New Directions for Biological Therapy in Rheumatoid Arthritis

Advances in our understanding of the pathogenesis of rheumatoid arthritis (RA), together with developments in hybridoma and molecular technology have opened the way for more directed therapy in this disease. In reviewing the experience so far with T-cell-directed biological agents, we show that the early promise displayed by anti-CD4 monoclonal antibodies in open clinical trials has not been sustained in controlled studies. This outcome provides a challenge to the concept that CD4+ T cells are of prime importance in RA, and prompts a search for alternative therapeutic targets. Agents directed towards other leucocyte antigens such as CD5, CDw52 or the receptor for interleukin 2 have induced clinical responses in early studies, but at the expense of significant toxicity. Newer therapies targeting the monokines tumour necrosis factor alpha (TNF-alpha), IL-1 and IL-6, and the leucocyte adhesion molecule intercellular adhesion molecule 1 (ICAM-1) have provided encouraging clinical improvements and, in the case of anti-TNF-alpha and anti-IL-6, impressive modulation of the acute-phase response. Strategies allowing long-term blockade of such molecules, including antibody reshaping and the use of soluble cytokine receptors are discussed. Finally, the potential for using biological agents in combination with other therapies is outlined.