An overview of immunomodulatory intervention in rheumatoid arthritis.
In recent years there has been exceptional progress in the development of immunomodulatory interventions for the treatment of rheumatoid arthritis (RA). Part of the impetus for the creation of novel therapies for RA has come from a growing appreciation of the substantial morbidity and mortality that this chronic, progressive disease causes for affected patients. In addition, there has been the realization that currently available therapeutics are suboptimal as regards both their efficacy and tolerability. The development of newer therapies has been facilitated by two factors; a greater understanding of the immunopathogenesis of RA and progress in biotechnology that has allowed the creation of specific inhibitors and other agents. Myriad studies performed by investigators throughout the world have helped delineate the immunologic basis of RA. It appears that various components of the immune system are involved in the initiation and propagation of this systemic inflammatory disease. T-cells, and in particular activated CD4(+) 'memory' T-cells, serve a central role in orchestrating the immune response that underlies rheumatoid inflammation. Other cells, including monocytes, fibroblasts, B-cells, dendritic cells, mast cells and neutrophils also contribute significantly to various aspects of disease. Adhesion molecules mediate many intercellular interactions, thus contributing to activities such as the accrual of cells within the synovium and the activation of cells. Cytokines, small peptides that exert numerous inflammatory activities and cause many of the signs and symptoms of RA, play a crucial role. Indeed, RA may be considered a disorder of 'cytokine dysregulation' in that the activity of proinflammatory cytokines such as TNF-alpha and IL-1 is enhanced, and overwhelms the effects of antiinflammatory factors. Finally, a host of other inflammatory mediators are involved in the disease process. Thus, many components of the immune response may be attractive therapeutic targets for immunomodulatory intervention in RA. Advances in biotechnology have permitted the creation of specific inhibitors of distinct components of the immune system. Monoclonal antibodies (MAbs) have been created to target various cell surface molecules and cytokines. At first, most MAbs were murine in origin, which can present problems as regards immunogenicity. More recently, progress in molecular biologic techniques has allowed the synthesis of hybrid antibodies that are partly human. Such techniques have also allowed the creation of cytokine receptors coupled to immunoglobulin molecules, and other constructs. These agents can be modified to provide optimal characteristics in terms of half-life, immunogenicity and specificity, and this is an exciting area of new development. Progress has also been made in molecular-based agents that directly modify the genes or gene products for specific targets. To date, a number of trials assessing novel immunomodulatory therapies have been undertaken. In some cases, such as with inhibitors of TNF-alpha, the results have been dramatic and exciting. Further development and refinement may allow the introduction of these agents into the clinic in the foreseeable future, and will provide an important area for further research. In other cases, for example with therapies targeting CD4(+) molecules, the results have not been as promising as was hoped. Nevertheless, critical analysis of the results of these studies has provided insights into the pathogenesis of RA which may prove quite valuable for future trials. A number of agents are being studied actively at the present time, and it is hoped that they too may generate novel therapies for, and a greater understanding of, this difficult disease. The future for immunomodulatory intervention in RA looks very promising. Greater understanding of the intricacies of the immune response that underlie this disease should continue to yield viable, specific targets for novel therapies. Advances in biopharmaceuticals should generate treatments that maximize efficacy while minimizing toxicity. This should allow the clinician truly to modify the disease and achieve tangible improvements in the lives of RA patients.
Kavanaugh
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The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 77030, USA.