Background/Purpose: Belimumab is a monoclonal antibody targeting B-lymphocyte stimulator (BLyS) used in the treatment of active systemic lupus erythematosus (SLE). Our objective was to investigate the comparative risk of all-cause mortality with belimumab use versus oral immunosuppressants (azathioprine, methotrexate or mycophenolate) for the treatment of non-renal SLE.

Methods: We performed a target trial emulation study of adult patients with SLE (defined as ≥2 ICD codes ≥2 months and ≤2 years apart) but without lupus nephritis who initiated belimumab, azathioprine, methotrexate, or mycophenolate using observational data from a U.S. multi-center electronic health record database (TriNetX) between 2011-2021. We evaluated the comparative risk of all-cause mortality with belimumab versus each of three oral immunosuppressants (azathioprine, methotrexate, or mycophenolate) for the treatment of SLE. In each comparison, we excluded patients who had previously used belimumab or the comparator oral immunosuppressant. Patients were followed until the earliest of the event (death), 5-year follow-up, or the end of the study period. We estimated the cumulative incidence and hazard ratios (HRs) of all-cause mortality comparing belimumab to each oral immunosuppressant. Propensity score overlap weighting was used to balance baseline covariates (including age, sex, race/ethnicity, geographic region, year of initiation, use of concomitant SLE medications [other oral immunosuppressants, glucocorticoids, hydroxychloroquine, rituximab, cyclophosphamide], Charlson comorbidity index, SLE severity index, chronic kidney disease, healthcare utilization, and prior infection history). In a primary per-protocol analysis, we adjusted for adherence to treatment strategy using inverse probability of treatment weighting.

Results: We identified 21,481 patients with non-renal SLE who met eligibility criteria (Figure 1). In these three hypothetical target trials, we compared 1) initiators of belimumab (n=2841) and azathioprine (n=6343), 2) initiators of belimumab (n=2642) and methotrexate (n=8242), and 3) initiators of belimumab (n=2813) and mycophenolate (n=8407). After propensity score overlap weighting, all covariates were balanced in each comparison group, with mean age 45 years and 94% females (Table 1). In the per-protocol analysis, belimumab was associated with a lower risk of all-cause mortality compared to azathioprine (HR 0.45 [95% CI 0.26-0.8]) and mycophenolate (HR 0.46 [95% CI 0.27–0.79]) (Table 2). In the intention-to-treat analysis, belimumab was associated with a lower risk of all-cause mortality compared to all three oral immunosuppressants: belimumab vs. azathioprine (HR 0.40 [95% CI 0.25-0.63]), belimumab vs. methotrexate (HR 0.61 [95% CI 0.38-0.96]), and belimumab vs. mycophenolate (HR 0.47 [95% CI 0.31–0.73]).

Conclusion: Belimumab use was associated with reduced all-cause mortality compared with oral immunosuppressants in this large cohort of patients using rigorous propensity score overlap weighting to emulate a target trial. These findings suggest that targeted immunomodulatory therapy with BLyS inhibitors in SLE has favorable outcomes.

Figure 1. Flow of Patients into the Study

Table 1. Baseline Characteristics of Belimumab and Azathioprine Initiators with Non-Renal Systemic Lupus Erythematosus

Table 2. Comparative Risk of All-Cause Mortality with Belimumab versus Oral Immunosuppressant use in Non-Renal Systemic Lupus Erythematosus

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/comparative-risk-of-all-cause-mortality-with-belimumab-versus-oral-immunosuppressant-use-in-patients-with-non-renal-systemic-lupus-erythematosus/