Predicting prevalence and severity of cytokine release syndrome after CAR T-cell therapy in patients with autoimmune disease: a retrospective cohort study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells are highly effective in depleting B cells and are therefore being tested for their safety and efficacy in autoimmune diseases. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are potential toxic effects of CAR T-cell therapy. We aimed to identify biomarkers predicting incidence and severity of CRS in CAR T-cell treated patients with autoimmune diseases. METHODS: This retrospective cohort study included patients with autoimmune diseases treated with autologous CAR T-cell therapy from six centres in Germany and one centre in China. Demographic and disease-specific characteristics were recorded. Patients from Germany were treated with CD19 targeting CAR T cells. Patients from China were treated with either dual target CD19-BCMA CAR T cells or co-infused with CD19 CAR T cells and BCMA CAR T cells. Baseline biomarkers (B-cell counts and concentrations of IL-6, C-reactive protein [CRP], and ferritin) were recorded at the eligibility assessment visit before study entry or named patient programme use. IL-6 was measured by ELISA. The primary outcomes were the occurrence of CRS and ICANS. The severity of CRS and ICANS was classified using the American Society for Transplantation and Cellular Therapy criteria. Multivariable logistic regression was used to define factors associated with CRS occurrence. There was no involvement of people with lived experience in study design. FINDINGS: Between March 1, 2021, and July 1, 2025, we included 108 patients with autoimmune diseases who received autologous CAR T-cell therapy. The median age at administration was 34 years (IQR 27-44). 76 (70%) of 108 patients were women and 32 (30%) were men. 86 (80%) of 108 patients developed CRS after CAR T-cell therapy (grade one in 71 [66%] patients, grade two in 14 [13%] patients, and grade three in one [1%] patient). ICANS occurred in three (3%) patients (grade one in two [2%] patients and grade two in one [1%] patient). Patients who developed CRS had significantly higher baseline B-cell counts (43 cells per μL [IQR 10-108] vs 6 cells per μL [0-18]; p=0·0002), IL-6 concentrations (10 pg/ml [IQR 4-62] vs 3 pg/ml [2-6]; p=0·0003), and CRP concentrations (5 mg/L [IQR 2-14] vs 3mg/L [1-5]; p=0·042) compared with patients without CRS. Multivariable logistic regression confirmed the association between CRS, B-cell counts (OR 1·31 [95% CI 1·06-1·67]; p=0·012) and IL-6 concentrations (OR 2·28 [95% CI 1·30-4·65]; p=0·0001). INTERPRETATION: Higher baseline B-cell counts and systemic inflammation are associated with the development of CRS after CAR T-cell therapy in patients with autoimmune diseases. These data might help to identify patients with autoimmune disease that are at higher risk of developing CRS after CAR T-cell therapy. FUNDING: Deutsche Forschungsgemeinschaft, Collaborative Research Centers, Clinician Scientist Program NOTICE.