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The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis

Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S, Kaplan I, Krishnaswami S, Luo Z, Bradley J, Firestein GS. - Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]

Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology.

A randomised, double-blind, phase II serial synovial biopsy study in 29 patients with RA with an inadequate methotrexate response was used to evaluate the effect of tofacitinib 10 mg twice daily on synovial tissue and blood biomarkers in active RA compared with placebo at Day 28. Secondary objectives were to evaluate the clinical efficacy, safety and tolerability of tofacitinib.

After 28 days, changes induced by tofacitinib included decreases in the expression of genes implicated in RA, including MMPs and chemokines, along with a rapid and sustained decrease in CXCL10. No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. The most important finding of the study was the correlation between suppression of STAT activation and 4-month clinical improvement.

The data suggest that, rather than blocking a single cytokine, tofacitinib modulates JAK1-mediated IL-6 and IFN signalling which play a key role in the rheumatoid synovium.

Keywords: JAK, Tofacitinib, Preclinical, MOA

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Upload date: December 2014

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