AB0068 NOVEL ANTI-ANGIOGENIC EFFECTS OF TOFACITINIB IN FIBROBLAST-LIKE SYNOVIOCYTES DERIVED FROM PATIENTS WITH RA

Background: Angiogenesis, which is the growth of new capillaries from pre-existing blood vessels, is an essential pathological feature of rheumatoid arthritis (RA). Gliostatin (GLS) is known to have angiogenic activity and thymidine phosphorylase activity. We have previously demonstrated that the production of GLS was enhanced by TNF-α and GLS induced vascular endothelial growth factor (VEGF) expression in fibroblast-like synoviocytes derived from patients with RA (RA-FLSs) [1]. The JAK/STAT signaling pathways mediate the effects of many cytokines and growth factors related RA. Tofacitinib is a novel oral JAK inhibitor and it has demonstrated high efficacy in RA, even in non-responder to anti-TNF treatment [2]. However it have been reported that RA-FLSs with the treatment of tofacitinib suppress the production of chemokines, IL-6 and granulocyte colony-stimulating factor [3, 4], the anti-angiogenic effects of tofacitinib remain to been elucidated. Objectives: The purpose of this study was to investigate the suppression of angiogenic factors such as VEGF, tenascin-C (TNC) and GLS in RA-FLSs treated with tofacitinib. Methods: RA-FLSs were stimulated by TNF-α with or without pre-treatment of tofacitinib. The expression levels of VEGF, TNC and GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Results: In cultured RA-FLSs, VEGF, TNC and GLS were significantly induced by stimulation with TNF-α alone and these inductions were significantly suppressed by treatment of tofacitinib in a dose-dependent manner. Conclusion: These findings indicate tofacitinib inhibits the VEGF, TNC and GLS production through blockade of a JAK/STAT pathway. Tofacitinib may extinguish inflammatory synovitis through preventing excessive angiogenic factors in RA-FLSs. References [1] Tanikawa T, et al. Gliostatin/thymidine phosphorylase-regulated vascular endothelial growth-factor production in human fibroblast-like synoviocytes. Rheumatol Int2007; 27:553-559. [2] Kawaguchi Y, et al. The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes. Clin Exp Rheumatol2018;36:559-567. [3] Migita K, et al. CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. Arthritis Res Ther2011;13:R72. [4] Rosengren S, et al. The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis2012;71:440-447. Acknowledgement: This research was supported by Grand-in-Aid for Scientific Research (C) (26462309) and 16K10913 from the Japan Society for the Promotion of Science. Disclosure of Interests: None declared