November 2013

Therapeutic Targeting of the JAK/STAT Pathway

Basic Clin Pharmacol Toxicol. 2013 Oct 24. doi: 10.1111/bcpt.12164

The inhibition of the JAK/STAT pathway has proven to be a powerful therapeutic tool in the treatment of autoimmune diseases. The authors review the role of the JAK/STAT pathway in human disease, including the role of mutations in defective function of this pathway. They discuss the rationale behind JAK inhibition and review the two JAK inhibitors currently approved by the FDA for clinical use; tofacitinib, for the treatment of RA, and ruxolitinib, for the treatment of polycythaemia vera and myel...

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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...

Ibrutinib and novel BTK inhibitors in clinical development

Journal of Hematology & Oncology 2013;6:59

Bruton’s tyrosine kinase (BTK) is a part of the cytokine signalling pathways involved in malignancies and autoimmune disorders.. Akinleye et al. provide a review of all the current BTK inhibitors in preclinical and clinical trials for B-cell malignancies and autoimmune disorders, including rheumatoid arthritis. Particular focus is placed on ibrutinib, a novel human BTK-inhibitor, currently in phase III clinical trials. The authors also discuss four new compounds with potential indications in rh...

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Inhibition of JAK/STAT signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds

Clin Exp Immunol. 2013 Aug 23. doi: 10.1111/cei.12190

Current JAK inhibitors CP-690,550 and INCB020850 have inhibitory effects on multiple JAK pathways, therefore Migita et al. tested whether selective inhibition of JAK3, using PF-956980, would be enough to ameliorate the rheumatoid inflammatory process. The results indicated that the inhibition of JAK3 alone is does not achieve control of STAT3-dependent signalling, and while it is suggested that the targeting of singular JAK pathways should lead to fewer adverse events, it appears that this appro...

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Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis

Ann Intern Med. 2013;159;253-261

Many patients with active RA have an inadequate response to biologic and nonbiologic DMARDs. Kremer et al carried out a one year, randomized trial studying the efficacy of tofacitinib in conjunction with background nonbiologic DMARDs (primarily methotrexate) in these patients. The results showed that using tofacitinib in combination with nonbiologic DMARDs rapidly improved physical function and reduced signs and symptoms of RA versus placebo, measured by ACR20 rates, DAS28 and HAQ-DI. The data f...

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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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Kinase Inhibitors: A new tool for the treatment of rheumatoid arthritis

Clinical Immunology 2013;148:66–78

Chakravaty et al. provide a comprehensive review of the scientific basis for kinase inhibitor use, and summarise experience from clinical trials in tofacitinib and fostamatinib, plus promising clinical data for p38-MAPK inhibitors and P13K? and P13Kd. The authors highlight potential future directions and challenges in kinase inhibitor research, including the emergence of kinases upstream of p38, such as MKK-3 and MKK-6, and the potential of BTK inhibition. One of the challenges of kinase inhibit...

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