Revisiting B-cell targeted therapies in rheumatoid arthritis: from paradoxical biology to deep immune reset

Targeted B-cell depletion via the anti-CD20 monoclonal antibody rituximab fundamentally altered the therapeutic algorithm for rheumatoid arthritis (RA). Despite its clinical entrenchment, approximately 40% of patients exhibit primary or secondary non-response, exposing critical limitations in conventional depletion strategies. This review critically deconstructs the mechanisms dictating therapeutic resistance and re-evaluates B-cell pathobiology through high-resolution transcriptomic and clinical cohort data. We challenge the monolithic perception of B-cell pathogenicity by detailing the emergence of protective, tolerogenic anti-citrullinated protein antibody (ACPA) clones (e.g., mC03, tACPA) and regulatory B cell (Breg) networks that actively suppress Th17 proliferation and Neutrophil Extracellular Trap (NET) formation. Mechanistic failure of rituximab is subsequently mapped to three biological evasions: the survival of CD20-negative plasmablasts within fortified synovial niches, the temporal-spatial persistence of highly mutated B-cell receptor (BCR) clonotypes, and the inadvertent eradication of IL-10/Granzyme B-producing Bregs, precipitating inflammatory rebound. Translating these molecular insights into clinical practice, we analyze the updated EULAR and ACR guidelines, defining the precise positioning of rituximab in high-risk patient strata, specifically those burdened with interstitial lung disease (RA-ILD) or recent malignancies. Finally, we evaluate the paradigm-shifting transition from superficial peripheral depletion to the "deep immune reset" orchestrated by CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy. Early clinical data validate that CAR-T cells actively penetrate solid tissues, collapse the follicular dendritic cell network, and eradicate long-lived autoreactive memory compartments, offering a tangible trajectory toward drug-free remission in multidrug-refractory RA.