Comparative Safety of Common Immunosuppressant Therapies in Systemic Lupus Erythematosus: A Target Trial Emulation Study

OBJECTIVE: Compare infection-related hospitalization risk among patients with non-renal SLE initiating commonly used immunosuppressants. METHODS: We emulated a target trial using Optum Labs Data Warehouse claims to compare the risk of infection-related hospitalization among patients initiating azathioprine, belimumab, methotrexate, or mycophenolic acid analogues (MPAA) between March 2011 and September 2023. We excluded patients with prior lupus nephritis, solid-organ or bone marrow transplantation, or rituximab/cyclophosphamide exposure. The primary outcome was time to first infection-related hospitalization, using intention-to-treat (ITT) and per-protocol (PP) analyses. We applied inverse probability of treatment weighting to account for baseline covariates and fitted marginal structural Cox models incorporating time-varying monthly glucocorticoid dose during follow-up. RESULTS: Among 6,168 patients, 24-month cumulative incidence of infection-related hospitalization was 10% (95%CI 8-12) for azathioprine, 8% (95%CI 5-10) for belimumab, 10% (95%CI 8-11) for methotrexate, and 13% (95%CI 10-15) for MPAA. In ITT analyses, MPAA had higher risk than belimumab (HR 1.55; 95%CI 1.07-2.25) and methotrexate (HR 1.32; 95%CI 1.04-1.68). In PP analyses, azathioprine (HR 2.04; 95%CI 1.01-4.16) and MPAA (HR 2.27; 95%CI 1.11-4.62) had higher risk compared with belimumab. After accounting for time-varying monthly glucocorticoid dose, between-treatment differences were no longer significant. CONCLUSIONS: Initial differences in the infection-related hospitalization risk were attenuated after accounting for time-varying glucocorticoid exposure. These findings highlight glucocorticoid exposure as an important factor associated with serious infection risk, while recognizing that post-baseline glucocorticoid use may reflect both evolving disease activity and a pathway through which therapies influence infection risk.