The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis
Ann Rheum Dis. 2014 Nov 14. pii: annrheumdis-2014-206028. doi: 10.1136/annrheumdis-2014-206028. [Epub ahead of print]
Targeting intracellular pathways such as JAK/STAT represents a novel approach to the treatment of RA. Tofacitinib is an oral JAK inhibitor, proven to be effective in the treatment of RA, yet the pathways affected by tofacitinib and the effects on gene expression in situ are unknown. In this study, Boyle et al. tested the hypothesis that tofacitinib targets cytokine signalling critical to the pathogenesis of rheumatoid synovitis by investigating tofacitinib effects on synovial pathobiology.
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Lipid profile changes in patients with chronic inflammatory arthritis treated with biologics and tofacitinib in randomized clinical trials: A systematic review and meta-analysis
Arthritis Rheumatol. 2015;67(1):117–127
Systemic inflammation, reflected by high levels of C-reactive protein and the erythrocyte sedimentation rate, has been identified as an independent risk factor for cardiovascular disease, the most important cause of death in RA and SpA. Studies with TNF antagonists have given contradictory results on cardiovascular risk. As such, this systemic literature search aimed to analyse lipid changes in RA and SpA subjects treated with biologics or tofacitinib in randomized clinical trials.
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An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy
Arthritis Rheumatol. 2015;67(2):372–380
The risk of cardiovascular (CV) disease among RA patients, compared with the general population is well documented. Alongside this, studies have been able to establish that risk factors in RA patients are not wholly associated with traditional CV risk factors such as such as diabetes mellitus, hypertension, smoking, and dyslipidemia, suggesting a relationship between parameters of RA disease activity and increased CV risk. Additionally, IL-6 has been linked with the development of coronary heart...
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Combined inhibition of TNFα and IL-17 as therapeutic opportunity for treatment in rheumatoid arthritis: Development and characterization of a novel bispecific antibody
Arthritis Rheumatol. 2015;67(1):51–62
Single cytokine inhibition, e.g. TNFα or IL-6, has fundamentally improved the therapeutic armamentarium for the treatment of RA; yet clinically meaningful responses are achieved in only about half of RA patients treated. In addition, it is now well established that the pathogenesis of RA involves multiple mechanisms of cell activation and cell recruitment. These two factors have led to the emergence of the concept of dual specificity, sparking interest in the biologic arena, with a focus o...
July 2014
Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation
Nature. 2014;510(7503):157–161.
The abnormal activation of skin immune cells, such as dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, by IL-23 is known to provoke psoriasis-type inflammation. What is less well known is how peripheral nerves regulate cutaneous immune responses. In this study, IL-23-dependent psoriasis-like inflammation was induced in mice to help determine the precise molecular mechanism of neuroimmune communication in the skin. Findings indicate nocic...
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June 2014
Differential regulation of anti-inflammatory genes by p38 MAP kinase kinase 6
Journal of Inflammation 2014, 11:14
Several p38α inhibitors have been developed and evaluated in RA. However, despite pre-clinical data showing promise, the compounds have been shown to have little therapeutic efficacy. Previous studies have suggested this may be a result of inhibitors blocking the role of p38 in limiting inflammation. Previous studies by the same authors have shown that the targeting of MKK3 or MKK 6, which are the upstream activators of p38, may be superior to p38 blockade as the anti-inflammatory effects ...
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Alternative p38 MAPKs Are Essential for Collagen-Induced Arthritis
Arthritis and Rheumatology Vol66, No. 5, May2014 pp 1208-1217
MAPK family proteins are regulatory proteins, affecting processes such as synthesis and release of proinflammatory molecules which contribute to the pathogenesis of RA. In particular, the p38 MAPK protein family is central to proinflammatory cytokine production. There are four member of the p38 group; p38α, p38β, p38γ and p38δ. This study sought to evaluate p38γ and p38δ deficiency in mice CIA model. In p38γ-/- or p38δ-/- mice, the percentage of mic...
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May 2014
14-3-3eta is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage
Arthritis Research and Therapy 2014, 16:R99
A major clinical imperative among rheumatologists is the ability to class patients into risk categories for radiographic progression. Indeed, identification of new independent biomarkers predictive of RA disease progression is a key target from OMERACT. This study by Maksymowych et al. sought to clarify the role of 14-3-3? in RA and whether it provided any clinically and/or serologically important prognostic information. First described as being elevated in RA in 2007, 14-3-3? has a strong corre...
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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...