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Targeting Cytokines, Chemokines and Adhesion Molecules in Rheumatoid Arthritis

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The therapy of rheumatoid arthritis (RA) was revolutionized by basic research studies and biopharmaceutical development of the first generation of anti-rheumatic biologic agents (i.e. biological response modifiers), which targeted the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-6 (IL-6). Further studies resulted in biological response modifiers that have also targeted activated T- and B-lymphocytes both of which play a prominent role in RA pathogenesis and disease progression. Despite the relatively impressive RA diseasemodifying effects of these biologic agents during the post-FDA approval period, there are reports of moderate to severe adverse events associated with their continuous use. Additionally, there is accumulating evidence indicating that antirheumatic biologic agents, while dampening RA disease activity as measured by the American College of Rheumatology (ACR) criteria in clinical trials or other arthritis disease activity instruments employed in studies after approval of these anti-rheumatic medicines by the FDA do not entirely halt the erosive joint cartilage and bone destruction characteristic of RA. There is also still some uncertainty as to how long the available anti-rheumatic biologics can be continuously employed as RA therapies. Since the development of TNF-α/IL-1/IL-6 anti-rheumatic biologics, several additional cytokines with pro-inflammatory activity as well as their receptors, which initiate upstream pathophysiologic effects, have been identified and characterized. In several cases, these cytokines have been cloned and sequenced. Thus, cytokines, such as IL-7, IL12/IL-23, IL-15, IL-16, IL-17/IL-18, IL-19/IL-20/IL-22 and IL-32, have been implicated in arthritis development in animal models of RA and measurements in synovial tissue and synovial fluid obtained from patients with RA also suggested a role for them in RA disease progression, if not in its pathogenesis. There has also been compelling evidence that cytokines with chemokine-activity and adhesion molecules also play a crucial role in RA via their capacity to recruit and retain leukocytes, macrophages, monocytes and endothelial-cell complexes in RA synovial joints. Taken together, non-TNF-α/non-IL-1/non-IL-6 cytokines, chemokines and their receptors as well as adhesion molecules appear to be worthwhile targets for drug development in RA.

Keywords: Adhesion molecule; chemokine; cytokine; fusion protein; inflammation; neutralizing antibody; rheumatoid arthritis

Document Type: Research Article

Publication date: November 1, 2008

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  • Current Rheumatology Reviews publishes frontier reviews on all the latest advances on rheumatology and its related areas e.g. pharmacology, pathogenesis, epidemiology, clinical care, and therapy. The journal's aim is to publish the highest quality review articles dedicated to clinical research in the field.

    The journal is essential reading for all researchers and clinicians in rheumatology.
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