RESUMEN
OBJECTIVES: This study aims to evaluate the safety and efficacy of BCMA-CD19 compound chimeric antigen receptor T cells (cCAR) to dual reset the humoral and B cell immune system in patients with systemic lupus erythematosus (SLE) with lupus nephritis (LN). METHODS: This is a single-arm open-label multicentre phase 1 study of BCMA and CD19-directed cCAR in patients suffering from SLE/LN with autoantibodies produced by B cells and plasma/long-lived plasma cells. In this clinical trial, we sequentially assigned biopsy-confirmed (classes III-V) LN patients to receive 3×106 cCAR cells/kg postcessation of all SLE medications and conditioning. The primary endpoint of safety and toxicity was assessed. Complete immune reset was indicated by B cell receptor (BCR) deep sequencing and flow cytometry analysis. Patient 11 (P11) had insufficient lymphocyte counts and was underdosed as compassionate use. RESULTS: P1 and P2 achieved symptom and medication-free remission (MFR) from SLE and complete remission from lymphoma. P3-P13 (excluding P11) received an initial dose of 3×106 cCAR cells /kg and were negative for all autoantibodies, including those derived from long-lived plasma cells, 3 months post-cCAR and the complement returned to normal levels. These patients achieved symptom and MFR with post-cCAR follow-up to 46 months. Complete recovery of B cells was seen in 2-6 months post-cCAR. Mean SLE Disease Activity Index 2000 reduced from 10.6 (baseline) to 2.7 (3 months), and renal function significantly improved in 10 LN patients ≤90 days post-cCAR. cCAR T therapy was well tolerant with mild cytokine-release syndrome. CONCLUSIONS: Data suggest that cCAR therapy was safe and effective in inducing MFR and depleting disease-causing autoantibodies in patients with SLE.
RESUMEN
OBJECTIVES: Overwork has been recognized as a risk factor for cerebrovascular and cardiovascular disease (CCVD). To our best knowledge, Japan is the first country in the world to implement an independent act (the 2014 Act) for the prevention of overwork-related disease, which was promoted through application of preventive measures, such as reductions in working hours. We assessed changes in working hours and overwork-related CCVD before and after introduction of the 2014 Act. METHODS: We calculated the overwork-related CCVD incidence rate and average monthly working hours for 10 industry groups in Japan with data from 2012 to 2018. We applied a causal mediation analysis to estimate the total effect of implementing the 2014 Act on the overwork-related CCVD and the effect mediated by working hours. RESULTS: An average of 271 for every 48 million employees developed overwork-related CCVD per year. After introducing the 2014 Act, the incidence rate ratio of overwork-related CCVD was 0.881-fold lower (95% CI 0.780-0.995) compared with before the policy change. The 2014 Act contributed to a decrease of 26% (78 cases per year; 95% CI 29-173) of the overwork-related CCVD incidence per year. Approximately 41% (32 cases per year) of this effect could be explained by reduced working hours. CONCLUSIONS: Our study highlights the impact of the 2014 Act in Japan on the reduction in working hours, which further contributes to the reduction in overwork-related CCVD. Policymakers should consider adopting our innovative approach to assess the mediation effect underlying the implementation of new policies.