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Interleukin (IL)-23-independent IL-17A production has been suggested to be involved in persistent manifestations of psoriatic disease, including anti-IL-12/23-refractory psoriatic plaques; this study aimed to test this hypothesis by investigating the clinical and molecular effects of direct IL-17A (with secukinumab) versus selective IL-23 inhibition (with guselkumab) in patients with anti-IL-12/23 (ustekinumab)-refractory psoriatic plaques. A 16-week, randomized, open-label, parallel-group, Phase IIa study (ARROW, NCT03553823) was conducted in patients with ≥1 active psoriatic plaque (total clinical score [TCS] ≥6) at screening despite treatment with ustekinumab, and a Psoriasis Area and Severity Index (PASI) score 1-10. Patients were randomized 1:1 to receive secukinumab 300 mg (n = 20) or guselkumab 100 mg (n = 20). Biopsies from one refractory ('target plaque') were obtained at baseline and Week 16. The primary endpoint was the proportion of patients whose ustekinumab-refractory target plaque achieved clear/almost clear status (TCS 0-2) at Week 16. Transcriptomic and histological analyses were conducted on target plaques to determine the molecular effects of direct IL-17A versus selective IL-23 inhibition. At Week 16, target plaque clear/almost clear status was achieved in 60.0% of patients treated with secukinumab versus 40.0% of patients treated with guselkumab (p = 0.1715). Molecular analyses identified that secukinumab modulated a greater proportion of psoriasis disease transcriptome genes (72.1% vs. 48.0%) and resulted in more histological responders (72.2% vs. 53.3%) compared with guselkumab. Secukinumab demonstrated a greater clinical and molecular effect on ustekinumab-refractory psoriatic plaques versus guselkumab. These results are consistent with the hypothesis that IL-23-independent IL-17 mechanisms may be relevant to the inflammation driving refractory manifestations of psoriasis., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: There is an unmet need for a treatment for psoriasis that results in complete skin clearance with a reliably quick response. Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. We aimed to compare the efficacy and safety of bimekizumab with placebo and ustekinumab in patients with moderate to severe plaque psoriasis over 52 weeks., Methods: BE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries in Asia, Australia, Europe, and North America. Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator's Global Assessment [IGA] score ≥3 on a five point scale) were included. Randomisation was stratified by geographical region and previous exposure to biologics; patients, investigators, and sponsors were masked to treatment assignment. Patients were randomly assigned (4:2:1) using an interactive response technology to bimekizumab 320 mg every 4 weeks, ustekinumab 45 mg or 90 mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. At week 16, patients receiving placebo switched to bimekizumab 320 mg every 4 weeks. All study treatments were administered as two subcutaneous injections. Coprimary endpoints were the proportion of patients with 90% improvement in the PASI (PASI90) and the proportion of patients with an IGA response of clear or almost clear (score 0 or 1) at week 16 (non-responder imputation). Efficacy analyses included the intention-to-treat population; safety analysis included patients who received at least one dose of study treatment. This trial was registered at ClinicalTrials.gov, NCT03370133 (completed)., Findings: Between Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were enrolled and randomly assigned (bimekizumab 320 mg every 4 weeks n=321, ustekinumab 45 mg or 90 mg every 12 weeks n=163, placebo n=83). At week 16, 273 (85%) of 321 patients in the bimekizumab group had PASI90 versus 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI 27-43]; p<0·0001) and four (5%) of 83 in the placebo group (risk difference 80 [74-86]; p<0·0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI 22-39]; p<0·0001) and four (5%) in the placebo group (risk difference 79 [73-85]; p<0·0001). Over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group (including those who switched from placebo at week 16) and 13 (8%) of 163 in the ustekinumab group., Interpretation: Bimekizumab was more efficacious than ustekinumab and placebo in the treatment of moderate to severe plaque psoriasis. The bimekizumab safety profile was consistent with that observed in previous studies., Funding: UCB Pharma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood., Objective: Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR)., Methods: Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-α (TNF-α) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy., Results: Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (≥12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-α inhibitor was associated with increased malignancy risk., Limitations: Cases and controls could belong to 1 or more therapy categories., Conclusions: Long-term (≥12 months) treatment with a TNF-α inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The effects of systemic therapy on mortality risk among patients with psoriasis are not fully understood.Objective: To evaluate the impact of systemic treatment on mortality risk in patients enrolled in the Psoriasis Longitudinal Assessment and Registry.Methods: Nested case-control analyses were performed to estimate mortality risk. Cases were defined as patients who died while participating in the Psoriasis Longitudinal Assessment and Registry. Cases were matched (1:4) with controls by age, race, sex, and geographic region. Evaluated treatments included methotrexate, ustekinumab, and tumor necrosis factor α inhibitors. Exposure was defined as at least 1 dose of treatment within 3 months before death and was stratified by duration of therapy.Results: Among 12,090 patients, 341 deaths occurred, matched to 1364 controls. Biologic treatment within the preceding 3 months was protective against mortality versus no exposure: odds ratio (OR) for exposure of less than 1 year, 0.08 (95% confidence interval [CI], 0.03-0.23); OR for exposure of 1 year or longer, 0.09 (95% CI, 0.06-0.13). Methotrexate was protective against mortality only with exposure for 1 year or longer (OR, 0.08; 95% CI, 0.02-0.28).Limitations: Observational studies are subject to unmeasured confounding.Conclusions: Biologic therapy was associated with reduced mortality risk in patients with moderate to severe psoriasis, regardless of treatment duration; methotrexate reduced risk only with exposure for 1 year or longer. [ABSTRACT FROM AUTHOR]

