• O Distler, U Müller-Ladner, J Schölmerich, R E Gay, and S Gay.
• Klinik und Poliklinik für Innere Medizin I, Universität Regensburg.
• Med Klin. 1999 Dec 15; 94 (12): 673-80.

BackgroundRheumatoid arthritis is a chronic systemic disorder of unknown etiology, that is characterized by inflammation, synovial hyperplasia and destruction of the affected joints. Novel molecular biology techniques have identified important cellular and molecular pathways in the pathogenesis of rheumatoid arthritis during the last years.ResultsThe cellular activation of aggressively growing, matrix-degrading synovial fibroblasts is a key event in the pathogenesis of rheumatoid arthritis. The cellular activation results in an altered expression of apoptosis regulating molecules (for example CD 95 and Sentrin) as well as of protooncogenes (for example RAS and MYC). Important extracellular stimuli such as the pro-inflammatory cytokines interleukin-1 and TNF-alpha are overexpressed in the rheumatoid arthritis synovium. First clinical trials with cytokine inhibiting molecules (interleukin-1 receptor antagonist, recombinant soluble TNF-alpha receptor/Etanercept and monoclonal TNF-alpha antibodies/Remicade) revealed promising results. Etanercept is now available for the treatment of rheumatoid arthritis in the USA. In addition, gene transfer methods could help to overcome the problem of a continuous expression of therapeutic molecules in the affected joints; gene delivery of the interleukin-1 receptor antagonist is currently tested in a human trial. Finally, the inhibition of matrix degrading enzymes such as matrix metalloproteinases, that mediate the joint destructive features of the activated synovial fibroblasts, could be another therapeutic approach.ConclusionsThe elucidation of important molecular and cellular pathways in the pathogenesis resulted in novel concepts in the therapy of rheumatoid arthritis. Gene transfer methods are of importance in studying the pathogenesis of the disease, however, their clinical safety and usefulness have to be proven in additional studies.

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