In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis

Abstract

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.

Inhibition of IL-17 as a Pharmacological Approach for IBD

“…However, the relevant literature suggests that Tofacitinib can attenuate IL-17 secretion by inhibiting the activation of JAK and STAT3 pathways [52,55]. Also, it is noteworthy that Tofacitinib effectively inhibited IL-6 plus IL-23-induced 1L-17 expression in CD4+ T-cells [53].…”

“…In contrast to the antibody approaches directed against IL-17 and the IL-17R, small molecules, such as Vidofludimus and Tofacitinib, have shown evidence of efficacy in early IBD clinical trials ( Table 2). As part of their overall mechanism of action, both drugs inhibit IL-17, among other cytokines including IFN-y, [4,24,[51][52][53].…”

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

“…Cytokine receptors containing the common γ-chain subunit that are relevant for cytokines participating in RA signal through JAK1 and JAK3. JAKs belong to the receptor-associated tyrosine kinases family of the tyrosine PK group 6. Tofacitinib is a pan-JAK inhibitor, baricitinib inhibits JAK1 and JAK2, GLPG-0634 JAK1, and vx-509 JAK3 7–9.…”

Review of tofacitinib in rheumatoid arthritis

“…Based on this, the effects of tofacitinib have been evaluated in different animal models (including inflammatory arthritis) and in patients with psoriasis, inflammatory bowel disease, dry eye disease and RA [15][16][17][18][19][20][21][22][23][24][25][26][27]. Ongoing clinical trials are being conducted to evaluate its efficacy and safety on ankylosing spondylitis, Crohn's disease, psoriasis, psoriatic arthritis and ulcerative colitis [18,28,29].…”