April 2014

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

Features of the synovium of individuals at risk of developing rheumatoid arthritis

Arthritis and Rheumatology March 2014:66;513-522

This study expands on previous findings that synovial inflammation does not coincide with the appearance of rheumatoid arthritis. This was a markedly larger study compared to previous, with 55 individuals assessed. All 55 subjects were positive for IgM rheumatoid factor and/or anti-citrillinated protein antibody as well as possessing no physical evidence of arthritis. 15 of the individuals tested developed arthritis after a median time of 13 months. In these patients the presence of inflammatory...

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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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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

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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Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implication for SYK inhibitors in autoimmune disease therapy

Arthritis Research and Therapy 2013 15:R146

Spleen tyrosine kinase (SYK) has already been described as a potential therapeutic target for the treatment of autoimmune diseases. Previously the SYK inhibitor fostamatinib was in clinical development for the treatment of rheumatoid arthritis, but has since been suspended. However, investigation into SYK inhibition continues with RO2091, a novel ATP-competitive inhibitor of SYK with reasonable selectivity, potency and oral bioavailability which has been shown to suppress various innate and adap...

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STA-21, a promising STAT3 inhibitor that reciprocally regulates Th17 and Treg, inhibits osteoclastgenesis and alleviates autoimmune inflammation

Arthritis and Rheumatism doi: 10.1002/art.38305

STAT3 (signal transducer and activator of transcription 3) is the major transcription factor in the differentiation of Th17 cells, which along with IL-17 are significant in the development of RA. STA-21 is a new small molecule with significant inhibitory effects on STAT3, impeding DNA binding activity, dimerization and STAT3-dependent luciferase activity. While the effect of STA-21 in RA has not been fully determined, it has been hypothesised that STA-21 will suppress arthritis in animal models ...

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