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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Effects of Janus Kinase Inhibitor tofacitinib on circulating serum amyloid A and interlukin-6 during treatment for rheumatoid arthritis

Clinical and Experimental Immunology doi.10.1111/cei.12234

Tofacitinib is a JAK inhibitor currently approved for the treatment of RA in some parts of the world. In this paper, Migita et al tested the effects of tofacitinib on circulating serum amyloid A (SAA). SAA is a major acute-phase reactant in RA and studies have shown it may be a better marker for the assessment of inflammatory joint disease compared with C-reactive protein. SAA is induced by the binding of IL-6 and the activation of the JAK/STAT pathway, which is inhibited by tofacitinib. Results...

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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

Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: 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-2013-204588

Systematic literature reviews were undertaken to assess the efficacy of csDMARDs, glucocorticoids and tofacitinib in the treatment of RA. The first two were updates to reviews conducted for the 2010 recommendations while the tofacitinib SLR was a complete review.Two studies identified by the csDMARD SLR, tREACH and TEAR, compared efficacy between MTX mono- and combination therapy (MTX+SSZ+HQ). Both of these studies found there was no benefit to immediate triple therapy.Further studies analysing ...

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The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans

DMD doi:10.1124/dmd.113.054940

The PK of tofacitinib has previously been described in several papers covering a range of diseases. This current study was used to better understand the PK, metabolism and clearance mechanisms of tofacitinib in healthy human subjects. Six subjects took a single 50mg dose of 14C-tofacitinib orally and consequently had urine, faeces and plasma collected. These were assayed for radioactivity and profiled for metabolites. Tofacitinib was found to be rapidly absorbed, with peak plasma concentrations ...

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Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infectious adverse events

Rheumatology doi:10.1093/rheumatology/ket466

Due to its function as a JAK1/3 inhibitor, tofacitinib has effects on a wide ranging variety of cells. The authors of this paper have previously reported a suppression in cytokine production by CD4+ T lymphocytes caused by tofacitinib, while others have reported reduced chemokine production from fibroblast-like synoviocytes. The effects of tofacitinib on other cells however remain largely unknown. This study focused on tofacitinib’s effects on CD4+ T lymphocyte proliferation and on subsets of ly...

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January 2014

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

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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