Pos0608 targeting the jak/stat pathway in myositis inhibits b cell proliferation, differentiation and antibody production

Background Idiopathic inflammatory myopathies (IIM) or myositis are characterized as inflammatory, autoimmune disorders with a wide spectrum of symptoms and affected tissues. The presence of circulating autoantibodies and B-lineage cells in affected tissues, point towards an essential role of B cells in the pathogenesis of IIM. This sparked interest in the B cell depleting anti-CD20 antibody rituximab as a new treatment opportunity in IIM. However, despite its beneficial effects, rituximab results in long-term B cell depletion and does not target CD20-negative, long-lived plasma cells, which may maintain the autoimmune response. Hence, further research aimed at more specific and reversible therapies targeting B and plasma cells is warranted. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signalling pathway is essential for several aspects of B cell biology, making it an attractive novel target for patients with IIM. Objectives To study whether targeting the JAK-STAT signalling pathway using tofacitinib, a small molecule inhibitor specific for JAK1/JAK3, impairs essential functions of B cells isolated from patients with IIM. Methods B lineage cell phenotyping was performed by flow cytometry, using PBMCs obtained from 3 IIM phenotypes (dermatomyositis, overlap-myositis, anti-synthetase syndrome) and healthy donors (HD). Functional assays were performed culturing PBMCs in the presence of tofacitinib, and the stimuli IL-21/anti-CD40 or IL-2/CpG to activate JAK/STAT signalling in a T cell-independent or T cell-dependent manner, respectively. After a 6-day culture, the effects of tofacitinib on B cell proliferation, differentiation, and antibody production were assessed by flow cytometry and ELISA. Results Peripheral blood B cell composition from patients with IIM showed reduced fractions of memory B cells, and an increase in transitional and naive B cells in comparison to HD reference values. Targeting JAK/STAT signalling using tofacitinib significantly reduced IL-21/anti-CD40 induced B cell proliferation, plasmablast differentiation and antibody production in B cells of patients with IIM and HD. However, this effect was observed to a lesser extent upon stimulation with IL-2/CpG. Interestingly, tofacitinib exerted its effects irrespective of the IIM phenotype. Conclusion Our data demonstrate that the composition of the peripheral B cell compartment in IIM patients is altered. Furthermore, tofacitinib treatment in vitro results in the inhibition of functional B cell responses, including proliferation, plasmablast differentiation, and antibody production, which was irrespective of the clinical phenotype. Consequently, targeting of JAK/STAT signalling may represent a novel treatment modality in myositis. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared.