P119 The effect of the Janus kinase-1 inhibitor filgotinib in proinflammatory cytokine production by ex-vivo myeloid and synovial derived cells from rheumatoid arthritis patients. Comparison to upadacitinib, tofacitinib and baricitinib

Abstract Background/Aims To compare the ex-vivo effect of the JAK1 inhibitor filgotinib with baricitinib, tofacitinib and upadacitinib on the spontaneous and cytokine-stimulated expression of pro-inflammatory mediators in synovial and peripheral blood cells from patients with Rheumatoid Arthritis (RA) and osteoarthritis (OA). Methods RA synovial membrane cells (SMCs) and fibroblast like synoviocytes (FLS) were isolated from the synovial membranes following arthroplasty using enzymatic digestion and cell propagation. CD14+ monocytes were isolated from PBMCs using microbeads and differentiated to macrophages. FLS and monocyte derived macrophages (MDMs) were stimulated with cytokines with or without one of the four JAK inhibitors. SMCs were cultured in the presence of JAK inhibitors without stimulation. Secreted cytokines were measured by ELISA and MSD. Results Despite similarities in inhibitory characteristics of all tested JAK inhibitors at the concentrations tested, filgotinib had the most consistent inhibitory effect on induction of IL-6, RANTES and MCP-1 in all RA and OA FLS (induced by TNFα, IL-1β and Oncostatin M). Upadacitinib and filgotinib most consistently inhibited spontaneous release by RA SMCs of a wide range of pro-inflammatory cytokines. Tofacitinib, baricitinib and upadacitinib were observed paradoxically to enhance the LPS response in MDMs, whereas filgotinib did not show this effect. Conclusion Our data demonstrates differences between the JAK inhibitors on inhibition of spontaneous proinflammatory cytokine release from RA SMCs and mitogen- and cytokine-induced release from RA and OA FLS. Furthermore, all JAK inhibitors except filgotinib paradoxically enhanced LPS responses in MDMs. Further research will be required to establish any differential benefit:risk clinical correlates in the treatment of RA. Disclosure S. Weston: None. J. MacDonald: None. N. Kang: None. S. Kiriakidis: None. P.C. Taylor: Consultancies; Alfasigma, Gilead, AbbVie, Eli Lilly. Grants/research support; Alfasigma.