Trends in Pharmacological Sciences
ReviewNovel therapeutic targets in rheumatoid arthritis
Section snippets
Progress in RA treatment
RA is a systemic autoimmune disease characterized by synovial inflammation and destruction of cartilage and bone. RA has a prevalence of 1% and affects three times more women than men. Although the exact etiology remains an active area of worldwide research, it is generally accepted that RA is a multifactorial disease in which both genetics as well as environmental factors have an important role. Genetic predispositions that affect T cell activation [such polymorphisms in the genes encoding
JAK inhibitors to fight RA
Recent recommendations by expert rheumatologists proposed tofacitinib as a targeted synthetic DMARD (tsDMARD) to be used in the treatment of RA after the failure of at least one biological DMARD [6]. Tofacitinib is the first therapeutic compound that targets the intracellular JAK signaling pathway. JAK is a family of intracellular tyrosine kinases that have a pivotal role in the transduction of cytokine-mediated signals via the JAK–STAT pathway (Figure 2). Following binding of a cytokine to its
Targeting the Th17 pathway in RA
Another ‘hot topic’ in the field of RA is the IL-17/Th17 pathway. IL-17 is a proinflammatory cytokine that is mainly, but not exclusively, produced by Th17 cells. Following the discovery of the Th17 cell 24, 25, research over the past decade has focused on both the differentiation process and the effector cytokines of this cell. Th17 differentiation from naïve CD4+ T cells is mediated by a combination of mediators, including IL-6, transforming growth factor (TGF)-β, and IL-23 [26], and is
Combination treatment and dual inhibitors
Different combinations of biologicals to treat RA are expected to achieve more complete control of joint inflammation and destruction, but the first trials blocking TNF in combination with anakinra or abatacept have shown that this could cause increased rates of infection 72, 73. However, TNF and IL-17 seem to be a more promising combination to target in the treatment of RA. Not only do TNF inhibitors increase Th17/IL-17 levels 30, 31, as mentioned above, but TNF and IL-17 have also been shown
Concluding remarks
RA is very heterogeneous disease, and treating a patient with RA with the right drugs at the right time is a major challenge. With JAK and Th17 inhibitors, rheumatologists have interesting new tools to treat patients with RA who do not (or no longer) respond well to the already existing biologicals. These new tools might seem diverse in many aspects (e.g., oral, once-daily synthetic DMARDs targeting intracellular pathways, versus biological DMARDs administered less frequent via injections
Acknowledgments
The Radboud UMC was sponsored by the Innovative Medicines Initiative Joint Undertaking funded project BTCure (grant number: agreement 115142-2).
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