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Comparative Safety of Common Immunosuppressant Therapies in Systemic Lupus Erythematosus: A Target Trial Emulation
Alí Duarte-García1,2, Marlon J Sandino-Bermúdez1, Mariana González-Treviño1
1Division of Rheumatology, Mayo Clinic, Rochester, Minnesota.
Objective:
The aim of this study was to compare infection-related hospitalization risk among patients with nonrenal systemic lupus erythematosus 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 (MPAAs) 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% confidence interval [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 MPAAs. In ITT analyses, MPAAs had higher risk than belimumab (hazard ratio [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 MPAAs (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.
Conclusion:
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 postbaseline glucocorticoid use may reflect both evolving disease activity and a pathway through which therapies influence infection risk.