The role of cytokines in rheumatoid arthritis: inhibition of cytokines in therapeutic trials.

Abstract

Although the precise role(s) of cytokines in rheumatoid arthritis (RA) is still being investigated, increasing evidence implicates interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha as contributing importantly to the inflammatory, and perhaps destructive manifestations of the disease. Several natural endogenous inhibitors of IL-1 and TNF-alpha have been identified; these include interleukin-1 receptor antagonist (IL-1RA), soluble IL-1 receptors (sIL-1R), and soluble TNF-alpha receptors (sTNFR). Although increased levels of these natural inhibitors occur in sera and at sites of inflammation in patients with RA, there is an excess of IL-1 and TNF-alpha in comparison with their respective natural inhibitors that favors the proinflammatory actions of these cytokines. Therefore, a potential therapeutic maneuver for treating RA is to neutralize these implicated cytokines. Biologic agents aimed at inhibiting the proinflammatory activities of these cytokines thus far have included cytokine receptor antagonists, anticytokine monoclonal antibodies (MAbs), fusion molecules consisting of soluble cytokine receptors combined with human fusion protein (Fc) constructs or polyethylene glycol (PEG), and counterregulatory cytokines which oppose actions of the target cytokine (e.g., IL-10, IL-4 and IL-11). Inhibitors of the processing and synthesis of IL-1 and TNF-alpha are also under development. The encouraging clinical results observed in short-term trials of TNF-alpha and IL-1 inhibitors using sTNFR:Fc fusion proteins, anti-TNF MAbs and recombinant human IL-1 receptor antagonist (rhuIL-1RA) clearly warrant further studies not only to determine whether these agents are capable of modifying the destructive component of the disease, but also whether they can be administered safely for long periods. Pivotal trials with these agents have potential therapeutic applicability to other autoimmune and inflammatory disorders.