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Safety of selective IL-23p19 inhibitors for the treatment of psoriasis.

ABSTRACT: Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. This article reviews published data on the safety of these IL-23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo- and active-controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk-benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL-23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL-23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long-term extension studies and patient registries will further establish the safety profile of IL-23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.

SUBMITTER: Crowley JJ

PROVIDER: S-EPMC6771721 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Safety of selective IL-23p19 inhibitors for the treatment of psoriasis.

Crowley J J JJ Warren R B RB Cather J C JC

Journal of the European Academy of Dermatology and Venereology : JEADV 20190627 9

Psoriasis is a chronic disease that requires long-term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)-23. Thi ...[more]

PMID: 31054215

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Project description:Importance:Use of systemic therapies for moderate to severe psoriasis in children is increasing, but comparative data on their use and toxicities are limited. Objective:To assess patterns of use and relative risks of systemic agents for moderate to severe psoriasis in children. Design, Setting, and Participants:A retrospective review was conducted at 20 centers in North America and Europe, and included all consecutive children with moderate to severe psoriasis who used systemic medications or phototherapy for at least 3 months from December 1, 1990, to September 16, 2014. Main Outcomes and Measures:The minimal core data set included age, sex, severity of psoriasis, systemic interventions, monitoring, adverse events (AEs), and reason for discontinuation. Results:For 390 children (203 girls and 187 boys; mean [SD] age at diagnosis, 8.4 [3.7] years) with psoriasis who used 1 or more systemic medications, the mean interval between diagnosis and starting systemic therapy was 3.0 years. Methotrexate was used by 270 patients (69.2%), biologic agents (primarily etanercept) by 106 (27.2%), acitretin by 57 (14.6%), cyclosporine by 30 (7.7%), fumaric acid esters by 19 (4.9%), and more than 1 medication was used by 73 (18.7%). Of 270 children taking methotrexate, 130 (48.1%) reported 1 or more AEs associated with methotrexate, primarily gastrointestinal (67 [24.8%]). Folic acid 6 days per week (odds ratio, 0.16; 95% CI, 0.06-0.41; P?<?.001) or 7 days per week (OR, 0.21; 95% CI, 0.08-0.58; P?=?.003) protected against gastrointestinal AEs more than once-weekly folic acid, regardless of the total weekly dosage. Methotrexate-associated hepatic transaminase elevations were associated with obesity (35 of 270 patients [13.0%]), but a folic acid regimen was not. Injection site reactions occurred in 20 of 106 patients (18.9%) treated with tumor necrosis factor inhibitors, but did not lead to discontinuation of treatment. Having 1 or more AEs related to medication, gastrointestinal AE, laboratory abnormality, or AE leading to discontinuation of the drug was more likely with methotrexate than tumor necrosis factor inhibitors, but having 1 or more infections related to medication (predominantly upper airway) was less likely. Six patients developed a serious treatment-related AE (methotrexate, 3; fumaric acid esters, 2; and adalimumab, 1), but methotrexate and biologic agents were taken for a mean duration that was 2-fold greater than the mean duration for cyclosporine or fumaric acid esters. No patient developed tuberculosis or a malignant neoplasm. Conclusions and Relevance:Medication-related AEs occur less often with tumor necrosis factor inhibitors than with methotrexate. Folic acid administration 6 or 7 times per week protected more against methotrexate-induced gastrointestinal AEs than did weekly administration. A prospective registry is needed to track the long-term risks of systemic agents for pediatric psoriasis.

Project description:BackgroundThe role of interleukin-12 (IL-12), interleukin-23 (IL-23), and interleukin-17 (IL-17) has been recognized in psoriasis pathogenesis, and new drugs targeting this axis have already been developed which may provide a new therapeutic approach for patients with moderate to severe psoriasis.ObjectiveTo compare the direct and indirect evidences of the efficacy and safety of brodalumab, secukinumab, ixekizumab, ustekinumab, guselkumab, tildrakizumab, and risankizumab in the short-term treatment of moderate to severe plaque psoriasis using network meta-analysis (NMA).MethodsA comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials for the available relevant studies. NMA was conducted by Stata 15.0 software using relative risks (RR) with 95% confidence interval to assess the clinical effectiveness and safety. Ranked the efficacy and safety for each drug accordance with the surface under the cumulative ranking curve (SUCRA).ResultsThis meta-analysis included 28 studies. All the interventions performed better than placebo in short-term achievement. Based on the result of SUCRA, ixekizumab 80 mg every 2 weeks ranked the highest in short-term achievement of PASI 75 (SUCRA = 93.0%). Brodalumab 210 mg ranked the highest in short-term achievement of PASI 100 (SUCRA = 85.0%). Secukinumab 300 mg ranked the highest in short-term achievement of sPGA 0/1 or IGA 0/1 or PGA 0/1 (SUCRA = 98.1%). In terms of having a risk of adverse events, the rates were higher in brodalumab, secukinumab, ixekizumab, and ustekinumab 45 mg compared with placebo. Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of adverse events during short-term treatment (SUCRA = 4.5%). Guselkumab 50 mg ranked the highest in the risk of serious adverse events during short-term treatment (SUCRA = 25.9%). Ixekizumab 80 mg every 4 weeks ranked the highest in the risk of discontinuations due to adverse events during short-ter treatment (SUCRA = 10.7%).ConclusionsIL-17, IL-12/23, and IL-23 inhibitors had high efficacy in the achievement of PASI 75, PASI 100, and sPGA 0/1 or IGA 0/1 or PGA 0/1 in moderate to severe plaque psoriasis after 12 or 16 weeks of treatment. IL-17 inhibitors showed superior efficacy. However, its clinical safety was poor. Risankizumab appeared to have relatively high efficacy and low risk. The clinical tolerance of other biological agents needs to be further observed.

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Safety of selective IL-23p19 inhibitors for the treatment of psoriasis.

Publications

Safety of selective IL-23p19 inhibitors for the treatment of psoriasis.

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