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insight review articles Evolving concepts of rheumatoid arthritis Gary S. Firestein Division of Rheumatology, Allergy and Immunology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0656, USA (e-mail: gfirestein@) Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumour-like behaviour of rheumatoid synovium have also been implicated. More recently, the contribution of autoantibodies has returned to the forefront. Based on the pathogenic mechanisms, specific therapeutic interventions can be designed to suppress synovial inflammation and joint destruction in rheumatoid arthritis. “Life can only be lived forwards, but must be understood backwards.” Søren Kierkegaard heumatoid arthritis (RA) is a symmetric complement and release chemotactic factors such as C5a. polyarticular arthritis that primarily affects the Inflammatory cells are subsequently recruited to the small diarthrodial joints of the hands and feet. rheumatoid joint along a chemotactic gradient where they In addition to inflammation in the synovium, are activated and contribute to local destruction. Neu- which is the joint lining, the aggressive front of trophils, in particular, accumulate in synovial fluid where R tissue called pannus invades and destroys local articular they engulf immune complexes and release proteolytic structures. The synovium is normally a relatively