Rheumatoid arthritis. Recent findings and new pathogenic concepts

: The etiology of rheumatoid arthritis (RA) is still unknown, and many uncertainties regarding its pathogenetic mechanisms persist. During the past decade, various hypotheses have been advanced, yet none of these has been able to explain the complexity of the disease. In light of the most recent research, a sub-division of the pathogenesis of RA, in four phases, has been proposed. The first phase is that of tissue damage, induced by unknown infective or traumatic factors with the liberation of possible arthrogenic antigens that are presented to the immune system. In the second phase the immune and inflammatory mechanisms should begin to function and, if they are effective, they should determine the resolution of the process; the failure of these mechanisms would create a further amplification of the immuno-inflammation response (the third phase). The fourth phase would then be a chronic inflammatory with progressive articular destruction, as well as anatomical and functional damage. This evolution, in response to common pathogenic agents, is dependent upon a particular hereditary genetic asset (not only the HLA system) that is able to control the production of citokines and also upon the neuroendocrine system. The final outcome of the process is, therefore, determinated by multiple interference between the inflammatory/immune system and other systems that also interact with it (the integrated pathogenetic hypothesis). This hypothesis reflects the complexity of the immune/inflammatory system that must be considered to be an acting part of an integrated network of diverse systems. A better knowledge of these interactions needed for the discovery of potential new therapies for RA.