in clinical practice at two dermatology clinics in Canada. METHODS: We conducted a retrospective chart analysis of 59 patients with moderate-to-severe psoriasis receiving CZP. Clinical efficacy was measured using the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), and Physician Global Assessment (PGA). Drug survival was analyzed using Kaplan-Meier plots. RESULTS: Of the 59 patients, 36 (61%) were female, of whom 23 (63.9%) were WOCBP. Twenty-three (39.0%) patients received CZP as their first biologic treatment. The main reasons for choosing CZP were its efficacy in both PsO and PsA, and for WOCBP due to little or no cross-placental transfer. Improvement of symptoms was observed after 3 months of treatment and was maintained for the 12-month analysis period. After 12 months of treatment, the patients' mean PASI score decreased from 13.0 (±5.8) at baseline to 2.3 (±4.3), mean BSA score from 13.1% (±6.7%) to 1.7% (±2.6%), and mean PGA score from 3.0 (±0.6) to 0.8 (±0.6). Overall CZP drug survival rate was 76.3% at 12 months, with no difference between biologic-naive and biologic-experienced patients. CONCLUSIONS: CZP was effective and well tolerated in this cohort of patients with moderate-to-severe PsO in a real-world setting.

Review and Practical Guidance on Managing Fungal Infections in Patients With Psoriasis Receiving Anti-IL-17 Therapies.

The IL-17 signalling pathway is a major target in treatment of plaque psoriasis. IL-17 signalling contributes to chronic inflammation and epidermal hyperplasia seen in psoriatic lesions. Blocking the IL-17 signalling cascade is an effective method in treating this disease. However, IL-17 also plays a role in the immunological protection against fungal infections and therefore, patients on IL-17 biologics experience an increased rate of fungal infections, specifically Candida albicans. It is prudent that patients and physicians are aware of this risk and understand how to recognize and manage Candida infections. In this review, we examine the Candida infection rates associated with IL-17 biologics, both in clinical trials and real-world practice. We discuss common presentations associated with various types of candidiasis and propose a recommended management approach to treating these infections.

Halobetasol Propionate 0.01% Lotion for Plaque Psoriasis and Corticosteroid-Responsive Dermatoses.

A novel topical corticosteroid, halobetasol propionate (HP) 0.01% lotion (Bryhali™), has recently been introduced for the treatment of plaque psoriasis and corticosteroid-responsive dermatoses in adults. Once daily application of HP 0.01% lotion is indicated for use up to 8 weeks. Treatment success for plaque psoriasis in the pivotal phase 3 clinical trials (defined as an Investigator Global Assessment [IGA] of clear/almost clear [IGA 0/1] with ≥2-grade improvement from baseline) occurred in over one-third of patients by week 8. Treatment-emergent adverse events were typically mild-to-moderate in intensity and usually limited to the application site(s). No treatment-related cases of skin atrophy have been reported from the studies. Counselling should be considered to optimize treatment outcomes.

A Review of Drug-Drug Interactions for Biologic Drugs Used in the Treatment of Psoriasis.

Biologic drugs are increasingly being prescribed for the treatment of psoriasis. Very little information is available in the literature regarding potential drug interactions with these medications. This paper serves as a guide for prescribers to be aware of possible interactions between biologic drugs approved for the treatment of psoriasis in North America and concomitant therapies. OBJECTIVE: To provide an overview of reported drug interactions between biologic drugs and concomitant therapies. METHODS: Reports of potential drug interactions were compiled through a search of Micromedex, drug monographs (Canadian, American, and European), as well as a PubMed search of each biologic drug with the term "drug interaction." CONCLUSION: Generally, caution should be exercised when multiple immunosuppressive therapies are prescribed due to increased risk of infection. However, this is more the result of a synergistic effect as opposed to a true drug interaction. There have been cases where multiple biologic therapies have been concomitantly used without adverse events, as their mechanisms involved different pathways. The sources used to compile this guide were often comprised of low levels of evidence, reinforcing the idea that further studies are required to better direct prescribers.

