Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms

Extra-articular ("nonarticular") manifestations of rheumatoid arthritis (RA) are common and greatly affect physical and emotional health, as well as prognosis, including survival. Several plausible mechanisms have been advanced for many nonarticular manifestations but there is increasing evidence that pro-inflammatory cytokines (eg, tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1, and IL-6) are also involved. The purpose of this review is to provide a concise appraisal of recent studies investigating the involvement of inflammatory cytokines in the pathogenesis of nonarticular RA manifestations.

A Medline search for articles published between January 1995 and October 2007 was conducted using the following keywords: rheumatoid arthritis, anemia, cardiovascular, atherosclerosis, bone loss, osteopenia, osteoporosis, pulmonary, thrombocytopenia, lymphadenopathy, keratoconjunctivitis sicca, uveitis, scleritis, keratitis. The review focused on articles describing a potential role of inflammatory mediators in these conditions.

Studies of many nonarticular manifestations strongly implicate pro-inflammatory cytokines and specific mechanisms by which these mediators are likely to act have even been elucidated. The inflammatory cytokines implicated are numerous but particularly include members of the TNF family and the interleukins, particularly IL-1 and IL-6. In bone loss, activated T-cells have been shown to express pro-inflammatory cytokines (eg, TNF, IL-1, IL-7, and IL-17) that differentially upregulate and downregulate mechanisms that mediate the balance between bone resorption and formation. Cytokine-mediated inflammation has also been implicated, for example, in the early stages of atherogenesis and this may explain the observed increase in cardiovascular disease among patients with RA. However, for some nonarticular manifestations, the association with pro-inflammatory cytokines has been less firmly established and potential mechanisms are more speculative.

Overall, further research in this area will add to our understanding of the mechanisms of extra-articular manifestations in RA patients. These insights should allow clinicians to select therapies to better match the spectrum of joint disease and nonarticular manifestations in individual patients. This may be particularly relevant for newer biologic agents with specific inhibitory effects on cytokines such as TNF-alpha and IL-6.