**1. Introduction**

110 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

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#### **1.1 Synovitis and the chicken or the egg dilemma**

The studies approaching pathogenesis of rheumatoid arthritis shifted over the years to show that non-immune factors could precede activation of immune cells and were therefore targetable (Firestein & Zvaifler, 1990). In opposition to the classic model, in which an initial challenge to the immune system would over time lead to the autoimmune attack of joints, it was suggested that early mechanisms of disease induction were to be found inside joints. It was observed in vitro, that cells from the joints of patients with rheumatoid arthritis spontaneously produced several cytokines (Brennan et al., 1989a). Further studies would confirm the role of tumour necrosis factor alpha (TNF) as a master cytokine, since its inhibition led to a drop in levels of the other soluble mediators (Brennan et al., 1989b), as well as reduction in the expression of HLA-DR molecules (Haworth et al., 1991). Interestingly, TNF was not lymphocyte restricted, but rather pleiotropic. Moreover, it was shown that its principal sources in the arthritic joint were resident macrophages and fibroblast-like cells. This new paradigm was followed by the successful introduction of anticytokine therapies, which have totally changed the clinical picture of RA.

Indeed, the rheumatoid lesion at joints is quite unique, and probably sufficient to define the disease. It is characterized by the development of synovitis, a tumour-like transformation of the synovial tissue (Arend, 1997). On one hand, synovitis leads to joint destruction and disability, and on the other it provides a stronghold for spreading the inflammatory process.