A Psoriatic Patient-Based Survey on the Understanding of the Use of Vaccines While on Biologics During the COVID-19 Pandemic [Formula: see text].

BACKGROUND: Psoriatic patients who are actively receiving biologic treatment have protocols in place to achieve optimal immunity. Inactivated vaccines are safe to use during biological treatment, without interruption. Conversely, live vaccines are used with caution and likely interruption of treatment. Given the novel coronavirus (SARS-CoV-2), nation-wide administration of vaccinations is underway. OBJECTIVE: This survey gathered information on the level of education psoriatic patients have concerning vaccinations. METHODS: An electronic survey was sent to 661 patients suffering from psoriasis. Patients originated from a single solo-practitioner community-based dermatology practice. RESULTS: The average percentage of patients who understand the difference between live and inactivated vaccines between the control and study group was 36.6%. The average response to not knowing the difference between the vaccines was 36.6% and 26.6% were "unsure." When asked if it was possible to receive inactivated vaccines while on a biologic, the mass response amidst the control and study group was "unsure" (66.9%). CONCLUSION: This questionnaire demonstrates that there is a need for supplementary education about vaccines for psoriatic patients on a biologic. Physicians will need to counsel their patients on the use of potential vaccines for SARS-Cov2 while on biologics.

The Incidence and Prevalence of Uveitis in Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: The systemic effects and comorbidities of psoriasis include ocular disorders, such as uveitis. Patients with psoriatic arthritis in particular have been demonstrated to have an elevated risk for developing uveitis. Presently, the risk of uveitis in psoriasis has yet to be fully elucidated and this systematic review seeks to address this gap. OBJECTIVE: To examine the prevalence and incidence of uveitis in psoriasis patients compared to non-psoriasis patients. METHODS: We conducted a systematic review search on MEDLINE, Embase, and CENTRAL electronic databases with no lower limit on year of publication. RESULTS: Fourteen articles met our inclusion criteria, with a total of 234 143 psoriasis subjects. Two studies found that participants with severe psoriasis were at a greater risk of uveitis than those with mild psoriasis. A random-effects meta-analysis of the 3 studies, which reported risk of incidence of uveitis in psoriasis patients compared to non-psoriasis controls, found a pooled risk ratio of 1.29 (95% CI, 1.10-1.51), indicating an increased risk of uveitis in psoriasis. Three studies compared risk of uveitis in psoriatic arthritis with psoriasis-only participants, all finding that psoriatic arthritis was associated with a greater risk of uveitis. CONCLUSIONS: In summary, our findings suggest that psoriasis is associated with an increased risk of uveitis, with or without psoriatic arthritis.

Management of Plaque Psoriasis With Biologic Therapies in Women of Child-Bearing Potential Consensus Paper.

BACKGROUND: Plaque psoriasis (PsO) is a chronic inflammatory disease that often presents at peak reproductive age in women of child-bearing potential (WOCBP). With the emergence of biologic therapies to treat PsO, guidance on disease management in WOCBP is needed to inform treatment decisions before, during, and after pregnancy. OBJECTIVES: To develop a practical, up-to-date consensus document, based on available evidence and expert opinion where evidence was lacking, in order to guide both Canadian and international clinicians treating PsO in WOCBP. METHODS: A panel of 9 Canadian dermatologists with extensive clinical experience managing PsO reviewed the relevant literature from the past 25 years in 3 key domains: overview of PsO in WOCBP and clinical considerations, treatment considerations, and postpartum considerations. The structured literature search focused on WOCBP treated with TNF-alpha inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab), IL-23 inhibitors (guselkumab, risankizumab, tildrakizumab), IL-12/23 inhibitors (ustekinumab), and IL-17 inhibitors (brodalumab, ixekizumab, secukinumab). This literature review, along with clinical expertise and opinion, was used to develop concise and clinically relevant consensus statements to guide practical management of PsO in WOCBP. Experts voted on the statements using a modified Delphi process and prespecified agreement cut-off of 75%. RESULTS AND IMPLICATIONS: After review, discussion, and voting on 19 draft consensus statements at an in-person meeting and remotely, 12 consensus statements were approved by the expert panel. The statements presented here will guide healthcare providers in practical disease management using biologic therapies for the treatment of PsO in WOCBP.

