The why, what, who and when of B cell depletion in systemic lupus erythematosus: Biological rationale, patient stratification and evolving therapeutic modalities.

Systemic lupus erythematosus (SLE) is driven by interconnected immune circuits in which B cells function as antigen-presenting cells, cytokine producers and precursors of autoantibody-secreting plasma cells. Therapeutic targeting of B cells aims to disrupt these self-reinforcing circuits rather than simply reduce autoantibody titres alone. Clinical experience with anti-CD20 monoclonal antibodies has validated B cells as therapeutic targets, while exposing key biological constraints, including incomplete tissue depletion, persistence of long-lived plasma cells, and BAFF-driven B cell repopulation. Recent advances including next-generation anti-CD20 monoclonal antibodies, bispecific T cell engagers, and chimeric antigen receptor (CAR) T cell therapies have shown promise but questions remain relating to which patients should be treated with what modality of therapy and when this should be timed within the disease course. Herein, we evaluate the current landscape of B cell targeting therapies with particular focus on patient selection, timing of therapy and type of treatment.