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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Janus kinases in immune cell signaling

Immunological Reviews 2009; 228:273-87

This review from 2009 describes the Janus Kinases (JAK) that includes JAK1, JAK2, and JAK3, a subgroup of non-receptor protein tyrosine kinases. This protein family has a diverse range of functions including roles in cell growth, survival, development, and differentiation of a variety of cells, and especially immune and haematopoietic cells. Current knowledge of protein structure, regulatory mechanisms, signalling pathways and intracellular interactions for the JAK family is reviewed. The paper ...

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Intracellular Signal Pathways: Potential for Therapies

Current Rheumatology Reports 2009; 11:378-85

With recent progress in the development of drugs targeting signalling pathways for rheumatoid arthritis, this review article from the National Institutes of Health (NIH) provides an overview of the key intracellular pathways involved in the pathogenesis of rheumatoid arthritis. This paper also discusses some of the limitations of current drug targets including lack of clinical efficacy, potential adverse effects and cost, and highlights important issues associated with the design of target drugs...

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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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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 ...

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Back to the future: oral targeted therapy for RA and other autoimmune diseases

Nature Reviews Rheumatology 2013; 9(3):173-82

This review paper considers how advances in understanding of the disease process underlying rheumatoid arthritis (RA) and the development of novel techniques have transformed the management of this progressively disabling condition. Physicians are no longer limited to prescribing symptomatic treatments such as non-steroidal anti-inflammatory drugs (NSAIDs) or choosing from a seemingly random array of drugs drawn from multiple disciplines, such as methotrexate and sulphasalazine, which are descri...

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Janus kinases inhibitors in autoimmune diseases

Annals of the Rheumatic Diseases 2013; 72:ii111-ii115

This review describes the role of various cytokines in rheumatoid arthritis (RA) and related diseases. This includes an overview of the different types of cytokine receptors including type I, which bind some of the interleukins (ILs), colony stimulating factors (CSFs) and hormones such as erythropoietin, prolactin and growth hormone (GH); and type II, which bind to interferons and IL-10-related proteins. In addition, the cytoplasmic domain of type I and II cytokine receptors bind to members of a...

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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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Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050

Journal of Immunology 2010; 184(9):5298-307

This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was sh...

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