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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Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha-induced interlukin-18 bioactivity by caspase-1 inhibition

Arthritis Research and Therapy 2014,16:R102

IL-18, a member of the IL-1 family, has been shown to play an important role in immune response and is involved in the pathogenesis of RA. The study objective was to examine the role of the JAK pathway in modulating TNFa-induced-IL18 bioactivity by reducing caspase-1 function. Caspase-1 is the protease that cleaves pro-IL-18 to IL-18, thereby activating it. In testing it was noted that by blocking the JAK pathway significantly decreased caspase-1 transcription, expression and activity showing th...

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Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants

Ann Rheum Dis Published Online First 24 April 2014 doi:10.1136/annrheumdis-2013-204143

Bruton’s tyrosine kinase, a downstream target of PI3K signalling, has been shown to be crucial in the B lymphocyte and myeloid cell contribution to murine models of arthritis. Synovial tissue samples were taken from biologically naïve RA (n=16) and PsA (n=12) patients in order to assess the expression of BTK. Separate RA synovial explants (n=8) were used to assess the effects of the specific BTK inhibitor RN486. BTK was expressed at equivalent levels in both RA and PsA synovial tissue, however e...

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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

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

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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