Background: Patients with psoriasis are known to have an increased number of cardiovascular (CV) risk factors and be at increased risk for CV events. Objectives: We sought to describe and characterize the underdiagnosis and undertreatment of CV risk factors in patients with moderate to severe psoriasis. Methods: Medical histories including diabetes, hypertension, and hyperlipidemia were obtained from 2899 patients in 3 phase III ustekinumab trials, a therapeutic anti-interleukin (IL)-12/IL-23p40 monoclonal antibody. Reported history was compared with measured fasting glucose, fasting lipids, and blood pressure. Ten-year Framingham risk scores and the proportion of patients achieving glycemic, lipid, and blood pressure targets were evaluated. Results: Significant risk factors existed in patients with moderate to severe psoriasis (58.6% and 28.8% of patients had ≥2 and ≥3 established CV risk factors, respectively). Based on Framingham risk score, 18.6% of patients were at high risk and 12.3% were at intermediate risk for CV events. At baseline, a small proportion of patients with diabetes (2.3%), hypertension (9.1%), or hyperlipidemia (4.9%) were previously without a diagnosis. However, 19.1%, 21.8%, and 38.6% of patients with diabetes, hypertension, or hyperlipidemia, respectively, were untreated at baseline, and the proportion at treatment goal was not ideal (hypertension 59.6% and hyperlipidemia 69.7%), especially for diabetes (36.7%). Limitations: Results are based on a clinical trial population and findings may not be generalizable to the general psoriasis population. Conclusions: In this moderate to severe psoriasis population, a high prevalence of undiagnosed and undertreated CV risk factors existed, emphasizing the importance of screening patients with psoriasis for CV risk factors. [Copyright &y& Elsevier]

Background: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. Objective: We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. Methods: Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. Results: During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. Limitations: Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. Conclusions: The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years. [ABSTRACT FROM AUTHOR]

