January 2014

Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implication for SYK inhibitors in autoimmune disease therapy

Arthritis Research and Therapy 2013 15:R146

Spleen tyrosine kinase (SYK) has already been described as a potential therapeutic target for the treatment of autoimmune diseases. Previously the SYK inhibitor fostamatinib was in clinical development for the treatment of rheumatoid arthritis, but has since been suspended. However, investigation into SYK inhibition continues with RO2091, a novel ATP-competitive inhibitor of SYK with reasonable selectivity, potency and oral bioavailability which has been shown to suppress various innate and adap...

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STA-21, a promising STAT3 inhibitor that reciprocally regulates Th17 and Treg, inhibits osteoclastgenesis and alleviates autoimmune inflammation

Arthritis and Rheumatism doi: 10.1002/art.38305

STAT3 (signal transducer and activator of transcription 3) is the major transcription factor in the differentiation of Th17 cells, which along with IL-17 are significant in the development of RA. STA-21 is a new small molecule with significant inhibitory effects on STAT3, impeding DNA binding activity, dimerization and STAT3-dependent luciferase activity. While the effect of STA-21 in RA has not been fully determined, it has been hypothesised that STA-21 will suppress arthritis in animal models ...

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Genome-wide association studies to advance our understanding of critical cell types and pathways in rheumatoid arthritis: recent findings and challenges

Curr. Opin. Rheumatol. 2014; 26:85–92. doi:10.1097/BOR.0000000000000012

A large number of loci implicated in disease susceptibility have been identified through genome-wide association studies (GWAS). In this review article, Diogo et al. discuss recent advances in GWAS in the context of rheumatoid arthritis pathogenesis and clinical applications. Relevant cells types and pathways in RA highlighted by GWAS to date include regulatory T-cells and CD4+ memory T cells as well as the JAK/STAT and NF-kB signalling pathways. The development of drugs targeting these pathways...

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Emerging cell and cytokine targets in rheumatoid arthritis

Nat Rev Rheumatol. 2013. doi:10.1038/nrrheum.2013.168

Despite major progress in the treatment of RA over the past decade, sustained clinical remission remains elusive. The identification of new treatment targets is therefore necessary, with much research currently being undertaken in this area. Novel therapeutic approaches currently being investigated include T cell-directed therapies targeting both T cell activation and regulation; and the targeting of pathogenic B cell functions, including the use of depleting and non-depleting B cell-directed an...

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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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November 2013

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update

Ann Rheum Dis. 2013 doi: 10.1136/annrheumdis-2013-204573

The 2010 EULAR recommendations represented a significant step forward in the management of rheumatoid arthritis, and they have been widely adopted across the world. However, in the rapidly evolving world of rheumatology, it was recognised that a substantial amount of new evidence has accumulated, both on agents approved at that time as well as data on new compounds that have become available over the last 3–4 years. This motivated EULAR to form an international task force to update their recomme...

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October 2013

Involvement of JAK/STAT signalling in the pathogenesis of inflammatory bowel disease

Pharmacological Research 2013; 76:1–8

The JAK/STAT signalling pathway has been implicated in the pathogenesis of several inflammatory diseases including inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). In this review, Coskun et al. provide an excellent background overview of the JAK/STAT cascade. They also highlight recent study findings investigating the mechanisms of the JAK/STAT pathway and the anti-inflammatory effects of novel JAK inhibitors in development and in clinical trials, particularly in IBD. In one study...

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Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases

Journal of Immunology 2013;191:3568–77

JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...

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Proposal for a new nomenclature of disease-modifying antirheumatic drugs

Ann Rheum Dis 2013. doi: 10.1136/annrhuemdis-2013-204317

With the recent emergence of new therapeutics for rheumatoid arthritis, new nomenclature for disease-modifying antirheumatic drugs (DMARDs) may be needed to more accurately describe the new agents. Currently, DMARDs are divided into two broad groups: synthetic DMARDs (sDMARDs) and biological DMARDs (bDMARDs). The authors propose dividing synthetic DMARDs into conventional synthetic DMARDs (csDMARDs) which would encompass traditional DMARDs (e.g. methotrexate, leflunomide), and targeted synthetic...

A meta-analysis of p38 mitogen-activated protein kinase inhibitors in patients with active rheumatoid arthritis

Clinical Rheumatology 2013 doi 10.1007/s10067-013-2340-1

The role of p38-MAPK inhibitors in treating RA is the subject of some debate. Li et al. therefore performed the first meta-analysis of the current data to evaluate the efficacy and safety of these compounds. The authors identified 3 papers, covering 4 RCTs, for analysis and the results showed that p38-MAPK inhibition achieves a better level of ACR20 improvement vs. placebo, but showed no meaningful difference in ACR50, DAS28 or CRP levels past week 12. Due to the inadequate number and quality of...

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