OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with systemic involvement causing widespread inflammation and tissue damage in affected organs. Limited success of available treatments requires novel therapies to address the high unmet need. This research aimed to identify efficacy and safety endpoints from RCTs assessing treatments for SLE. METHODS: A SLR was conducted according to standard guidelines, including RCTs assessing treatments of SLE published in PubMed, Embase, and Cochrane (1999–2019). Outcomes of interest included any efficacy and safety endpoints. RESULTS: Of 14,083 initial hits, 54 publications were included. Among these, 46 reported efficacy outcomes, 42 described safety outcomes. Belimumab and anifrolumab were analyzed in 8 and 3 studies, respectively. Nine other investigational agents were tested in 2 respective studies. Mean patient age ranged 18.5–55.3 years; 93.1% were female. Mean disease duration from first diagnosis to RCT enrollment was 8.0 years. The most frequently reported efficacy endpoints were SLE responder index (SRI-4) (18/54), change in corticosteroid use (18/54), change in British Isles Lupus Assessment Group (BILAG) index (14/54), occurrence of flares (12/54) and BILAG-based Combined Lupus Assessment (BICLA) (10/54). The average difference in SRI-4 and BICLA between active interventions against placebo was 15% and 11% at Week 24 and 9% and 14% at Week 52, respectively. The rates of serious adverse events ranged 0%–40% across treatment arms. Death occurred in 15 RCTs (0.3%–11% for active treatments, ≤2% for placebo). CONCLUSIONS: This research revealed a high heterogeneity of study designs, population baseline characteristics and endpoint selection across RCTs in SLE. Efficacy levels of SLE treatments vary depending on the endpoint used, with overall high placebo rates observed. The revealed methodological challenges need to be addressed for indirect treatment comparisons to be able to inform formal value assessments of therapies aiming to improve the currently limited treatment success in SLE.