Summarize: ABSTRACT Objective To generate comparative efficacy evidence of belimumab versus anifrolumab in SLE that can inform treatment practices. Methods The SLE Responder Index (SRI)- 4 response at 52 weeks of belimumab versus anifrolumab was evaluated with an indirect treatment comparison. The evidence base consisted of randomised trials that were compiled through a systemic literature review. A feasibility assessment was performed to comprehensively compare the eligible trials and to determine the most appropriate indirect treatment comparison analysis method. A multilevel network meta- regression (ML- NMR) was implemented that adjusted for differences across trials in four baseline characteristics: SLE Disease Activity Index- 2K, anti–double- stranded DNA antibody positive, low complement (C)3 and low C4. Additional analyses were conducted to explore if the results were robust to different sets of baseline characteristics included for adjustment, alternative adjustment methods and changes to the trials included in the evidence base. Results The ML- NMR included eight trials: five belimumab trials (BLISS- 52, BLISS- 76, NEA, BLISS- SC, EMBRACE) and three anifrolumab trials (MUSE, TULIP- 1, TULIP- 2). Belimumab and anifrolumab were comparable in terms of SRI- 4 response (OR (95% credible interval), 1.04 (0.74–1.45)), with the direction of the point estimate slightly favouring belimumab. Belimumab had a 0.58 probability of being the more effective treatment. The results were highly consistent across all analysis scenarios. Conclusions Our results suggest that the SRI- 4 response of belimumab and anifrolumab are similar at 52 weeks in the general SLE population, but the level of uncertainty around the point estimate means we cannot rule out the possibility of a clinically meaningful benefit for either treatment. It remains to be seen if specific groups of patients could derive a greater benefit from anifrolumab or from belimumab, and there is certainly an unmet need to identify robust predictors towards more personalised selection of available biological agents in SLE. INTRODUCTION SLE is characterised by chronic inflammation leading to significant morbidity and mortality.1 Treatment of SLE aims to minimise disease activity, decrease the incidence of disease flares and prevent organ damage.2 Conventional treatment options include antimalarials, glucocorticoids and immunosuppressive agents.2 3 Although such treatments can be initially successful, patients often require WHAT IS ALREADY KNOWN ON THIS TOPIC ⇒Belimuma