April 2014

What is the future of targeted therapy in rheumatology: biologics or small molecules?

BMC Medicine 2014, 12:43

Our understanding of inflammatory rheumatic diseases such as rheumatoid arthritis has significantly increased over the last 20 years. With this greater understanding we have seen a significant improvement in the therapy of RA and other inflammatory rheumatic diseases. In this review, Moscai et al. discuss the improvements in therapies for the treatment of these diseases from the introduction of methotrexate as a frontline therapy through to the current era and approval of the first small molecul...

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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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Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis

. ARD published online first 13 Feb 2014. Doi: 10.1136/annrheumdis-2013-204105

Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3...

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March 2014

Emergence of proinflammaotry autoreactive T-cell responses in preclinical rheumatoid arthritis

The Lancet, Volume 383, Page S22, 26 February 2014

Before the onset of clinically apparent disease, the pathogenesis of RA goes through a number of sequential phases. The presence of autoimmunity through RF and ACPAs can be detected up to 13 years before the onset of clinical synovitis. An important component of the immune system is Treg cells which limit damage caused by excessive immune activity. These cells have been found to be dysfunctional in RA. This study aimed to identify autoreactive T cells to a known RA-associated antigen and determi...

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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

Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets

Rheumatology doi:10.1093/rheumatology/ket414

Despite biologic therapies greatly improving the treatment of rheumatoid arthritis, many patients do not respond to current treatments or do not maintain response to these treatments. This review covers the evidence for the newly discovered role of Th17 cells, IL-12 and IL-17 family of cytokines in the pathogenesis of RA as well as the development of new therapies targeting these cytokines. With current biologics targeting cytokines such as TNF, IL-1ß and IL-6, the discovery of the Th17 subset o...

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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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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

PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models

Chemistry and Biology Nov 13 20, 1364-1374

Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in murine...

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