Adverse Events Associated With Anti-IL-23 Agents: Clinical Evidence and Possible Mechanisms

Abstract

Background: Anti-interleukin (IL)-23 agents are widely used for autoimmune disease treatment; however, the safety and risks of specific symptoms have not been systematically assessed.

Objectives: The aim of this study was to summarize the characteristics and mechanisms of occurrence of five immunological and non-immunological adverse events caused by different anti-IL-23 agents.

Methods: The Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched for eligible randomized clinical trials published from inception through May 1, 2020. Randomized clinical trials that reported at least one type of adverse event after treatment were included, regardless of sex, age, ethnicity, and diagnosis. Two investigators independently screened and extracted the characteristics of the studies, participants, drugs, and adverse event types. The Cochrane Handbook was used to assess the methodological quality of the included randomized clinical trials. Heterogeneity was assessed using the I² statistic. Meta-regression was applied to determine the sources of heterogeneity, and subgroup analysis was used to identify the factors contributing to adverse events.

Results: Forty-eight studies were included in the meta-analysis, comprising 25,624 patients treated with anti-IL-23 agents. Serious immunological or non-immunological adverse events were rare. Anti-IL-12/23-p40 agents appeared to cause adverse events more easily than anti-IL-23-p19 agents. The incidence of cancer did not appear to be related to anti-IL-23 agent treatment, and long-term medication could lead to mental diseases. The prevention of complications should be carefully monitored when administered for over approximately 40 weeks to avoid further adverse reactions, and the incidence of infection was the highest among general immunological adverse events.

Conclusions: The application of anti-IL-23 agents induced a series of immunological and non-immunological adverse events, but these agents tend to be well-tolerated with good safety profiles.

Keywords: adverse events; anti-IL-23; biologics; meta-analysis; systematic review.

Figure 1

(A) Box diagram for subgroup analysis. Box diagram for the incidence of changes in adverse events with different medication courses. (B) Heat map of different types of symptoms caused by different drugs. Red areas indicate greater relative probability of occurrence and lighter colored areas indicate a slight or null relative probability of occurrence. All data included in the heat map are statistically significant (P < 0.05).

Figure 2

Schematic of the induction and effects of IL-23 subunits and their corresponding receptors and signaling molecules. IL-23 is an essential factor required for the expansion of naive CD4⁺ T lymphocyte populations. The functional IL-23 receptors include IL-12Rβ1 and IL-23R. The downstream signaling molecule of IL-23R is STAT3, which drives T_H17 and T_H22 responses. The downstream signaling molecule of IL-12Rβ1 is STAT4, which drives the T_H1 response. Under stimulation with different cell factor combinations, naive CD4⁺ cells differentiate into T helper (T_H1, T_H17, and T_H22) cells to produce corresponding inflammatory factors and execute their functional activities. Inhibiting the upstream subunits (IL-12Rβ1 or IL-23R) can govern both upstream and downstream processes in the cascade to improve clinical symptoms. IFN, interferon; IL, interleukin; STAT, signal transducer and activator of transcription; T_H, T helper; TGF, transforming growth factor; TNF, tumor necrosis factor.