January 2014

Preclinical to Clinical Translation of Tofacitinib, a Janus Kinase Inhibitor, in Rheumatoid Arthritis

J Pharmacol Exp Ther. 2013. DOI:10.1124/jpet.113.209304

Preclinical studies can provide insight into mechanisms of efficacy and optimal dosing regimens. In this study, Dowty et al. compare the pharmacokinetic / pharmacodynamic profiles of tofacitinib in a murine arthritis model and in patients with rheumatoid arthritis from tofacitinib clinical trials. The main driver of efficacy in both preclinical murine arthritis models and clinical RA was found to be inhibition of JAK1 heterodimer signalling, where total drug exposure (Cave) was a predictor of pr...

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September 2013

Inhibitors of switch kinase ‘spleen tyrosine kinase’ in inflammation and immune-mediated disorders: A review

European Journal of Medicinal Chemistry 2013 67:434–446

SYK plays a significant role in the immune cell signalling of B cells, mast cells, macrophages and neutrophils. Kaur et al. provide a comprehensive review of the molecule, its role in autoimmune disease and clinical data on its inhibition. The paper covers the basic chemistry of SYK including structure, mechanism of action, synthetic derivatives and function, and the relevance of SYK as a therapeutic target for many autoimmune diseases is discussed. The SYK inhibitors currently in clinical trial...

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June 2013

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 ...

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Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes

Best Practice & Research Clinical Rheumatology 2010; 24:513-26

This article reviews data from animal and phase 2 clinical studies assessing the immunomodulatory effects and pharmacokinetics of CP-690,550 (now known as tofacitinib), as well as its efficacy and safety in patients with rheumatoid arthritis (RA). In two rodent models of arthritis, CP-690,550 produced dose-dependent decreases in signs of disease activity compared with untreated controls, reductions in histologically assessed inflammation and articular cartilage damage, and statistically signific...

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The pathogenesis of rheumatoid arthritis

The New England Journal of Medicine 2011; 365:2205-19

This review article describes the pathogenic processes involved in rheumatoid arthritis (RA) and discusses the genetic factors and environmental triggers implicated in the disease. Data from twin studies are discussed along with candidate genes with single nucleotide polymorphisms (SNPs) that have been linked to RA. It is now thought a multistep progression to the development of RA occurs via environmental factors, epigenetic modification of susceptible genes that leads to altered post-transcrip...

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Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor

Clinical Immunology 2007; 124:244-57

This study investigated the capacity of the novel oral spleen tyrosine kinase (Syk) inhibitor R406, and its prodrug R788 (fostamatinib), to suppress the reversed passive Arthrus reaction (RPA) and collagen-induced arthritis (CIA) in rats. R406 (0.1, 1, 5 and 10 mg/kg) and R788 (10 and 30 mg/kg) reduced the cutaneous RPA reaction and inflammatory oedema in a dose-dependent manner, with statistically significant reductions in extravascular leakage and tissue swelling (72% reduction with R406 10 mg...

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