August 2013

Safety profile of protein kinase inhibitors in rheumatoid arthritis: a systematic review and meta-analysis

Ann Rheum Dis April 2013; doi:10.1136/annrheumdis-2012-203116

Salgado and colleagues conducted a systematic literature review of the safety profiles of protein kinase inhibitors (PKis) used for the treatment of rheumatoid arthritis (RA). Additionally, the study aims included identification of any class and molecule-related target and off-target adverse events. Data from 11,858 patients across 41 publications (phase 2 and 3 studies and two pooled analyses) were analysed. As well as published trials of PKi in RA, studies on healthy individuals and patients w...

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Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives

Pharmacol Ther. 2013 May; 138(2):294–309

This review focuses on targeting spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK) inhibitors as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders with SYK inhibition showing encouraging efficacy in patients with RA. The paper describes the role of SYK and BTK in several therapy areas including autoimmune diseases, allergic inflammatory disorders and haematological cancers as well as their role in innate immunity and regulators of adaptive...

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Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial

Ann Rheum Dis. 2013 May; 72(5):741–4

This phase2 trial assessed the efficacy of GLPG0259, a first-in-class ATP-competitive inhibitor of MAPKAPK5. The trail involved 31 patients with active RA and an inadequate response MTX. Patients received either 50 mg/day GLPG0259 with MTX or a placebo with MTX (patients randomised 2:1) for 12 weeks with the primary efficacy variable being ACR 20 response at week 12. Analysis showed that 5 patients (26.3%) in the GLPG0259 group and 3 patients (27.3%) in the placebo group achieved ACR 20 at 12 we...

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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...

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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...

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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...

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Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease

Molecular Immunology 2007; 44:2497-506

This review from 2007 provides an overview of the largest cytokine receptor family, the haematopoietin receptors, as well as other key components involved in one of the major cytokine signalling pathways implicated in autoimmune and inflammatory diseases. This includes the Janus kinases (Jaks), signal transducers and activators of transcription (Stats) and suppressors of cytokine signalling genes (Socs). Essentially, when a cytokine binds to a receptor from this group a functional cytokine recep...

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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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