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Interleukins and Janus Kinases: Emerging Therapeutic Targets in Rheumatoid Arthritis
Rupal Mansukhani, PharmD
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Rheumatoid Arthritis: The Next Generation of Treatment Post Test

Interleukins and Janus Kinases: Emerging Therapeutic Targets in Rheumatoid Arthritis

Rupal Mansukhani, PharmD
Treatment of rheumatoid arthritis (RA) has evolved from the use of conventional treatments, such as methotrexate, to disease-modifying biologic agents that can slow the disease process and make remission possible for some patients. Although these targeted therapies have improved the clinical management of patients with active RA, no current approach meets the goals of therapy for RA: slowing disease progression while improving the patient’s well-being and, ideally, creating complete clinical remission that is verifiable by radiography and patient report. Consequently, investigators continue to look for additional drivers of RA and for interventions that will target specific pathways with few adverse effects.
Aberrant helper T (Th)-cell activation has been implicated as a mechanism leading to several autoimmune diseases that seem to have common roots (RA, psoriatic arthritis, and Crohn’s disease). Research into the pathophysiology of RA is focusing on Th cells, as well as molecules involved in intracellular signaling. Through kinase inhibition, it may be possible to interrupt signal transduction and potentially reduce proinflammatory cytokine production. Two promising targets are interleukins and Janus kinases. Oral inhibitors of interleukins or Janus kinases may enable more patients to achieve disease remission.
Am J Manag Care. 2016;22:-S0
Advances in the understanding of the pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA), have led to new treatments that improve quality of life.1 The use of empiric treatments, such as methotrexate (MTX), has given way to newer biologic therapies that target specific molecules and cellular structures known to be involved in the chronic inflammatory process. For some individuals, these disease-modifying biologic agents can slow or even reverse the deleterious physical effects associated with RA, making remission possible. Nevertheless, despite the availability of various biologic agents for the treatment of RA, some patients do not achieve the desired response, do not maintain treatment responses over time, or experience intolerable adverse effects (AEs) that lead to treatment discontinuation. In addition, these treatments can be expensive and require subcutaneous (SC) or intravenous (IV) administration. This unmet need has prompted investigation into alternative drivers of RA pathogenesis that may serve as therapeutic targets.1

Ongoing research is focusing on molecules that are involved in intracellular signaling following ligand binding to receptors on inflammatory cells.1 Through inhibition of 1 or more of the kinases involved in signal transduction, it may be possible to interrupt intracellular signaling, modulate the function of cellular structures, and subdue the inflammatory process.
Currently, investigators are exploring 2 promising targets in RA: interleukins (ILs) and intracellular Janus kinases (JAKs). Small molecular agents targeting IL-17, such as secukinumab and ixekizumab, are already being used clinically for patients with psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis.2,3 Tofacitinib, an oral JAK inhibitor, is approved for RA unresponsive or intolerant to MTX.4
 
The Interleukin-Cytokine Family
Intracellular signaling pathways transmit information regulating cellular responses and gene transcription to the cellular cytoplasm and nucleus.5 Cytokines carry out many crucial biological processes like cell growth, proliferation, differentiation, inflammation, tissue repair, and regulation of the immune response. IL-1, IL-6, and IL-17 use a variety of signaling cascades that are being investigated as therapeutic targets. These cytokines are substantially involved in the pathogenesis of RA and are responsible for the associated inflammation and joint destruction.5 Inflammation is caused by the predominance of proinflammatory cytokines over anti-inflammatory cytokines. Patients with RA exhibit an imbalance between IL-1 receptor antagonist (IL-1Ra) and IL-1 levels. High concentrations of IL-1b in plasma and synovial fluid are associated with increases in RA disease markers, as well as morning stiffness. IL-1 increases the release of synovial fibroblast cytokine, prostaglandins, and matrix metalloproteinases. Osteoclast activation and expression of endothelial cell adhesion molecules have also been observed.5
 
Involvement in Autoimmunity and Chronic Inflammation
Regulatory T cells (Tregs) are a specialized group of CD4+ T cells that are considered to be involved in autoimmunity and chronic inflammation.6,7 To achieve effective immunologic homeostasis, there must be a steady balance between Th-cell activation and Treg suppression.6 When an imbalance occurs, homeostasis is disrupted. Consequently, the immune system becomes activated, leaving the host susceptible to autoimmunity. Experts have proposed that an imbalance between Th17 and Treg cells, as well as elevated levels of IL-17, may contribute to the development and progression of RA.6,7

Compared with healthy individuals, patients with RA, including those with treatment-naïve early-stage disease, have increased numbers of Th17 cells and elevated expression of IL-17 in peripheral circulation, as well as in the synovium and synovial fluid.7,8 Tregs also accumulate in the joints of patients with RA.8 The inflammatory cytokine environment in a rheumatoid joint may contribute to an imbalance between Th17 and Treg cells in some way. IL-17–producing Th17 cells mediate 3 phases of RA: inflammation, cartilage destruction, and bone erosion.6
 
Effects on Inflammation
IL-1 and IL-6 are key mediators of cell migration and inflammation in RA.9 IL-6 acts directly on neutrophils via IL-6R, which promotes inflammation by secreting proteolytic enzymes and reactive oxygen intermediates.9 IL-17 plays a central role in inducing and promoting the chronic inflammatory disease response through the induction of proinflammatory cytokines from various cell types, such as synovial fibroblasts, monocytes, macrophages, chondrocytes, and osteoblasts.10 Not only do these proinflammatory cytokines contribute to RA flares, but they also create chronic inflammation.11 The effects of chronic inflammation can lead to cartilage damage and bone erosion.



 
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