IntroductionMany patients with SLE struggle to achieve remission despite therapy with multiple drugs, emphasizing the need for effective treatments to improve symptoms, quality of life, and reduce medication burden. The objective of this review was to evaluate the safety and tolerability of combination rituximab and belimumab therapy in SLE.MethodsA systematic review was conducted in accordance with PRISMA standards. Embase, MEDLINE, and Web of Science were searched through June 2025. Studies evaluating safety and tolerability of combination rituximab and belimumab use in adults with SLE were included. For the purposes of this review, "combination therapy" was defined as administration of 1-2 doses of rituximab then initiation of belimumab ≥2 weeks after the last dose of rituximab. Studies evaluating simultaneous rituximab and belimumab therapy and those with no safety or tolerability data were excluded.ResultsSeven studies, comprised of two randomized controlled trials and five non-randomized trials, were included for a total of 185 unique patients. Commonly reported treatment-emergent adverse events (TEAEs) included infection, arthralgia, myalgia, rash, and hypogammaglobulinemia. Seven patients discontinued treatment due to TEAEs.DiscussionThe results of this review provide insight into TEAEs and tolerability of combination rituximab and belimumab therapy. Adverse effects are common on this treatment, and there is potential for serious adverse events. Many of the TEAEs reported in the included studies are also symptoms of uncontrolled SLE, adverse effects of concomitant immunosuppressive medications, or infections commonly seen amongst SLE patients. Ethical and logistical issues make it difficult to eliminate confounding factors and determine whether these adverse effects are truly due to study treatment. Further investigation is needed to compare efficacy to potential drawbacks of this therapy.ConclusionDue to the prevalence and severity of adverse effects associated with this therapy, more research is needed to determine if it is as safe as existing therapies for SLE.