Rheumatoid arthritis: New molecular and cellular aspects

Background: Rheumatoid arthritis is a chronic systemic disorder of unknown etiology, that is characterized by inflammation, synovial hyperplasia and d estruction 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. Results: The cellular activation of aggressively growing, matrix-degrading synovial fibroblasts is a key event in the pathogenesis of rheumatoid arthr itis. The cellular activation results in an altered expression of apoptosis regulating molecules (for example CD 95 and Sentrin) as well a of protoonc ogenes (for example RAS and MYC). Important extracellular stimuli such as t he proinflammatory cytokines interleukin-1 and TNF-alpha are overexpressed in the rheumatoid arthritis synovium. First clinical trials with cytokine i nhibiting 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 cou ld help to overcome the problem of a continuous expression of therapeutic m olecules in the affected joints; gene delivery of the interleukin-1 recepto r 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, coul d be another therapeutic approach. Conclusions: The elucidation of important molecular and cellular pathways i n the pathogenesis resulted in novel concepts in the therapy of rheumatoid arthritis. Gene transfer methods are of importance in studying the pathogen esis of the disease, however, their clinical safety and usefulness have to br proven ill additional studies.