Anifrolumab Versus Belimumab for Cardiovascular Disease Risk in Systemic Lupus Erythematosus.

OBJECTIVE:Current guidelines recommend anifrolumab and belimumab as comparably viable immunosuppressive therapies for active systemic lupus erythematosus (SLE), yet comparative evidence remains limited. Patients with SLE have increased cardiovascular disease (CVD) risk, with dysregulated type I interferon (IFN-I) signaling implicated in disease pathogenesis. We evaluated whether anifrolumab, an IFN-I receptor antagonist, or belimumab confers differing CVD risks to inform treatment selection and patient counseling. METHODS:We conducted an emulated target trial using electronic health record data from 67 health care organizations in the TriNetX network (2020-2025). Adults with SLE initiating anifrolumab or belimumab without prior CVD were included. Propensity score matching balanced demographics, comorbidities, laboratory data, and medication use. Outcomes included three-year risks of myocardial infarction (MI), heart failure (HF), ischemic stroke, and major adverse cardiovascular events (MACEs). Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS:Before matching, 1,091 patients received anifrolumab and 7,492 received belimumab (mean ages 45.6 and 43.7 years, respectively). After matching, the cohort included 1,084 pairs with mean ages of 45.6 and 46.0 years, respectively. Compared with belimumab, anifrolumab treatment was associated with lower risks of MI (HR 0.63; 95% CI 0.40-0.91), HF (0.55; 0.39-0.75), ischemic stroke (0.50; 0.26-0.94), and MACE (0.65; 0.37-0.89). CONCLUSION:Anifrolumab treatment was associated with lower CVD risk compared with belimumab in patients with SLE, supporting its consideration as a safe therapeutic option, particularly for populations with increased CVD risk. Prospective studies are needed to firmly establish causality.