What we have learned from trials of immunomodulatory agents in rheumatoid arthritis: Future directions

In recent years substantial progress has been made in understanding the mec hanisms of inflammation and autoimmunity. in an attempt to interfere with s elected stages of the immune response, a variety of biological agents has b een designed that specifically targets elements of the immune system. In rh eumatoid arthritis (RA), a number of open-labeled clinical trials with immu nomodulatory agents, such as monoclonal antibodies or recombinant proteins, has provided encouraging initial clinical results. However, with the recen t exceptions of biologics inhibiting the activity of proinflammatory cytoki nes, randomized, controlled studies have largely failed to demonstrate a si gnificant benefit of these agents over placebo. Nevertheless, the clinical trials have provided an excellent opportunity to test the consequences of i nterfering with specific interactions involved in immunity. Moreover, from the results and experiences from these studies new therapeutic strategies a re constantly emerging. Some new approaches, including the application of a gents that target a diverse array of substances such as cytokines, chemokin es, enzymes, cell surface molecules involved in adhesion or signaling, and nitric oxide, are currently tested in animal models of human rheumatic dise ases. in this article, trials of immunomodulatory agents in RA are reviewed , with an emphasis on what we have learned so far and what we have yet to l earn. We will discuss recent advantages in the understanding of the pathoge nesis of the disease and delineate new therapeutic approaches for chronic a rthritis. (C) 1999 Prous Science. All rights reserved.