Cell immunotherapy in autoimmune rheumatic diseases: a paradigm shift in the therapy of autoimmune inflammatory...

Autoimmune inflammatory rheumatic diseases (AIRDs) remain a major cause of chronic morbidity worldwide despite substantial advances in biologic and targeted synthetic disease-modifying antirheumatic drugs. A considerable proportion of patients experience inadequate disease control, intolerance, or primary nonresponse, highlighting the need for fundamentally different therapeutic strategies. Cell-based immunotherapies represent a paradigm shift, aiming not merely to suppress inflammation but to re-establish immune tolerance and restore physiological immune homeostasis. Mesenchymal stem cell (MSC) therapy, regulatory T cell (Treg) immunotherapy, chimeric antigen receptor (CAR)-T cell therapy, and emerging exosome-based approaches are at the forefront of this transformation. MSCs exert broad immunomodulatory, anti-inflammatory, and reparative effects through coordinated actions on innate and adaptive immune cells, paracrine signalling, extracellular vesicles, and metabolic and epigenetic reprogramming. Early-phase clinical studies in refractory rheumatoid arthritis and systemic lupus erythematosus demonstrate clinically meaningful improvements with acceptable short-term safety, although heterogeneity in cell sources, manufacturing, and treatment protocols remains a key limitation. Treg-based therapies seek to correct defective immune tolerance by restoring regulatory cell number and function, offering the potential for durable disease control but currently constrained by cost, technical complexity, and safety considerations. CAR-T cell therapy, initially developed for haematological malignancies, has shown unprecedented efficacy in selected refractory autoimmune diseases by selectively depleting pathogenic immune cell populations, with reports of sustained, and in some cases drug-free, remission. Exosome-based therapies provide a promising cell-free alternative, potentially improving safety, scalability, and standardisation. Optimal patient selection, early intervention, and long-term safety will be critical determinants of success. Cell immunotherapy has the potential to redefine AIRD management, shifting from chronic immunosuppression toward sustained remission and possible cure.