Targeting pathogenic Th17.1 cells via JAK-STAT3 pathway: A novel approach with tofacitinib for refractory myasthenia gravis.

There remains a critical unmet need for effective, accessible, and well-tolerated therapies for myasthenia gravis (MG) who are refractory to current immunotherapies. The janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a pivotal role in maintaining immune homeostasis by regulating cytokine-mediated responses. However, insights into the involvement of the JAK-STAT signaling in MG pathogenesis are still preliminary. In this study, we observed elevated levels of JAK2 in MG and further assessed the clinical efficacy of the pan-JAK inhibitor, tofacitinib, administered over 24 weeks in a cohort of 19 patients with refractory MG (NCT04431895). Tofacitinib significantly reduces the glucocorticoid dose and improves MG-relevant clinical scores and quality of life. The immunomodulatory effects of tofacitinib were mediated through downregulation of p-STAT3, IL-6, and IL-23, resulting in suppression of pathogenic Th17.1 cells in MG. Collectively, our results suggest that a novel approach to suppress pathogenic Th17.1 cells via the JAK-STAT3 signalling pathway with tofacitinib is effective and well-tolerated for treating patients with refractory MG.