Review
Novel therapeutic targets in rheumatoid arthritis

https://doi.org/10.1016/j.tips.2015.02.001Get rights and content

Highlights

  • Small molecule inhibitors targeting the JAK pathway are a promising new treatment strategy for RA.

  • The Th17 pathway, including IL-17, IL-21, IL-22, and GM-CSF, offers interesting new targets for RA.

  • Dual cytokine inhibition in RA might increase clinical response.

Rheumatoid arthritis (RA) is an autoimmune disease that leads to inflammation and destruction of synovial joints. Despite the broad spectrum of antirheumatic drugs, this heterogeneous disease is still not well controlled in up to 30% of patients. Here, we discuss two pathways that are regarded as interesting novel therapeutic targets in the field of rheumatology: the Janus kinase (JAK) pathway and the T helper-17 (Th17) pathway [including interleukin (IL)-17, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. We also review the therapy potential of biologicals and small-molecule inhibitors blocking these pathways. Advances in combination therapy in addition to progress in biomarker screening will help us to further achieve effective and personalized healthcare for patients with RA.

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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