A perspective on anti-cytokine and anti-T cell-directed therapies in rheumatoid arthritis.

Clinical trials have provided a unique opportunity to test the consequences of specific interactions between biologically therapeutic modalities--mainly monoclonal antibodies (mabs) and recombinant proteins--and molecular targets in RA. Biological agents directed against T cell surface markers effectively deplete CD4+ lymphocytes, in some instances for prolonged periods. To date such therapies have shown promising results in 'open label' trials, but in those instances in which randomized placebo-controlled trials have been undertaken, there has been a failure to demonstrate significant benefit over placebo. In contrast, randomized clinical trials with a single cycle of neutralizing anti-TNF alpha mabs have shown substantial benefit in the majority of patients, with marked reduction in CRP lasting several weeks. IL-1 blockade with IL-1 ra and soluble IL-1 R showed possible efficacy in early trials but their performance is much less striking when compared with anti-TNF alpha therapy. Overall the results of trials with anti-T cell and cytokine blockade may reflect on the biological properties of the agents chosen for trial, rather than giving a conclusive answer on the relative merits of targeting these molecules in RA. Nevertheless, promising new directions for therapy and concepts of disease pathogenesis are emerging from the new era of hypothesis testing by specific biological therapies.