May 2014

Safety and Efficacy of Tofacitinib, an Oral Janus Kinse Inhibitor, for the Treatment of Rheumatoid Arthritis, in Open-Label Longterm Extension Studies

J Rheumatol 2014;41;837-852

This study pooled data from two LTE studies involving patients who had previously participated in qualifying phase I, II and III studies. Data up to 60 months was included for safety aspects and efficacy data up to 48 months. However data for 10 mg BID and tofacitinib monotherapy was limited after 24 and 36 months respectively. Over the two studies, 4102 patients were treated for a total of 5963 patient years.Herpes zoster, both serious and non-serious, had a higher incidence rate in tofacitinib...

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April 2014

Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors

Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279

Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...

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March 2014

Inhibition of TAK1 and/or JAK can rescue impaired chondrogenic differentiation of human mesenchymal stem cells in osteoarthritis-like conditions

Tissue Engineering Part A doi:10/1089/ten.TEA.2013.0553

As it is nonvascularized and noninnervated, articular cartilage has a limited capacity to repair which presents a major clinical problem. In order to circumvent this inability to repair, stem cells can be placed into the joint or stimulated within the bone marrow. However, as the cartilage requiring repair is often in diseased joints, the factors involved in the disease state are potentially non-beneficial to the chondrogenesis of mesenchymal stem cells. In this study van Beuningen et al. invest...

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February 2014

Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis

Ann Rheum Dis doi:10.1136/annrheumdis-2013-204575

Two systematic literature reviews were undertaken to update the safety findings on synthetic and biological DMARDs in order to inform the updates to the EULAR recommendations to the treatment of RA. Of 10,559 articles screened, 49 were included for review covering a diverse range of outcomes. In the main these showed the patients on bDMARDs had a significantly greater risk of serious infections and tuberculosis compared with csDMARDs, while differences in data between studies mean a slight incre...

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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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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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June 2013

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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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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Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis

The New England Journal of Medicine 2012; 367(6):495-507

This is the first phase 3 study to be published for the oral Janus kinase (JAK) inhibitor tofacitinib. This study investigated tofacitinib as a monotherapy in adults with active rheumatoid arthritis who previously failed to respond to disease modifying anti-rheumatic drugs (DMARDs). The study demonstrated that tofacitinib, compared to placebo, was more likely to be associated with reductions in the signs and symptoms of rheumatoid arthritis and improvement in physical function. 59.8% of patients...

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