Cryptococcosis After Initiation of Janus Kinase Inhibitors or Biologic DMARDs in Rheumatoid Arthritis: Three Pairwise Active-Comparator Analyses of Propensity Score-Matched TriNetX Cohorts, 2005–2025

Background/Objectives: Comparative safety evidence for cryptococcosis during advanced rheumatoid arthritis (RA) therapy is limited. We compared newly recorded cryptococcosis after initiation of Janus kinase inhibitors (JAKi), tumor necrosis factor (TNF) inhibitors (TNFi), and non-TNF biologic disease-modifying antirheumatic drugs (non-TNF bDMARDs). Methods: Three retrospective active-comparator analyses were conducted in the TriNetX Global Collaborative Network: JAKi versus TNFi, JAKi versus non-TNF bDMARDs, and TNFi versus non-TNF bDMARDs. After 1:1 propensity score matching, outcomes from day 1 to 10 years after initiation, capped at 30 June 2025, were analyzed using Cox proportional hazards models. E-values assessed sensitivity to unmeasured confounding. Results: Matched cohorts included 27,833, 32,440, and 37,351 patients per group, respectively; all absolute standardized mean differences were <0.10. Events occurred in 20 JAKi and 12 TNFi initiators (hazard ratio [HR], 2.20; 95% confidence interval [CI], 1.06–4.54) and in 22 JAKi and 13 non-TNF bDMARD initiators (HR, 2.15; 95% CI, 1.07–4.31). In the secondary comparison, 17 TNFi and 19 non-TNF bDMARD initiators had events (HR, 0.83; 95% CI, 0.43–1.60). Point-estimate E-values for the JAKi comparisons were 3.82 and 3.72; CI-limit E-values were 1.31 and 1.34. Conclusions: JAKi initiation was associated with an approximately twofold higher hazard of newly recorded cryptococcosis than either biologic comparator, while estimated 10-year cumulative event probabilities were below 0.2% in all groups. The separately selected and matched populations do not support an indirect ranking of treatment classes. Low event counts, wide CIs, possible outcome misclassification, fixed exposure classification, and residual confounding preclude causal conclusions. The findings require independent confirmation.