August 2013

The JAK inhibitor tofacitinib for active rheumatoid arthritis: results from phase III trials

International Journal of Clinical Rheumatology June 2013; 8(3):311–13

The tofacitinib ORAL research program involves six phase 3 trials (Standard, Solo, Step, Scan, Sync and Start) to assess the safety and efficacy of tofacitinib 5 and 10 mg twice daily as monotherapy, or with either background MTX or traditional DMARD therapy. This report by Salgado et al. provides an overall analysis of the each of the study designs and the clinical results to date. The results show that tofacitinib effectively controlled the signs and symptoms of RA across a range of patient po...

Keywords:

June 2013

Physiology of cytokine pathways in rheumatoid arthritis

Arthritis Care & Research 2001; 45(1):101-6

This review from 2001 describes the main cytokines involved in the pathophysiology of rheumatoid synovitis, and the redundant and synergistic nature of cytokine pathways in rheumatoid arthritis (RA). The self-regulating nature of cytokines are explained through the actions of anti-inflammatory cytokines, opposing cytokines, cytokine receptor antagonists, and naturally occurring antibodies. The paper explains that as disease often results when an imbalance develops in the cytokine network, therap...

Keywords:

Cytokine networks—towards new therapies for rheumatoid arthritis

Nature Clinical Practice 2005; 1(1):31-9

This review describes cytokines and the cytokine network in chronic inflammatory diseases such as rheumatoid arthritis (RA). It also discusses how therapies that target cytokines may be feasible and efficacious treatments option for RA. Various targets are considered including blockade of tumour necrosis factor (TNF) and interleukin-1 (IL-1), as well as the targeting of cytokines that play a central role in immune regulation and tissue matrix destruction such as IL-6, IL-15, interferon-gamma (IF...

Keywords:

Cytokines in the pathogenesis of rheumatoid arthritis

Nature Reviews Immunology 2007; 7:429-42

The imbalance between the activity of pro- and anti-inflammatory cytokines favouring induction of autoimmunity, chronic inflammation and joint damage is well known, but how cytokines are organised within a hierarchical regulatory network and which cytokines are the best targets for clinical intervention is uncertain. This review therefore examines the effector function of cytokines in the immunological processes central to the pathogenesis of rheumatoid arthritis (RA). The paper aims to try and ...

Keywords:

Small molecules targeting JAKs—a new approach in the treatment of rheumatoid arthritis

Rheumatology 2013: doi: 10.1093/rheumatology/kes417

This article focuses on the development of new small molecular inhibitors of Janus kinases (Jaks) in clinical trials for rheumatoid arthritis (RA). Of these, tofacitinib is at the most advanced stage of its clinical development and this article includes an overview of the results from the main tofacitinib clinical trials to date. These include the ORAL-Start study in methotrexate (MTX)-naïve patients; ORAL-Scan in inadequate responders to MTX; ORAL-Solo and ORAL-Sync in inadequate responders to ...

Keywords:

The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type 1 interferon

Annals of Rheumatic Diseases 2012; 71:440-47

This study investigated the effect of the novel Janus kinase (JAK) inhibitor CP-690,550 [tofacitinib] in fibroblast-like synoviocytes (FLSs) collected from patients with rheumatoid arthritis (RA). Human FLSs were cultured from the synovial tissue of patients with RA who were undergoing arthroplastic surgery, cultured and then serum-starved 48 hours prior to stimulation. Quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) or multiplex bead assay were used to...

Keywords:

Tofacitinib or adalimumab versus placebo in rheumatoid arthritis

The New England Journal of Medicine 2012; 367(6):508-19

The ORAL Standard trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 12-month, phase 3 study compared the efficacy of tofacitinib with the TNF inhibitor adalimumab or placebo. Patients with active RA despite background methotrexate (MTX) were randomised to 5 or 10 mg tofacitinib twice daily, 40 mg adalimumab fortnightly, or placebo, which was switched to tofacitinib at month 3 in non-responders and month 6 f...

Keywords:

Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial

The Lancet 2013; 381(9865):451-60

The ORAL Step trial is one of six studies conducted as part of the phase 3 research programme for the oral Janus kinase (JAK) inhibitor tofacitinib. This 6-month, double-blind, parallel-group phase 3 study investigated the efficacy and safety of tofacitinib in adults with moderate to severe rheumatoid arthritis (RA) with an inadequate response to tumour necrosis factor (TNF) inhibitors. Patients were randomised to 5 or 10 mg tofacitinib twice daily or placebo, which was switched to tofacitinib a...

Keywords: