CAR T-cell therapy induces remission in multiorgan IgG4-related disease with hepatobiliary involvement.

IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder in which IgG4+ B cells and T cells interact to drive chronic organ inflammation. Patients with multiorgan involvement may become refractory to standard therapy, resulting in progressive organ damage and risk of organ failure. Here, we report a patient with treatment-refractory multiorgan IgG4-RD treated with CD19-directed chimeric antigen receptor (CAR) T cells and describe the clinical and immunologic effects over more than 12 months of follow-up. A 60-year-old man with IgG4-RD involving the pancreas, hepatobiliary tract, and lungs, who was refractory to long-term immunosuppression, received autologous CD19-directed CAR T cells. Disease course was monitored longitudinally and multimodal immune profiling was performed on peripheral blood. CAR T cell therapy was well tolerated, with only grade 1 cytokine release syndrome, no neurotoxicity, and transient cytopenias without infections. Treatment induced B-cell aplasia lasting 6 months, while serum IgG4 levels normalized by month 8 and remained within the reference range thereafter. FAPI (fibroblast activation protein inhibitor) PET/CT demonstrated regression of fibroinflammatory activity, accompanied by improved lung function and quality of life. Immunosuppressive therapy was completely discontinued without disease flares for more than 12 months. B cell reconstitution consisted predominantly of naïve and transitional subsets. This was paralleled by a decline in T follicular helper cells and CD4+ cytotoxic T cells and attenuation of fibro-inflammatory and B cell-mediated signaling networks on interactome analyses. In this treatment-refractory case of multiorgan IgG4-RD, CD19-directed CAR T cell therapy induced durable, treatment-free remission with normalization of serum IgG4 and improvement across multiple clinical endpoints. Multimodal immune profiling indicates that CAR T cells can reset the B cell compartment and dampen pathogenic T cell and stromal interactions, supporting prospective evaluation of CAR T cell therapy in IgG4-RD.