Objective: To assess the effect of ustekinumab on productivity and work limitations among 1230 psoriasis patients treated with ustekinumab 45 mg or 90 mg or placebo during the Phase III PHOENIX 2 trial. Methods: The self-administered Work Limitations Questionnaire (WLQ) was used to determine the on-the-job limitations at baseline and weeks 12 and 24. Productivity was assessed using a Visual Analog Scale (VAS), and the number of work days missed due to psoriasis was recorded. Results: At baseline, work limitations and productivity were similar across treatment groups. At week 12, improvement in productivity VAS scores was significantly ( p < 0.001) higher in the 45 mg (72.6%) and 90 mg (71.4%) ustekinumab groups versus placebo (no change), and the proportion of patients who missed work days was significantly lower (2.0% for each ustekinumab group vs 8.3% for placebo; p < 0.001). Mean improvements from baseline to week 12 were greater with ustekinumab than with placebo for WLQ domains, including time management (6.6/9.1 vs -0.7), mental-interpersonal (7.8/7.5 vs -1.1), and output demands (6.8/7.0 vs -1.1) ( p < 0.001 for ustekinumab 45 mg/90 mg vs placebo). Improvements were maintained through week 24. Conclusions: Ustekinumab 45 mg or 90 mg significantly increased productivity, reduced work days missed, and improved work limitations compared with placebo in patients with moderate-to-severe psoriasis. [ABSTRACT FROM AUTHOR]

Background: Patients with psoriasis tend to be overweight, and the efficacy of fixed-dose biologics may be compromised by high body weight. Objective: We sought to determine whether the optimal dose of ustekinumab is affected by weight in patients with psoriasis. Methods: Patients were randomized in two phase III trials (PHOENIX 1 and 2) to receive 45 mg or 90 mg of ustekinumab every 12 weeks (n = 1331) or placebo with crossover to ustekinumab at week 12 (n = 665). Efficacy and serum ustekinumab concentrations were to be evaluated by 10-kg increments of body weight at week 28 (steady-state trough level). Results: Mean baseline weight was 93.9 and 91.0 kg in PHOENIX 1 and 2, respectively. Based on the analyses by 10-kg increments, a cutoff of 100 kg was determined to best differentiate the dose response. The proportion of patients with at least 75% improvement from baseline in Psoriasis Area and Severity Index score was 74.2% for 90 mg and 54.6% for 45 mg in heavier patients (>100 kg), but the proportion with a response of at least 75% improvement from baseline in Psoriasis Area and Severity Index score was similar between doses (80.8% vs 76.9%) in lighter patients (≤100 kg). Serum ustekinumab concentrations were also affected by weight, with lower serum concentrations observed in heavier patients at each dose. Safety was not affected by weight. Limitations: Low numbers of patients at the extremes of body weight may limit the analyses of these subgroups. Conclusion: Results of weight-based analyses of clinical and pharmacokinetic data indicate that fixed dosing of ustekinumab based on weight is appropriate for the treatment of patients with psoriasis. [ABSTRACT FROM AUTHOR]

Background: Anxiety, depression, and impaired health-related quality of life (HRQoL) are common in patients with psoriasis. Objective: We sought to analyze the effect of ustekinumab on these conditions in patients with moderate-to-severe psoriasis. Methods: Patients with moderate-to-severe psoriasis (n = 1230) were randomized 1:1:1 to receive 45 mg of ustekinumab, 90 mg of ustekinumab, or placebo. The Hospital Anxiety and Depression Scale was used to measure anxiety and depression, and the Dermatology Life Quality Index to measure HRQoL. Results: At baseline, 40.3% and 26.7% of patients reported symptoms of anxiety and depression, respectively, and 54.6% reported Dermatology Life Quality Index scores greater than 10, indicating a very high impact of disease on HRQoL. Greater improvements at week 12 in mean Hospital Anxiety and Depression Scale-Anxiety (13.9%), Hospital Anxiety and Depression Scale-Depression (29.3%), and Dermatology Life Quality Index (76.2%) scores were reported in ustekinumab groups compared with placebo (P < .001 each). Limitations: Results for these measures are reported only through 24 weeks. Conclusion: Patients receiving ustekinumab reported significant improvements in symptoms of anxiety, depression, and HRQoL. [ABSTRACT FROM AUTHOR]