**1. Introduction**

132 Rheumatoid Arthritis – Treatment

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Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that primarily affects the joints. Approximately 0.5% of the adult population worldwide suffer from RA. The functional disability that results from progressive joint destruction is associated with substantial cost, significant morbidity and premature mortality [Carmona et al, 2010]. Pain and inflammation are initial symptoms followed by various degree of bone and cartilage destruction. During the last few decades' tremendous improvements have been made in search of therapies against RA. Disease modifying anti-rheumatic drugs (DMARDs) and biological therapies such as antagonists against TNF-α or IL-1 have provided efficient treatments and changed the shape of this disorder. However, the side effects, availability, and their focused approach to reduce inflammation have limited their scope. Thus there is a need of therapies targeting inflammation as well as reducing inflammatory pain and joint destruction in RA.

Cytokines are key players in pathogenesis of RA [Brennan & McInnes, 2008]. Synovial fluid from RA joints contains large quantities of cytokines secreted by macrophages, dendritic cells, neutrophils and synovial fibroblasts [Raza et al, 2005]. Cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interleukin-17 (IL-17) stimulate the production of destructive proteases. Synthesis of these pro-inflammatory mediators is regulated by the transcription factor NF-κB, controlled by the ubiquitin proteasome system (UPS) [Baldwin, 1996]. UPS is a multicatalytic system of protein degradation and present in all cell types including neurons and glia cells and regulates numerous cellular functions by selectively degrading cellular proteins.