Ixekizumab improves patient-reported outcomes in patients with active psoriatic arthritis and inadequate response to tumour necrosis factor inhibitors: SPIRIT-P2 results to 52 weeks.

OBJECTIVES: To report patient-reported outcomes (PROs) of ixekizumab-treated patients with psoriatic arthritis (PsA) and an inadequate response (IR) or intolerance to tumour necrosis factor inhibitors (TNFi) to 52 weeks. METHODS: In SPIRIT-P2, patients with active PsA and an IR or intolerance to TNFi were randomised to ixekizumab 80 mg every 4 weeks (IXEQ4W; N=122) or every 2 weeks (IXEQ2W; N=123), or placebo (PBO; N=118) during the initial 24-week double-blind treatment period. At Week 16, background therapy was modified for IRs; additionally, IRs in the placebo group were re-randomised (1:1) to IXEQ2W or IXEQ4W. Patients receiving ixekizumab at Week 24 received the same dose during the study remainder. Patients completed several PROs for PsA disease activity, skin, health-related quality of life (HRQOL, and work through Week 52. RESULTS: Ixekizumab-treated patients reported significant improvements versus PBO in 36-Item Short Form Health Survey version 2, European Quality of Life 5 Dimensions visual analogue scale, Bath Ankylosing Spondylitis Disease Activity Index (total score and question 2), and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (3 of 4 domains) through Week 24. At Week 24, 9% (PBO), 52% (IXEQ4W), and 50% (IXEQ2W) of patients reported Dermatology Life Quality Index scores of 0 or 1; 0% (PBO) and 24% (IXEQ4W and IXEQ2W) reported Itch Numeric Rating Scale score of 0. Where data were collected, improvements persisted through Week 52. CONCLUSIONS: In patients with PsA and an IR or intolerance to TNFi, ixekizumab significantly improved disease activity, skin symptoms, HRQOL, and work productivity to 52 weeks.

Cohort Using a Ceramides Containing Cleanser and Cream With Salicylic Acid for Dry, Flaking, and Scaling Skin Conditions

Introduction: The skin of subjects with dry, flaking, and/or scaling conditions is characterized by decreased water and skin lipids content among other findings. It is well understood that daily use of gentle cleansers and moisturizers may help to restore and maintain an optimal skin barrier function. A cohort study of patients with dry skin was developed to evaluate efficacy of daily use of a ceramide containing cleanser and cream that also has salicylic acid. Methods: Thirty-five adults with mild-to-moderate dry skin conditions were recruited from four dermatology centers in Canada. With consent, the subjects received twice daily treatment with the ceramides containing cleanser and cream that also has salicylic acid. Physician and subject assessed skin condition comparing baseline versus (day 0) versus day 28 (end) was scored using the Dry skin classification scale and the Global Aesthetic Improvement Scale (GAIS). Subjects also rated satisfaction, product features, quality of life aspects, safety, and tolerability. Results: Thirty-four subjects completed the treatment and study period; one was lost to follow up. Daily use of the evaluated cleanser and moisturizer significantly improved skin condition when comparing day 0 versus day 28 (+/- 5 days (end)) results. Both the physicians and subjects using the dry skin classification scale and GAIS scored a significant improvement of the dry skin condition. After treatment subjects reported a significant improvement in the quality of their professional life, self-image, and social life. The products were shown to be safe, comfortable, and well tolerated. Conclusion: The results indicated the cleanser and moisturizer to offer an effective, easy and comfortable option for dry skin conditions. J Drugs Dermatol. 2019;18(1):80-85.