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Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease, which involves the production of class-switched autoantibodies against intracellular antigens, particularly nuclear antigens, leading to tissue damage and immune complex deposition in multiple organs. Strategies for B cell modulation include direct depletion using monoclonal antibodies, such as rituximab, or indirect impairment of survival via targeting B cell activating factors, notably belimumab. While the pursuit of autoreactive B cell modulation has yielded progress, challenges persist, including modest therapeutic responses, allergic reactions and infections. Thus, to overcome these challenges and focus on achieving a more effective B cell depletion, new strategies may involve fully humanized monoclonal antibodies, such as obinutuzumab, which demonstrated promising results in the NOBILITY study, involving patients with lupus nephritis, Another approach is the use of  chimeric antigen receptor T cells therapy, a strategy that has been approved for the treatment of patients with relapsed or refractory B-cell malignancies and has been shown in lupus patients to lead to a rapid and sustained breakdown of the B cell-mediated autoimmune response, reported to lead  to drug-free remission of refractory SLE. In addition, combinations of existing therapies and innovative cellular approaches, such rituximab plus belimumab, have been studied. There have now been four studies describing the use of a rituximab plus belimumab in lupus nephritis and non-renal lupus. In the BEAT-LUPUS, the primary endpoint (reduction in anti-double strand DNA) was achieved, however, in BLISS-BELIEVE study the primary endpoint (Systemic Lupus Erythematosus Disease Activity Index 2000) was not met. The CALIBRATE trial was a safety study. The SynBioSe 1 study demonstrated clinical improvement, as indicated by the Systemic Lupus Erythematosus Disease Activity Index and Lupus Low Disease Activity State indices.

This review will provide a brief review of the established conventional approaches to B cell depletion and then discuss the trends towards innovative concepts aimed at achieving this goal.