Propensity-Matched Case Control Study of Anti-Interleukin-23 Therapies in Clostridioides difficile Infection

Background Clostridioides difficile infection remains a major cause of infectious morbidity and mortality, largely driven by a dysregulated, toxin-mediated host immune response that current pathogen-targeted therapies fail to address. Interleukin-23-driven Th17 responses and subsequent neutrophil activation play a major role in disease severity and intestinal injury. Observational data suggest that targeting this pathway with anti-IL-23 monoclonal antibodies (therapies already used for inflammatory bowel disease, psoriasis) may significantly reduce mortality in these patients. Methods We conducted a retrospective cohort study of adult patients hospitalized with C. difficile infection using the Epic Cosmos electronic health record database (> 300 million patients across 1,949 healthcare organizations). Propensity score matching (10:1) was used to balance baseline demographic and clinical covariates between patients exposed an available anti-IL-23 monoclonal antibody therapy (ustekinumab, guselkumab, tildrakizumab, risankizumab, mirikizumab) within 90 days prior to diagnosis and unexposed controls. The primary outcome was 30-day all-cause mortality, evaluated using a multivariable Cox proportional hazards regression model, adjusted by ATLAS severity. Results The propensity-matched cohort included 328 index cases of C. difficile infection exposed to anti-IL-23 within 90-days and 3,155 controls. Anti-IL-23 exposure was associated with a significantly reduced hazard of 30-day mortality (HR 0.341, 95% CI 0.121–0.962, P  = 0.042). Heterogeneity of treatment effect analysis revealed a statistically significant positive interaction between baseline ATLAS severity and anti-IL-23 efficacy ( P  = 0.029). No significant difference was observed in 180-day recurrent infection-free survival between groups (HR 0.808, 95% CI 0.514–1.27, P  = 0.355). Conclusions Antecedent anti-IL-23 therapy is associated with a significant reduction in 30-day mortality following C. difficile infection. These findings support the concept that inhibiting IL-23 mediated inflammation alongside standard anti- C. difficile antibiotics may improve outcomes in C. difficile infection. The significant interaction with baseline severity suggests that the clinical utility of this immunomodulatory therapy may lie in high-risk patient phenotypes. Further prospective studies are warranted to confirm these observations and evaluate the clinical role for IL-23 inhibition in C. difficile infection.