CAR-T therapy for autoimmune rheumatic diseases: navigating clinical frontiers between breakthroughs and uncertainties

Chimeric antigen receptor (CAR) T-cell therapy, a transformative breakthrough originally pioneered in oncology, is being successfully repurposed for the treatment of refractory autoimmune rheumatic diseases (ARDs). By enabling profound depletion of pathogenic B cells—a central driver in conditions such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myopathies (IIM)—CAR-T offers a promising therapeutic strategy for patients who have failed conventional therapies. Preliminary clinical evidence from early-phase trials indicates encouraging short-term efficacy across these ARDs. In SLE, treatment with CD19-directed CAR-T has been associated with high rates of lupus low disease activity state and a drug-free remission in a majority of patients. In SSc, CAR-T effectively suppresses inflammatory activity, although established fibrosis often requires continued adjunctive therapy. Promising clinical responses have also been observed in refractory IIM. The short-term safety profile appears favorable, with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome being predominantly low-grade and manageable. Nevertheless, significant challenges remain. Key knowledge gaps include the long-term durability of responses, the patterns and functional competence of B-cell reconstitution, potential risks of secondary malignancies, and the substantial economic burden of current autologous platforms. Future translation efforts should focus on optimizing patient selection, developing next-generation CAR constructs (including allogeneic “off-the-shelf” products), exploring rational combination strategies, and establishing standardized outcome measures through larger prospective studies with extended follow-up. If validated in rigorous clinical development, CAR-T cell therapy may offer a novel and potent treatment option for carefully selected patients with severe, refractory autoimmune rheumatic diseases.