AB0250\u2005TOFACITINIB SUPPRESSES SEVERAL JAK-STAT PATHWAYS IN RHEUMATOID ARTHRITIS AND BASELINE SIGNALING PROFILE ASSOCIATES WITH TREATMENT RESPONSE

Abstract

Cytokines are important mediators of inflammation and tissue destruction in rheumatoid arthritis (RA) 1. Several cytokines involved in RA pathogenesis act through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway 2. The effects of JAK-inhibitor tofacitinib on cytokine signaling in vitro are well established, while in vivo evidence in patients remains scarce.To investigate in vivo in rheumatoid arthritis patients i) which JAK-STAT pathways are inhibited by tofacitinib and ii) if baseline signaling profile is associated with the treatment response.Sixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5\u2009mg twice daily for three months. Levels of basal and cytokine-induced phosphorylated STATs and total STAT1 and STAT3 in peripheral blood monocytes, T cells and B cells were measured by flow cytometry. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response (the change from baseline in disease activity score (DAS28)) was studied by calculating correlation coefficients.Treatment with tofacitinib and csDMARDs decreased median DAS28 from 4.4 to 2.6 (p < 0.001). Tofacitinib significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. Basal STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was downregulated by tofacitinib. No changes were observed in STAT1 and STAT3 protein levels, while gene expression of STAT3, STAT4, STAT5A, JAK1, JAK3 and all studied SOCSs was significantly suppressed. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.Tofacitinib suppresses multiple JAK-STAT pathways in RA patients in vivo. Baseline JAK-STAT signaling profile may be applicable as a prognostic marker for treatment response to tofacitinib.[1]McInnes, I. B., Buckley, C. D. & Isaacs, J. D. Cytokines in rheumatoid arthritis-shaping the immunological landscape. Nature Reviews Rheumatology vol. 12 63–68 (2016).[2]Schwartz, D. M., Bonelli, M., Gadina, M. & O’Shea, J. J. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol.12, 25–36 (2016).This study was supported by Pfizer Inc.Maaria Palmroth Consultant of: Pfizer and from 1/21 a part-time employee of MedEngine and consultant for Pfizer, Krista Kuuliala Grant/research support from: Pfizer, Ritva Peltomaa Speakers bureau: Boehringer Ingelmheim, Pfizer, Sanofi, Paid instructor for: Boehringer Ingelheim, Eli Lilly and Company, Janssen, Abbvie, UCB Pharma, Anniina Virtanen: None declared, Antti Kuuliala: None declared, Antti Kurttila: None declared, Anna Kinnunen: None declared, Marjatta Leirisalo-Repo: None declared, Olli Silvennoinen Speakers bureau: Pfizer, AbbVie, Pia Isomäki Speakers bureau: Abbvie, Eli Lilly and Company, Pfizer, Roche, Paid instructor for: Abbvie, Eli Lilly and Company, Pfizer, Roche, Grant/research support from: Pfizer