Chimeric antigen receptor T-cell therapy for rheumatic diseases: from B-cell depletion to immune reset and beyond

Rheumatic and autoimmune diseases have long relied on glucocorticoids and immunosuppressants for disease control, yet a true cure remains elusive; patients oscillate between remission and relapse and progressively accumulate irreversible organ damage. Chimeric antigen receptor (CAR) T cells targeting CD19 or B-cell maturation antigen (BCMA) achieve deep depletion of pathogenic B-lineage cells, enabling a subset of patients with systemic lupus erythematosus, idiopathic inflammatory myopathy, and systemic sclerosis to attain sustained remission after withdrawal of all immunosuppressants, accompanied by seroconversion of autoantibodies, normalization of complement, and reconstitution of the B-cell pool with a naive phenotype. This phenomenon suggests that, if B-cell depletion can reach the secondary lymphoid organs and inflamed tissues beyond the peripheral blood, it may "reset" the disrupted immune homeostasis rather than merely suppress it transiently. Compared with the oncology setting, the target-cell burden in autoimmune disease is lower, cytokine release syndrome is mostly mild and self-limiting, and neurotoxicity is rare; nevertheless, prolonged B-cell aplasia, hypogammaglobulinemia, and infection risk still require disciplined management, while signals of long-term secondary malignancy await validation through longer follow-up. Next-generation engineering strategies-including CD19/BCMA dual targeting, allogeneic universal products, CAR regulatory T cells (CAR-Treg), and logic gating with safety switches-are broadening indications, lowering costs, and enhancing precision and controllability. This review systematically examines the engineering principles, pharmacodynamics, cross-disease clinical evidence, distinctive safety profile, and frontier advances of CAR-T in rheumatic disease and discusses how this therapy may shift the treatment paradigm from "chronic suppression" toward a "one-time reset", as well as the questions of durability, patient stratification, and health economics that must be answered on the path to a "cure."