Matrix metalloproteinases (MMPs) as a potential future therapeutic target in rheumatoid arthritis (RA) were discussed by Professor TIM CAWSTON (rheumatology department, University of Newcastle upon Tyne).
MMPs were involved in the degradation of cartilage tissue in arthritis and could be seen in synovial fluid in both osteoarthritis (OA) and RA. Two cytokines were involved in the production of MMP, oncostatin M and interleukin-17. Inhibiting cytokines, eg, through an antibody to oncostatin M, had been shown to protect the joint. Another approach would be to inhibit these enzymes once they had been made.
However, recent trials of Roche's MMP inhibitor, Trocade, had been discontinued because of a lack of efficacy. A trial of 1,000 patients had compared methotrexate with Trocade and, despite the fact that in in vitro and in vivo models Trocade had been effective in protecting cartilage, no difference between the treatment groups was seen in the clinical trial. This raised questions about whether the wrong MMP was being targeted. It was also unclear whether the drug reached the joint.
Dr BHARAT AGGARWAL (department of bioimmunotherapy, University of Texas, US) said that NFkB (nuclear factor of kB cells) played a critical role in the pathogenesis of arthritis. It was involved in regulating the influx of inflammatory cells into the synovium, the activation of inflammatory cells in the synovium and the degradation of cartilage and bone. Among existing compounds, some experiments had shown that lefunomide could downregulate NFkB. Any drug that could inhibit NFkB had the potential to be a drug for treating RA, he concluded.
Another potential therapeutic target, interleukin-1 (IL-1), was discussed at an Amgen-sponsored satellite symposium. IL-1 was a pro-inflammatory cytokine involved in the destructive processes occurring in RA, said Professor JEAN-MICHEL DAYER (professor of medicine, University of Geneva, Switzerland). IL-1 induced the production of metalloproteinases. Studies had shown that inhibition of IL-1, using an IL-1 receptor antagonist, might be beneficial in the sustained treatment of chronic, destructive disease, he said. IL-1 and TNF (also a proinflammatory cytokine) had a synergistic effect and blocking both would enhance the beneficial effect.
Professor BARRY BRESNIHAN (professor of rheumatology, University College, Dublin) described clinical trials of a recombinant IL-1 receptor antagonist, anakinra. In a placebo controlled trial of 472 patients with severe RA, 43 per cent of patients on 150mg/kg anakrina and 27 per cent of placebo group achieved the therapeutic end point (20 per cent improvement) and this difference was statistically significant. Analysis of joint damage suggested that treatment had a positive effect. Another trial showed that anakinra provided a significant additional clinical improvement to patients who were only partially responding to methotrexate alone. Anakinra was generally well tolerated, except for injection site reactions. Further phase III trials were now in progress, he added.
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