Novel Approaches to the Therapy of Rheumatoid Arthritis based on an Understanding of Disease Mechanisms

As for any disease, unravelling the underlying mechanisms involved in the pathogenicity of rheumatoid arthritis is key to providing clues for designing effective therapeutic strategies that can ultimately translate from the laboratory to the clinic. Here, we provide an overview of rheumatoid arthritis and discuss experimental evidence suggesting how genetic and environmental factors, such as MHC genes, smoking and female sex hormones, can contribute to disease susceptibility. In established disease, the role of T cells is discussed in light of increased numbers of T cells in the arthritic versus healthy joint and the observed therapeutic effects of T cell modifying agents such as anti-CD4, anti-TCR and anti- IL2R antibodies in animal models of rheumatoid arthritis. As a vital tool, crucial to furthering our understanding of disease mechanisms, we elaborate on various animal models of rheumatoid arthritis being extensively exploited in arthritis research, including adjuvant-induced arthritis, collagen-induced arthritis, and transgenic mice expressing TNFα or IL-1β genes. Such experimental disease models have led to significant discoveries relating to the importance of proinflammatory cytokines in the pathogenesis of rheumatoid arthritis, resulting from a disregulation of the normally finely tuned balance of pro- and anti-inflammatory cytokine signalling. Indeed, the most successful therapeutic to date for rheumatoid arthritis, anti-TNFα, was initially studied in collagen-induced arthritis. It is concluded that mechanistic based research is essential to elucidate and evaluate new candidate therapies for the treatment of rheumatoid arthritis, and other autoimmune diseases.