Adverse events associated with IL-23 and IL-12/23 inhibitors in the clinical management of psoriasis: a comprehensive pharmacovigilance analysis

Background: Interleukin-23 (IL-23) inhibitors and the IL-12/23 inhibitor ustekinumab constitute a pivotal class of therapeutic agents employed in the clinical management of Psoriasis, a chronic immune-mediated skin disorder. Notwithstanding their therapeutic efficacy, concerns have arisen due to the emergence of multiple adverse events (AEs) associated with their usage. This study aims to provide a comprehensive examination of the distribution and characteristics of these AEs concerning IL-23 and IL-12/23 inhibitors, with a specific focus on guselkumab, tildrakizumab, risankizumab, and ustekinumab.

Methods: In this research endeavor, we conducted an extensive analysis of data extracted from the FDA Adverse Event Reporting System (FAERS), spanning the timeframe from January 1, 2014, to September 30, 2022. To identify potential signals of AEs, we rigorously applied disproportionality analysis, utilizing both reporting odds ratio (ROR) and information component (IC) metrics. A signal was considered present when the lower limit of the 95% confidence interval (CI) for ROR (ROR025) exceeded one or when IC (IC025) surpassed zero, with a minimum requirement of three or more reported cases.

Results: Our investigation encompassed a substantial dataset, comprising a total of 41,408,408 reports detailing drug-AE associations and involving 13,271,168 individuals. Among these, 704, 13,164, and 11,399 patients were identified as users of the IL-23 inhibitors tildrakizumab, guselkumab, and risankizumab, respectively, while 62,853 patients were identified as users of the IL-12/23 inhibitor ustekinumab. The analysis revealed the presence of 8, 20, 107, and 115 signals for these respective drugs. Significantly, the System Organ Class (SOC) exhibiting the highest incidence was "infections and infestations," with documented occurrences in tildrakizumab (6/8), guselkumab (5/20), ustekinumab (50/107), and risankizumab (25/115).

Conclusion: Our pharmacovigilance analysis has brought to light a substantial frequency of AEs linked to IL-23 and IL-12/23 inhibitors. These findings underscore the pivotal role of IL-23 and IL-12/23 inhibitors in modulating immune function and raise concerns regarding their potential to heighten susceptibility to infections and malignancies. However, limitations inherent to the FAERS database, including underreporting, lack of denominator data, potential duplicate records, and inability to confirm causality, should be acknowledged of particular significance is risankizumab, which, despite having fewer reported cases and a later market introduction compared to ustekinumab, exhibited a higher incidence of AEs. These results emphasize the necessity for ongoing vigilance, further investigation, and a reevaluation of the safety profile of IL-23 and IL-12/23 inhibitors in the clinical management of Psoriasis.