{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:49:02Z","timestamp":1793116142695,"version":"4.5.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 \u201cdeep immune reset\u201d 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1809668","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:32:17Z","timestamp":1777872737000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Revisiting B-cell targeted therapies in rheumatoid arthritis: from paradoxical biology to deep immune reset"],"prefix":"10.3389","volume":"17","author":[{"given":"Min","family":"Huang","sequence":"first","affiliation":[{"name":"Affiliated Calmette Hospital of Kunming Medical University\/Kunming First People\u2019s Hospital","place":["Kunming, 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