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 mechanisms of inflammation and autoimmunity. In an attempt to interfere with selected stages of the immune response, a variety of biological agents has been designed that specifically targets elements of the immune system. In rheumatoid arthritis (RA), a number of open-labeled clinical trials with immunomodulatory agents, such as monoclonal antibodies or recombinant proteins, has provided encouraging initial clinical results. However, with the recent exceptions of biologics inhibiting the activity of proinflammatory cytokines, randomized, controlled studies have largely failed to demonstrate a significant benefit of these agents over placebo. Nevertheless, the clinical trials have provided an excellent opportunity to test the consequences of interfering with specific interactions involved in immunity. Moreover, from the results and experiences from these studies new therapeutic strategies are constantly emerging. Some new approaches, including the application of agents that target a diverse array of substances such as cytokines, chemokines, enzymes, cell surface molecules involved in adhesion or signaling, and nitric oxide, are currently tested in animal models of human rheumatic diseases. 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 learn. We will discuss recent advantages in the understanding of the pathogenesis of the disease and delineate new therapeutic approaches for chronic arthritis.