Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid 
arthritis (RA). The appropriate intracellular signalling pathways must be 
activated via cytokine receptors on the cell surface, and the tyrosine kinases 
transduce the first 'outside to in' signals to be phosphorylated after receptor 
binding to its ligand. Among them, members of the Janus kinase (JAK) family are 
essential for the signalling pathways of various cytokines and are implicated in 
the pathogenesis of RA. The in vitro, ex vivo and in vivo effects of a JAK 
inhibitor CP-690,550 (tofacitinib) for the treatment of RA are reported. In 
vitro experiments indicated that the effects of tofacitinib were mediated 
through suppression of interleukin 17 (IL-17) and interferon γ production and 
proliferation of CD4 T cells, presumably Th1 and Th17. A treatment study was 
conducted in the severe combined immunodeficiency (SCID)-HuRAg mice, an RA 
animal model using SCID mice implanted with synovium and cartilage from 
patients. Tofacitinib reduced serum levels of human IL-6 and IL-8 in the mice 
and also reduced synovial inflammation and invasion into the implanted 
cartilage. A phase 2 double-blind study using tofacitinib was carried out in 
Japanese patients with active RA and inadequate response to methotrexate (MTX). 
A total of 140 patients were randomised to tofacitinib 1, 3, 5, 10 mg or placebo 
twice daily and the American College of Rheumatology 20% improvement criteria 
(ACR20) response rate at week 12, a primary end point, was significant for all 
tofacitinib treatment groups. Thus, an orally available tofacitinib in 
combination with MTX was efficacious and had a manageable safety profile. 
Tofacitinib at 5 and 10 mg twice a day appears suitable for further evaluation 
to optimise the treatment of RA.