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...
January 2014
Romatoid Artrit de kritik hücre tipleri ve yolaklarının anlaşılmasında genom ilişki çalışmalarının öncüllüğü: Son bulgular ve zorluklar
Curr. Opin. Rheumatol. 2014; 26:85–92. doi:10.1097/BOR.0000000000000012
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...
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Romatoid artritte yeni hücreler ve sitokin hedefleri
Nat Rev Rheumatol. 2013. doi:10.1038/nrrheum.2013.168
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...
Romatoid Artrit de Januz Kinaz İnhibitörü Tofasitinibin Preklinikten Kliniğe Geçişi
J Pharmacol Exp Ther. 2013. DOI:10.1124/jpet.113.209304
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...
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November 2013
Therapeutic Targeting of the JAK/STAT Pathway
Basic Clin Pharmacol Toxicol. 2013 Oct 24. doi: 10.1111/bcpt.12164
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...
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update
Ann Rheum Dis. 2013 doi: 10.1136/annrheumdis-2013-204573
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...
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October 2013
Involvement of JAK/STAT signalling in the pathogenesis of inflammatory bowel disease
Pharmacological Research 2013; 76:1–8
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...
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Selektif JAK1 inhibitörü GLPG0634 nin inflamatuar hastalıkların tedavisinde preklinik özellikleri
Journal of Immunology 2013;191:3568–77
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...
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JAK inhibitörü Tofasitinib İnsan Monosit Kökenli Dendritik Hücrelerinin T hücre stimülator kapasitesini azaltır
Ann Rheum Dis 2013. doi: 10.1136/annrheumdis-2013-203756
The role of JAKs is highly important in lymphocyte differentiation, but their function in dendritic cells in unknown. In this study, the authors used tofacitinib, a JAK inhibitor, to assess the function of these kinases in dendritic cell activity. The results show that tofacitinib reduced the expression of CD80/CD86 by suppressing the activation of interferon regulatory factor (IRF)-7 and production of type 1 interferon (IFN), and also decreased T cell stimulatory capability. This suggests a nov...
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Hastalık-modifiye edici antiromatizmal ilaçların terminolojisinde yeni öneri
Ann Rheum Dis 2013. doi: 10.1136/annrhuemdis-2013-204317
With the recent emergence of new therapeutics for rheumatoid arthritis, new nomenclature for disease-modifying antirheumatic drugs (DMARDs) may be needed to more accurately describe the new agents. Currently, DMARDs are divided into two broad groups: synthetic DMARDs (sDMARDs) and biological DMARDs (bDMARDs). The authors propose dividing synthetic DMARDs into conventional synthetic DMARDs (csDMARDs) which would encompass traditional DMARDs (e.g. methotrexate, leflunomide), and targeted synthetic...