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Belimumab (BEL) is a monoclonal antibody that selectively binds to BLyS, a survival factor for B cells, while anifrolumab (ANI) is a monoclonal antibody that binds to the type I interferon (IFN) receptor, thereby inhibiting all type I IFNs.In the 2023 update of the EULAR recommendations for the management of systemic lupus erythematosus (SLE), BEL and ANI were placed at the same level. According to EMA indications, they share identical approvals: both are ‘indicated as add-on therapy’ in patients with ‘active, autoantibody-positive SLE’ who remain symptomatic ‘despite standard therapy.’1 When analyzing the clinical drivers of BEL and ANI treatment, particularly the SLEDAI domains, the subgroups of patients who responded better to BEL and ANI compared to placebo were remarkably similar—primarily involving mucocutaneous and musculoskeletal manifestations. Two post hoc analyses have attempted to identify predictors of response: One, based on the pooled population of the BLISS studies, found that predictors of BEL response included SLEDAI ≥10, positive anti-dsDNA, low C3, low C4, and glucocorticoid use—all markers of high disease activity.2 The other, based on pooled data from TULIP-1 and TULIP-2, found that better responses to ANI were observed in patients with a high IFN signature and those with at least one serological abnormality at baseline.3 Thus, there are currently no definitive evidence-based clinical drivers distinguishing the use of BEL versus ANI. When facing a patient who may require biologic therapy, clinicians must apply a reasoned and individualized approach.We know that both BLyS and type I IFNs are overexpressed in SLE and correlate with disease activity, yet their biological mechanisms differ: BAFF (BLyS) exerts its effects via the BAFF receptor (BAFF-R) on transitional B cells in the bone marrow, blood, and spleen, as well as on follicular and marginal zone B cells. BAFF is involved in the initiation and maintenance of adaptive immune responses, and anti-BAFF therapy helps modulate systemic SLE activity and prevent flares; type I IFNs, on the other hand, act through IFNAR, which is expressed not only on immune cells but also on nearly all cells in the body. As a result, type I IFNs have roles in both innate and adaptive immune responses and can trigger organ-specific effects. Therefore, anti-IFNAR therapy modulates disease activity and may exert organ-specific immunomodulatory effects.Notably, type I IFNs can also induce transcription of pro-inflammatory genes and promote the production of pro-inflammatory cytokines in various tissues. Conversely, studies have shown that patients with subacute or chronic cutaneous lupus often do not respond to B-cell depletion therapies, suggesting that these lesions may not be B-cell dependent.If we compare the key efficacy endpoints of BEL and ANI in their respective Phase 3 RCTs—namely TULIP-1 and TULIP-2 for ANI, and BLISS-52 and BLISS-76 for BEL—we note the following: BEL met its primary endpoint (SRI-4) in the BLISS trials and ANI met its primary endpoint (BICLA) in TULIP-2, but, among secondary endpoints, only ANI (in TULIP-2) significantly reduced daily glucocorticoid dosage and, conversely, only BEL (in BLISS-52 and BLISS-76) significantly reduced flare rates and improved serological markers.4–7 Based on this evidence, we can tentatively suggest the following: BEL may be more suitable for patients withactive mucocutaneous, articular, or renal involvement; active serology (e.g., anti-dsDNA, low complement); relapsing-remitting disease pattern. BEL is generally very safe but should be used with caution in patients with a history of depression. ANI may be more suitable for patients with active mucocutaneous and articular involvement; chronic, persistent inflammation; high type I IFN signatureCaution is warranted in patients at risk for viral infections, and vaccination against herpes zoster and influenza should be considered prior to treatment.Learning Objectives Discuss the different mechanisms of action of belimumab and anifrolumab and their roles in modulating immune pathways in SLEExplain the clinical indications, efficacy data, and trial outcomes (BLISS and TULIP studies) of BEL and ANI in systemic lupus erythematosusApply clinical reasoning to choose between BEL and ANI based on patient phenotype, disease activity, and safety considerationsReferences Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15–29. doi: 10.1136/ard-2023-224762Gatto M, Saccon F, Zen M, et al. Early disease and low baseline damage as predictors of response to belimumab in patients with systemic lupus erythematosus in a real-life setting. Arthritis Rheumatol. 2020;72(8):1314–24. doi: 10.1002/art.41253Gatto M, Zen M, Cruciani C, et al. Navigating the landscape of sle treatment: an expert viewpoint on the rationality and limitations of early biologic intervention. Autoimmun Rev. 2024;23(10):103612. doi: 10.1016/j.autrev.2024.103612Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits blymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63(12):3918–30. doi: 10.1002/art.30613Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377(9767):721–31. doi: 10.1016/s0140-6736(10)61354-2Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1(4):e208–e19. doi: 10.1016/s2665-9913(19)30076-1Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020;382(3):211–21. doi: 10.1056/NEJMoa1912196