CAR-T as a salvage treatment in polyrefractory rheumatoid arthritis

OBJECTIVES: To evaluate the utility of CD19-directed chimeric antigen receptor T cell (CAR-T) therapy in patients with persistent inflammatory refractory rheumatoid arthritis (PIRRA), who failed ≥5 biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARD) classes. METHODS: Three women with long-standing, seropositive PIRRA received autologous anti-CD19 CAR-T therapy with CD 28 co-stimulation. After lymphodepletion with fludarabine and cyclophosphamide, an infusion of 0.6-1 × 106 CAR-T cells/kg was administered. Clinical, laboratory, imaging and histological outcomes were assessed up to 18 months. RESULTS: Median age was 54 years (range 39-68), and median disease duration was 14 ± 3.1 years. All developed grade 3 cytokine release syndrome (CRS), and one developed grade 4 ICANS. No long-term toxicities were observed, except for hypogammaglobulinemia, that has not required replacement therapy. Within 3 months, two patients achieved remission, and onehad low disease activity. At the last follow-up, two remained in drug-free remission, and one attained low disease activity with abatacept and methotrexate. HAQ-DI scores improved from severe disability to near-normal. RF and ACPA titers markedly declined. Furthermore, imaging demonstrated resolution of synovitis and clearance of CD19+B cells from the synovium establishing histological remission. CONCLUSION: CD19 CAR-T therapy induced profound, durable responses in extremely severe patients with seropositive PIRRA. Despite significant acute toxicities, recovery was complete, and long-term safety was favorable. These findings suggest that CAR-T may provide a transformative benefit in severe RA, warranting controlled clinical trials.