View and download slide summaries of the latest original articles focusing on therapies in immune-mediated inflammatory diseases including rheumatology, dermatology, and gastroenterology. All materials produced by the team are subsequently reviewed and approved by individual Steering Committee members.
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...
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 ...
Ibrutinib is a first-in-class, orally available Btk (Bruton’s tyrosine kinase) inhibitor which has been shown to be effective in the treatment against certain types of leukemia and autoimmune disorders. Btk regulates the expression of genes involved in the differentiation and function of osteoclasts, and therefore inhibiting Btk suppresses osteoclastic bone resorption. Results from in vitro testing showed the suppressive effects on osteoclasts and murine models of RA showed ibrutinib treatment p...
A large number of loci implicated in disease susceptibility have been identified through genome-wide association studies (GWAS). In this review article, Diogo et al. discuss recent advances in GWAS in the context of rheumatoid arthritis pathogenesis and clinical applications. Relevant cells types and pathways in RA highlighted by GWAS to date include regulatory T-cells and CD4+ memory T cells as well as the JAK/STAT and NF-kB signalling pathways. The development of drugs targeting these pathways...
Despite major progress in the treatment of RA over the past decade, sustained clinical remission remains elusive. The identification of new treatment targets is therefore necessary, with much research currently being undertaken in this area. Novel therapeutic approaches currently being investigated include T cell-directed therapies targeting both T cell activation and regulation; and the targeting of pathogenic B cell functions, including the use of depleting and non-depleting B cell-directed an...
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...
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...
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...
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...
JAK inhibitors have been identified as having a critical role as therapeutic targets for autoimmune, inflammatory and oncological diseases. GLPG0634 was shown to inhibit JAK1/JAK2 but with a much greater effect on JAK1, a critical pathway in the signal transduction of many inflammatory cytokines. In rodent testing, GLPG0634 showed significant dose-dependent reduction in disease progression in collagen-induced arthritis models, with comparable efficacy to etanercept. An orally bioavailable treatm...